T E X T B O O K of Medical Physiology T E X T B O O K of Medical Physiology E L E V E N T H E D I T I O N Arthur C. Guyton, M.D.† Professor Emeritus Department of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi † Deceased John E. Hall, Ph.D. Professor and Chairman Department of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi Elsevier Inc. 1600 John F. Kennedy Blvd., Suite 1800 Philadelphia, Pennsylvania 19103-2899 TEXTBOOK OF MEDICAL PHYSIOLOGY ISBN 0-7216-0240-1 International Edition ISBN 0-8089-2317-X Copyright © 2006, 2000, 1996, 1991, 1986, 1981, 1976, 1971, 1966, 1961, 1956 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: healthpermissions@elsevier.com. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions”. NOTICE Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Author assumes any liability for any injury and/or damage to persons or property arising out or related to any use of the material contained in this book. Library of Congress Cataloging-in-Publication Data Guyton, Arthur C. Textbook of medical physiology / Arthur C. Guyton, John E. Hall.—11th ed. p. ; cm. Includes bibliographical references and index. ISBN 0-7216-0240-1 1. Human physiology. 2. Physiology, Pathological. I. Title: Medical physiology. John E. (John Edward) III. Title. [DNLM: 1. Physiological Processes. QT 104 G992t 2006] QP34.5.G9 2006 612—dc22 II. Hall, 2004051421 Publishing Director: Linda Belfus Acquisitions Editor: William Schmitt Managing Editor: Rebecca Gruliow Publishing Services Manager: Tina Rebane Project Manager: Mary Anne Folcher Design Manager: Steven Stave Marketing Manager: John Gore Cover illustration is a detail from Opus 1972 by Virgil Cantini, Ph.D., with permission of the artist and Mansfield State College, Mansfield, Pennsylvania. Chapter opener credits: Chapter 43, modified from © Getty Images 21000058038; Chapter 44, modified from © Getty Images 21000044598; Chapter 84, modified from © Corbis. Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1 To My Family For their abundant support, for their patience and understanding, and for their love To Arthur C. Guyton For his imaginative and innovative research For his dedication to education For showing us the excitement and joy of physiology And for serving as an inspirational role model Arthur C. Guyton, M.D. 1919–2003 I N M E M O R I A M The sudden loss of Dr. Arthur C. Guyton in an automobile accident on April 3, 2003, stunned and saddened all who were privileged to know him. Arthur Guyton was a giant in the fields of physiology and medicine, a leader among leaders, a master teacher, and an inspiring role model throughout the world. Arthur Clifton Guyton was born in Oxford, Mississippi, to Dr. Billy S. Guyton, a highly respected eye, ear, nose, and throat specialist, who later became Dean of the University of Mississippi Medical School, and Kate Smallwood Guyton, a mathematics and physics teacher who had been a missionary in China before marriage. During his formative years, Arthur enjoyed watching his father work at the Guyton Clinic, playing chess and swapping stories with William Faulkner, and building sailboats (one of which he later sold to Faulkner). He also built countless mechanical and electrical devices, which he continued to do throughout his life. His brilliance shone early as he graduated top in his class at the University of Mississippi. He later distinguished himself at Harvard Medical School and began his postgraduate surgical training at Massachusetts General Hospital. His medical training was interrupted twice—once to serve in the Navy during World War II and again in 1946 when he was stricken with poliomyelitis during his final year of residency training. Suffering paralysis in his right leg, left arm, and both shoulders, he spent nine months in Warm Springs, Georgia, recuperating and applying his inventive mind to building the first motorized wheelchair controlled by a “joy stick,” a motorized hoist for lifting patients, special leg braces, and other devices to aid the handicapped. For those inventions he received a Presidential Citation. He returned to Oxford where he devoted himself to teaching and research at the University of Mississippi School of Medicine and was named Chair of the Department of Physiology in 1948. In 1951 he was named one of the ten outstanding men in the nation. When the University of Mississippi moved its Medical School to Jackson in 1955, he rapidly developed one of the world’s premier cardiovascular research programs. His remarkable life as a scientist, author, and devoted father is detailed in a biography published on the occasion of his “retirement” in 1989.1 A Great Physiologist. Arthur Guyton’s research contributions, which include more than 600 papers and 40 books, are legendary and place him among the greatest physiologists in history. His research covered virtually all areas of cardiovascular regulation and led to many seminal concepts that are now an integral part of our understanding of cardiovascular disorders, such as hypertension, heart failure, and edema. It is difficult to discuss cardiovascular physiology without including his concepts of cardiac output and venous return, negative interstitial fluid pressure and regulation of tissue fluid volume and edema, regulation of tissue blood flow and whole body blood flow autoregulation, renal-pressure natriuresis, and long-term blood pressure regulation. Indeed, his concepts of cardiovascular regulation are found in virtually every major textbook of physiology. They have become so familiar that their origin is sometimes forgotten. One of Dr. Guyton’s most important scientific legacies was his application of principles of engineering and systems analysis to cardiovascular regulation. He used mathematical and graphical methods to quantify various aspects of circulatory function before computers were widely available. He built analog computers and pioneered the application of large-scale systems analysis to modeling the cardiovascular system before the advent of digital computers. As digital computers became available, his cardiovascular models expanded dramatically to include the kidneys and body fluids, hormones, and the autonomic nervous system, as well as cardiac and circulatory functions.2 He also provided the first comprehensive systems analysis of blood pressure regulation. This unique approach to physiological research preceded the emergence of biomedical vii viii In Memoriam engineering—a field that he helped to establish and to promote in physiology, leading the discipline into a quantitative rather than a descriptive science. It is a tribute to Arthur Guyton’s genius that his concepts of cardiovascular regulation often seemed heretical when they were first presented, yet stimulated investigators throughout the world to test them experimentally. They are now widely accepted. In fact, many of his concepts of cardiovascular regulation are integral components of what is now taught in most medical physiology courses. They continue to be the foundation for generations of cardiovascular physiologists. Dr. Guyton received more than 80 major honors from diverse scientific and civic organizations and universities throughout the world. A few of these that are especially relevant to cardiovascular research include the Wiggers Award of the American Physiological Society, the Ciba Award from the Council for High Blood Pressure Research, The William Harvey Award from the American Society of Hypertension, the Research Achievement Award of the American Heart Association, and the Merck Sharp & Dohme Award of the International Society of Hypertension. It was appropriate that in 1978 he was invited by the Royal College of Physicians in London to deliver a special lecture honoring the 400th anniversary of the birth of William Harvey, who discovered the circulation of the blood. Dr. Guyton’s love of physiology was beautifully articulated in his president’s address to the American Physiological Society in 1975,3 appropriately entitled Physiology, a Beauty and a Philosophy. Let me quote just one sentence from his address: What other person, whether he be a theologian, a jurist, a doctor of medicine, a physicist, or whatever, knows more than you, a physiologist, about life? For physiology is indeed an explanation of life. What other subject matter is more fascinating, more exciting, more beautiful than the subject of life? A Master Teacher. Although Dr. Guyton’s research accomplishments are legendary, his contributions as an educator have probably had an even greater impact. He and his wonderful wife Ruth raised ten children, all of whom became outstanding physicians—a remarkable educational achievement. Eight of the Guyton children graduated from Harvard Medical School, one from Duke Medical School, and one from The University of Miami Medical School after receiving a Ph.D. from Harvard. An article published in Reader’s Digest in 1982 highlighted their extraordinary family life.4 The success of the Guyton children did not occur by chance. Dr. Guyton’s philosophy of education was to “learn by doing.” The children participated in countless family projects that included the design and construction of their home and its heating system, the swimming pool, tennis court, sailboats, go-carts and electrical cars, household gadgets, and electronic instruments for their Oxford Instruments Company. Television programs such as Good Morning America and 20/20 described the remarkable home environment that Arthur and Ruth Guyton created to raise their family. His devotion to family is beautifully expressed in the dedication of his Textbook of Medical Physiology5: To My father for his uncompromising principles that guided my life My mother for leading her children into intellectual pursuits My wife for her magnificent devotion to her family My children for making everything worthwhile Dr. Guyton was a master teacher at the University of Mississippi for over 50 years. Even though he was always busy with service responsibilities, research, writing, and teaching, he was never too busy to talk with a student who was having difficulty. He would never accept an invitation to give a prestigious lecture if it conflicted with his teaching schedule. His contributions to education are also far reaching through generations of physiology graduate students and postdoctoral fellows. He trained over 150 scientists, at least 29 of whom became chairs of their own departments and six of whom became presidents of the American Physiological Society. He gave students confidence in their abilities and emphasized his belief that “People who are really successful in the research world are self-taught.” He insisted that his trainees integrate their experimental findings into a broad conceptual framework that included other interacting systems. This approach usually led them to develop a quantitative analysis and a better understanding of the particular physiological systems that they were studying. No one has been more prolific in training leaders of physiology than Arthur Guyton. Dr. Guyton’s Textbook of Medical Physiology, first published in 1956, quickly became the best-selling medical physiology textbook in the world. He had a gift for communicating complex ideas in a clear and interesting manner that made studying physiology fun. He wrote the book to teach his students, not to impress his professional colleagues. Its popularity with students has made it the most widely used physiology textbook in history. This accomplishment alone was enough to ensure his legacy. The Textbook of Medical Physiology began as lecture notes in the early 1950s when Dr. Guyton was teaching the entire physiology course for medical students at the University of Mississippi. He discovered that the students were having difficulty with the textbooks that were available and began distributing copies of his lecture notes. In describing his experience, Dr. Guyton stated that “Many textbooks of medical physiology had become discursive, written primarily by teachers of physiology for other teachers of physiology, and written in language understood by other teachers but not easily understood by the basic student of medical physiology.”6 Through his Textbook of Medical Physiology, which is translated into 13 languages, he has probably done In Memoriam more to teach physiology to the world than any other individual in history. Unlike most major textbooks, which often have 20 or more authors, the first eight editions were written entirely by Dr. Guyton—a feat that is unprecedented for any major medical textbook. For his many contributions to medical education, Dr. Guyton received the 1996 Abraham Flexner Award from the Association of American Medical Colleges (AAMC). According to the AAMC, Arthur Guyton “. . . for the past 50 years has made an unparalleled impact on medical education.” He is also honored each year by The American Physiological Society through the Arthur C. Guyton Teaching Award. ix We celebrate the magnificent life of Arthur Guyton, recognizing that we owe him an enormous debt. He gave us an imaginative and innovative approach to research and many new scientific concepts. He gave countless students throughout the world a means of understanding physiology and he gave many of us exciting research careers. Most of all, he inspired us— with his devotion to education, his unique ability to bring out the best in those around him, his warm and generous spirit, and his courage. We will miss him tremendously, but he will remain in our memories as a shining example of the very best in humanity. Arthur Guyton was a real hero to the world, and his legacy is everlasting. An Inspiring Role Model. Dr. Guyton’s accomplish- ments extended far beyond science, medicine, and education. He was an inspiring role model for life as well as for science. No one was more inspirational or influential on my scientific career than Dr. Guyton. He taught his students much more than physiology— he taught us life, not so much by what he said but by his unspoken courage and dedication to the highest standards. He had a special ability to motivate people through his indomitable spirit. Although he was severely challenged by polio, those of us who worked with him never thought of him as being handicapped. We were too busy trying to keep up with him! His brilliant mind, his indefatigable devotion to science, education, and family, and his spirit captivated students and trainees, professional colleagues, politicians, business leaders, and virtually everyone who knew him. He would not succumb to the effects of polio. His courage challenged and inspired us. He expected the best and somehow brought out the very best in people. References 1. Brinson C, Quinn J: Arthur C. Guyton—His Life, His Family, His Achievements. Jackson, MS, Hederman Brothers Press, 1989. 2. Guyton AC, Coleman TG, Granger HJ: Circulation: overall regulation. Ann Rev Physiol 34:13–46, 1972. 3. Guyton AC: Past-President’s Address. Physiology, a Beauty and a Philosophy. The Physiologist 8:495–501, 1975. 4. Bode R: A Doctor Who’s Dad to Seven Doctors—So Far! Readers’ Digest, December, 1982, pp. 141–145. 5. Guyton AC: Textbook of Medical Physiology. Philadelphia, Saunders, 1956. 6. Guyton AC: An author’s philosophy of physiology textbook writing. Adv Physiol Ed 19: s1–s5, 1998. John E. Hall Jackson, Mississippi P R E The first edition of the Textbook of Medical Physiology was written by Arthur C. Guyton almost 50 years ago. Unlike many major medical textbooks, which often have 20 or more authors, the first eight editions of the Textbook of Medical Physiology were written entirely by Dr. Guyton with each new edition arriving on schedule for nearly 40 years. Over the years, Dr. Guyton’s textbook became widely used throughout the world and was translated into 13 languages. A major reason for the book’s unprecedented success was his uncanny ability to explain complex physiologic principles in language easily understood by students. His main goal with each edition was to instruct students in physiology, not to impress his professional colleagues. His writing style always maintained the tone of a teacher talking to his students. I had the privilege of working closely with Dr. Guyton for almost 30 years and the honor of helping him with the 9th and 10th editions. For the 11th edition, I have the same goal as in previous editions—to explain, in language easily understood by students, how the different cells, tissues, and organs of the human body work together to maintain life. This task has been challenging and exciting because our rapidly increasing knowledge of physiology continues to unravel new mysteries of body functions. Many new techniques for learning about molecular and cellular physiology have been developed. We can present more and more the physiology principles in the terminology of molecular and physical sciences rather than in merely a series of separate and unexplained biological phenomena. This change is welcomed, but it also makes revision of each chapter a necessity. In this edition, I have attempted to maintain the same unified organization of the text that has been useful to students in the past and to ensure that the book is comprehensive enough that students will wish to use it in later life as a basis for their professional careers. I hope that this textbook conveys the majesty of the human body and its many functions and that it stimulates students to study physiology throughout their careers. Physiology is the link between the basic sciences and medicine. The great beauty of physiology is that it integrates the individual functions of all the body’s different cells, tissues, and organs into a functional whole, the human body. Indeed, the human body is much more than the sum of its parts, and life relies upon this total function, not just on the function of individual body parts in isolation from the others. This brings us to an important question: How are the separate organs and systems coordinated to maintain proper function of the entire body? Fortunately, our bodies are endowed with a vast network of feedback controls that achieve the necessary balances without which we would not be able to live. Physiologists call this high level of internal bodily control homeostasis. In disease states, functional balances are often seriously disturbed and homeostasis is impaired. And, when even a single disturbance reaches a limit, the whole body can no longer live. One of the goals of this text, therefore, is to emphasize the effectiveness and beauty of the body’s homeostasis mechanisms as well as to present their abnormal function in disease. Another objective is to be as accurate as possible. Suggestions and critiques from many physiologists, students, and clinicians throughout the world have been sought and then used to check factual accuracy as well as balance in the text. Even so, because of the likelihood of error in sorting through many thousands of bits of information, I wish to issue still a further request to all readers to send along notations of error or inaccuracy. Physiologists understand the importance of feedback for proper function of the human body; so, too, is feedback important for progressive improvement of a textbook of physiology. To the many persons who have already helped, I send sincere thanks. xi F A C E xii Preface A brief explanation is needed about several features of the 11th edition. Although many of the chapters have been revised to include new principles of physiology, the text length has been closely monitored to limit the book size so that it can be used effectively in physiology courses for medical students and health care professionals. Many of the figures have also been redrawn and are now in full color. New references have been chosen primarily for their presentation of physiologic principles, for the quality of their own references, and for their easy accessibility. Most of the selected references are from recently published scientific journals that can be freely accessed from the PubMed internet site at http:// www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed. Use of these references, as well as cross-references from them, can give the student almost complete coverage of the entire field of physiology. Another feature is that the print is set in two sizes. The material in small print is of several different kinds: first, anatomical, chemical, and other information that is needed for immediate discussion but that most students will learn in more detail in other courses; second, physiologic information of special importance to certain fields of clinical medicine; and, third, information that will be of value to those students who may wish to study particular physiologic mechanisms more deeply. The material in large print constitutes the fundamental physiologic information that students will require in virtually all their medical activities and studies. I wish to express my thanks to many other persons who have helped in preparing this book, including my colleagues in the Department of Physiology & Biophysics at the University of Mississippi Medical Center who provided valuable suggestions. I am also grateful to Ivadelle Osberg Heidke, Gerry McAlpin, and Stephanie Lucas for their excellent secretarial services, and to William Schmitt, Rebecca Gruliow, Mary Anne Folcher, and the rest of the staff of Elsevier Saunders for continued editorial and production excellence. Finally, I owe an enormous debt to Arthur Guyton for an exciting career in physiology, for his friendship, for the great privilege of contributing to the Textbook of Medical Physiology, and for the inspiration that he provided to all who knew him. John E. Hall Jackson, Mississippi TA B L E O F C O N T E N T S U N I T The DNA Code in the Cell Nucleus Is Transferred to an RNA Code in the Cell Cytoplasm—The Process of Transcription Synthesis of RNA Assembly of the RNA Chain from Activated Nucleotides Using the DNA Strand as a Template—The Process of “Transcription” Messenger RNA—The Codons Transfer RNA—The Anticodons Ribosomal RNA Formation of Proteins on the Ribosomes— The Process of “Translation” Synthesis of Other Substances in the Cell Control of Gene Function and Biochemical Activity in Cells Genetic Regulation Control of Intracellular Function by Enzyme Regulation The DNA-Genetic System Also Controls Cell Reproduction Cell Reproduction Begins with Replication of DNA Chromosomes and Their Replication Cell Mitosis Control of Cell Growth and Cell Reproduction Cell Differentiation Apoptosis—Programmed Cell Death Cancer I Introduction to Physiology: The Cell and General Physiology C H A P T E R 1 Functional Organization of the Human Body and Control of the “Internal Environment” Cells as the Living Units of the Body Extracellular Fluid—The “Internal Environment” “Homeostatic” Mechanisms of the Major Functional Systems Homeostasis Extracellular Fluid Transport and Mixing System—The Blood Circulatory System Origin of Nutrients in the Extracellular Fluid Removal of Metabolic End Products Regulation of Body Functions Reproduction Control Systems of the Body Examples of Control Mechanisms Characteristics of Control Systems Summary—Automaticity of the Body C H A P T E R 2 The Cell and Its Functions Organization of the Cell Physical Structure of the Cell Membranous Structures of the Cell Cytoplasm and Its Organelles Nucleus Nuclear Membrane Nucleoli and Formation of Ribosomes Comparison of the Animal Cell with Precellular Forms of Life Functional Systems of the Cell Ingestion by the Cell—Endocytosis Digestion of Pinocytotic and Phagocytic Foreign Substances Inside the Cell— Function of the Lysosomes Synthesis and Formation of Cellular Structures by Endoplasmic Reticulum and Golgi Apparatus Extraction of Energy from Nutrients— Function of the Mitochondria Locomotion of Cells Ameboid Movement Cilia and Ciliary Movement C H A P T E R 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction Genes in the Cell Nucleus Genetic Code 3 3 3 4 4 4 5 5 5 6 6 6 7 9 11 11 12 12 14 17 17 18 U N I T 30 30 31 31 32 33 33 35 35 35 36 37 37 38 38 39 40 40 40 I I Membrane Physiology, Nerve, and Muscle 18 19 19 C H A P T E R 4 Transport of Substances Through the Cell Membrane 20 The Lipid Barrier of the Cell Membrane, and Cell Membrane Transport Proteins Diffusion Diffusion Through the Cell Membrane Diffusion Through Protein Channels, and “Gating” of These Channels Facilitated Diffusion Factors That Affect Net Rate of Diffusion Osmosis Across Selectively Permeable Membranes—“Net Diffusion” of Water “Active Transport” of Substances Through Membranes Primary Active Transport Secondary Active Transport—Co-Transport and Counter-Transport Active Transport Through Cellular Sheets 20 22 24 24 24 27 27 29 xiii 45 45 46 46 47 49 50 51 52 53 54 55 xiv C H A P T E R 5 Membrane Potentials and Action Potentials Basic Physics of Membrane Potentials Membrane Potentials Caused by Diffusion Measuring the Membrane Potential Resting Membrane Potential of Nerves Origin of the Normal Resting Membrane Potential Nerve Action Potential Voltage-Gated Sodium and Potassium Channels Summary of the Events That Cause the Action Potential Roles of Other Ions During the Action Potential Initiation of the Action Potential Propagation of the Action Potential Re-establishing Sodium and Potassium Ionic Gradients After Action Potentials Are Completed—Importance of Energy Metabolism Plateau in Some Action Potentials Rhythmicity of Some Excitable Tissues— Repetitive Discharge Special Characteristics of Signal Transmission in Nerve Trunks Excitation—The Process of Eliciting the Action Potential “Refractory Period” After an Action Potential Recording Membrane Potentials and Action Potentials Inhibition of Excitability—“Stabilizers” and Local Anesthetics C H A P T E R 6 Contraction of Skeletal Muscle Physiologic Anatomy of Skeletal Muscle Skeletal Muscle Fiber General Mechanism of Muscle Contraction Molecular Mechanism of Muscle Contraction Molecular Characteristics of the Contractile Filaments Effect of Amount of Actin and Myosin Filament Overlap on Tension Developed by the Contracting Muscle Relation of Velocity of Contraction to Load Energetics of Muscle Contraction Work Output During Muscle Contraction Sources of Energy for Muscle Contraction Characteristics of Whole Muscle Contraction Mechanics of Skeletal Muscle Contraction Remodeling of Muscle to Match Function Rigor Mortis Table of Contents 57 57 57 58 59 60 61 62 64 64 65 65 66 66 67 68 69 70 70 70 72 72 72 74 74 C H A P T E R 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling Transmission of Impulses from Nerve Endings to Skeletal Muscle Fibers: The Neuromuscular Junction Secretion of Acetylcholine by the Nerve Terminals Molecular Biology of Acetyline Formation and Release Drugs That Enhance or Block Transmission at the Neuromuscular Junction Myasthenia Gravis Muscle Action Potential Spread of the Action Potential to the Interior of the Muscle Fiber by Way of “Transverse Tubules” Excitation-Contraction Coupling Transverse Tubule–Sarcoplasmic Reticulum System Release of Calcium Ions by the Sarcoplasmic Reticulum C H A P T E R 8 Contraction and Excitation of Smooth Muscle Contraction of Smooth Muscle Types of Smooth Muscle Contractile Mechanism in Smooth Muscle Regulation of Contraction by Calcium Ions Nervous and Hormonal Control of Smooth Muscle Contraction Neuromuscular Junctions of Smooth Muscle Membrane Potentials and Action Potentials in Smooth Muscle Effect of Local Tissue Factors and Hormones to Cause Smooth Muscle Contraction Without Action Potentials Source of Calcium Ions That Cause Contraction (1 ) Through the Cell Membrane and (2 ) from the Sarcoplasmic Reticulum U N I T 85 85 85 88 88 89 89 89 89 89 90 92 92 92 93 95 95 95 96 98 99 I I I The Heart 75 77 78 78 78 79 80 81 82 83 C H A P T E R 9 Heart Muscle; The Heart as a Pump and Function of the Heart Valves Physiology of Cardiac Muscle Physiologic Anatomy of Cardiac Muscle Action Potentials in Cardiac Muscle The Cardiac Cycle Diastole and Systole Relationship of the Electrocardiogram to the Cardiac Cycle Function of the Atria as Primer Pumps Function of the Ventricles as Pumps 103 103 103 104 106 106 107 107 108 Table of Contents Function of the Valves Aortic Pressure Curve Relationship of the Heart Sounds to Heart Pumping Work Output of the Heart Graphical Analysis of Ventricular Pumping Chemical Energy Required for Cardiac Contraction: Oxygen Utilization by the Heart Regulation of Heart Pumping Intrinsic Regulation of Heart Pumping— The Frank-Starling Mechanism Effect of Potassium and Calcium Ions on Heart Function Effect of Temperature on Heart Function Increasing the Arterial Pressure Load (up to a Limit) Does Not Decrease the Cardiac Output C H A P T E R 1 0 Rhythmical Excitation of the Heart Specialized Excitatory and Conductive System of the Heart Sinus (Sinoatrial) Node Internodal Pathways and Transmission of the Cardiac Impulse Through the Atria Atrioventricular Node, and Delay of Impulse Conduction from the Atria to the Ventricles Rapid Transmission in the Ventricular Purkinje System Transmission of the Cardiac Impulse in the Ventricular Muscle Summary of the Spread of the Cardiac Impulse Through the Heart Control of Excitation and Conduction in the Heart The Sinus Node as the Pacemaker of the Heart Role of the Purkinje System in Causing Synchronous Contraction of the Ventricular Muscle Control of Heart Rhythmicity and Impulse Conduction by the Cardiac Nerves: The Sympathetic and Parasympathetic Nerves C H A P T E R 1 1 The Normal Electrocardiogram Characteristics of the Normal Electrocardiogram Depolarization Waves Versus Repolarization Waves Relationship of Atrial and Ventricular Contraction to the Waves of the Electrocardiogram Voltage and Time Calibration of the Electrocardiogram Methods for Recording Electrocardiograms Pen Recorder Flow of Current Around the Heart During the Cardiac Cycle Recording Electrical Potentials from a Partially Depolarized Mass of Syncytial Cardiac Muscle 109 109 109 110 110 111 111 111 113 114 114 116 116 116 118 118 119 119 120 120 120 121 121 123 123 123 125 125 126 126 126 126 xv Flow of Electrical Currents in the Chest Around the Heart Electrocardiographic Leads Three Bipolar Limb Leads Chest Leads (Precordial Leads) Augmented Unipolar Limb Leads 126 127 127 129 129 C H A P T E R 1 2 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis 131 Principles of Vectorial Analysis of Electrocardiograms Use of Vectors to Represent Electrical Potentials Direction of a Vector Is Denoted in Terms of Degrees Axis for Each Standard Bipolar Lead and Each Unipolar Limb Lead Vectorial Analysis of Potentials Recorded in Different Leads Vectorial Analysis of the Normal Electrocardiogram Vectors That Occur at Successive Intervals During Depolarization of the Ventricles— The QRS Complex Electrocardiogram During Repolarization— The T Wave Depolarization of the Atria—The P Wave Vectorcardiogram Mean Electrical Axis of the Ventricular QRS—And Its Significance Determining the Electrical Axis from Standard Lead Electrocardiograms Abnormal Ventricular Conditions That Cause Axis Deviation Conditions That Cause Abnormal Voltages of the QRS Complex Increased Voltage in the Standard Bipolar Limb Leads Decreased Voltage of the Electrocardiogram Prolonged and Bizarre Patterns of the QRS Complex Prolonged QRS Complex as a Result of Cardiac Hypertrophy or Dilatation Prolonged QRS Complex Resulting from Purkinje System Blocks Conditions That Cause Bizarre QRS Complexes Current of Injury Effect of Current of Injury on the QRS Complex The J Point—The Zero Reference Potential for Analyzing Current of Injury Coronary Ischemia as a Cause of Injury Potential Abnormalities in the T Wave Effect of Slow Conduction of the Depolarization Wave on the Characteristics of the T Wave Shortened Depolarization in Portions of the Ventricular Muscle as a Cause of T Wave Abnormalities 131 131 131 132 133 134 134 134 136 136 137 137 138 140 140 140 141 141 141 141 141 141 142 143 145 145 145 xvi Table of Contents C H A P T E R 1 3 Cardiac Arrhythmias and Their Electrocardiographic Interpretation Abnormal Sinus Rhythms Tachycardia Bradycardia Sinus Arrhythmia Abnormal Rhythms That Result from Block of Heart Signals Within the Intracardiac Conduction Pathways Sinoatrial Block Atrioventricular Block Incomplete Atrioventricular Heart Block Incomplete Intraventricular Block— Electrical Alternans Premature Contractions Premature Atrial Contractions A-V Nodal or A-V Bundle Premature Contractions Premature Ventricular Contractions Paroxysmal Tachycardia Atrial Paroxysmal Tachycardia Ventricular Paroxysmal Tachycardia Ventricular Fibrillation Phenomenon of Re-entry—“Circus Movements” as the Basis for Ventricular Fibrillation Chain Reaction Mechanism of Fibrillation Electrocardiogram in Ventricular Fibrillation Electroshock Defibrillation of the Ventricle Hand Pumping of the Heart (Cardiopulmonary Resuscitation) as an Aid to Defibrillation Atrial Fibrillation Atrial Flutter Cardiac Arrest U N I T 147 147 147 147 148 148 148 148 149 150 150 150 150 151 151 152 152 152 153 153 154 154 155 155 156 156 I V The Circulation C H A P T E R 1 4 Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance Physical Characteristics of the Circulation Basic Theory of Circulatory Function Interrelationships Among Pressure, Flow, and Resistance Blood Flow Blood Pressure Resistance to Blood Flow Effects of Pressure on Vascular Resistance and Tissue Blood Flow C H A P T E R 1 5 Vascular Distensibility and Functions of the Arterial and Venous Systems Vascular Distensibility Vascular Compliance (or Vascular Capacitance) 161 161 163 164 164 166 167 170 171 171 171 Volume-Pressure Curves of the Arterial and Venous Circulations Arterial Pressure Pulsations Transmission of Pressure Pulses to the Peripheral Arteries Clinical Methods for Measuring Systolic and Diastolic Pressures Veins and Their Functions Venous Pressures—Right Atrial Pressure (Central Venous Pressure) and Peripheral Venous Pressures Blood Reservoir Function of the Veins C H A P T E R 1 6 The Microcirculation and the Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow Structure of the Microcirculation and Capillary System Flow of Blood in the Capillaries— Vasomotion Average Function of the Capillary System Exchange of Water, Nutrients, and Other Substances Between the Blood and Interstitial Fluid Diffusion Through the Capillary Membrane The Interstitium and Interstitial Fluid Fluid Filtration Across Capillaries Is Determined by Hydrostatic and Colloid Osmotic Pressures, and Capillary Filtration Coefficient Capillary Hydrostatic Pressure Interstitial Fluid Hydrostatic Pressure Plasma Colloid Osmotic Pressure Interstitial Fluid Colloid Osmotic Pressure Exchange of Fluid Volume Through the Capillary Membrane Starling Equilibrium for Capillary Exchange Lymphatic System Lymph Channels of the Body Formation of Lymph Rate of Lymph Flow Role of the Lymphatic System in Controlling Interstitial Fluid Protein Concentration, Interstitial Fluid Volume, and Interstitial Fluid Pressure C H A P T E R 1 7 Local and Humoral Control of Blood Flow by the Tissues Local Control of Blood Flow in Response to Tissue Needs Mechanisms of Blood Flow Control Acute Control of Local Blood Flow Long-Term Blood Flow Regulation Development of Collateral Circulation—A Phenomenon of Long-Term Local Blood Flow Regulation Humoral Control of the Circulation Vasoconstrictor Agents Vasodilator Agents Vascular Control by Ions and Other Chemical Factors 172 173 174 175 176 176 179 181 181 182 183 183 183 184 185 186 187 188 188 189 189 190 190 191 192 193 195 195 196 196 200 201 201 201 202 202 xvii Table of Contents C H A P T E R 1 8 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure 204 Nervous Regulation of the Circulation Autonomic Nervous System Role of the Nervous System in Rapid Control of Arterial Pressure Increase in Arterial Pressure During Muscle Exercise and Other Types of Stress Reflex Mechanisms for Maintaining Normal Arterial Pressure Central Nervous System Ischemic Response—Control of Arterial Pressure by the Brain’s Vasomotor Center in Response to Diminished Brain Blood Flow Special Features of Nervous Control of Arterial Pressure Role of the Skeletal Nerves and Skeletal Muscles in Increasing Cardiac Output and Arterial Pressure Respiratory Waves in the Arterial Pressure Arterial Pressure “Vasomotor” Waves— Oscillation of Pressure Reflex Control Systems C H A P T E R 1 9 Dominant Role of the Kidney in LongTerm Regulation of Arterial Pressure and in Hypertension: The Integrated System for Pressure Control Renal–Body Fluid System for Arterial Pressure Control Quantitation of Pressure Diuresis as a Basis for Arterial Pressure Control Chronic Hypertension (High Blood Pressure) Is Caused by Impaired Renal Fluid Excretion The Renin-Angiotensin System: Its Role in Pressure Control and in Hypertension Components of the Renin-Angiotensin System Types of Hypertension in Which Angiotensin Is Involved: Hypertension Caused by a Renin-Secreting Tumor or by Infusion of Angiotensin II Other Types of Hypertension Caused by Combinations of Volume Loading and Vasoconstriction “Primary (Essential) Hypertension” Summary of the Integrated, Multifaceted System for Arterial Pressure Regulation C H A P T E R 2 0 Cardiac Output, Venous Return, and Their Regulation Normal Values for Cardiac Output at Rest and During Activity Control of Cardiac Output by Venous Return—Role of the Frank-Starling Mechanism of the Heart 204 204 208 208 209 212 213 213 214 214 216 216 217 220 223 223 226 227 228 230 Cardiac Output Regulation Is the Sum of Blood Flow Regulation in All the Local Tissues of the Body—Tissue Metabolism Regulates Most Local Blood Flow The Heart Has Limits for the Cardiac Output That It Can Achieve What Is the Role of the Nervous System in Controlling Cardiac Output? Pathologically High and Pathologically Low Cardiac Outputs High Cardiac Output Caused by Reduced Total Peripheral Resistance Low Cardiac Output A More Quantitative Analysis of Cardiac Output Regulation Cardiac Output Curves Used in the Quantitative Analysis Venous Return Curves Analysis of Cardiac Output and Right Atrial Pressure, Using Simultaneous Cardiac Output and Venous Return Curves Methods for Measuring Cardiac Output Pulsatile Output of the Heart as Measured by an Electromagnetic or Ultrasonic Flowmeter Measurement of Cardiac Output Using the Oxygen Fick Principle Indicator Dilution Method for Measuring Cardiac Output C H A P T E R 2 1 Muscle Blood Flow and Cardiac Output During Exercise; the Coronary Circulation and Ischemic Heart Disease Blood Flow in Skeletal Muscle and Blood Flow Regulation During Exercise Rate of Blood Flow Through the Muscles Control of Blood Flow Through the Skeletal Muscles Total Body Circulatory Readjustments During Exercise Coronary Circulation Physiologic Anatomy of the Coronary Blood Supply Normal Coronary Blood Flow Control of Coronary Blood Flow Special Features of Cardiac Muscle Metabolism Ischemic Heart Disease Causes of Death After Acute Coronary Occlusion Stages of Recovery from Acute Myocardial Infarction Function of the Heart After Recovery from Myocardial Infarction Pain in Coronary Heart Disease Surgical Treatment of Coronary Disease 233 234 235 236 236 237 237 237 238 241 243 243 244 244 246 246 246 247 247 249 249 249 250 251 252 253 254 255 255 256 232 232 232 C H A P T E R Cardiac Failure 2 2 Dynamics of the Circulation in Cardiac Failure 258 258 xviii Acute Effects of Moderate Cardiac Failure Chronic Stage of Failure—Fluid Retention Helps to Compensate Cardiac Output Summary of the Changes That Occur After Acute Cardiac Failure—“Compensated Heart Failure” Dynamics of Severe Cardiac Failure— Decompensated Heart Failure Unilateral Left Heart Failure Low-Output Cardiac Failure— Cardiogenic Shock Edema in Patients with Cardiac Failure Cardiac Reserve Quantitative Graphical Method for Analysis of Cardiac Failure C H A P T E R 2 3 Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects Heart Sounds Normal Heart Sounds Valvular Lesions Abnormal Circulatory Dynamics in Valvular Heart Disease Dynamics of the Circulation in Aortic Stenosis and Aortic Regurgitation Dynamics of Mitral Stenosis and Mitral Regurgitation Circulatory Dynamics During Exercise in Patients with Valvular Lesions Abnormal Circulatory Dynamics in Congenital Heart Defects Patent Ductus Arteriosus—A Left-to-Right Shunt Tetralogy of Fallot—A Right-to-Left Shunt Causes of Congenital Anomalies Use of Extracorporeal Circulation During Cardiac Surgery Hypertrophy of the Heart in Valvular and Congenital Heart Disease C H A P T E R 2 4 Circulatory Shock and Physiology of Its Treatment Physiologic Causes of Shock Circulatory Shock Caused by Decreased Cardiac Output Circulatory Shock That Occurs Without Diminished Cardiac Output What Happens to the Arterial Pressure in Circulatory Shock? Tissue Deterioration Is the End Result of Circulatory Shock, Whatever the Cause Stages of Shock Shock Caused by Hypovolemia— Hemorrhagic Shock Relationship of Bleeding Volume to Cardiac Output and Arterial Pressure Progressive and Nonprogressive Hemorrhagic Shock Irreversible Shock Hypovolemic Shock Caused by Plasma Loss Hypovolemic Shock Caused by Trauma Table of Contents 258 259 260 260 262 262 263 264 265 Neurogenic Shock—Increased Vascular Capacity Anaphylactic Shock and Histamine Shock Septic Shock Physiology of Treatment in Shock Replacement Therapy Treatment of Shock with Sympathomimetic Drugs—Sometimes Useful, Sometimes Not Other Therapy Circulatory Arrest Effect of Circulatory Arrest on the Brain U N I T 285 285 286 286 286 287 287 287 287 V The Body Fluids and Kidneys 269 269 269 271 272 272 273 273 274 274 274 276 276 276 278 278 278 278 279 279 279 279 279 280 284 284 285 C H A P T E R 2 5 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema Fluid Intake and Output Are Balanced During Steady-State Conditions Daily Intake of Water Daily Loss of Body Water Body Fluid Compartments Intracellular Fluid Compartment Extracellular Fluid Compartment Blood Volume Constituents of Extracellular and Intracellular Fluids Ionic Composition of Plasma and Interstitial Fluid Is Similar Important Constituents of the Intracellular Fluid Measurement of Fluid Volumes in the Different Body Fluid Compartments— The Indicator-Dilution Principle Determination of Volumes of Specific Body Fluid Compartments Regulation of Fluid Exchange and Osmotic Equilibrium Between Intracellular and Extracellular Fluid Basic Principles of Osmosis and Osmotic Pressure Osmotic Equilibrium Is Maintained Between Intracellular and Extracellular Fluids Volume and Osmolality of Extracellular and Intracellular Fluids in Abnormal States Effect of Adding Saline Solution to the Extracellular Fluid Glucose and Other Solutions Administered for Nutritive Purposes Clinical Abnormalities of Fluid Volume Regulation: Hyponatremia and Hypernatremia Causes of Hyponatremia: Excess Water or Loss of Sodium Causes of Hypernatremia: Water Loss or Excess Sodium Edema: Excess Fluid in the Tissues Intracellular Edema Extracellular Edema 291 291 291 291 292 293 293 293 293 293 295 295 295 296 296 298 299 299 301 301 301 302 302 302 302 Table of Contents Summary of Causes of Extracellular Edema Safety Factors That Normally Prevent Edema Fluids in the “Potential Spaces” of the Body C H A P T E R 2 6 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control Multiple Functions of the Kidneys in Homeostasis Physiologic Anatomy of the Kidneys General Organization of the Kidneys and Urinary Tract Renal Blood Supply The Nephron Is the Functional Unit of the Kidney Micturition Physiologic Anatomy and Nervous Connections of the Bladder Transport of Urine from the Kidney Through the Ureters and into the Bladder Innervation of the Bladder Filling of the Bladder and Bladder Wall Tone; the Cystometrogram Micturition Reflex Facilitation or Inhibition of Micturition by the Brain Abnormalities of Micturition Urine Formation Results from Glomerular Filtration, Tubular Reabsorption, and Tubular Secretion Filtration, Reabsorption, and Secretion of Different Substances Glomerular Filtration—The First Step in Urine Formation Composition of the Glomerular Filtrate GFR Is About 20 Per Cent of the Renal Plasma Flow Glomerular Capillary Membrane Determinants of the GFR Increased Glomerular Capillary Filtration Coefficient Increases GFR Increased Bowman’s Capsule Hydrostatic Pressure Decreases GFR Increased Glomerular Capillary Colloid Osmotic Pressure Decreases GFR Increased Glomerular Capillary Hydrostatic Pressure Increases GFR Renal Blood Flow Renal Blood Flow and Oxygen Consumption Determinants of Renal Blood Flow Blood Flow in the Vasa Recta of the Renal Medulla Is Very Low Compared with Flow in the Renal Cortex Physiologic Control of Glomerular Filtration and Renal Blood Flow Sympathetic Nervous System Activation Decreases GFR Hormonal and Autacoid Control of Renal Circulation Autoregulation of GFR and Renal Blood Flow 303 304 305 Importance of GFR Autoregulation in Preventing Extreme Changes in Renal Excretion Role of Tubuloglomerular Feedback in Autoregulation of GFR Myogenic Autoregulation of Renal Blood Flow and GFR Other Factors That Increase Renal Blood Flow and GFR: High Protein Intake and Increased Blood Glucose xix 323 323 325 325 307 307 308 308 309 310 311 311 312 312 312 313 313 313 314 315 316 316 316 316 317 318 318 318 319 320 320 320 321 321 321 322 323 C H A P T E R 2 7 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Reabsorption and Secretion by the Renal Tubules Tubular Reabsorption Is Selective and Quantitatively Large Tubular Reabsorption Includes Passive and Active Mechanisms Active Transport Passive Water Reabsorption by Osmosis Is Coupled Mainly to Sodium Reabsorption Reabsorption of Chloride, Urea, and Other Solutes by Passive Diffusion Reabsorption and Secretion Along Different Parts of the Nephron Proximal Tubular Reabsorption Solute and Water Transport in the Loop of Henle Distal Tubule Late Distal Tubule and Cortical Collecting Tubule Medullary Collecting Duct Summary of Concentrations of Different Solutes in the Different Tubular Segments Regulation of Tubular Reabsorption Glomerulotubular Balance—The Ability of the Tubules to Increase Reabsorption Rate in Response to Increased Tubular Load Peritubular Capillary and Renal Interstitial Fluid Physical Forces Effect of Arterial Pressure on Urine Output—The Pressure-Natriuresis and Pressure-Diuresis Mechanisms Hormonal Control of Tubular Reabsorption Sympathetic Nervous System Activation Increases Sodium Reabsorption Use of Clearance Methods to Quantify Kidney Function Inulin Clearance Can Be Used to Estimate GFR Creatine Clearance and Plasma Creatinine Clearance Can Be Used to Estimate GFR PAH Clearance Can Be Used to Estimate Renal Plasma Flow Filtration Fraction Is Calculated from GFR Divided by Renal Plasma Flow Calculation of Tubular Reabsorption or Secretion from Renal Clearance 327 327 327 328 328 332 332 333 333 334 336 336 337 338 339 339 339 341 342 343 343 344 344 345 346 346 xx C H A P T E R 2 8 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration The Kidneys Excrete Excess Water by Forming a Dilute Urine Antidiuretic Hormone Controls Urine Concentration Renal Mechanisms for Excreting a Dilute Urine The Kidneys Conserve Water by Excreting a Concentrated Urine Obligatory Urine Volume Requirements for Excreting a Concentrated Urine—High ADH Levels and Hyperosmotic Renal Medulla Countercurrent Mechanism Produces a Hyperosmotic Renal Medullary Interstitium Role of Distal Tubule and Collecting Ducts in Excreting a Concentrated Urine Urea Contributes to Hyperosmotic Renal Medullary Interstitium and to a Concentrated Urine Countercurrent Exchange in the Vasa Recta Preserves Hyperosmolarity of the Renal Medulla Summary of Urine Concentrating Mechanism and Changes in Osmolarity in Different Segments of the Tubules Quantifying Renal Urine Concentration and Dilution: “Free Water” and Osmolar Clearances Disorders of Urinary Concentrating Ability Control of Extracellular Fluid Osmolarity and Sodium Concentration Estimating Plasma Osmolarity from Plasma Sodium Concentration Osmoreceptor-ADH Feedback System ADH Synthesis in Supraoptic and Paraventricular Nuclei of the Hypothalamus and ADH Release from the Posterior Pituitary Cardiovascular Reflex Stimulation of ADH Release by Decreased Arterial Pressure and/or Decreased Blood Volume Quantitative Importance of Cardiovascular Reflexes and Osmolarity in Stimulating ADH Secretion Other Stimuli for ADH Secretion Role of Thirst in Controlling Extracellular Fluid Osmolarity and Sodium Concentration Central Nervous System Centers for Thirst Stimuli for Thirst Threshold for Osmolar Stimulus of Drinking Integrated Responses of Osmoreceptor-ADH and Thirst Mechanisms in Controlling Extracellular Fluid Osmolarity and Sodium Concentration Role of Angiotensin II and Aldosterone in Controlling Extracellular Fluid Osmolarity and Sodium Concentration Salt-Appetite Mechanism for Controlling Extracellular Fluid Sodium Concentration and Volume Table of Contents 348 348 348 349 350 350 350 351 352 353 354 355 357 357 358 358 358 359 360 360 360 361 361 361 362 362 362 363 C H A P T E R 2 9 Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume Regulation of Potassium Excretion and Potassium Concentration in Extracellular Fluid Regulation of Internal Potassium Distribution Overview of Renal Potassium Excretion Potassium Secretion by Principal Cells of Late Distal and Cortical Collecting Tubules Summary of Factors That Regulate Potassium Secretion: Plasma Potassium Concentration, Aldosterone, Tubular Flow Rate, and Hydrogen Ion Concentration Control of Renal Calcium Excretion and Extracellular Calcium Ion Concentration Control of Calcium Excretion by the Kidneys Regulation of Renal Phosphate Excretion Control of Renal Magnesium Excretion and Extracellular Magnesium Ion Concentration Integration of Renal Mechanisms for Control of Extracellular Fluid Sodium Excretion Is Precisely Matched to Intake Under Steady-State Conditions Sodium Excretion Is Controlled by Altering Glomerular Filtration or Tubular Sodium Reabsorption Rates Importance of Pressure Natriuresis and Pressure Diuresis in Maintaining Body Sodium and Fluid Balance Pressure Natriuresis and Diuresis Are Key Components of a Renal-Body Fluid Feedback for Regulating Body Fluid Volumes and Arterial Pressure Precision of Blood Volume and Extracellular Fluid Volume Regulation Distribution of Extracellular Fluid Between the Interstitial Spaces and Vascular System Nervous and Hormonal Factors Increase the Effectiveness of Renal-Body Fluid Feedback Control Sympathetic Nervous System Control of Renal Excretion: Arterial Baroreceptor and Low-Pressure Stretch Receptor Reflexes Role of Angiotensin II In Controlling Renal Excretion Role of Aldosterone in Controlling Renal Excretion Role of ADH in Controlling Renal Water Excretion Role of Atrial Natriuretic Peptide in Controlling Renal Excretion Integrated Responses to Changes in Sodium Intake Conditions That Cause Large Increases in Blood Volume and Extracellular Fluid Volume 365 365 366 367 367 368 371 372 372 373 373 373 374 374 375 376 376 377 377 377 378 379 378 380 380 Table of Contents Increased Blood Volume and Extracellular Fluid Volume Caused by Heart Diseases Increased Blood Volume Caused by Increased Capacity of Circulation Conditions That Cause Large Increases in Extracellular Fluid Volume but with Normal Blood Volume Nephrotic Syndrome—Loss of Plasma Proteins in Urine and Sodium Retention by the Kidneys Liver Cirrhosis—Decreased Synthesis of Plasma Proteins by the Liver and Sodium Retention by the Kidneys C H A P T E R 3 0 Regulation of Acid-Base Balance Hydrogen Ion Concentration Is Precisely Regulated Acids and Bases—Their Definitions and Meanings Defenses Against Changes in Hydrogen Ion Concentration: Buffers, Lungs, and Kidneys Buffering of Hydrogen Ions in the Body Fluids Bicarbonate Buffer System Quantitative Dynamics of the Bicarbonate Buffer System Phosphate Buffer System Proteins: Important Intracellular Buffers Respiratory Regulation of Acid-Base Balance Pulmonary Expiration of CO2 Balances Metabolic Formation of CO2 Increasing Alveolar Ventilation Decreases Extracellular Fluid Hydrogen Ion Concentration and Raises pH Increased Hydrogen Ion Concentration Stimulates Alveolar Ventilation Renal Control of Acid-Base Balance Secretion of Hydrogen Ions and Reabsorption of Bicarbonate Ions by the Renal Tubules Hydrogen Ions Are Secreted by Secondary Active Transport in the Early Tubular Segments Filtered Bicarbonate Ions Are Reabsorbed by Interaction with Hydrogen Ions in the Tubules Primary Active Secretion of Hydrogen Ions in the Intercalated Cells of Late Distal and Collecting Tubules Combination of Excess Hydrogen Ions with Phosphate and Ammonia Buffers in the Tubule—A Mechanism for Generating “New” Bicarbonate Ions Phosphate Buffer System Carries Excess Hydrogen Ions into the Urine and Generates New Bicarbonate Excretion of Excess Hydrogen Ions and Generation of New Bicarbonate by the Ammonia Buffer System Quantifying Renal Acid-Base Excretion Regulation of Renal Tubular Hydrogen Ion Secretion 380 380 381 381 381 383 383 383 384 385 385 385 387 387 388 388 388 389 390 390 391 391 392 392 393 393 394 395 Renal Correction of Acidosis—Increased Excretion of Hydrogen Ions and Addition of Bicarbonate Ions to the Extracellular Fluid Acidosis Decreases the Ratio of HCO3-/H+ in Renal Tubular Fluid Renal Correction of Alkalosis—Decreased Tubular Secretion of Hydrogen Ions and Increased Excretion of Bicarbonate Ions Alkalosis Increases the Ratio of HCO3-/H+ in Renal Tubular Fluid Clinical Causes of Acid-Base Disorders Respiratory Acidosis Is Caused by Decreased Ventilation and Increased PCO2 Respiratory Alkalosis Results from Increased Ventilation and Decreased PCO2 Metabolic Acidosis Results from Decreased Extracellular Fluid Bicarbonate Concentration Treatment of Acidosis or Alkalosis Clinical Measurements and Analysis of Acid-Base Disorders Complex Acid-Base Disorders and Use of the Acid-Base Nomogram for Diagnosis Use of Anion Gap to Diagnose Acid-Base Disorders C H A P T E R 3 1 Kidney Diseases and Diuretics Diuretics and Their Mechanisms of Action Osmotic Diuretics Decrease Water Reabsorption by Increasing Osmotic Pressure of Tubular Fluid “Loop” Diuretics Decrease Active Sodium-Chloride-Potassium Reabsorption in the Thick Ascending Loop of Henle Thiazide Diuretics Inhibit Sodium-Chloride Reabsorption in the Early Distal Tubule Carbonic Anhydrase Inhibitors Block Sodium-Bicarbonate Reabsorption in the Proximal Tubules Competitive Inhibitors of Aldosterone Decrease Sodium Reabsorption from and Potassium Secretion into the Cortical Collecting Tubule Diuretics That Block Sodium Channels in the Collecting Tubules Decrease Sodium Reabsorption Kidney Diseases Acute Renal Failure Prerenal Acute Renal Failure Caused by Decreased Blood Flow to the Kidney Intrarenal Acute Renal Failure Caused by Abnormalities within the Kidney Postrenal Acute Renal Failure Caused by Abnormalities of the Lower Urinary Tract Physiologic Effects of Acute Renal Failure Chronic Renal Failure: An Irreversible Decrease in the Number of Functional Nephrons Vicious Circle of Chronic Renal Failure Leading to End-Stage Renal Disease Injury to the Renal Vasculature as a Cause of Chronic Renal Failure xxi 396 396 396 396 397 397 397 397 398 398 399 400 402 402 402 403 404 404 404 404 404 404 405 405 406 406 406 407 408 xxii Table of Contents Injury to the Glomeruli as a Cause of Chronic Renal Failure— Glomerulonephritis Injury to the Renal Interstitium as a Cause of Chronic Renal Failure— Pyelonephritis Nephrotic Syndrome—Excretion of Protein in the Urine Because of Increased Glomerular Permeability Nephron Function in Chronic Renal Failure Effects of Renal Failure on the Body Fluids—Uremia Hypertension and Kidney Disease Specific Tubular Disorders Treatment of Renal Failure by Dialysis with an Artificial Kidney U N I T 408 409 409 409 411 412 413 414 V I Blood Cells, Immunity, and Blood Clotting C H A P T E R 3 2 Red Blood Cells, Anemia, and Polycythemia Red Blood Cells (Erythrocytes) Production of Red Blood Cells Formation of Hemoglobin Iron Metabolism Life Span and Destruction of Red Blood Cells Anemias Effects of Anemia on Function of the Circulatory System Polycythemia Effect of Polycythemia on Function of the Circulatory System C H A P T E R 3 3 Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System, and Inflammation Leukocytes (White Blood Cells) General Characteristics of Leukocytes Genesis of the White Blood Cells Life Span of the White Blood Cells Neutrophils and Macrophages Defend Against Infections Phagocytosis Monocyte-Macrophage Cell System (Reticuloendothelial System) Inflammation: Role of Neutrophils and Macrophages Inflammation Macrophage and Neutrophil Responses During Inflammation Eosinophils Basophils Leukopenia The Leukemias Effects of Leukemia on the Body 419 419 420 424 425 426 426 427 427 428 429 429 429 430 431 431 431 432 C H A P T E R 3 4 Resistance of the Body to Infection: II. Immunity and Allergy Innate Immunity Acquired (Adaptive) Immunity Basic Types of Acquired Immunity Both Types of Acquired Immunity Are Initiated by Antigens Lymphocytes Are Responsible for Acquired Immunity Preprocessing of the T and B Lymphocytes T Lymphocytes and B-Lymphocyte Antibodies React Highly Specifically Against Specific Antigens—Role of Lymphocyte Clones Origin of the Many Clones of Lymphocytes Specific Attributes of the B-Lymphocyte System—Humoral Immunity and the Antibodies Special Attributes of the T-Lymphocyte System–Activated T Cells and CellMediated Immunity Several Types of T Cells and Their Different Functions Tolerance of the Acquired Immunity System to One’s Own Tissues—Role of Preprocessing in the Thymus and Bone Marrow Immunization by Injection of Antigens Passive Immunity Allergy and Hypersensitivity Allergy Caused by Activated T Cells: Delayed-Reaction Allergy Allergies in the “Allergic” Person, Who Has Excess IgE Antibodies C H A P T E R 3 5 Blood Types; Transfusion; Tissue and Organ Transplantation Antigenicity Causes Immune Reactions of Blood O-A-B Blood Types A and B Antigens—Agglutinogens Agglutinins Agglutination Process In Transfusion Reactions Blood Typing Rh Blood Types Rh Immune Response Transfusion Reactions Resulting from Mismatched Blood Types Transplantation of Tissues and Organs Attempts to Overcome Immune Reactions in Transplanted Tissue 434 434 C H A P T E R 3 6 Hemostasis and Blood Coagulation 434 436 436 436 437 437 Events in Hemostasis Vascular Constriction Formation of the Platelet Plug Blood Coagulation in the Ruptured Vessel Fibrous Organization or Dissolution of the Blood Clot 439 439 439 440 440 440 440 442 442 443 446 446 448 448 449 449 449 449 451 451 451 451 452 452 453 453 453 454 455 455 457 457 457 457 458 458 Table of Contents Mechanism of Blood Coagulation Conversion of Prothrombin to Thrombin Conversion of Fibrinogen to Fibrin— Formation of the Clot Vicious Circle of Clot Formation Initiation of Coagulation: Formation of Prothrombin Activator Prevention of Blood Clotting in the Normal Vascular System—Intravascular Anticoagulants Lysis of Blood Clots—Plasmin Conditions That Cause Excessive Bleeding in Human Beings Decreased Prothrombin, Factor VII, Factor IX,and Factor X Caused by Vitamin K Deficiency Hemophilia Thrombocytopenia Thromboembolic Conditions in the Human Being Femoral Venous Thrombosis and Massive Pulmonary Embolism Disseminated Intravascular Coagulation Anticoagulants for Clinical Use Heparin as an Intravenous Anticoagulant Coumarins as Anticoagulants Prevention of Blood Coagulation Outside the Body Blood Coagulation Tests Bleeding Time Clotting Time Prothrombin Time U N I T 459 459 460 460 461 463 464 464 464 465 465 465 466 466 466 466 466 466 467 467 467 467 V I I Respiration C H A P T E R Pulmonary Ventilation 3 7 Mechanics of Pulmonary Ventilation Muscles That Cause Lung Expansion and Contraction Movement of Air In and Out of the Lungs and the Pressures That Cause the Movement Effect of the Thoracic Cage on Lung Expansibility Pulmonary Volumes and Capacities Recording Changes in Pulmonary Volume— Spirometry Abbreviations and Symbols Used in Pulmonary Function Tests Determination of Functional Residual Capacity, Residual Volume, and Total Lung Capacity—Helium Dilution Method Minute Respiratory Volume Equals Respiratory Rate Times Tidal Volume Alveolar Ventilation “Dead Space” and Its Effect on Alveolar Ventilation Rate of Alveolar Ventilation Functions of the Respiratory Passageways Trachea, Bronchi, and Bronchioles Normal Respiratory Functions of the Nose 471 471 471 472 474 475 475 476 476 477 477 477 478 478 478 480 C H A P T E R 3 8 Pulmonary Circulation, Pulmonary Edema, Pleural Fluid Physiologic Anatomy of the Pulmonary Circulatory System Pressures in the Pulmonary System Blood Volume of the Lungs Blood Flow Through the Lungs and Its Distribution Effect of Hydrostatic Pressure Gradients in the Lungs on Regional Pulmonary Blood Flow Zones 1, 2, and 3 of Pulmonary Blood Flow Effect of Increased Cardiac Output on Pulmonary Blood Flow and Pulmonary Arterial Pressure During Heavy Exercise Function of the Pulmonary Circulation When the Left Atrial Pressure Rises as a Result of Left-Sided Heart Failure Pulmonary Capillary Dynamics Capillary Exchange of Fluid in the Lungs, and Pulmonary Interstitial Fluid Dynamics Pulmonary Edema Fluid in the Pleural Cavity C H A P T E R 3 9 Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Through the Respiratory Membrane Physics of Gas Diffusion and Gas Partial Pressures Molecular Basis of Gas Diffusion Gas Pressures in a Mixture of Gases— “Partial Pressures” of Individual Gases Pressures of Gases Dissolved in Water and Tissues Vapor Pressure of Water Diffusion of Gases Through Fluids— Pressure Difference Causes Net Diffusion Diffusion of Gases Through Tissues Composition of Alveolar Air—Its Relation to Atmospheric Air Rate at Which Alveolar Air Is Renewed by Atmospheric Air Oxygen Concentration and Partial Pressure in the Alveoli CO2 Concentration and Partial Pressure in the Alveoli Expired Air Diffusion of Gases Through the Respiratory Membrane Factors That Affect the Rate of Gas Diffusion Through the Respiratory Membrane Diffusing Capacity of the Respiratory Membrane Effect of the Ventilation-Perfusion Ratio on .Alveolar Gas Concentration . PO2-PCO2, VA/Q Diagram Concept of . the . “Physiological Shunt” (When VA/Q Is Greater Than Normal) Abnormalities of Ventilation-Perfusion Ratio xxiii 483 483 483 484 485 485 485 486 487 487 487 488 489 491 491 491 491 492 492 493 493 493 494 494 495 495 496 498 498 499 500 500 501 xxiv C H A P T E R 4 0 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids Transport of Oxygen from the Lungs to the Body Tissues Diffusion of Oxygen from the Alveoli to the Pulmonary Capillary Blood Transport of Oxygen in the Arterial Blood Diffusion of Oxygen from the Peripheral Capillaries into the Tissue Fluid Diffusion of Oxygen from the Peripheral Capillaries to the Tissue Cells Diffusion of Carbon Dioxide from the Peripheral Tissue Cells into the Capillaries and from the Pulmonary Capillaries into the Alveoli Role of Hemoglobin in Oxygen Transport Reversible Combination of Oxygen with Hemoglobin Effect of Hemoglobin to “Buffer” the Tissue PO2 Factors That Shift the Oxygen-Hemoglobin Dissociation Curve—Their Importance for Oxygen Transport Metabolic Use of Oxygen by the Cells Transport of Oxygen in the Dissolved State Combination of Hemoglobin with Carbon Monoxide—Displacement of Oxygen Transport of Carbon Dioxide in the Blood Chemical Forms in Which Carbon Dioxide Is Transported Carbon Dioxide Dissociation Curve When Oxygen Binds with Hemoglobin, Carbon Dioxide Is Released (the Haldane Effect) to Increase CO2 Transport Change in Blood Acidity During Carbon Dioxide Transport Respiratory Exchange Ratio C H A P T E R 4 1 Regulation of Respiration Respiratory Center Dorsal Respiratory Group of Neurons—Its Control of Inspiration and of Respiratory Rhythm A Pneumotaxic Center Limits the Duration of Inspiration and Increases the Respiratory Rate Ventral Respiratory Group of Neurons— Functions in Both Inspiration and Expiration Lung Inflation Signals Limit Inspiration— The Hering-Breuer Inflation Reflex Control of Overall Respiratory Center Activity Chemical Control of Respiration Direct Chemical Control of Respiratory Center Activity by Carbon Dioxide and Hydrogen Ions Peripheral Chemoreceptor System for Control of Respiratory Activity—Role of Oxygen in Respiratory Control Effect of Low Arterial PO2 to Stimulate Alveolar Ventilation When Arterial Carbon Dioxide and Hydrogen Ion Concentrations Remain Normal Table of Contents 502 502 502 503 503 504 504 505 505 507 507 508 509 509 510 510 511 511 512 512 514 514 514 514 515 515 516 516 516 518 519 Chronic Breathing of Low Oxygen Stimulates Respiration Even More—The Phenomenon of “Acclimatization” Composite Effects of PCO2, pH, and PO2 on Alveolar Ventilation Regulation of Respiration During Exercise Other Factors That Affect Respiration Sleep Apnea C H A P T E R 4 2 Respiratory Insufficiency— Pathophysiology, Diagnosis, Oxygen Therapy Useful Methods for Studying Respiratory Abnormalities Study of Blood Gases and Blood pH Measurement of Maximum Expiratory Flow Forced Expiratory Vital Capacity and Forced Expiratory Volume Physiologic Peculiarities of Specific Pulmonary Abnormalities Chronic Pulmonary Emphysema Pneumonia Atelectasis Asthma Tuberculosis Hypoxia and Oxygen Therapy Oxygen Therapy in Different Types of Hypoxia Cyanosis Hypercapnia Dyspnea Artificial Respiration U N I T 519 519 520 521 522 524 524 524 525 526 526 526 527 528 529 530 530 530 531 531 532 532 V I I I Aviation, Space, and Deep-Sea Diving Physiology C H A P T E R 4 3 Aviation, High-Altitude, and Space Physiology Effects of Low Oxygen Pressure on the Body Alveolar PO2 at Different Elevations Effect of Breathing Pure Oxygen on Alveolar PO2 at Different Altitudes Acute Effects of Hypoxia Acclimatization to Low PO2 Natural Acclimatization of Native Human Beings Living at High Altitudes Reduced Work Capacity at High Altitudes and Positive Effect of Acclimatization Acute Mountain Sickness and High-Altitude Pulmonary Edema Chronic Mountain Sickness Effects of Acceleratory Forces on the Body in Aviation and Space Physiology Centrifugal Acceleratory Forces Effects of Linear Acceleratory Forces on the Body 537 537 537 538 538 539 540 540 540 541 541 541 542 Table of Contents “Artificial Climate” in the Sealed Spacecraft Weightlessness in Space C H A P T E R 4 4 Physiology of Deep-Sea Diving and Other Hyperbaric Conditions Effect of High Partial Pressures of Individual Gases on the Body Nitrogen Narcosis at High Nitrogen Pressures Oxygen Toxicity at High Pressures Carbon Dioxide Toxicity at Great Depths in the Sea Decompression of the Diver After Excess Exposure to High Pressure Scuba (Self-Contained Underwater Breathing Apparatus) Diving Special Physiologic Problems in Submarines Hyperbaric Oxygen Therapy U N I T 543 543 545 545 545 546 547 547 549 550 550 I X The Nervous System: A. General Principles and Sensory Physiology C H A P T E R 4 5 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” General Design of the Nervous System Central Nervous System Neuron: The Basic Functional Unit Sensory Part of the Nervous System— Sensory Receptors Motor Part of the Nervous System— Effectors Processing of Information—“Integrative” Function of the Nervous System Storage of Information—Memory Major Levels of Central Nervous System Function Spinal Cord Level Lower Brain or Subcortical Level Higher Brain or Cortical Level Comparison of the Nervous System with a Computer Central Nervous System Synapses Types of Synapses—Chemical and Electrical Physiologic Anatomy of the Synapse Chemical Substances That Function as Synaptic Transmitters Electrical Events During Neuronal Excitation Electrical Events During Neuronal Inhibition Special Functions of Dendrites for Exciting Neurons Relation of State of Excitation of the Neuron to Rate of Firing Some Special Characteristics of Synaptic Transmission 555 555 555 555 556 556 557 557 557 558 558 558 559 559 559 562 564 566 568 569 570 C H A P T E R 4 6 Sensory Receptors, Neuronal Circuits for Processing Information Types of Sensory Receptors and the Sensory Stimuli They Detect Differential Sensitivity of Receptors Transduction of Sensory Stimuli into Nerve Impulses Local Electrical Currents at Nerve Endings— Receptor Potentials Adaptation of Receptors Nerve Fibers That Transmit Different Types of Signals, and Their Physiologic Classification Transmission of Signals of Different Intensity in Nerve Tracts—Spatial and Temporal Summation Transmission and Processing of Signals in Neuronal Pools Relaying of Signals Through Neuronal Pools Prolongation of a Signal by a Neuronal Pool—“Afterdischarge” Instability and Stability of Neuronal Circuits Inhibitory Circuits as a Mechanism for Stabilizing Nervous System Function Synaptic Fatigue as a Means for Stabilizing the Nervous System C H A P T E R 4 7 Somatic Sensations: I. General Organization, the Tactile and Position Senses CLASSIFICATION OF SOMATIC SENSES Detection and Transmission of Tactile Sensations Detection of Vibration TICKLE AND ITCH Sensory Pathways for Transmitting Somatic Signals into the Central Nervous System Dorsal Column–Medial Lemniscal System Anterolateral System Transmission in the Dorsal Column— Medial Lemniscal System Anatomy of the Dorsal Column—Medial Lemniscal System Somatosensory Cortex Somatosensory Association Areas Overall Characteristics of Signal Transmission and Analysis in the Dorsal Column–Medial Lemniscal System Position Senses Interpretation of Sensory Stimulus Intensity Judgment of Stimulus Intensity Position Senses Transmission of Less Critical Sensory Signals in the Anterolateral Pathway Anatomy of the Anterolateral Pathway Some Special Aspects of Somatosensory Function Function of the Thalamus in Somatic Sensation xxv 572 572 572 573 573 575 576 577 578 579 581 583 583 583 585 585 585 587 587 587 588 588 588 588 589 592 592 594 593 594 594 595 595 596 596 xxvi Table of Contents Cortical Control of Sensory Sensitivity— “Corticofugal” Signals Segmental Fields of Sensation—The Dermatomes C H A P T E R 4 8 Somatic Sensations: II. Pain, Headache, and Thermal Sensations Types of Pain and Their Qualities— Fast Pain and Slow Pain Pain Receptors and Their Stimulation Rate of Tissue Damage as a Stimulus for Pain Dual Pathways for Transmission of Pain Signals into the Central Nervous System Dual Pain Pathways in the Cord and Brain Stem—The Neospinothalamic Tract and the Paleospinothalamic Tract Pain Suppression (“Analgesia”) System in the Brain and Spinal Cord Brain’s Opiate System—Endorphins and Enkephalins Inhibition of Pain Transmission by Simultaneous Tactile Sensory Signals Treatment of Pain by Electrical Stimulation Referred Pain Visceral Pain Causes of True Visceral Pain “Parietal Pain” Caused by Visceral Disease Localization of Visceral Pain—“Visceral” and the “Parietal” Pain Transmission Pathways Some Clinical Abnormalities of Pain and Other Somatic Sensations Hyperalgesia Herpes Zoster (Shingles) Tic Douloureux Brown-Séquard Syndrome Headache Headache of Intracranial Origin Thermal Sensations Thermal Receptors and Their Excitation Transmission of Thermal Signals in the Nervous System U N I T 597 597 598 598 598 599 600 600 602 602 603 603 603 603 604 604 604 605 605 605 605 606 606 606 607 607 609 X The Nervous System: B. The Special Senses C H A P T E R 4 9 The Eye: I. Optics of Vision Physical Principles of Optics Refraction of Light Application of Refractive Principles to Lenses Focal Length of a Lens Formation of an Image by a Convex Lens Measurement of the Refractive Power of a Lens—“Diopter” Optics of the Eye The Eye as a Camera Mechanism of “Accommodation” 613 613 613 613 615 616 616 617 617 617 Pupillary Diameter Errors of Refraction Visual Acuity Determination of Distance of an Object from the Eye—“Depth Perception” Ophthalmoscope Fluid System of the Eye—Intraocular Fluid Formation of Aqueous Humor by the Ciliary Body Outflow of Aqueous Humor from the Eye Intraocular Pressure C H A P T E R 5 0 The Eye: II. Receptor and Neural Function of the Retina Anatomy and Function of the Structural Elements of the Retina Photochemistry of Vision Rhodopsin-Retinal Visual Cycle, and Excitation of the Rods Automatic Regulation of Retinal Sensitivity— Light and Dark Adaptation Color Vision Tricolor Mechanism of Color Detection Color Blindness Neural Function of the Retina Neural Circuitry of the Retina Ganglion Cells and Optic Nerve Fibers Excitation of the Ganglion Cells C H A P T E R 5 1 The Eye: III. Central Neurophysiology of Vision Visual Pathways Function of the Dorsal Lateral Geniculate Nucleus of the Thalamus Organization and Function of the Visual Cortex Layered Structure of the Primary Visual Cortex Two Major Pathways for Analysis of Visual Information—(1) The Fast “Position” and “Motion” Pathway; (2) The Accurate Color Pathway Neuronal Patterns of Stimulation During Analysis of the Visual Image Detection of Color Effect of Removing the Primary Visual Cortex Fields of Vision; Perimetry Eye Movements and Their Control Fixation Movements of the Eyes “Fusion” of the Visual Images from the Two Eyes Autonomic Control of Accommodation and Pupillary Aperture Control of Accommodation (Focusing the Eyes) Control of Pupillary Diameter C H A P T E R The Sense of Hearing 618 619 621 621 622 623 623 623 624 626 626 628 629 631 632 632 633 633 633 636 637 640 640 640 641 642 643 643 644 644 644 645 645 647 648 649 649 5 2 Tympanic Membrane and the Ossicular System 651 651 Table of Contents Conduction of Sound from the Tympanic Membrane to the Cochlea Transmission of Sound Through Bone Cochlea Functional Anatomy of the Cochlea Transmission of Sound Waves in the Cochlea—“Traveling Wave” Function of the Organ of Corti Determination of Sound Frequency—The “Place” Principle Determination of Loudness Central Auditory Mechanisms Auditory Nervous Pathways Function of the Cerebral Cortex in Hearing Determination of the Direction from Which Sound Comes Centrifugal Signals from the Central Nervous System to Lower Auditory Centers Hearing Abnormalities Types of Deafness C H A P T E R 5 3 The Chemical Senses—Taste and Smell Sense of Taste Primary Sensations of Taste Taste Bud and Its Function Transmission of Taste Signals into the Central Nervous System Taste Preference and Control of the Diet Sense of Smell Olfactory Membrane Stimulation of the Olfactory Cells Transmission of Smell Signals into the Central Nervous System U N I T 651 652 652 652 654 655 656 656 657 657 658 660 660 660 660 663 663 663 664 665 666 667 667 667 668 X I The Nervous System: C. Motor and Integrative Neurophysiology C H A P T E R 5 4 Motor Functions of the Spinal Cord; the Cord Reflexes Organization of the Spinal Cord for Motor Functions Muscle Sensory Receptors—Muscle Spindles and Golgi Tendon Organs— And Their Roles in Muscle Control Receptor Function of the Muscle Spindle Muscle Stretch Reflex Role of the Muscle Spindle in Voluntary Motor Activity Clinical Applications of the Stretch Reflex Golgi Tendon Reflex Function of the Muscle Spindles and Golgi Tendon Organs in Conjunction with Motor Control from Higher Levels of the Brain Flexor Reflex and the Withdrawal Reflexes Crossed Extensor Reflex 673 673 675 675 676 678 678 679 680 680 681 Reciprocal Inhibition and Reciprocal Innervation Reflexes of Posture and Locomotion Postural and Locomotive Reflexes of the Cord Scratch Reflex Spinal Cord Reflexes That Cause Muscle Spasm Autonomic Reflexes in the Spinal Cord Spinal Cord Transection and Spinal Shock C H A P T E R 5 5 Cortical and Brain Stem Control of Motor Function MOTOR CORTEX AND CORTICOSPINAL TRACT Primary Motor Cortex Premotor Area Supplementary Motor Area Some Specialized Areas of Motor Control Found in the Human Motor Cortex Transmission of Signals from the Motor Cortex to the Muscles Incoming Fiber Pathways to the Motor Cortex Red Nucleus Serves as an Alternative Pathway for Transmitting Cortical Signals to the Spinal Cord “Extrapyramidal” System Excitation of the Spinal Cord Motor Control Areas by the Primary Motor Cortex and Red Nucleus Role of the Brain Stem in Controlling Motor Function Support of the Body Against Gravity— Roles of the Reticular and Vestibular Nuclei Vestibular Sensations and Maintenance of Equilibrium Vestibular Apparatus Function of the Utricle and Saccule in the Maintenance of Static Equilibrium Detection of Head Rotation by the Semicircular Ducts Vestibular Mechanisms for Stabilizing the Eyes Other Factors Concerned with Equilibrium Functions of Brain Stem Nuclei in Controlling Subconscious, Stereotyped Movements C H A P T E R 5 6 Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control Cerebellum and Its Motor Functions Anatomical Functional Areas of the Cerebellum Neuronal Circuit of the Cerebellum Function of the Cerebellum in Overall Motor Control Clinical Abnormalities of the Cerebellum xxvii 681 682 682 683 683 683 684 685 685 685 686 686 686 687 688 688 689 689 691 691 692 692 694 695 696 696 697 698 698 699 700 703 706 xxviii Basal Ganglia—Their Motor Functions Function of the Basal Ganglia in Executing Patterns of Motor Activity—The Putamen Circuit Role of the Basal Ganglia for Cognitive Control of Sequences of Motor Patterns— The Caudate Circuit Function of the Basal Ganglia to Change the Timing and to Scale the Intensity of Movements Functions of Specific Neurotransmitter Substances in the Basal Ganglial System Integration of the Many Parts of the Total Motor Control System Spinal Level Hindbrain Level Motor Cortex Level What Drives Us to Action? C H A P T E R 5 7 Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory Physiologic Anatomy of the Cerebral Cortex Functions of Specific Cortical Areas Association Areas Comprehensive Interpretative Function of the Posterior Superior Temporal Lobe— “Wernicke’s Area” (a General Interpretative Area) Functions of the Parieto-occipitotemporal Cortex in the Nondominant Hemisphere Higher Intellectual Functions of the Prefrontal Association Areas Function of the Brain in Communication—Language Input and Language Output Function of the Corpus Callosum and Anterior Commissure to Transfer Thoughts, Memories, Training, and Other Information Between the Two Cerebral Hemispheres Thoughts, Consciousness, and Memory Memory—Roles of Synaptic Facilitation and Synaptic Inhibition Short-Term Memory Intermediate Long-Term Memory Long-Term Memory Consolidation of Memory C H A P T E R 5 8 Behavioral and Motivational Mechanisms of the Brain—The Limbic System and the Hypothalamus Activating-Driving Systems of the Brain Control of Cerebral Activity by Continuous Excitatory Signals from the Brain Stem Neurohormonal Control of Brain Activity Limbic System Functional Anatomy of the Limbic System; Key Position of the Hypothalamus Table of Contents 707 708 709 709 710 712 712 712 712 713 714 714 715 716 718 719 719 720 722 723 723 724 724 725 725 728 728 728 730 731 731 Hypothalamus, a Major Control Headquarters for the Limbic System Vegetative and Endocrine Control Functions of the Hypothalamus Behavioral Functions of the Hypothalamus and Associated Limbic Structures “Reward” and “Punishment” Function of the Limbic System Importance of Reward or Punishment in Behavior Specific Functions of Other Parts of the Limbic System Functions of the Hippocampus Functions of the Amygdala Function of the Limbic Cortex C H A P T E R 5 9 States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses Sleep Slow-Wave Sleep REM Sleep (Paradoxical Sleep, Desynchronized Sleep) Basic Theories of Sleep Physiologic Effects of Sleep Brain Waves Origin of Brain Waves Effect of Varying Levels of Cerebral Activity on the Frequency of the EEG Changes in the EEG at Different Stages of Wakefulness and Sleep Epilepsy Grand Mal Epilepsy Petit Mal Epilepsy Focal Epilepsy Psychotic Behavior and Dementia— Roles of Specific Neurotransmitter Systems Depression and Manic-Depressive Psychoses—Decreased Activity of the Norepinephrine and Serotonin Neurotransmitter Systems Schizophrenia—Possible Exaggerated Function of Part of the Dopamine System Alzheimer’s Disease—Amyloid Plaques and Depressed Memory C H A P T E R 6 0 The Autonomic Nervous System and the Adrenal Medulla General Organization of the Autonomic Nervous System Physiologic Anatomy of the Sympathetic Nervous System Preganglionic and Postganglionic Sympathetic Neurons Physiologic Anatomy of the Parasympathetic Nervous System Basic Characteristics of Sympathetic and Parasympathetic Function Cholinergic and Adrenergic Fibers— Secretion of Acetylcholine or Norepinephrine Receptors on the Effector Organs 732 733 734 735 736 736 736 737 738 739 739 739 740 740 741 741 742 743 743 743 743 744 744 745 745 745 746 748 748 748 748 750 750 750 752 Table of Contents Excitatory and Inhibitory Actions of Sympathetic and Parasympathetic Stimulation Effects of Sympathetic and Parasympathetic Stimulation on Specific Organs Function of the Adrenal Medullae Relation of Stimulus Rate to Degree of Sympathetic and Parasympathetic Effect Sympathetic and Parasympathetic “Tone” Denervation Supersensitivity of Sympathetic and Parasympathetic Organs after Denervation Autonomic Reflexes Stimulation of Discrete Organs in Some Instances and Mass Stimulation in Other Instances by the Sympathetic and Parasympathetic Systems “Alarm” or “Stress” Response of the Sympathetic Nervous System Medullary, Pontine, and Mesencephalic Control of the Autonomic Nervous System Pharmacology of the Autonomic Nervous System Drugs That Act on Adrenergic Effector Organs—Sympathomimetic Drugs Drugs That Act on Cholinergic Effector Organs Drugs That Stimulate or Block Sympathetic and Parasympathetic Postganglionic Neurons C H A P T E R 6 1 Cerebral Blood Flow, Cerebrospinal Fluid, and Brain Metabolism Cerebral Blood Flow Normal Rate of Cerebral Blood Flow Regulation of Cerebral Blood Flow Cerebral Microcirculation Cerebral Stroke Occurs When Cerebral Blood Vessels are Blocked Cerebrospinal Fluid System Cushioning Function of the Cerebrospinal Fluid Formation, Flow, and Absorption of Cerebrospinal Fluid Cerebrospinal Fluid Pressure Obstruction to Flow of Cerebrospinal Fluid Can Cause Hydrocephalus Blood–Cerebrospinal Fluid and Blood-Brain Barriers Brain Edema Brain Metabolism U N I T 753 753 755 756 756 756 757 757 758 758 Physiological Anatomy of the Gastrointestinal Wall Neural Control of Gastrointestinal Function—Enteric Nervous System Differences Between the Myenteric and Submucosal Plexuses Types of Neurotransmitters Secreted by Enteric Neurons Hormonal Control of Gastrointestinal Motility Functional Types of Movements in the Gastrointestinal Tract Propulsive Movements—Peristalsis Mixing Movements Gastrointestinal Blood Flow— “Splanchnic Circulation” Anatomy of the Gastrointestinal Blood Supply Effect of Gut Activity and Metabolic Factors on Gastrointestinal Blood Flow Nervous Control of Gastrointestinal Blood Flow xxix 771 773 774 775 776 776 776 777 777 778 778 779 759 759 759 759 761 761 761 761 763 763 763 763 764 765 C H A P T E R 6 3 Propulsion and Mixing of Food in the Alimentary Tract Ingestion of Food Mastication (Chewing) Swallowing (Deglutition) Motor Functions of the Stomach Storage Function of the Stomach Mixing and Propulsion Of Food in the Stomach—The Basic Electrical Rhythm of the Stomach Wall Stomach Emptying Regulation of Stomach Emptying Movements of the Small Intestine Mixing Contractions (Segmentation Contractions) Propulsive Movements Function of the Ileocecal Valve Movements of the Colon Defecation Other Autonomic Reflexes That Affect Bowel Activity 781 781 781 782 784 784 784 785 785 786 786 787 788 788 789 790 766 766 766 767 X I I Gastrointestinal Physiology C H A P T E R 6 2 General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation 771 General Principles of Gastrointestinal Motility 771 C H A P T E R 6 4 Secretory Functions of the Alimentary Tract General Principles of Alimentary Tract Secretion Anatomical Types of Glands Basic Mechanisms of Stimulation of the Alimentary Tract Glands Basic Mechanism of Secretion by Glandular Cells Lubricating and Protective Properties of Mucus, and Importance of Mucus in the Gastrointestinal Tract Secretion of Saliva Nervous Regulation of Salivary Secretion Esophageal Secretion 791 791 791 791 791 793 793 794 795 xxx Gastric Secretion Characteristics of the Gastric Secretions Pyloric Glands—Secretion of Mucus and Gastrin Surface Mucous Cells Stimulation of Gastric Acid Secretion Regulation of Pepsinogen Secretion Inhibition of Gastric Secretion by Other Post-Stomach Intestinal Factors Chemical Composition of Gastrin And Other Gastrointestinal Hormones Pancreatic Secretion Pancreatic Digestive Enzymes Secretion of Bicarbonate Ions Regulation of Pancreatic Secretion Secretion of Bile by the Liver; Functions of the Biliary Tree Physiologic Anatomy of Biliary Secretion Function of Bile Salts in Fat Digestion and Absorption Liver Secretion of Cholesterol and Gallstone Formation Secretions of the Small Intestine Secretion of Mucus by Brunner’s Glands in the Duodenum Secretion of Intestinal Digestive Juices by the Crypts of Lieberkühn Regulation of Small Intestine Secretion— Local Stimuli Secretions of the Large Intestine C H A P T E R 6 5 Digestion and Absorption in the Gastrointestinal Tract Digestion of the Various Foods by Hydrolysis Digestion of Carbohydrates Digestion of Proteins Digestion of Fats Basic Principles of Gastrointestinal Absorption Anatomical Basis of Absorption Absorption in the Small Intestine Absorption of Water Absorption of Ions Absorption of Nutrients Absorption in the Large Intestine: Formation of Feces C H A P T E R 6 6 Physiology of Gastrointestinal Disorders Disorders of Swallowing and of the Esophagus Disorders of the Stomach Peptic Ulcer Specific Causes of Peptic Ulcer in the Human Being Disorders of the Small Intestine Abnormal Digestion of Food in the Small Intestine—Pancreatic Failure Malabsorption by the Small Intestine Mucosa—Sprue Disorders of the Large Intestine Constipation Table of Contents 794 794 797 797 797 798 Diarrhea Paralysis of Defecation in Spinal Cord Injuries General Disorders of the Gastrointestinal Tract Vomiting Nausea Gastrointestinal Obstruction 822 823 823 823 824 824 798 799 799 799 800 800 802 802 804 804 805 805 805 806 806 808 808 809 810 811 812 812 813 814 814 815 817 819 819 819 820 821 821 821 822 822 822 U N I T X I I I Metabolism and Temperature Regulation C H A P T E R 6 7 Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate Release of Energy from Foods, and the Concept of “Free Energy” Role of Adenosine Triphosphate in Metabolism Central Role of Glucose in Carbohydrate Metabolism Transport of Glucose Through the Cell Membrane Insulin Increases Facilitated Diffusion of Glucose Phosphorylation of Glucose Glycogen Is Stored in Liver and Muscle Glycogenesis—The Process of Glycogen Formation Removal of Stored Glycogen— Glycogenolysis Release of Energy from the Glucose Molecule by the Glycolytic Pathway Summary of ATP Formation During the Breakdown of Glucose Control of Energy Release from Stored Glycogen When the Body Needs Additional Energy Anaerobic Release of Energy—“Anaerobic Glycolysis” Release of Energy from Glucose by the Pentose Phosphate Pathway Glucose Conversion to Glycogen or Fat Formation of Carbohydrates from Proteins and Fats—“Gluconeogenesis” Blood Glucose C H A P T E R Lipid Metabolism 829 829 829 830 831 831 831 831 832 832 832 836 836 836 837 838 838 839 6 8 Transport of Lipids in the Body Fluids Transport of Triglycerides and Other Lipids from the Gastrointestinal Tract by Lymph—The Chylomicrons Removal of the Chylomicrons from the Blood “Free Fatty Acids” Are Transported in the Blood in Combination with Albumin 840 840 840 841 841 Table of Contents Lipoproteins—Their Special Function in Transporting Cholesterol and Phospholipids Fat Deposits Adipose Tissue Liver Lipids Use of Triglycerides for Energy: Formation of Adenosine Triphosphate Formation of Acetoacetic Acid in the Liver and Its Transport in the Blood Synthesis of Triglycerides from Carbohydrates Synthesis of Triglycerides from Proteins Regulation of Energy Release from Triglycerides Obesity Phospholipids and Cholesterol Phospholipids Cholesterol Cellular Structural Functions of Phospholipids and Cholesterol— Especially for Membranes Atherosclerosis Basic Causes of Atherosclerosis—The Roles of Cholesterol and Lipoproteins Other Major Risk Factors for Atherosclerosis Prevention of Atherosclerosis C H A P T E R Protein Metabolism 842 844 844 845 846 846 846 846 847 848 848 850 850 850 6 9 Basic Properties Amino Acids Transport and Storage of Amino Acids Blood Amino Acids Storage of Amino Acids as Proteins in the Cells Functional Roles of the Plasma Proteins Essential and Nonessential Amino Acids Obligatory Degradation of Proteins Hormonal Regulation of Protein Metabolism C H A P T E R The Liver as an Organ 841 842 842 842 852 852 852 854 854 854 855 855 857 857 7 0 Physiologic Anatomy of the Liver Hepatic Vascular and Lymph Systems Blood Flows Through the Liver from the Portal Vein and Hepatic Artery The Liver Functions as a Blood Reservoir The Liver Has Very High Lymph Flow Regulation of Liver Mass—Regeneration Hepatic Macrophage System Serves a Blood-Cleansing Function Metabolic Functions of the Liver Carbohydrate Metabolism Fat Metabolism Protein Metabolism Other Metabolic Functions of the Liver Measurement of Bilirubin in the Bile as a Clinical Diagnostic Tool Jaundice—Excess Bilirubin in the Extracellular Fluid 859 859 859 860 860 860 860 861 861 861 861 862 862 862 863 C H A P T E R 7 1 Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals Energy Intake and Output Are Balanced Under Steady-State Conditions Dietary Balances Energy Available in Foods Methods for Determining Metabolic Utilization of Proteins, Carbohydrates, and Fats Regulation of Food Intake and Energy Storage Neural Centers Regulate Food Intake Factors That Regulate Quantity of Food Intake Obesity Decreased Physical Activity and Abnormal Feeding Regulation as Causes of Obesity Treatment of Obesity Inanition, Anorexia, and Cachexia Starvation Vitamins Vitamin A Thiamine (Vitamin B1) Niacin Riboflavin (Vitamin B2) Vitamin B12 Folic Acid (Pteroylglutamic Acid) Pyridoxine (Vitamin B6) Pantothenic Acid Ascorbic Acid (Vitamin C) Vitamin D Vitamin E Vitamin K Mineral Metabolism C H A P T E R 7 2 Energetics and Metabolic Rate Adenosine Triphosphate (ATP) Functions as an “Energy Currency” in Metabolism Phosphocreatine Functions as an Accessory Storage Depot for Energy and as an “ATP Buffer” Anaerobic Versus Aerobic Energy Summary of Energy Utilization by the Cells Control of Energy Release in the Cell Metabolic Rate Measurement of the Whole-Body Metabolic Rate Energy Metabolism—Factors That Influence Energy Output Overall Energy Requirements for Daily Activities Basal Metabolic Rate (BMR)—The Minimum Energy Expenditure for the Body to Exist Energy Used for Physical Activities Energy Used for Processing Food— Thermogenic Effect of Food Energy Used for Nonshivering Thermogenesis—Role of Sympathetic Stimulation xxxi 865 865 865 865 866 865 867 870 872 872 873 874 874 875 875 875 876 876 876 877 877 877 877 878 878 878 878 881 881 882 882 883 884 884 885 885 885 886 887 887 887 xxxii Table of Contents C H A P T E R 7 3 Body Temperature, Temperature Regulation, and Fever Normal Body Temperatures Body Temperature Is Controlled by Balancing Heat Production Against Heat Loss Heat Production Heat Loss Regulation of Body Temperature—Role of the Hypothalamus Neuronal Effector Mechanisms That Decrease or Increase Body Temperature Concept of a “Set-Point” for Temperature Control Behavioral Control of Body Temperature Abnormalities of Body Temperature Regulation Fever Exposure of the Body to Extreme Cold U N I T 896 897 Growth Hormone Promotes Growth of Many Body Tissues Growth Hormone Has Several Metabolic Effects Growth Hormone Stimulates Cartilage and Bone Growth Growth Hormone Exerts Much of Its Effect Through Intermediate Substances Called “Somatomedins” (Also Called “Insulin-Like Growth Factors”) Regulation of Growth Hormone Secretion Abnormalities of Growth Hormone Secretion Posterior Pituitary Gland and Its Relation to the Hypothalamus Chemical Structures of ADH and Oxytocin Physiological Functions of ADH Oxytocic Hormone 898 898 900 C H A P T E R 7 6 Thyroid Metabolic Hormones 889 889 889 889 890 894 895 X I V Endocrinology and Reproduction C H A P T E R 7 4 Introduction to Endocrinology Coordination of Body Functions by Chemical Messengers Chemical Structure and Synthesis of Hormones Hormone Secretion, Transport, and Clearance from the Blood Feedback Control of Hormone Secretion Transport of Hormones in the Blood “Clearance” of Hormones from the Blood Mechanisms of Action of Hormones Hormone Receptors and Their Activation Intracellular Signaling After Hormone Receptor Activation Second Messenger Mechanisms for Mediating Intracellular Hormonal Functions Hormones That Act Mainly on the Genetic Machinery of the Cell Measurement of Hormone Concentrations in the Blood Radioimmunoassay Enzyme-Linked Immunosorbent Assay (ELISA) C H A P T E R 7 5 Pituitary Hormones and Their Control by the Hypothalamus Pituitary Gland and Its Relation to the Hypothalamus Hypothalamus Controls Pituitary Secretion Hypothalamic-Hypophysial Portal Blood Vessels of the Anterior Pituitary Gland Physiological Functions of Growth Hormone 905 905 906 908 909 909 909 910 910 910 912 915 915 915 916 Synthesis and Secretion of the Thyroid Metabolic Hormones Iodine Is Required for Formation of Thyroxine Iodide Pump (Iodide Trapping) Thyroglobulin, and Chemistry of Thyroxine and Triiodothyronine Formation Release of Thyroxine and Triiodothyronine from the Thyroid Gland Transport of Thyroxine and Triiodothyronine to Tissues Physiologic Functions of the Thyroid Hormones Thyroid Hormones Increase the Transcription of Large Numbers of Genes Thyroid Hormones Increase Cellular Metabolic Activity Effect of Thyroid Hormone on Growth Effects of Thyroid Hormone on Specific Bodily Mechanisms Regulation of Thyroid Hormone Secretion Anterior Pituitary Secretion of TSH Is Regulated by Thyrotropin-Releasing Hormone from the Hypothalamus Feedback Effect of Thyroid Hormone to Decrease Anterior Pituitary Secretion of TSH Diseases of the Thyroid Hyperthyroidism Symptoms of Hyperthyroidism Hypothyroidism Cretinism C H A P T E R 7 7 Adrenocortical Hormones 918 918 919 920 921 Synthesis and Secretion of Adrenocortical Hormones Functions of the MineralocorticoidsAldosterone Renal and Circulatory Effects of Aldosterone Aldosterone Stimulates Sodium and Potassium Transport in Sweat Glands, Salivary Glands, and Intestinal Epithelial Cells 922 922 923 923 924 926 927 928 928 929 931 931 931 932 932 933 934 934 934 934 936 936 938 938 939 940 940 940 941 942 944 944 947 948 949 Table of Contents Cellular Mechanism of Aldosterone Action Possible Nongenomic Actions of Aldosterone and Other Steroid Hormones Regulation of Aldosterone Secretion Functions of the Glucocorticoids Effects of Cortisol on Carbohydrate Metabolism Effects of Cortisol on Protein Metabolism Effects of Cortisol on Fat Metabolism Cortisol Is Important in Resisting Stress and Inflammation Other Effects of Cortisol Cellular Mechanism of Cortisol Action Regulation of Cortisol Secretion by Adrenocorticotropic Hormone from the Pituitary Gland Adrenal Androgens Abnormalities of Adrenocortical Secretion Hypoadrenalism-Addison’s Disease Hyperadrenalism-Cushing’s Syndrome Primary Aldosteronism (Conn’s Syndrome) Adrenogenital Syndrome C H A P T E R 7 8 Insulin, Glucagon, and Diabetes Mellitus Insulin and Its Metabolic Effects Effect of Insulin on Carbohydrate Metabolism Effect of Insulin on Fat Metabolism Effect of Insulin on Protein Metabolism and on Growth Mechanisms of Insulin Secretion Control of Insulin Secretion Other Factors That Stimulate Insulin Secretion Role of Insulin (and Other Hormones) in “Switching” Between Carbohydrate and Lipid Metabolism Glucagon and Its Functions Effects on Glucose Metabolism Regulation of Glucagon Secretion Somatostatin Inhibits Glucagon and Insulin Secretion Summary of Blood Glucose Regulation Diabetes Mellitus Type I Diabetes—Lack of Insulin Production by Beta Cells of the Pancreas Type II Diabetes—Resistance to the Metabolic Effects of Insulin Physiology of Diagnosis of Diabetes Mellitus Treatment of Diabetes Insulinoma—Hyperinsulinism 950 950 950 950 951 952 952 952 954 954 955 957 957 957 958 959 959 961 961 963 965 966 967 968 969 969 970 970 971 971 971 972 972 974 975 976 976 C H A P T E R 7 9 Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth 978 Overview of Calcium and Phosphate Regulation in the Extracellular Fluid and Plasma 978 Calcium in the Plasma and Interstitial Fluid Inorganic Phosphate in the Extracellular Fluids Non-Bone Physiologic Effects of Altered Calcium and Phosphate Concentrations in the Body Fluids Absorption and Excretion of Calcium and Phosphate Bone and Its Relation to Extracellular Calcium and Phosphate Precipitation and Absorption of Calcium and Phosphate in Bone—Equilibrium with the Extracellular Fluids Calcium Exchange Between Bone and Extracellular Fluid Deposition and Absorption of Bone— Remodeling of Bone Vitamin D Actions of Vitamin D Parathyroid Hormone Effect of Parathyroid Hormone on Calcium and Phosphate Concentrations in the Extracellular Fluid Control of Parathyroid Secretion by Calcium Ion Concentration Calcitonin Summary of Control of Calcium Ion Concentration Pathophysiology of Parathyroid Hormone, Vitamin D, and Bone Disease Primary Hyperparathyroidism Secondary Parathyroidism Rickets—Vitamin D Deficiency Osteoporosis—Decreased Bone Matrix Physiology of the Teeth Function of the Different Parts of the Teeth Dentition Mineral Exchange in Teeth Dental Abnormalities C H A P T E R 8 0 Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland) Physiologic Anatomy of the Male Sexual Organs Spermatogenesis Steps of Spermatogenesis Function of the Seminal Vesicles Function of the Prostate Gland Semen Male Sexual Act Abnormal Spermatogenesis and Male Fertility Neuronal Stimulus for Performance of the Male Sexual Act Stages of the Male Sexual Act Testosterone and Other Male Sex Hormones Secretion, Metabolism, and Chemistry of the Male Sex Hormone Functions of Testosterone Basic Intracellular Mechanism of Action of Testosterone xxxiii 978 979 979 980 980 981 982 982 983 985 985 986 988 988 989 990 990 991 991 991 992 992 993 993 994 996 996 996 996 999 999 999 1001 1001 1001 1002 1003 1003 1004 1006 xxxiv Control of Male Sexual Functions by Hormones from the Hypothalamus and Anterior Pituitary Gland Abnormalities of Male Sexual Function Prostate Gland and Its Abnormalities Hypogonadism in the Male Testicular Tumors and Hypergonadism in the Male Pineal Gland—Its Function in Controlling Seasonal Fertility in Some Animals C H A P T E R 8 1 Female Physiology Before Pregnancy and Female Hormones Physiologic Anatomy of the Female Sexual Organs Female Hormonal System Monthly Ovarian Cycle; Function of the Gonadotropic Hormones Gonadotropic Hormones and Their Effects on the Ovaries Ovarian Follicle Growth—The “Follicular” Phase of the Ovarian Cycle Corpus Luteum—“Luteal” Phase of the Ovarian Cycle Summary Functions of the Ovarian Hormones— Estradiol and Progesterone Chemistry of the Sex Hormones Functions of the Estrogens—Their Effects on the Primary and Secondary Female Sex Characteristics Functions of Progesterone Monthly Endometrial Cycle and Menstruation Regulation of the Female Monthly Rhythm—Interplay Between the Ovarian and Hypothalamic-Pituitary Hormones Feedback Oscillation of the HypothalamicPituitary-Ovarian System Puberty and Menarche Menopause Abnormalities of Secretion by the Ovaries Female Sexual Act Female Fertility C H A P T E R 8 2 Pregnancy and Lactation Maturation and Fertilization of the Ovum Transport of the Fertilized Ovum in the Fallopian Tube Implantation of the Blastocyst in the Uterus Early Nutrition of the Embryo Function of the Placenta Developmental and Physiologic Anatomy of the Placenta Hormonal Factors in Pregnancy Human Chorionic Gonadotropin and Its Effect to Cause Persistence of the Corpus Luteum and to Prevent Menstruation Secretion of Estrogens by the Placenta Secretion of Progesterone by the Placenta Human Chorionic Somatomammotropin Other Hormonal Factors in Pregnancy Table of Contents 1006 1008 1008 1008 1009 1009 1011 1011 1011 1012 1012 1013 1014 1015 1016 1016 1017 1018 1018 1019 1021 1021 1022 1023 1023 1024 1027 1027 1028 1029 1029 1029 1029 1031 1032 1032 1033 1033 1034 Response of the Mother’s Body to Pregnancy Changes in the Maternal Circulatory System During Pregnancy Parturition Increased Uterine Excitability Near Term Onset of Labor—A Positive Feedback Mechanism for Its Initiation Abdominal Muscle Contractions During Labor Mechanics of Parturition Separation and Delivery of the Placenta Labor Pains Involution of the Uterus After Parturition Lactation Development of the Breasts Initiation of Lactation—Function of Prolactin Ejection (or “Let-Down”) Process in Milk Secretion—Function of Oxytocin Milk Composition and the Metabolic Drain on the Mother Caused by Lactation C H A P T E R 8 3 Fetal and Neonatal Physiology Growth and Functional Development of the Fetus Development of the Organ Systems Adjustments of the Infant to Extrauterine Life Onset of Breathing Circulatory Readjustments at Birth Nutrition of the Neonate Special Functional Problems in the Neonate Respiratory System Circulation Fluid Balance, Acid-Base Balance, and Renal Function Liver Function Digestion, Absorption, and Metabolism of Energy Foods; and Nutrition Immunity Endocrine Problems Special Problems of Prematurity Immature Development of the Premature Infant Instability of the Homeostatic Control Systems in the Premature Infant Danger of Blindness Caused by Excess Oxygen Therapy in the Premature Infant Growth and Development of the Child Behavioral Growth U N I T 1034 1035 1036 1036 1037 1037 1037 1038 1038 1038 1038 1038 1039 1040 1041 1042 1042 1042 1044 1044 1045 1047 1047 1047 1047 1048 1048 1048 1049 1049 1050 1050 1050 1051 1051 1052 X V Sports Physiology C H A P T E R Sports Physiology 8 4 Muscles in Exercise Strength, Power, and Endurance of Muscles Muscle Metabolic Systems in Exercise Phosphocreatine-Creatine System 1055 1055 1055 1056 1057 Table of Contents Nutrients Used During Muscle Activity Effect of Athletic Training on Muscles and Muscle Performance Respiration in Exercise Cardiovascular System in Exercise Body Heat in Exercise 1059 1060 1061 1062 1065 xxxv Body Fluids and Salt in Exercise Drugs and Athletes Body Fitness Prolongs Life 1065 1065 1066 Index 1067 U N I Introduction to Physiology: The Cell and General Physiology 1. Functional Organization of the Human Body and Control of the “Internal Environment” 2. The Cell and Its Functions 3. Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction T I C H A P T E R 1 Functional Organization of the Human Body and Control of the “Internal Environment” The goal of physiology is to explain the physical and chemical factors that are responsible for the origin, development, and progression of life. Each type of life, from the simple virus to the largest tree or the complicated human being, has its own functional characteristics. Therefore, the vast field of physiology can be divided into viral physiology, bacterial physiology, cellular physiology, plant physiology, human physiology, and many more subdivisions. Human Physiology. In human physiology, we attempt to explain the specific characteristics and mechanisms of the human body that make it a living being. The very fact that we remain alive is almost beyond our control, for hunger makes us seek food and fear makes us seek refuge. Sensations of cold make us look for warmth. Other forces cause us to seek fellowship and to reproduce. Thus, the human being is actually an automaton, and the fact that we are sensing, feeling, and knowledgeable beings is part of this automatic sequence of life; these special attributes allow us to exist under widely varying conditions. Cells as the Living Units of the Body The basic living unit of the body is the cell. Each organ is an aggregate of many different cells held together by intercellular supporting structures. Each type of cell is specially adapted to perform one or a few particular functions. For instance, the red blood cells, numbering 25 trillion in each human being, transport oxygen from the lungs to the tissues. Although the red cells are the most abundant of any single type of cell in the body, there are about 75 trillion additional cells of other types that perform functions different from those of the red cell. The entire body, then, contains about 100 trillion cells. Although the many cells of the body often differ markedly from one another, all of them have certain basic characteristics that are alike. For instance, in all cells, oxygen reacts with carbohydrate, fat, and protein to release the energy required for cell function. Further, the general chemical mechanisms for changing nutrients into energy are basically the same in all cells, and all cells deliver end products of their chemical reactions into the surrounding fluids. Almost all cells also have the ability to reproduce additional cells of their own kind. Fortunately, when cells of a particular type are destroyed from one cause or another, the remaining cells of this type usually generate new cells until the supply is replenished. Extracellular Fluid—The “Internal Environment” About 60 per cent of the adult human body is fluid, mainly a water solution of ions and other substances. Although most of this fluid is inside the cells and is called intracellular fluid, about one third is in the spaces outside the cells and 3 4 Unit I Introduction to Physiology: The Cell and General Physiology is called extracellular fluid. This extracellular fluid is in constant motion throughout the body. It is transported rapidly in the circulating blood and then mixed between the blood and the tissue fluids by diffusion through the capillary walls. In the extracellular fluid are the ions and nutrients needed by the cells to maintain cell life. Thus, all cells live in essentially the same environment—the extracellular fluid. For this reason, the extracellular fluid is also called the internal environment of the body, or the milieu intérieur, a term introduced more than 100 years ago by the great 19th-century French physiologist Claude Bernard. Cells are capable of living, growing, and performing their special functions as long as the proper concentrations of oxygen, glucose, different ions, amino acids, fatty substances, and other constituents are available in this internal environment. Extracellular Fluid Transport and Mixing System—The Blood Circulatory System Extracellular fluid is transported through all parts of the body in two stages. The first stage is movement of blood through the body in the blood vessels, and the second is movement of fluid between the blood capillaries and the intercellular spaces between the tissue cells. Figure 1–1 shows the overall circulation of blood. All the blood in the circulation traverses the entire circulatory circuit an average of once each minute when the body is at rest and as many as six times each minute when a person is extremely active. As blood passes through the blood capillaries, continual exchange of extracellular fluid also occurs between the plasma portion of the blood and the Differences Between Extracellular and Intracellular Fluids. The extracellular fluid contains large amounts of sodium, chloride, and bicarbonate ions plus nutrients for the cells, such as oxygen, glucose, fatty acids, and amino acids. It also contains carbon dioxide that is being transported from the cells to the lungs to be excreted, plus other cellular waste products that are being transported to the kidneys for excretion. The intracellular fluid differs significantly from the extracellular fluid; specifically, it contains large amounts of potassium, magnesium, and phosphate ions instead of the sodium and chloride ions found in the extracellular fluid. Special mechanisms for transporting ions through the cell membranes maintain the ion concentration differences between the extracellular and intracellular fluids. These transport processes are discussed in Chapter 4. Lungs CO2 O2 Right heart pump Left heart pump Gut “Homeostatic” Mechanisms of the Major Functional Systems Nutrition and excretion Kidneys Homeostasis The term homeostasis is used by physiologists to mean maintenance of nearly constant conditions in the internal environment. Essentially all organs and tissues of the body perform functions that help maintain these constant conditions. For instance, the lungs provide oxygen to the extracellular fluid to replenish the oxygen used by the cells, the kidneys maintain constant ion concentrations, and the gastrointestinal system provides nutrients. A large segment of this text is concerned with the manner in which each organ or tissue contributes to homeostasis. To begin this discussion, the different functional systems of the body and their contributions to homeostasis are outlined in this chapter; then we briefly outline the basic theory of the body’s control systems that allow the functional systems to operate in support of one another. Regulation of electrolytes Excretion Venous end Arterial end Capillaries Figure 1–1 General organization of the circulatory system. Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment” 5 the gastrointestinal tract. Here different dissolved nutrients, including carbohydrates, fatty acids, and amino acids, are absorbed from the ingested food into the extracellular fluid of the blood. Arteriole Liver and Other Organs That Perform Primarily Metabolic Functions. Not all substances absorbed from the gastroin- Venule Figure 1–2 Diffusion of fluid and dissolved constituents through the capillary walls and through the interstitial spaces. interstitial fluid that fills the intercellular spaces. This process is shown in Figure 1–2. The walls of the capillaries are permeable to most molecules in the plasma of the blood, with the exception of the large plasma protein molecules. Therefore, large amounts of fluid and its dissolved constituents diffuse back and forth between the blood and the tissue spaces, as shown by the arrows. This process of diffusion is caused by kinetic motion of the molecules in both the plasma and the interstitial fluid. That is, the fluid and dissolved molecules are continually moving and bouncing in all directions within the plasma and the fluid in the intercellular spaces, and also through the capillary pores. Few cells are located more than 50 micrometers from a capillary, which ensures diffusion of almost any substance from the capillary to the cell within a few seconds. Thus, the extracellular fluid everywhere in the body—both that of the plasma and that of the interstitial fluid—is continually being mixed, thereby maintaining almost complete homogeneity of the extracellular fluid throughout the body. Origin of Nutrients in the Extracellular Fluid Respiratory System. Figure 1–1 shows that each time the blood passes through the body, it also flows through the lungs. The blood picks up oxygen in the alveoli, thus acquiring the oxygen needed by the cells. The membrane between the alveoli and the lumen of the pulmonary capillaries, the alveolar membrane, is only 0.4 to 2.0 micrometers thick, and oxygen diffuses by molecular motion through the pores of this membrane into the blood in the same manner that water and ions diffuse through walls of the tissue capillaries. Gastrointestinal Tract. A large portion of the blood pumped by the heart also passes through the walls of testinal tract can be used in their absorbed form by the cells. The liver changes the chemical compositions of many of these substances to more usable forms, and other tissues of the body—fat cells, gastrointestinal mucosa, kidneys, and endocrine glands—help modify the absorbed substances or store them until they are needed. Musculoskeletal System. Sometimes the question is asked, How does the musculoskeletal system fit into the homeostatic functions of the body? The answer is obvious and simple: Were it not for the muscles, the body could not move to the appropriate place at the appropriate time to obtain the foods required for nutrition. The musculoskeletal system also provides motility for protection against adverse surroundings, without which the entire body, along with its homeostatic mechanisms, could be destroyed instantaneously. Removal of Metabolic End Products Removal of Carbon Dioxide by the Lungs. At the same time that blood picks up oxygen in the lungs, carbon dioxide is released from the blood into the lung alveoli; the respiratory movement of air into and out of the lungs carries the carbon dioxide to the atmosphere. Carbon dioxide is the most abundant of all the end products of metabolism. Kidneys. Passage of the blood through the kidneys removes from the plasma most of the other substances besides carbon dioxide that are not needed by the cells. These substances include different end products of cellular metabolism, such as urea and uric acid; they also include excesses of ions and water from the food that might have accumulated in the extracellular fluid. The kidneys perform their function by first filtering large quantities of plasma through the glomeruli into the tubules and then reabsorbing into the blood those substances needed by the body, such as glucose, amino acids, appropriate amounts of water, and many of the ions. Most of the other substances that are not needed by the body, especially the metabolic end products such as urea, are reabsorbed poorly and pass through the renal tubules into the urine. Regulation of Body Functions Nervous System. The nervous system is composed of three major parts: the sensory input portion, the central nervous system (or integrative portion), and the motor output portion. Sensory receptors detect the state of the body or the state of the surroundings. For instance, 6 Unit I Introduction to Physiology: The Cell and General Physiology receptors in the skin apprise one whenever an object touches the skin at any point. The eyes are sensory organs that give one a visual image of the surrounding area. The ears also are sensory organs. The central nervous system is composed of the brain and spinal cord. The brain can store information, generate thoughts, create ambition, and determine reactions that the body performs in response to the sensations. Appropriate signals are then transmitted through the motor output portion of the nervous system to carry out one’s desires. A large segment of the nervous system is called the autonomic system. It operates at a subconscious level and controls many functions of the internal organs, including the level of pumping activity by the heart, movements of the gastrointestinal tract, and secretion by many of the body’s glands. Hormonal System of Regulation. Located in the body are eight major endocrine glands that secrete chemical substances called hormones. Hormones are transported in the extracellular fluid to all parts of the body to help regulate cellular function. For instance, thyroid hormone increases the rates of most chemical reactions in all cells, thus helping to set the tempo of bodily activity. Insulin controls glucose metabolism; adrenocortical hormones control sodium ion, potassium ion, and protein metabolism; and parathyroid hormone controls bone calcium and phosphate. Thus, the hormones are a system of regulation that complements the nervous system. The nervous system regulates mainly muscular and secretory activities of the body, whereas the hormonal system regulates many metabolic functions. Reproduction Sometimes reproduction is not considered a homeostatic function. It does, however, help maintain homeostasis by generating new beings to take the place of those that are dying. This may sound like a permissive usage of the term homeostasis, but it illustrates that, in the final analysis, essentially all body structures are organized such that they help maintain the automaticity and continuity of life. Control Systems of the Body The human body has thousands of control systems in it. The most intricate of these are the genetic control systems that operate in all cells to help control intracellular function as well as extracellular function. This subject is discussed in Chapter 3. Many other control systems operate within the organs to control functions of the individual parts of the organs; others operate throughout the entire body to control the interrelations between the organs. For instance, the respiratory system, operating in association with the nervous system, regulates the concentration of carbon dioxide in the extracellular fluid. The liver and pancreas regulate the concentration of glucose in the extracellular fluid, and the kidneys regulate concentrations of hydrogen, sodium, potassium, phosphate, and other ions in the extracellular fluid. Examples of Control Mechanisms Regulation of Oxygen and Carbon Dioxide Concentrations in the Extracellular Fluid. Because oxygen is one of the major substances required for chemical reactions in the cells, it is fortunate that the body has a special control mechanism to maintain an almost exact and constant oxygen concentration in the extracellular fluid. This mechanism depends principally on the chemical characteristics of hemoglobin, which is present in all red blood cells. Hemoglobin combines with oxygen as the blood passes through the lungs. Then, as the blood passes through the tissue capillaries, hemoglobin, because of its own strong chemical affinity for oxygen, does not release oxygen into the tissue fluid if too much oxygen is already there. But if the oxygen concentration in the tissue fluid is too low, sufficient oxygen is released to re-establish an adequate concentration. Thus, regulation of oxygen concentration in the tissues is vested principally in the chemical characteristics of hemoglobin itself. This regulation is called the oxygen-buffering function of hemoglobin. Carbon dioxide concentration in the extracellular fluid is regulated in a much different way. Carbon dioxide is a major end product of the oxidative reactions in cells. If all the carbon dioxide formed in the cells continued to accumulate in the tissue fluids, the mass action of the carbon dioxide itself would soon halt all energy-giving reactions of the cells. Fortunately, a higher than normal carbon dioxide concentration in the blood excites the respiratory center, causing a person to breathe rapidly and deeply. This increases expiration of carbon dioxide and, therefore, removes excess carbon dioxide from the blood and tissue fluids. This process continues until the concentration returns to normal. Regulation of Arterial Blood Pressure. Several systems con- tribute to the regulation of arterial blood pressure. One of these, the baroreceptor system, is a simple and excellent example of a rapidly acting control mechanism. In the walls of the bifurcation region of the carotid arteries in the neck, and also in the arch of the aorta in the thorax, are many nerve receptors called baroreceptors, which are stimulated by stretch of the arterial wall. When the arterial pressure rises too high, the baroreceptors send barrages of nerve impulses to the medulla of the brain. Here these impulses inhibit the vasomotor center, which in turn decreases the number of impulses transmitted from the vasomotor center through the sympathetic nervous system to the heart and blood vessels. Lack of these impulses causes diminished pumping activity by the heart and also Chapter 1 7 Functional Organization of the Human Body and Control of the “Internal Environment” dilation of the peripheral blood vessels, allowing increased blood flow through the vessels. Both of these effects decrease the arterial pressure back toward normal. Conversely, a decrease in arterial pressure below normal relaxes the stretch receptors, allowing the vasomotor center to become more active than usual, thereby causing vasoconstriction and increased heart pumping, and raising arterial pressure back toward normal. Normal Ranges and Physical Characteristics of Important Extracellular Fluid Constituents Table 1–1 lists the more important constituents and physical characteristics of extracellular fluid, along with their normal values, normal ranges, and maximum limits without causing death. Note the narrowness of the normal range for each one. Values outside these ranges are usually caused by illness. Most important are the limits beyond which abnormalities can cause death. For example, an increase in the body temperature of only 11°F (7°C) above normal can lead to a vicious cycle of increasing cellular metabolism that destroys the cells. Note also the narrow range for acid-base balance in the body, with a normal pH value of 7.4 and lethal values only about 0.5 on either side of normal. Another important factor is the potassium ion concentration, because whenever it decreases to less than one third normal, a person is likely to be paralyzed as a result of the nerves’ inability to carry signals. Alternatively, if the potassium ion concentration increases to two or more times normal, the heart muscle is likely to be severely depressed. Also, when the calcium ion concentration falls below about one half of normal, a person is likely to experience tetanic contraction of muscles throughout the body because of the spontaneous generation of excess nerve impulses in the peripheral nerves. When the glucose concentration falls below one half of normal, a person frequently develops extreme mental irritability and sometimes even convulsions. These examples should give one an appreciation for the extreme value and even the necessity of the vast numbers of control systems that keep the body operating in health; in the absence of any one of these controls, serious body malfunction or death can result. Characteristics of Control Systems The aforementioned examples of homeostatic control mechanisms are only a few of the many thousands in the body, all of which have certain characteristics in common. These characteristics are explained in this section. Negative Feedback Nature of Most Control Systems Most control systems of the body act by negative feedback, which can best be explained by reviewing some of the homeostatic control systems mentioned previously. In the regulation of carbon dioxide concentration, a high concentration of carbon dioxide in the extracellular fluid increases pulmonary ventilation. This, in turn, decreases the extracellular fluid carbon dioxide concentration because the lungs expire greater amounts of carbon dioxide from the body. In other words, the high concentration of carbon dioxide initiates events that decrease the concentration toward normal, which is negative to the initiating stimulus. Conversely, if the carbon dioxide concentration falls too low, this causes feedback to increase the concentration. This response also is negative to the initiating stimulus. In the arterial pressure–regulating mechanisms, a high pressure causes a series of reactions that promote a lowered pressure, or a low pressure causes a series of reactions that promote an elevated pressure. In both instances, these effects are negative with respect to the initiating stimulus. Therefore, in general, if some factor becomes excessive or deficient, a control system initiates negative feedback, which consists of a series of changes that return the factor toward a certain mean value, thus maintaining homeostasis. “Gain” of a Control System. The degree of effectiveness with which a control system maintains constant Table 1–1 Important Constituents and Physical Characteristics of Extracellular Fluid Oxygen Carbon dioxide Sodium ion Potassium ion Calcium ion Chloride ion Bicarbonate ion Glucose Body temperature Acid-base Normal Value Normal Range Approximate Short-Term Nonlethal Limit Unit 40 40 142 4.2 1.2 108 28 85 98.4 (37.0) 7.4 35–45 35–45 138–146 3.8–5.0 1.0–1.4 103–112 24–32 75–95 98–98.8 (37.0) 7.3–7.5 10–1000 5–80 115–175 1.5–9.0 0.5–2.0 70–130 8–45 20–1500 65–110 (18.3–43.3) 6.9–8.0 mm Hg mm Hg mmol/L mmol/L mmol/L mmol/L mmol/L mg/dl ∞F (∞C) pH Unit I Introduction to Physiology: The Cell and General Physiology conditions is determined by the gain of the negative feedback. For instance, let us assume that a large volume of blood is transfused into a person whose baroreceptor pressure control system is not functioning, and the arterial pressure rises from the normal level of 100 mm Hg up to 175 mm Hg. Then, let us assume that the same volume of blood is injected into the same person when the baroreceptor system is functioning, and this time the pressure increases only 25 mm Hg. Thus, the feedback control system has caused a “correction” of –50 mm Hg—that is, from 175 mm Hg to 125 mm Hg. There remains an increase in pressure of +25 mm Hg, called the “error,” which means that the control system is not 100 per cent effective in preventing change. The gain of the system is then calculated by the following formula: 5 Pumping effectiveness of heart (Liters pumped per minute) 8 Bled 1 liter 3 2 Positive Feedback Can Sometimes Cause Vicious Cycles and Death One might ask the question, Why do essentially all control systems of the body operate by negative feedback rather than positive feedback? If one considers the nature of positive feedback, one immediately sees that positive feedback does not lead to stability but to instability and often death. Figure 1–3 shows an example in which death can ensue from positive feedback. This figure depicts the pumping effectiveness of the heart, showing that the heart of a healthy human being pumps about 5 liters of blood per minute. If the person is suddenly bled 2 liters, the amount of blood in the body is decreased to such a low level that not enough blood is available for the heart to pump effectively. As a result, the arterial pressure falls, and the flow of blood to the heart muscle through the coronary vessels diminishes. This results in weakening of the heart, further diminished pumping, a further decrease in coronary blood flow, and still more weakness of the heart; the cycle repeats itself again and again until death occurs. Note that each cycle in the feedback results in further weakening of the heart. In other words, the initiating stimulus causes more of the same, which is positive feedback. Bled 2 liters 1 Death 0 2 1 3 Hours Correction Gain = Error Thus, in the baroreceptor system example, the correction is –50 mm Hg and the error persisting is +25 mm Hg. Therefore, the gain of the person’s baroreceptor system for control of arterial pressure is –50 divided by +25, or –2. That is, a disturbance that increases or decreases the arterial pressure does so only one third as much as would occur if this control system were not present. The gains of some other physiologic control systems are much greater than that of the baroreceptor system. For instance, the gain of the system controlling internal body temperature when a person is exposed to moderately cold weather is about –33. Therefore, one can see that the temperature control system is much more effective than the baroreceptor pressure control system. Return to normal 4 Figure 1–3 Recovery of heart pumping caused by negative feedback after 1 liter of blood is removed from the circulation. Death is caused by positive feedback when 2 liters of blood are removed. Positive feedback is better known as a “vicious cycle,” but a mild degree of positive feedback can be overcome by the negative feedback control mechanisms of the body, and the vicious cycle fails to develop. For instance, if the person in the aforementioned example were bled only 1 liter instead of 2 liters, the normal negative feedback mechanisms for controlling cardiac output and arterial pressure would overbalance the positive feedback and the person would recover, as shown by the dashed curve of Figure 1–3. Positive Feedback Can Sometimes Be Useful. In some instances, the body uses positive feedback to its advantage. Blood clotting is an example of a valuable use of positive feedback. When a blood vessel is ruptured and a clot begins to form, multiple enzymes called clotting factors are activated within the clot itself. Some of these enzymes act on other unactivated enzymes of the immediately adjacent blood, thus causing more blood clotting. This process continues until the hole in the vessel is plugged and bleeding no longer occurs. On occasion, this mechanism can get out of hand and cause the formation of unwanted clots. In fact, this is what initiates most acute heart attacks, which are caused by a clot beginning on the inside surface of an atherosclerotic plaque in a coronary artery and then growing until the artery is blocked. Childbirth is another instance in which positive feedback plays a valuable role. When uterine contractions become strong enough for the baby’s head to begin pushing through the cervix, stretch of the cervix sends signals through the uterine muscle back to the Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment” body of the uterus, causing even more powerful contractions. Thus, the uterine contractions stretch the cervix, and the cervical stretch causes stronger contractions. When this process becomes powerful enough, the baby is born. If it is not powerful enough, the contractions usually die out, and a few days pass before they begin again. Another important use of positive feedback is for the generation of nerve signals. That is, when the membrane of a nerve fiber is stimulated, this causes slight leakage of sodium ions through sodium channels in the nerve membrane to the fiber’s interior. The sodium ions entering the fiber then change the membrane potential, which in turn causes more opening of channels, more change of potential, still more opening of channels, and so forth. Thus, a slight leak becomes an explosion of sodium entering the interior of the nerve fiber, which creates the nerve action potential. This action potential in turn causes electrical current to flow along both the outside and the inside of the fiber and initiates additional action potentials. This process continues again and again until the nerve signal goes all the way to the end of the fiber. In each case in which positive feedback is useful, the positive feedback itself is part of an overall negative feedback process. For example, in the case of blood clotting, the positive feedback clotting process is a negative feedback process for maintenance of normal blood volume. Also, the positive feedback that causes nerve signals allows the nerves to participate in thousands of negative feedback nervous control systems. More Complex Types of Control Systems— Adaptive Control Later in this text, when we study the nervous system, we shall see that this system contains great numbers of interconnected control mechanisms. Some are simple feedback systems similar to those already discussed. Many are not. For instance, some movements of the body occur so rapidly that there is not enough time for nerve signals to travel from the peripheral parts of the body all the way to the brain and then back to the periphery again to control the movement. Therefore, the brain uses a principle called feed-forward control to cause required muscle contractions. That is, sensory nerve signals from the moving parts apprise the brain whether the movement is performed correctly. If not, the brain corrects the feed-forward signals that it sends to the muscles the next time the movement is required. Then, if still further correction is needed, this will be done again for subsequent movements. This is called adaptive control. Adaptive control, in a sense, is delayed negative feedback. Thus, one can see how complex the feedback control systems of the body can be. A person’s life depends on all of them. Therefore, a major share of this text is devoted to discussing these life-giving mechanisms. 9 Summary—Automaticity of the Body The purpose of this chapter has been to point out, first, the overall organization of the body and, second, the means by which the different parts of the body operate in harmony. To summarize, the body is actually a social order of about 100 trillion cells organized into different functional structures, some of which are called organs. Each functional structure contributes its share to the maintenance of homeostatic conditions in the extracellular fluid, which is called the internal environment. As long as normal conditions are maintained in this internal environment, the cells of the body continue to live and function properly. Each cell benefits from homeostasis, and in turn, each cell contributes its share toward the maintenance of homeostasis. This reciprocal interplay provides continuous automaticity of the body until one or more functional systems lose their ability to contribute their share of function.When this happens, all the cells of the body suffer. Extreme dysfunction leads to death; moderate dysfunction leads to sickness. References Adolph EF: Physiological adaptations: hypertrophies and superfunctions. Am Sci 60:608, 1972. Bernard C: Lectures on the Phenomena of Life Common to Animals and Plants. Springfield, IL: Charles C Thomas, 1974. Cabanac M: Regulation and the ponderostat. Int J Obes Relat Metab Disord 25(Suppl 5):S7, 2001. Cannon WB: The Wisdom of the Body. New York: WW Norton, 1932. Conn PM, Goodman HM: Handbook of Physiology: Cellular Endocrinology. Bethesda: American Physiological Society, 1997. Csete ME, Doyle JC: Reverse engineering of biological complexity. Science 295:1664, 2002. Danzler WH (ed): Handbook of Physiology, Sec 13: Comparative Physiology. Bethesda: American Physiological Society, 1997. Dickinson MH, Farley CT, Full RJ, et al: How animals move: an integrative view. Science 288:100, 2000. Garland T Jr, Carter PA: Evolutionary physiology.Annu Rev Physiol 56:579, 1994. Gelehrter TD, Collins FS: Principles of Medical Genetics. Baltimore: Williams & Wilkins, 1995. Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Saunders, 1980. Guyton AC, Jones CE, Coleman TG: Cardiac Output and Its Regulation. Philadelphia: WB Saunders, 1973. Guyton AC, Taylor AE, Granger HJ: Dynamics and Control of the Body Fluids. Philadelphia: WB Saunders, 1975. Hoffman JF, Jamieson JD: Handbook of Physiology: Cell Physiology. Bethesda: American Physiological Society, 1997. Krahe R, Gabbiani F: Burst firing in sensory systems. Nat Rev Neurosci 5:13, 2004. Lewin B: Genes VII. New York: Oxford University Press, 2000. 10 Unit I Introduction to Physiology: The Cell and General Physiology Masoro EJ (ed): Handbook of Physiology, Sec 11: Aging. Bethesda: American Physiological Society, 1995. Milhorn HT: The Application of Control Theory to Physiological Systems. Philadelphia: WB Saunders, 1966. Orgel LE: The origin of life on the earth. Sci Am 271:76, 1994. Smith HW: From Fish to Philosopher. New York: Doubleday, 1961. Thomson RC: Biomaterials Regulating Cell Function and Tissue Development. Warrendale, PA: Materials Research Society, 1998. Tjian R: Molecular machines that control genes. Sci Am 272:54, 1995. C H A P T E R 2 The Cell and Its Functions Each of the 100 trillion cells in a human being is a living structure that can survive for months or many years, provided its surrounding fluids contain appropriate nutrients. To understand the function of organs and other structures of the body, it is essential that we first understand the basic organization of the cell and the functions of its component parts. Organization of the Cell A typical cell, as seen by the light microscope, is shown in Figure 2–1. Its two major parts are the nucleus and the cytoplasm. The nucleus is separated from the cytoplasm by a nuclear membrane, and the cytoplasm is separated from the surrounding fluids by a cell membrane, also called the plasma membrane. The different substances that make up the cell are collectively called protoplasm. Protoplasm is composed mainly of five basic substances: water, electrolytes, proteins, lipids, and carbohydrates. Water. The principal fluid medium of the cell is water, which is present in most cells, except for fat cells, in a concentration of 70 to 85 per cent. Many cellular chemicals are dissolved in the water. Others are suspended in the water as solid particulates. Chemical reactions take place among the dissolved chemicals or at the surfaces of the suspended particles or membranes. Ions. The most important ions in the cell are potassium, magnesium, phosphate, sulfate, bicarbonate, and smaller quantities of sodium, chloride, and calcium. These are all discussed in more detail in Chapter 4, which considers the interrelations between the intracellular and extracellular fluids. The ions provide inorganic chemicals for cellular reactions. Also, they are necessary for operation of some of the cellular control mechanisms. For instance, ions acting at the cell membrane are required for transmission of electrochemical impulses in nerve and muscle fibers. Proteins. After water, the most abundant substances in most cells are proteins, which normally constitute 10 to 20 per cent of the cell mass. These can be divided into two types: structural proteins and functional proteins. Structural proteins are present in the cell mainly in the form of long filaments that themselves are polymers of many individual protein molecules. A prominent use of such intracellular filaments is to form microtubules that provide the “cytoskeletons” of such cellular organelles as cilia, nerve axons, the mitotic spindles of mitosing cells, and a tangled mass of thin filamentous tubules that hold the parts of the cytoplasm and nucleoplasm together in their respective compartments. Extracellularly, fibrillar proteins are found especially in the collagen and elastin fibers of connective tissue and in blood vessel walls, tendons, ligaments, and so forth. The functional proteins are an entirely different type of protein, usually composed of combinations of a few molecules in tubular-globular form. These 11 12 Unit I Introduction to Physiology: The Cell and General Physiology Cell membrane Cytoplasm Nucleolus Nuclear membrane Nucleoplasm surrounding extracellular fluid so that it is readily available to the cell. Also, a small amount of carbohydrate is virtually always stored in the cells in the form of glycogen, which is an insoluble polymer of glucose that can be depolymerized and used rapidly to supply the cells’ energy needs. Nucleus Figure 2–1 Structure of the cell as seen with the light microscope. proteins are mainly the enzymes of the cell and, in contrast to the fibrillar proteins, are often mobile in the cell fluid. Also, many of them are adherent to membranous structures inside the cell. The enzymes come into direct contact with other substances in the cell fluid and thereby catalyze specific intracellular chemical reactions. For instance, the chemical reactions that split glucose into its component parts and then combine these with oxygen to form carbon dioxide and water while simultaneously providing energy for cellular function are all catalyzed by a series of protein enzymes. Lipids. Lipids are several types of substances that are grouped together because of their common property of being soluble in fat solvents. Especially important lipids are phospholipids and cholesterol, which together constitute only about 2 per cent of the total cell mass. The significance of phospholipids and cholesterol is that they are mainly insoluble in water and, therefore, are used to form the cell membrane and intracellular membrane barriers that separate the different cell compartments. In addition to phospholipids and cholesterol, some cells contain large quantities of triglycerides, also called neutral fat. In the fat cells, triglycerides often account for as much as 95 per cent of the cell mass. The fat stored in these cells represents the body’s main storehouse of energy-giving nutrients that can later be dissoluted and used to provide energy wherever in the body it is needed. Physical Structure of the Cell The cell is not merely a bag of fluid, enzymes, and chemicals; it also contains highly organized physical structures, called intracellular organelles. The physical nature of each organelle is as important as the cell’s chemical constituents for cell function. For instance, without one of the organelles, the mitochondria, more than 95 per cent of the cell’s energy release from nutrients would cease immediately. The most important organelles and other structures of the cell are shown in Figure 2–2. Membranous Structures of the Cell Most organelles of the cell are covered by membranes composed primarily of lipids and proteins.These membranes include the cell membrane, nuclear membrane, membrane of the endoplasmic reticulum, and membranes of the mitochondria, lysosomes, and Golgi apparatus. The lipids of the membranes provide a barrier that impedes the movement of water and water-soluble substances from one cell compartment to another because water is not soluble in lipids. However, protein molecules in the membrane often do penetrate all the way through the membrane, thus providing specialized pathways, often organized into actual pores, for passage of specific substances through the membrane. Also, many other membrane proteins are enzymes that catalyze a multitude of different chemical reactions, discussed here and in subsequent chapters. Cell Membrane The cell membrane (also called the plasma membrane), which envelops the cell, is a thin, pliable, elastic structure only 7.5 to 10 nanometers thick. It is composed almost entirely of proteins and lipids. The approximate composition is proteins, 55 per cent; phospholipids, 25 per cent; cholesterol, 13 per cent; other lipids, 4 per cent; and carbohydrates, 3 per cent. Lipid Barrier of the Cell Membrane Impedes Water Penetration. Carbohydrates. Carbohydrates have little structural function in the cell except as parts of glycoprotein molecules, but they play a major role in nutrition of the cell. Most human cells do not maintain large stores of carbohydrates; the amount usually averages about 1 per cent of their total mass but increases to as much as 3 per cent in muscle cells and, occasionally, 6 per cent in liver cells. However, carbohydrate in the form of dissolved glucose is always present in the Figure 2–3 shows the structure of the cell membrane. Its basic structure is a lipid bilayer, which is a thin, double-layered film of lipids—each layer only one molecule thick—that is continuous over the entire cell surface. Interspersed in this lipid film are large globular protein molecules. The basic lipid bilayer is composed of phospholipid molecules. One end of each phospholipid molecule is soluble in water; that is, it is hydrophilic. The other end is soluble only in fats; that is, it is hydrophobic. The Chapter 2 13 The Cell and Its Functions Chromosomes and DNA Centrioles Secretory granule Golgi apparatus Microtubules Nuclear membrane Cell membrane Nucleolus Glycogen Ribosomes Lysosome Figure 2–2 Reconstruction of a typical cell, showing the internal organelles in the cytoplasm and in the nucleus. Mitochondrion Granular endoplasmic reticulum phosphate end of the phospholipid is hydrophilic, and the fatty acid portion is hydrophobic. Because the hydrophobic portions of the phospholipid molecules are repelled by water but are mutually attracted to one another, they have a natural tendency to attach to one another in the middle of the membrane, as shown in Figure 2–3. The hydrophilic phosphate portions then constitute the two surfaces of the complete cell membrane, in contact with intracellular water on the inside of the membrane and extracellular water on the outside surface. The lipid layer in the middle of the membrane is impermeable to the usual water-soluble substances, such as ions, glucose, and urea. Conversely, fat-soluble substances, such as oxygen, carbon dioxide, and alcohol, can penetrate this portion of the membrane with ease. The cholesterol molecules in the membrane are also lipid in nature because their steroid nucleus is highly fat soluble. These molecules, in a sense, are dissolved in the bilayer of the membrane. They mainly help determine the degree of permeability (or impermeability) of the bilayer to water-soluble constituents of Smooth (agranular) endoplasmic reticulum Microfilaments body fluids. Cholesterol controls much of the fluidity of the membrane as well. Cell Membrane Proteins. Figure 2–3 also shows globular masses floating in the lipid bilayer. These are membrane proteins, most of which are glycoproteins. Two types of proteins occur: integral proteins that protrude all the way through the membrane, and peripheral proteins that are attached only to one surface of the membrane and do not penetrate all the way through. Many of the integral proteins provide structural channels (or pores) through which water molecules and water-soluble substances, especially ions, can diffuse between the extracellular and intracellular fluids. These protein channels also have selective properties that allow preferential diffusion of some substances over others. Other integral proteins act as carrier proteins for transporting substances that otherwise could not penetrate the lipid bilayer. Sometimes these even transport substances in the direction opposite to their natural direction of diffusion, which is called “active transport.” Still others act as enzymes. 14 Unit I Introduction to Physiology: The Cell and General Physiology Carbohydrate Extracellular fluid Integral protein Lipid bilayer Peripheral protein Intracellular fluid Cytoplasm Integral protein Integral membrane proteins can also serve as receptors for water-soluble chemicals, such as peptide hormones, that do not easily penetrate the cell membrane. Interaction of cell membrane receptors with specific ligands that bind to the receptor causes conformational changes in the receptor protein. This, in turn, enzymatically activates the intracellular part of the protein or induces interactions between the receptor and proteins in the cytoplasm that act as second messengers, thereby relaying the signal from the extracellular part of the receptor to the interior of the cell. In this way, integral proteins spanning the cell membrane provide a means of conveying information about the environment to the cell interior. Peripheral protein molecules are often attached to the integral proteins. These peripheral proteins function almost entirely as enzymes or as controllers of transport of substances through the cell membrane “pores.” Figure 2–3 Structure of the cell membrane, showing that it is composed mainly of a lipid bilayer of phospholipid molecules, but with large numbers of protein molecules protruding through the layer. Also, carbohydrate moieties are attached to the protein molecules on the outside of the membrane and to additional protein molecules on the inside. (Redrawn from Lodish HF, Rothman JE: The assembly of cell membranes. Sci Am 240:48, 1979. Copyright George V. Kevin.) cell surface. Many other carbohydrate compounds, called proteoglycans—which are mainly carbohydrate substances bound to small protein cores—are loosely attached to the outer surface of the cell as well. Thus, the entire outside surface of the cell often has a loose carbohydrate coat called the glycocalyx. The carbohydrate moieties attached to the outer surface of the cell have several important functions: (1) Many of them have a negative electrical charge, which gives most cells an overall negative surface charge that repels other negative objects. (2) The glycocalyx of some cells attaches to the glycocalyx of other cells, thus attaching cells to one another. (3) Many of the carbohydrates act as receptor substances for binding hormones, such as insulin; when bound, this combination activates attached internal proteins that, in turn, activate a cascade of intracellular enzymes. (4) Some carbohydrate moieties enter into immune reactions, as discussed in Chapter 34. Membrane Carbohydrates—The Cell “Glycocalyx.” Mem- brane carbohydrates occur almost invariably in combination with proteins or lipids in the form of glycoproteins or glycolipids. In fact, most of the integral proteins are glycoproteins, and about one tenth of the membrane lipid molecules are glycolipids. The “glyco” portions of these molecules almost invariably protrude to the outside of the cell, dangling outward from the Cytoplasm and Its Organelles The cytoplasm is filled with both minute and large dispersed particles and organelles. The clear fluid portion of the cytoplasm in which the particles are dispersed is called cytosol; this contains mainly dissolved proteins, electrolytes, and glucose. Chapter 2 Dispersed in the cytoplasm are neutral fat globules, glycogen granules, ribosomes, secretory vesicles, and five especially important organelles: the endoplasmic reticulum, the Golgi apparatus, mitochondria, lysosomes, and peroxisomes. Endoplasmic Reticulum Figure 2–2 shows a network of tubular and flat vesicular structures in the cytoplasm; this is the endoplasmic reticulum. The tubules and vesicles interconnect with one another. Also, their walls are constructed of lipid bilayer membranes that contain large amounts of proteins, similar to the cell membrane. The total surface area of this structure in some cells—the liver cells, for instance—can be as much as 30 to 40 times the cell membrane area. The detailed structure of a small portion of endoplasmic reticulum is shown in Figure 2–4. The space inside the tubules and vesicles is filled with endoplasmic matrix, a watery medium that is different from the fluid in the cytosol outside the endoplasmic reticulum. Electron micrographs show that the space inside the endoplasmic reticulum is connected with the space between the two membrane surfaces of the nuclear membrane. Substances formed in some parts of the cell enter the space of the endoplasmic reticulum and are then conducted to other parts of the cell. Also, the vast surface area of this reticulum and the multiple enzyme systems attached to its membranes provide machinery for a major share of the metabolic functions of the cell. Ribosomes and the Granular Endoplasmic 15 The Cell and Its Functions Reticulum. Attached to the outer surfaces of many parts of the endoplasmic reticulum are large numbers of minute granular particles called ribosomes. Where these are present, the reticulum is called the granular endoplasmic reticulum. The ribosomes are composed of a mixture of RNA and proteins, and they function to synthesize new protein molecules in the cell, as discussed later in this chapter and in Chapter 3. Agranular Endoplasmic Reticulum. Part of the endoplasmic reticulum has no attached ribosomes. This part is called the agranular, or smooth, endoplasmic reticulum. The agranular reticulum functions for the synthesis of lipid substances and for other processes of the cells promoted by intrareticular enzymes. Golgi Apparatus The Golgi apparatus, shown in Figure 2–5, is closely related to the endoplasmic reticulum. It has membranes similar to those of the agranular endoplasmic reticulum. It usually is composed of four or more stacked layers of thin, flat, enclosed vesicles lying near one side of the nucleus. This apparatus is prominent in secretory cells, where it is located on the side of the cell from which the secretory substances are extruded. The Golgi apparatus functions in association with the endoplasmic reticulum. As shown in Figure 2–5, small “transport vesicles” (also called endoplasmic reticulum vesicles, or ER vesicles) continually pinch off from the endoplasmic reticulum and shortly thereafter fuse with the Golgi apparatus. In this way, substances entrapped in the ER vesicles are transported from the endoplasmic reticulum to the Golgi apparatus. The transported substances are then processed in the Golgi apparatus to form lysosomes, secretory vesicles, and other cytoplasmic components that are discussed later in the chapter. Golgi vesicles Matrix Golgi apparatus ER vesicles Granular endoplasmic reticulum Endoplasmic reticulum Agranular endoplasmic reticulum Figure 2–4 Figure 2–5 Structure of the endoplasmic reticulum. (Modified from DeRobertis EDP, Saez FA, DeRobertis EMF: Cell Biology, 6th ed. Philadelphia: WB Saunders, 1975.) A typical Golgi apparatus and its relationship to the endoplasmic reticulum (ER) and the nucleus. 16 Unit I Introduction to Physiology: The Cell and General Physiology Lysosomes Lysosomes, shown in Figure 2–2, are vesicular organelles that form by breaking off from the Golgi apparatus and then dispersing throughout the cytoplasm. The lysosomes provide an intracellular digestive system that allows the cell to digest (1) damaged cellular structures, (2) food particles that have been ingested by the cell, and (3) unwanted matter such as bacteria. The lysosome is quite different in different types of cells, but it is usually 250 to 750 nanometers in diameter. It is surrounded by a typical lipid bilayer membrane and is filled with large numbers of small granules 5 to 8 nanometers in diameter, which are protein aggregates of as many as 40 different hydrolase (digestive) enzymes. A hydrolytic enzyme is capable of splitting an organic compound into two or more parts by combining hydrogen from a water molecule with one part of the compound and combining the hydroxyl portion of the water molecule with the other part of the compound. For instance, protein is hydrolyzed to form amino acids, glycogen is hydrolyzed to form glucose, and lipids are hydrolyzed to form fatty acids and glycerol. Ordinarily, the membrane surrounding the lysosome prevents the enclosed hydrolytic enzymes from coming in contact with other substances in the cell and, therefore, prevents their digestive actions. However, some conditions of the cell break the membranes of some of the lysosomes, allowing release of the digestive enzymes. These enzymes then split the organic substances with which they come in contact into small, highly diffusible substances such as amino acids and glucose. Some of the more specific functions of lysosomes are discussed later in the chapter. Secretory granules Figure 2–6 Secretory granules (secretory vesicles) in acinar cells of the pancreas. Outer membrane Inner membrane Matrix Crests Outer chamber Oxidative phosphorylation enzymes Figure 2–7 Peroxisomes Peroxisomes are similar physically to lysosomes, but they are different in two important ways. First, they are believed to be formed by self-replication (or perhaps by budding off from the smooth endoplasmic reticulum) rather than from the Golgi apparatus. Second, they contain oxidases rather than hydrolases. Several of the oxidases are capable of combining oxygen with hydrogen ions derived from different intracellular chemicals to form hydrogen peroxide (H2O2). Hydrogen peroxide is a highly oxidizing substance and is used in association with catalase, another oxidase enzyme present in large quantities in peroxisomes, to oxidize many substances that might otherwise be poisonous to the cell. For instance, about half the alcohol a person drinks is detoxified by the peroxisomes of the liver cells in this manner. Secretory Vesicles One of the important functions of many cells is secretion of special chemical substances. Almost all such secretory substances are formed by the endoplasmic reticulum–Golgi apparatus system and are then released from the Golgi apparatus into the cytoplasm in the form of storage vesicles called secretory vesicles or secretory granules. Figure 2–6 shows typical secretory vesicles inside pancreatic acinar cells; these Structure of a mitochondrion. (Modified from DeRobertis EDP, Saez FA, DeRobertis EMF: Cell Biology, 6th ed. Philadelphia: WB Saunders, 1975.) vesicles store protein proenzymes (enzymes that are not yet activated). The proenzymes are secreted later through the outer cell membrane into the pancreatic duct and thence into the duodenum, where they become activated and perform digestive functions on the food in the intestinal tract. Mitochondria The mitochondria, shown in Figures 2–2 and 2–7, are called the “powerhouses” of the cell. Without them, cells would be unable to extract enough energy from the nutrients, and essentially all cellular functions would cease. Mitochondria are present in all areas of each cell’s cytoplasm, but the total number per cell varies from less than a hundred up to several thousand, depending on the amount of energy required by the cell. Further, the mitochondria are concentrated in those portions of the cell that are responsible for the major share of its energy metabolism. They are also variable in size and shape. Some are only a few hundred nanometers Chapter 2 The Cell and Its Functions in diameter and globular in shape, whereas others are elongated—as large as 1 micrometer in diameter and 7 micrometers long; still others are branching and filamentous. The basic structure of the mitochondrion, shown in Figure 2–7, is composed mainly of two lipid bilayer–protein membranes: an outer membrane and an inner membrane. Many infoldings of the inner membrane form shelves onto which oxidative enzymes are attached. In addition, the inner cavity of the mitochondrion is filled with a matrix that contains large quantities of dissolved enzymes that are necessary for extracting energy from nutrients. These enzymes operate in association with the oxidative enzymes on the shelves to cause oxidation of the nutrients, thereby forming carbon dioxide and water and at the same time releasing energy. The liberated energy is used to synthesize a “high-energy” substance called adenosine triphosphate (ATP). ATP is then transported out of the mitochondrion, and it diffuses throughout the cell to release its own energy wherever it is needed for performing cellular functions.The chemical details of ATP formation by the mitochondrion are given in Chapter 67, but some of the basic functions of ATP in the cell are introduced later in this chapter. Mitochondria are self-replicative, which means that one mitochondrion can form a second one, a third one, and so on, whenever there is a need in the cell for increased amounts of ATP. Indeed, the mitochondria contain DNA similar to that found in the cell nucleus. In Chapter 3 we will see that DNA is the basic chemical of the nucleus that controls replication of the cell. The DNA of the mitochondrion plays a similar role, controlling replication of the mitochondrion itself. Filament and Tubular Structures of the Cell The fibrillar proteins of the cell are usually organized into filaments or tubules. These originate as precursor protein molecules synthesized by ribosomes in the cytoplasm. The precursor molecules then polymerize to form filaments. As an example, large numbers of actin filaments frequently occur in the outer zone of the cytoplasm, called the ectoplasm, to form an elastic support for the cell membrane. Also, in muscle cells, actin and myosin filaments are organized into a special contractile machine that is the basis for muscle contraction, as discussed in detail in Chapter 6. A special type of stiff filament composed of polymerized tubulin molecules is used in all cells to construct very strong tubular structures, the microtubules. Figure 2–8 shows typical microtubules that were teased from the flagellum of a sperm. Another example of microtubules is the tubular skeletal structure in the center of each cilium that radiates upward from the cell cytoplasm to the tip of the cilium. This structure is discussed later in the chapter and is illustrated in Figure 2–17. Also, both the centrioles and the mitotic spindle of the mitosing cell are composed of stiff microtubules. Thus, a primary function of microtubules is to act as a cytoskeleton, providing rigid physical structures for certain parts of cells. 17 Figure 2–8 Microtubules teased from the flagellum of a sperm. (From Wolstenholme GEW, O’Connor M, and The publisher, JA Churchill, 1967. Figure 4, page 314. Copyright the Novartis Foundation formerly the Ciba Foundation.) Nucleus The nucleus is the control center of the cell. Briefly, the nucleus contains large quantities of DNA, which are the genes. The genes determine the characteristics of the cell’s proteins, including the structural proteins, as well as the intracellular enzymes that control cytoplasmic and nuclear activities. The genes also control and promote reproduction of the cell itself. The genes first reproduce to give two identical sets of genes; then the cell splits by a special process called mitosis to form two daughter cells, each of which receives one of the two sets of DNA genes. All these activities of the nucleus are considered in detail in the next chapter. Unfortunately, the appearance of the nucleus under the microscope does not provide many clues to the mechanisms by which the nucleus performs its control activities. Figure 2–9 shows the light microscopic appearance of the interphase nucleus (during the period between mitoses), revealing darkly staining chromatin material throughout the nucleoplasm. During mitosis, the chromatin material organizes in the form of highly structured chromosomes, which can then be easily identified using the light microscope, as illustrated in the next chapter. Nuclear Membrane The nuclear membrane, also called the nuclear envelope, is actually two separate bilayer membranes, one inside the other. The outer membrane is continuous with the endoplasmic reticulum of the cell cytoplasm, and the space between the two nuclear membranes is also continuous with the space inside the endoplasmic reticulum, as shown in Figure 2–9. 18 Unit I Pores Introduction to Physiology: The Cell and General Physiology Nucleoplasm 15 nm — Small virus 150 nm — Large virus Endoplasmic reticulum 350 nm — Rickettsia Nucleolus 1 mm Bacterium Nuclear envelope – outer and inner membranes Cell Chromatin material (DNA) Cytoplasm 5 – 10 mm + Figure 2–9 Figure 2–10 Structure of the nucleus. Comparison of sizes of precellular organisms with that of the average cell in the human body. The nuclear membrane is penetrated by several thousand nuclear pores. Large complexes of protein molecules are attached at the edges of the pores so that the central area of each pore is only about 9 nanometers in diameter. Even this size is large enough to allow molecules up to 44,000 molecular weight to pass through with reasonable ease. Nucleoli and Formation of Ribosomes The nuclei of most cells contain one or more highly staining structures called nucleoli. The nucleolus, unlike most other organelles discussed here, does not have a limiting membrane. Instead, it is simply an accumulation of large amounts of RNA and proteins of the types found in ribosomes. The nucleolus becomes considerably enlarged when the cell is actively synthesizing proteins. Formation of the nucleoli (and of the ribosomes in the cytoplasm outside the nucleus) begins in the nucleus. First, specific DNA genes in the chromosomes cause RNA to be synthesized. Some of this is stored in the nucleoli, but most of it is transported outward through the nuclear pores into cytoplasm. Here, it is used in conjunction with specific proteins to assemble “mature” ribosomes that play an essential role in forming cytoplasmic proteins, as discussed more fully in Chapter 3. Comparison of the Animal Cell with Precellular Forms of Life Many of us think of the cell as the lowest level of life. However, the cell is a very complicated organism that required many hundreds of millions of years to develop after the earliest form of life, an organism similar to the present-day virus, first appeared on earth. Figure 2–10 shows the relative sizes of (1) the smallest known virus, (2) a large virus, (3) a rickettsia, (4) a bacterium, and (5) a nucleated cell, demonstrating that the cell has a diameter about 1000 times that of the smallest virus and, therefore, a volume about 1 billion times that of the smallest virus. Correspondingly, the functions and anatomical organization of the cell are also far more complex than those of the virus. The essential life-giving constituent of the small virus is a nucleic acid embedded in a coat of protein. This nucleic acid is composed of the same basic nucleic acid constituents (DNA or RNA) found in mammalian cells, and it is capable of reproducing itself under appropriate conditions. Thus, the virus propagates its lineage from generation to generation and is therefore a living structure in the same way that the cell and the human being are living structures. As life evolved, other chemicals besides nucleic acid and simple proteins became integral parts of the organism, and specialized functions began to develop in different parts of the virus. A membrane formed around the virus, and inside the membrane, a fluid matrix appeared. Specialized chemicals then developed inside the fluid to perform special functions; many protein enzymes appeared that were capable of catalyzing chemical reactions and, therefore, determining the organism’s activities. In still later stages of life, particularly in the rickettsial and bacterial stages, organelles developed inside the organism, representing physical structures of chemical aggregates that perform functions in a more efficient manner than can be achieved by dispersed chemicals throughout the fluid matrix. Finally, in the nucleated cell, still more complex organelles developed, the most important of which is the nucleus itself. The nucleus distinguishes this type of cell from all lower forms of life; the nucleus provides a control center for all cellular activities, and it provides for exact reproduction of new cells generation after generation, each new cell having almost exactly the same structure as its progenitor. Chapter 2 19 The Cell and Its Functions Functional Systems of the Cell Proteins In the remainder of this chapter, we discuss several representative functional systems of the cell that make it a living organism. Ingestion by the Cell—Endocytosis If a cell is to live and grow and reproduce, it must obtain nutrients and other substances from the surrounding fluids. Most substances pass through the cell membrane by diffusion and active transport. Diffusion involves simple movement through the membrane caused by the random motion of the molecules of the substance; substances move either through cell membrane pores or, in the case of lipidsoluble substances, through the lipid matrix of the membrane. Active transport involves the actual carrying of a substance through the membrane by a physical protein structure that penetrates all the way through the membrane. These active transport mechanisms are so important to cell function that they are presented in detail in Chapter 4. Very large particles enter the cell by a specialized function of the cell membrane called endocytosis. The principal forms of endocytosis are pinocytosis and phagocytosis. Pinocytosis means ingestion of minute particles that form vesicles of extracellular fluid and particulate constituents inside the cell cytoplasm. Phagocytosis means ingestion of large particles, such as bacteria, whole cells, or portions of degenerating tissue. Pinocytosis. Pinocytosis occurs continually in the cell membranes of most cells, but it is especially rapid in some cells. For instance, it occurs so rapidly in macrophages that about 3 per cent of the total macrophage membrane is engulfed in the form of vesicles each minute. Even so, the pinocytotic vesicles are so small—usually only 100 to 200 nanometers in diameter—that most of them can be seen only with the electron microscope. Pinocytosis is the only means by which most large macromolecules, such as most protein molecules, can enter cells. In fact, the rate at which pinocytotic vesicles form is usually enhanced when such macromolecules attach to the cell membrane. Figure 2–11 demonstrates the successive steps of pinocytosis, showing three molecules of protein attaching to the membrane. These molecules usually attach to specialized protein receptors on the surface of the membrane that are specific for the type of protein that is to be absorbed. The receptors generally are concentrated in small pits on the outer surface of the cell membrane, called coated pits. On the inside of the cell membrane beneath these pits is a latticework of fibrillar protein called clathrin, as well as other proteins, perhaps including contractile filaments of actin and myosin. Once the protein molecules have bound with the receptors, the surface properties of the local Receptors Coated pit Clathrin A B Actin and myosin C Dissolving clathrin D Figure 2–11 Mechanism of pinocytosis. membrane change in such a way that the entire pit invaginates inward, and the fibrillar proteins surrounding the invaginating pit cause its borders to close over the attached proteins as well as over a small amount of extracellular fluid. Immediately thereafter, the invaginated portion of the membrane breaks away from the surface of the cell, forming a pinocytotic vesicle inside the cytoplasm of the cell. What causes the cell membrane to go through the necessary contortions to form pinocytotic vesicles remains mainly a mystery.This process requires energy from within the cell; this is supplied by ATP, a highenergy substance discussed later in the chapter. Also, it requires the presence of calcium ions in the extracellular fluid, which probably react with contractile protein filaments beneath the coated pits to provide the force for pinching the vesicles away from the cell membrane. Phagocytosis. Phagocytosis occurs in much the same way as pinocytosis, except that it involves large particles rather than molecules. Only certain cells have the capability of phagocytosis, most notably the tissue macrophages and some of the white blood cells. Phagocytosis is initiated when a particle such as a bacterium, a dead cell, or tissue debris binds with receptors on the surface of the phagocyte. In the case of bacteria, each bacterium usually is already attached to a specific antibody, and it is the antibody that attaches to the phagocyte receptors, dragging the bacterium along with it. This intermediation of antibodies is called opsonization, which is discussed in Chapters 33 and 34. Phagocytosis occurs in the following steps: 1. The cell membrane receptors attach to the surface ligands of the particle. 2. The edges of the membrane around the points of attachment evaginate outward within a fraction of a second to surround the entire particle; then, progressively more and more membrane receptors 20 Unit I Introduction to Physiology: The Cell and General Physiology attach to the particle ligands. All this occurs suddenly in a zipper-like manner to form a closed phagocytic vesicle. 3. Actin and other contractile fibrils in the cytoplasm surround the phagocytic vesicle and contract around its outer edge, pushing the vesicle to the interior. 4. The contractile proteins then pinch the stem of the vesicle so completely that the vesicle separates from the cell membrane, leaving the vesicle in the cell interior in the same way that pinocytotic vesicles are formed. Digestion of Pinocytotic and Phagocytic Foreign Substances Inside the Cell—Function of the Lysosomes Almost immediately after a pinocytotic or phagocytic vesicle appears inside a cell, one or more lysosomes become attached to the vesicle and empty their acid hydrolases to the inside of the vesicle, as shown in Figure 2–12. Thus, a digestive vesicle is formed inside the cell cytoplasm in which the vesicular hydrolases begin hydrolyzing the proteins, carbohydrates, lipids, and other substances in the vesicle. The products of digestion are small molecules of amino acids, glucose, phosphates, and so forth that can diffuse through the membrane of the vesicle into the cytoplasm. What is left of the digestive vesicle, called the residual body, represents indigestible substances. In most instances, this is finally excreted through the cell membrane by a process called exocytosis, which is essentially the opposite of endocytosis. Thus, the pinocytotic and phagocytic vesicles containing lysosomes can be called the digestive organs of the cells. occurs in the uterus after pregnancy, in muscles during long periods of inactivity, and in mammary glands at the end of lactation. Lysosomes are responsible for much of this regression. The mechanism by which lack of activity in a tissue causes the lysosomes to increase their activity is unknown. Another special role of the lysosomes is removal of damaged cells or damaged portions of cells from tissues. Damage to the cell—caused by heat, cold, trauma, chemicals, or any other factor—induces lysosomes to rupture. The released hydrolases immediately begin to digest the surrounding organic substances. If the damage is slight, only a portion of the cell is removed, followed by repair of the cell. If the damage is severe, the entire cell is digested, a process called autolysis. In this way, the cell is completely removed, and a new cell of the same type ordinarily is formed by mitotic reproduction of an adjacent cell to take the place of the old one. The lysosomes also contain bactericidal agents that can kill phagocytized bacteria before they can cause cellular damage. These agents include (1) lysozyme, which dissolves the bacterial cell membrane; (2) lysoferrin, which binds iron and other substances before they can promote bacterial growth; and (3) acid at a pH of about 5.0, which activates the hydrolases and inactivates bacterial metabolic systems. Synthesis and Formation of Cellular Structures by Endoplasmic Reticulum and Golgi Apparatus Specific Functions of the Endoplasmic Reticulum Pinocytotic or phagocytic vesicle The extensiveness of the endoplasmic reticulum and the Golgi apparatus in secretory cells has already been emphasized. These structures are formed primarily of lipid bilayer membranes similar to the cell membrane, and their walls are loaded with protein enzymes that catalyze the synthesis of many substances required by the cell. Most synthesis begins in the endoplasmic reticulum. The products formed there are then passed on to the Golgi apparatus, where they are further processed before being released into the cytoplasm. But first, let us note the specific products that are synthesized in specific portions of the endoplasmic reticulum and the Golgi apparatus. Digestive vesicle Proteins Are Formed by the Granular Endoplasmic Reticulum. Regression of Tissues and Autolysis of Cells. Tissues of the body often regress to a smaller size. For instance, this Lysosomes Residual body Excretion Figure 2–12 Digestion of substances in pinocytotic or phagocytic vesicles by enzymes derived from lysosomes. The granular portion of the endoplasmic reticulum is characterized by large numbers of ribosomes attached to the outer surfaces of the endoplasmic reticulum membrane. As we discuss in Chapter 3, protein molecules are synthesized within the structures of the ribosomes. The ribosomes extrude some of the synthesized protein molecules directly into the cytosol, but they also extrude many more through the wall of the endoplasmic reticulum to the interior of the endoplasmic vesicles and tubules, that is, into the endoplasmic matrix. Chapter 2 21 The Cell and Its Functions Synthesis of Lipids by the Smooth Endoplasmic Reticulum. The endoplasmic reticulum also synthesizes lipids, especially phospholipids and cholesterol. These are rapidly incorporated into the lipid bilayer of the endoplasmic reticulum itself, thus causing the endoplasmic reticulum to grow more extensive. This occurs mainly in the smooth portion of the endoplasmic reticulum. To keep the endoplasmic reticulum from growing beyond the needs of the cell, small vesicles called ER vesicles or transport vesicles continually break away from the smooth reticulum; most of these vesicles then migrate rapidly to the Golgi apparatus. Other Functions of the Endoplasmic Reticulum. Other significant functions of the endoplasmic reticulum, especially the smooth reticulum, include the following: 1. It provides the enzymes that control glycogen breakdown when glycogen is to be used for energy. 2. It provides a vast number of enzymes that are capable of detoxifying substances, such as drugs, that might damage the cell. It achieves detoxification by coagulation, oxidation, hydrolysis, conjugation with glycuronic acid, and in other ways. Specific Functions of the Golgi Apparatus Synthetic Functions of the Golgi Apparatus. Although the major function of the Golgi apparatus is to provide additional processing of substances already formed in the endoplasmic reticulum, it also has the capability of synthesizing certain carbohydrates that cannot be formed in the endoplasmic reticulum. This is especially true for the formation of large saccharide polymers bound with small amounts of protein; the most important of these are hyaluronic acid and chondroitin sulfate. A few of the many functions of hyaluronic acid and chondroitin sulfate in the body are as follows: (1) they are the major components of proteoglycans secreted in mucus and other glandular secretions; (2) they are the major components of the ground substance outside the cells in the interstitial spaces, acting as filler between collagen fibers and cells; and (3) they are principal components of the organic matrix in both cartilage and bone. Processing of Endoplasmic Secretions by the Golgi Apparatus— Formation of Vesicles. Figure 2–13 summarizes the major functions of the endoplasmic reticulum and Golgi apparatus. As substances are formed in the endoplasmic reticulum, especially the proteins, they are transported through the tubules toward portions of the smooth endoplasmic reticulum that lie nearest the Golgi apparatus. At this point, small transport vesicles composed of small envelopes of smooth endoplasmic reticulum continually break away and diffuse to the deepest layer of the Golgi apparatus. Inside these vesicles are the synthesized proteins and other products from the endoplasmic reticulum. The transport vesicles instantly fuse with the Golgi apparatus and empty their contained substances into the vesicular spaces of the Golgi apparatus. Here, Protein Ribosomes formation Glycosylation Granular endoplasmic reticulum Lipid formation Lysosomes Secretory vesicles Transport vesicles Smooth Golgi endoplasmic apparatus reticulum Figure 2–13 Formation of proteins, lipids, and cellular vesicles by the endoplasmic reticulum and Golgi apparatus. additional carbohydrate moieties are added to the secretions. Also, an important function of the Golgi apparatus is to compact the endoplasmic reticular secretions into highly concentrated packets. As the secretions pass toward the outermost layers of the Golgi apparatus, the compaction and processing proceed. Finally, both small and large vesicles continually break away from the Golgi apparatus, carrying with them the compacted secretory substances, and in turn, the vesicles diffuse throughout the cell. To give an idea of the timing of these processes: When a glandular cell is bathed in radioactive amino acids, newly formed radioactive protein molecules can be detected in the granular endoplasmic reticulum within 3 to 5 minutes. Within 20 minutes, newly formed proteins are already present in the Golgi apparatus, and within 1 to 2 hours, radioactive proteins are secreted from the surface of the cell. Types of Vesicles Formed by the Golgi Apparatus—Secretory Vesicles and Lysosomes. In a highly secretory cell, the vesicles formed by the Golgi apparatus are mainly secretory vesicles containing protein substances that are to be secreted through the surface of the cell membrane. These secretory vesicles first diffuse to the cell membrane, then fuse with it and empty their substances to the exterior by the mechanism called exocytosis. Exocytosis, in most cases, is stimulated by the entry of calcium ions into the cell; calcium ions interact with the vesicular membrane in some way that is not understood and cause its fusion with the cell membrane, followed by exocytosis—that is, opening of the membrane’s outer surface and extrusion of its contents outside the cell. Some vesicles, however, are destined for intracellular use. 22 Unit I Introduction to Physiology: The Cell and General Physiology Use of Intracellular Vesicles to Replenish Cellular Membranes. Some of the intracellular vesicles formed by the Golgi apparatus fuse with the cell membrane or with the membranes of intracellular structures such as the mitochondria and even the endoplasmic reticulum. This increases the expanse of these membranes and thereby replenishes the membranes as they are used up. For instance, the cell membrane loses much of its substance every time it forms a phagocytic or pinocytotic vesicle, and the vesicular membranes of the Golgi apparatus continually replenish the cell membrane. In summary, the membranous system of the endoplasmic reticulum and Golgi apparatus represents a highly metabolic organ capable of forming new intracellular structures as well as secretory substances to be extruded from the cell. all these digestive and metabolic functions are given in Chapters 62 through 72. Briefly, almost all these oxidative reactions occur inside the mitochondria, and the energy that is released is used to form the high-energy compound ATP. Then, ATP, not the original foodstuffs, is used throughout the cell to energize almost all the subsequent intracellular metabolic reactions. Functional Characteristics of ATP NH2 N HC N Extraction of Energy from Nutrients— Function of the Mitochondria The principal substances from which cells extract energy are foodstuffs that react chemically with oxygen—carbohydrates, fats, and proteins. In the human body, essentially all carbohydrates are converted into glucose by the digestive tract and liver before they reach the other cells of the body. Similarly, proteins are converted into amino acids and fats into fatty acids. Figure 2–14 shows oxygen and the foodstuffs—glucose, fatty acids, and amino acids—all entering the cell. Inside the cell, the foodstuffs react chemically with oxygen, under the influence of enzymes that control the reactions and channel the energy released in the proper direction. The details of 2ADP Glucose Gl Fatty acids FA Amino acids AA 2ATP Pyruvic acid Acetoacetic acid 36 ADP Acetyl-CoA Acetyl-CoA O2 O2 CO2 CO2 H2O O2 ADP CO2+H2O ATP H2O Mitochondrion 36 ATP Nucleus Cell membrane Figure 2–14 Formation of adenosine triphosphate (ATP) in the cell, showing that most of the ATP is formed in the mitochondria. ADP, adenosine diphosphate. C C N C CH N O H Adenine CH2 O C H H C C C H O O O P O~P O~P O- OPhosphate O- O- OH OH Ribose Adenosine triphosphate ATP is a nucleotide composed of (1) the nitrogenous base adenine, (2) the pentose sugar ribose, and (3) three phosphate radicals. The last two phosphate radicals are connected with the remainder of the molecule by so-called high-energy phosphate bonds, which are represented in the formula above by the symbol ~. Under the physical and chemical conditions of the body, each of these high-energy bonds contains about 12,000 calories of energy per mole of ATP, which is many times greater than the energy stored in the average chemical bond, thus giving rise to the term high-energy bond. Further, the high-energy phosphate bond is very labile, so that it can be split instantly on demand whenever energy is required to promote other intracellular reactions. When ATP releases its energy, a phosphoric acid radical is split away, and adenosine diphosphate (ADP) is formed. This released energy is used to energize virtually all of the cell’s other functions, such as synthesis of substances and muscular contraction. To reconstitute the cellular ATP as it is used up, energy derived from the cellular nutrients causes ADP and phosphoric acid to recombine to form new ATP, and the entire process repeats over and over again. For these reasons,ATP has been called the energy currency of the cell because it can be spent and remade continually, having a turnover time of only a few minutes. Chemical Processes in the Formation of ATP—Role of the Mitochondria. On entry into the cells, glucose is sub- jected to enzymes in the cytoplasm that convert it into pyruvic acid (a process called glycolysis). A small amount of ADP is changed into ATP by the energy released during this conversion, but this amount Chapter 2 23 The Cell and Its Functions accounts for less than 5 per cent of the overall energy metabolism of the cell. By far, the major portion of the ATP formed in the cell, about 95 per cent, is formed in the mitochondria. The pyruvic acid derived from carbohydrates, fatty acids from lipids, and amino acids from proteins are eventually converted into the compound acetyl-CoA in the matrix of the mitochondrion. This substance, in turn, is further dissoluted (for the purpose of extracting its energy) by another series of enzymes in the mitochondrion matrix, undergoing dissolution in a sequence of chemical reactions called the citric acid cycle, or Krebs cycle. These chemical reactions are so important that they are explained in detail in Chapter 67. In this citric acid cycle, acetyl-CoA is split into its component parts, hydrogen atoms and carbon dioxide. The carbon dioxide diffuses out of the mitochondria and eventually out of the cell; finally, it is excreted from the body through the lungs. The hydrogen atoms, conversely, are highly reactive, and they combine instantly with oxygen that has also diffused into the mitochondria. This releases a tremendous amount of energy, which is used by the mitochondria to convert very large amounts of ADP to ATP. The processes of these reactions are complex, requiring the participation of large numbers of protein enzymes that are integral parts of mitochondrial membranous shelves that protrude into the mitochondrial matrix. The initial event is removal of an electron from the hydrogen atom, thus converting it to a hydrogen ion. The terminal event is combination of hydrogen ions with oxygen to form water plus the release of tremendous amounts of energy to large globular proteins, called ATP synthetase, that protrude like knobs from the membranes of the mitochondrial shelves. Finally, the enzyme ATP synthetase uses the energy from the hydrogen ions to cause the conversion of ADP to ATP. The newly formed ATP is transported out of the mitochondria into all parts of the cell cytoplasm and nucleoplasm, where its energy is used to energize multiple cell functions. This overall process for formation of ATP is called the chemiosmotic mechanism of ATP formation. The chemical and physical details of this mechanism are presented in Chapter 67, and many of the detailed metabolic functions of ATP in the body are presented in Chapters 67 through 71. Uses of ATP for Cellular Function. Energy from ATP is used to promote three major categories of cellular functions: (1) transport of substances through multiple membranes in the cell, (2) synthesis of chemical compounds throughout the cell, and (3) mechanical work. These uses of ATP are illustrated by examples in Figure 2–15: (1) to supply energy for the transport of sodium through the cell membrane, (2) to promote protein synthesis by the ribosomes, and (3) to supply the energy needed during muscle contraction. In addition to membrane transport of sodium, energy from ATP is required for membrane transport of potassium ions, calcium ions, magnesium ions, phos- Ribosomes Membrane transport Na+ Na+ Endoplasmic reticulum Protein synthesis ATP ADP ADP Mitochondrion ATP ATP ADP ATP ADP Muscle contraction Figure 2–15 Use of adenosine triphosphate (ATP) (formed in the mitochondrion) to provide energy for three major cellular functions: membrane transport, protein synthesis, and muscle contraction. ADP, adenosine diphosphate. phate ions, chloride ions, urate ions, hydrogen ions, and many other ions and various organic substances. Membrane transport is so important to cell function that some cells—the renal tubular cells, for instance— use as much as 80 per cent of the ATP that they form for this purpose alone. In addition to synthesizing proteins, cells synthesize phospholipids, cholesterol, purines, pyrimidines, and a host of other substances. Synthesis of almost any chemical compound requires energy. For instance, a single protein molecule might be composed of as many as several thousand amino acids attached to one another by peptide linkages; the formation of each of these linkages requires energy derived from the breakdown of four high-energy bonds; thus, many thousand ATP molecules must release their energy as each protein molecule is formed. Indeed, some cells use as much as 75 per cent of all the ATP formed in the cell simply to synthesize new chemical compounds, especially protein molecules; this is particularly true during the growth phase of cells. The final major use of ATP is to supply energy for special cells to perform mechanical work. We see in Chapter 6 that each contraction of a muscle fiber requires expenditure of tremendous quantities of ATP energy. Other cells perform mechanical work in other ways, especially by ciliary and ameboid motion, which are described later in this chapter. The source of energy for all these types of mechanical work is ATP. In summary, ATP is always available to release its energy rapidly and almost explosively wherever in the cell it is needed. To replace the ATP used by the cell, 24 Unit I Introduction to Physiology: The Cell and General Physiology much slower chemical reactions break down carbohydrates, fats, and proteins and use the energy derived from these to form new ATP. More than 95 per cent of this ATP is formed in the mitochondria, which accounts for the mitochondria being called the “powerhouses” of the cell. Locomotion of Cells By far the most important type of movement that occurs in the body is that of the muscle cells in skeletal, cardiac, and smooth muscle, which constitute almost 50 per cent of the entire body mass. The specialized functions of these cells are discussed in Chapters 6 through 9. Two other types of movement—ameboid locomotion and ciliary movement—occur in other cells. Ameboid Movement Ameboid movement is movement of an entire cell in relation to its surroundings, such as movement of white blood cells through tissues. It receives its name from the fact that amebae move in this manner and have provided an excellent tool for studying the phenomenon. Typically, ameboid locomotion begins with protrusion of a pseudopodium from one end of the cell. The pseudopodium projects far out, away from the cell body, and partially secures itself in a new tissue area. Then the remainder of the cell is pulled toward the pseudopodium. Figure 2–16 demonstrates this process, showing an elongated cell, the right-hand end of which is a protruding pseudopodium. The membrane of this end of the cell is continually moving forward, and the membrane at the left-hand end of the cell is continually following along as the cell moves. Mechanism of Ameboid Locomotion. Figure 2–16 shows the general principle of ameboid motion. Basically, it results from continual formation of new cell membrane at the leading edge of the pseudopodium and continual absorption of the membrane in mid and rear portions of the cell. Also, two other effects are essential for forward movement of the cell. The first effect is attachment of the pseudopodium to surrounding tissues so that it becomes fixed in its leading position, while the Movement of cell Endocytosis Pseudopodium Exocytosis Surrounding tissue remainder of the cell body is pulled forward toward the point of attachment. This attachment is effected by receptor proteins that line the insides of exocytotic vesicles. When the vesicles become part of the pseudopodial membrane, they open so that their insides evert to the outside, and the receptors now protrude to the outside and attach to ligands in the surrounding tissues. At the opposite end of the cell, the receptors pull away from their ligands and form new endocytotic vesicles. Then, inside the cell, these vesicles stream toward the pseudopodial end of the cell, where they are used to form still new membrane for the pseudopodium. The second essential effect for locomotion is to provide the energy required to pull the cell body in the direction of the pseudopodium. Experiments suggest the following as an explanation: In the cytoplasm of all cells is a moderate to large amount of the protein actin. Much of the actin is in the form of single molecules that do not provide any motive power; however, these polymerize to form a filamentous network, and the network contracts when it binds with an actin-binding protein such as myosin. The whole process is energized by the high-energy compound ATP. This is what happens in the pseudopodium of a moving cell, where such a network of actin filaments forms anew inside the enlarging pseudopodium. Contraction also occurs in the ectoplasm of the cell body, where a preexisting actin network is already present beneath the cell membrane. Types of Cells That Exhibit Ameboid Locomotion. The most common cells to exhibit ameboid locomotion in the human body are the white blood cells when they move out of the blood into the tissues in the form of tissue macrophages. Other types of cells can also move by ameboid locomotion under certain circumstances. For instance, fibroblasts move into a damaged area to help repair the damage, and even the germinal cells of the skin, though ordinarily completely sessile cells, move toward a cut area to repair the rent. Finally, cell locomotion is especially important in development of the embryo and fetus after fertilization of an ovum. For instance, embryonic cells often must migrate long distances from their sites of origin to new areas during development of special structures. Control of Ameboid Locomotion—Chemotaxis. The most important initiator of ameboid locomotion is the process called chemotaxis. This results from the appearance of certain chemical substances in the tissues. Any chemical substance that causes chemotaxis to occur is called a chemotactic substance. Most cells that exhibit ameboid locomotion move toward the source of a chemotactic substance—that is, from an area of lower concentration toward an area of higher concentration—which is called positive chemotaxis. Some cells move away from the source, which is called negative chemotaxis. But how does chemotaxis control the direction of ameboid locomotion? Although the answer is not certain, it is known that the side of the cell most exposed to the chemotactic substance develops membrane changes that cause pseudopodial protrusion. Receptor binding Cilia and Ciliary Movements Figure 2–16 Ameboid motion by a cell. A second type of cellular motion, ciliary movement, is a whiplike movement of cilia on the surfaces of cells. This Chapter 2 The Cell and Its Functions Tip Ciliary stalk Membrane Cross section Filament Forward stroke Basal plate Cell membrane Backward stroke Basal body Rootlet Figure 2–17 Structure and function of the cilium. (Modified from Satir P: Cilia. Sci Am 204:108, 1961. Copyright Donald Garber: Executor of the estate of Bunji Tagawa.) occurs in only two places in the human body: on the sufaces of the respiratory airways and on the inside surfaces of the uterine tubes (fallopian tubes) of the reproductive tract. In the nasal cavity and lower respiratory airways, the whiplike motion of cilia causes a layer of mucus to move at a rate of about 1 cm/min toward the pharynx, in this way continually clearing these passageways of mucus and particles that have become trapped in the mucus. In the uterine tubes, the cilia cause slow movement of fluid from the ostium of the uterine tube toward the uterus cavity; this movement of fluid transports the ovum from the ovary to the uterus. As shown in Figure 2–17, a cilium has the appearance of a sharp-pointed straight or curved hair that projects 2 to 4 micrometers from the surface of the cell. Many cilia often project from a single cell—for instance, as many as 200 cilia on the surface of each epithelial cell inside the respiratory passageways. The cilium is covered by an outcropping of the cell membrane, and it is supported by 11 microtubules—9 double tubules located around the periphery of the cilium, and 2 single tubules down the center, as demonstrated in the cross section shown in Figure 2–17. Each cilium is an outgrowth of a structure that lies immediately beneath the cell membrane, called the basal body of the cilium. 25 The flagellum of a sperm is similar to a cilium; in fact, it has much the same type of structure and same type of contractile mechanism. The flagellum, however, is much longer and moves in quasi-sinusoidal waves instead of whiplike movements. In the inset of Figure 2–17, movement of the cilium is shown. The cilium moves forward with a sudden, rapid whiplike stroke 10 to 20 times per second, bending sharply where it projects from the surface of the cell. Then it moves backward slowly to its initial position. The rapid forward-thrusting, whiplike movement pushes the fluid lying adjacent to the cell in the direction that the cilium moves; the slow, dragging movement in the backward direction has almost no effect on fluid movement. As a result, the fluid is continually propelled in the direction of the fast-forward stroke. Because most ciliated cells have large numbers of cilia on their surfaces and because all the cilia are oriented in the same direction, this is an effective means for moving fluids from one part of the surface to another. Mechanism of Ciliary Movement. Although not all aspects of ciliary movement are clear, we do know the following: First, the nine double tubules and the two single tubules are all linked to one another by a complex of protein cross-linkages; this total complex of tubules and crosslinkages is called the axoneme. Second, even after removal of the membrane and destruction of other elements of the cilium besides the axoneme, the cilium can still beat under appropriate conditions. Third, there are two necessary conditions for continued beating of the axoneme after removal of the other structures of the cilium: (1) the availability of ATP and (2) appropriate ionic conditions, especially appropriate concentrations of magnesium and calcium. Fourth, during forward motion of the cilium, the double tubules on the front edge of the cilium slide outward toward the tip of the cilium, while those on the back edge remain in place. Fifth, multiple protein arms composed of the protein dynein, which has ATPase enzymatic activity, project from each double tubule toward an adjacent double tubule. Given this basic information, it has been determined that the release of energy from ATP in contact with the ATPase dynein arms causes the heads of these arms to “crawl” rapidly along the surface of the adjacent double tubule. If the front tubules crawl outward while the back tubules remain stationary, this will cause bending. The way in which cilia contraction is controlled is not understood. The cilia of some genetically abnormal cells do not have the two central single tubules, and these cilia fail to beat. Therefore, it is presumed that some signal, perhaps an electrochemical signal, is transmitted along these two central tubules to activate the dynein arms. References Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell. New York: Garland Science, 2002. Bonifacino JS, Glick BS: The mechanisms of vesicle budding and fusion. Cell 116:153, 2004. Calakos N, Scheller RH: Synaptic vesicle biogenesis, docking, and fusion: a molecular description. Physiol Rev 76:1, 1996. Danial NN, Korsmeyer SJ: Cell death: critical control points. Cell 116:205, 2004. 26 Unit I Introduction to Physiology: The Cell and General Physiology Deutsch C: The birth of a channel. Neuron 40:265, 2003. Dröge W: Free radicals in the physiological control of cell function. Physiol Rev 82:47, 2002. Duchen MR: Roles of mitochondria in health and disease. Diabetes 53(Suppl 1):S96, 2004. Edidin M: Lipids on the frontier: a century of cell-membrane bilayers. Nat Rev Mol Cell Biol 4:414, 2003. Gerbi SA, Borovjagin AV, Lange TS: The nucleolus: a site of ribonucleoprotein maturation. Curr Opin Cell Biol 15:318, 2003. Hamill OP, Martinac B: Molecular basis of mechanotransduction in living cells. Physiol Rev 81:685, 2001. Lange K: Role of microvillar cell surfaces in the regulation of glucose uptake and organization of energy metabolism. Am J Physiol Cell Physiol 282:C1, 2002. Mattaj IW: Sorting out the nuclear envelope from the endoplasmic reticulum. Nat Rev Mol Cell Biol 5:65, 2004. Maxfield FR, McGraw TE: Endocytic recycling. Nat Rev Mol Cell Biol 5:121, 2004. Mazzanti M, Bustamante JO, Oberleithner H: Electrical dimension of the nuclear envelope. Physiol Rev 81:1, 2001. Perrios M: Nuclear Structure and Function. San Diego: Academic Press, 1998. Ridley AJ, Schwartz MA, Burridge K, et al: Cell migration: integrating signals from front to back. Science 302:1704, 2003. Scholey JM: Intraflagellar transport. Annu Rev Cell Dev Biol 19:423, 2003. Schwab A: Function and spatial distribution of ion channels and transporters in cell migration. Am J Physiol Renal Physiol 280:F739, 2001. Vereb G, Szollosi J, Matko J, et al: Dynamic, yet structured: the cell membrane three decades after the SingerNicolson model. Proc Natl Acad Sci U S A 100:8053, 2003. C H A P T E R 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction Virtually everyone knows that the genes, located in the nuclei of all cells of the body, control heredity from parents to children, but most people do not realize that these same genes also control day-today function of all the body’s cells. The genes control cell function by determining which substances are synthesized within the cell—which structures, which enzymes, which chemicals. Figure 3–1 shows the general schema of genetic control. Each gene, which is a nucleic acid called deoxyribonucleic acid (DNA), automatically controls the formation of another nucleic acid, ribonucleic acid (RNA); this RNA then spreads throughout the cell to control the formation of a specific protein. Because there are more than 30,000 different genes in each cell, it is theoretically possible to form a very large number of different cellular proteins. Some of the cellular proteins are structural proteins, which, in association with various lipids and carbohydrates, form the structures of the various intracellular organelles discussed in Chapter 2. However, by far the majority of the proteins are enzymes that catalyze the different chemical reactions in the cells. For instance, enzymes promote all the oxidative reactions that supply energy to the cell, and they promote synthesis of all the cell chemicals, such as lipids, glycogen, and adenosine triphosphate (ATP). Genes in the Cell Nucleus In the cell nucleus, large numbers of genes are attached end on end in extremely long double-stranded helical molecules of DNA having molecular weights measured in the billions. A very short segment of such a molecule is shown in Figure 3–2. This molecule is composed of several simple chemical compounds bound together in a regular pattern, details of which are explained in the next few paragraphs. Basic Building Blocks of DNA. Figure 3–3 shows the basic chemical compounds involved in the formation of DNA. These include (1) phosphoric acid, (2) a sugar called deoxyribose, and (3) four nitrogenous bases (two purines, adenine and guanine, and two pyrimidines, thymine and cytosine). The phosphoric acid and deoxyribose form the two helical strands that are the backbone of the DNA molecule, and the nitrogenous bases lie between the two strands and connect them, as illustrated in Figure 3–6. Nucleotides. The first stage in the formation of DNA is to combine one molecule of phosphoric acid, one molecule of deoxyribose, and one of the four bases to form an acidic nucleotide. Four separate nucleotides are thus formed, one for each of the four bases: deoxyadenylic, deoxythymidylic, deoxyguanylic, and deoxycytidylic acids. Figure 3–4 shows the chemical structure of deoxyadenylic acid, and Figure 3–5 shows simple symbols for the four nucleotides that form DNA. Organization of the Nucleotides to Form Two Strands of DNA Loosely Bound to Each Other. Figure 3–6 shows the manner in which multiple numbers of nucleotides are 27 28 Introduction to Physiology: The Cell and General Physiology Unit I Gene (DNA) RNA formation Protein formation Cell structure Figure 3–2 Cell enzymes The helical, double-stranded structure of the gene. The outside strands are composed of phosphoric acid and the sugar deoxyribose. The internal molecules connecting the two strands of the helix are purine and pyrimidine bases; these determine the “code” of the gene. Cell function Figure 3–1 General schema by which the genes control cell function. Phosphoric acid O H O P O H O H H Deoxyribose H O H H C C O C H H C O C H H H O H Bases H N H N H H C C N C C O C N N O N C H C N C H H H C C H H H Thymine Adenine H O N H C N C N H C H N C N C O N H H H Guanine Purines H C H C C N N C H Cytosine Pyrimidines Figure 3–3 The basic building blocks of DNA. H H H Phosphate H O H O C P O H O C H 29 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction Chapter 3 Adenine N C C C N O C H O N H C N N T A H C P D Deoxyadenylic acid C H Deoxyribose C H P D Deoxythymidylic acid H G H C P D Deoxyguanylic acid P D Deoxycytidylic acid Figure 3–4 Deoxyadenylic acid, one of the nucleotides that make up DNA. Figure 3–5 Symbols for the four nucleotides that combine to form DNA. Each nucleotide contains phosphoric acid (P), deoxyribose (D), and one of the four nucleotide bases: A, adenine; T, thymine; G, guanine; or C, cytosine. D P D P D P D P D P D P D P D P D G G C A G A C T T C G T C T G A A D P D P D P D P D P D P D P D P P P P C D Figure 3–6 Arrangement of deoxyribose nucleotides in a double strand of DNA. bound together to form two strands of DNA. The two strands are, in turn, loosely bonded with each other by weak cross-linkages, illustrated in Figure 3–6 by the central dashed lines. Note that the backbone of each DNA strand is comprised of alternating phosphoric acid and deoxyribose molecules. In turn, purine and pyrimidine bases are attached to the sides of the deoxyribose molecules. Then, by means of loose hydrogen bonds (dashed lines) between the purine and pyrimidine bases, the two respective DNA strands are held together. But note the following: 1. Each purine base adenine of one strand always bonds with a pyrimidine base thymine of the other strand, and 2. Each purine base guanine always bonds with a pyrimidine base cytosine. Thus, in Figure 3–6, the sequence of complementary pairs of bases is CG, CG, GC, TA, CG, TA, GC, AT, and AT. Because of the looseness of the hydrogen bonds, the two strands can pull apart with ease, and they do so many times during the course of their function in the cell. To put the DNA of Figure 3–6 into its proper physical perspective, one could merely pick up the two ends and twist them into a helix. Ten pairs of nucleotides are present in each full turn of the helix in the DNA molecule, as shown in Figure 3–2. Genetic Code The importance of DNA lies in its ability to control the formation of proteins in the cell. It does this by means of the so-called genetic code. That is, when the two strands of a DNA molecule are split apart, this exposes the purine and pyrimidine bases projecting to the side of each DNA strand, as shown by the top strand in Figure 3–7. It is these projecting bases that form the genetic code. 30 Introduction to Physiology: The Cell and General Physiology Unit I DNA strand D P D P D P D C A G A C P D P D G R P R P R P R G RNA molecule P T P G T D P U P R C D P U P R G D P C P C A R P R Figure 3–7 Triphosphate P P P P RNA polymerase C P R C P R Proline G P R U P R C P R U P Serine R G P R A P R A P Glutamic acid The genetic code consists of successive “triplets” of bases—that is, each three successive bases is a code word. The successive triplets eventually control the sequence of amino acids in a protein molecule that is to be synthesized in the cell. Note in Figure 3–6 that the top strand of DNA, reading from left to right, has the genetic code GGC, AGA, CTT, the triplets being separated from one another by the arrows. As we follow this genetic code through Figures 3–7 and 3–8, we see that these three respective triplets are responsible for successive placement of the three amino acids, proline, serine, and glutamic acid, in a newly formed molecule of protein. The DNA Code in the Cell Nucleus Is Transferred to an RNA Code in the Cell Cytoplasm—The Process of Transcription Because the DNA is located in the nucleus of the cell, yet most of the functions of the cell are carried out in the cytoplasm, there must be some means for the DNA genes of the nucleus to control the chemical reactions of the cytoplasm. This is achieved through the intermediary of another type of nucleic acid, RNA, the formation of which is controlled by the DNA of the nucleus. Thus, as shown in Figure 3–7, the code is transferred to the RNA; this process is called transcription. R Combination of ribose nucleotides with a strand of DNA to form a molecule of RNA that carries the genetic code from the gene to the cytoplasm. The RNA polymerase enzyme moves along the DNA strand and builds the RNA molecule. Figure 3–8 Portion of an RNA molecule, showing three RNA “codons”—CCG, UCU, and GAA—which control attachment of the three amino acids proline, serine, and glutamic acid, respectively, to the growing RNA chain. The RNA, in turn, diffuses from the nucleus through nuclear pores into the cytoplasmic compartment, where it controls protein synthesis. Synthesis of RNA During synthesis of RNA, the two strands of the DNA molecule separate temporarily; one of these strands is used as a template for synthesis of an RNA molecule. The code triplets in the DNA cause formation of complementary code triplets (called codons) in the RNA; these codons, in turn, will control the sequence of amino acids in a protein to be synthesized in the cell cytoplasm. Basic Building Blocks of RNA. The basic building blocks of RNA are almost the same as those of DNA, except for two differences. First, the sugar deoxyribose is not used in the formation of RNA. In its place is another sugar of slightly different composition, ribose, containing an extra hydroxyl ion appended to the ribose ring structure. Second, thymine is replaced by another pyrimidine, uracil. Formation of RNA Nucleotides. The basic building blocks of RNA form RNA nucleotides, exactly as previously described for DNA synthesis. Here again, four separate nucleotides are used in the formation of RNA. These nucleotides contain the bases adenine, guanine, cytosine, and uracil. Note that these are the same bases Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction as in DNA, except that uracil in RNA replaces thymine in DNA. “Activation” of the RNA Nucleotides. The next step in the synthesis of RNA is “activation” of the RNA nucleotides by an enzyme, RNA polymerase. This occurs by adding to each nucleotide two extra phosphate radicals to form triphosphates (shown in Figure 3–7 by the two RNA nucleotides to the far right during RNA chain formation). These last two phosphates are combined with the nucleotide by high-energy phosphate bonds derived from ATP in the cell. The result of this activation process is that large quantities of ATP energy are made available to each of the nucleotides, and this energy is used to promote the chemical reactions that add each new RNA nucleotide at the end of the developing RNA chain. Assembly of the RNA Chain from Activated Nucleotides Using the DNA Strand as a Template—The Process of “Transcription” Assembly of the RNA molecule is accomplished in the manner shown in Figure 3–7 under the influence of an enzyme, RNA polymerase. This is a large protein enzyme that has many functional properties necessary for formation of the RNA molecule. They are as follows: 1. In the DNA strand immediately ahead of the initial gene is a sequence of nucleotides called the promoter. The RNA polymerase has an appropriate complementary structure that recognizes this promoter and becomes attached to it. This is the essential step for initiating formation of the RNA molecule. 2. After the RNA polymerase attaches to the promoter, the polymerase causes unwinding of about two turns of the DNA helix and separation of the unwound portions of the two strands. 3. Then the polymerase moves along the DNA strand, temporarily unwinding and separating the two DNA strands at each stage of its movement. As it moves along, it adds at each stage a new activated RNA nucleotide to the end of the newly forming RNA chain by the following steps: a. First, it causes a hydrogen bond to form between the end base of the DNA strand and the base of an RNA nucleotide in the nucleoplasm. b. Then, one at a time, the RNA polymerase breaks two of the three phosphate radicals away from each of these RNA nucleotides, liberating large amounts of energy from the broken high-energy phosphate bonds; this energy is used to cause covalent linkage of the remaining phosphate on the nucleotide with the ribose on the end of the growing RNA chain. 31 c. When the RNA polymerase reaches the end of the DNA gene, it encounters a new sequence of DNA nucleotides called the chain-terminating sequence; this causes the polymerase and the newly formed RNA chain to break away from the DNA strand. Then the polymerase can be used again and again to form still more new RNA chains. d. As the new RNA strand is formed, its weak hydrogen bonds with the DNA template break away, because the DNA has a high affinity for rebonding with its own complementary DNA strand. Thus, the RNA chain is forced away from the DNA and is released into the nucleoplasm. Thus, the code that is present in the DNA strand is eventually transmitted in complementary form to the RNA chain. The ribose nucleotide bases always combine with the deoxyribose bases in the following combinations: DNA Base guanine cytosine adenine thymine RNA Base .................................. .................................. .................................. .................................. cytosine guanine uracil adenine Three Different Types of RNA. There are three different types of RNA, each of which plays an independent and entirely different role in protein formation: 1. Messenger RNA, which carries the genetic code to the cytoplasm for controlling the type of protein formed. 2. Transfer RNA, which transports activated amino acids to the ribosomes to be used in assembling the protein molecule. 3. Ribosomal RNA, which, along with about 75 different proteins, forms ribosomes, the physical and chemical structures on which protein molecules are actually assembled. Messenger RNA—The Codons Messenger RNA molecules are long, single RNA strands that are suspended in the cytoplasm. These molecules are composed of several hundred to several thousand RNA nucleotides in unpaired strands, and they contain codons that are exactly complementary to the code triplets of the DNA genes. Figure 3–8 shows a small segment of a molecule of messenger RNA. Its codons are CCG, UCU, and GAA. These are the codons for the amino acids proline, serine, and glutamic acid. The transcription of these codons from the DNA molecule to the RNA molecule is shown in Figure 3–7. RNA Codons for the Different Amino Acids. Table 3–1 gives the RNA codons for the 20 common amino acids 32 Unit I Introduction to Physiology: The Cell and General Physiology found in protein molecules. Note that most of the amino acids are represented by more than one codon; also, one codon represents the signal “start manufacturing the protein molecule,” and three codons represent “stop manufacturing the protein molecule.” In Table 3–1, these two types of codons are designated CI for “chain-initiating” and CT for “chain-terminating.” Transfer RNA—The Anticodons Another type of RNA that plays an essential role in protein synthesis is called transfer RNA, because it transfers amino acid molecules to protein molecules as the protein is being synthesized. Each type of transfer RNA combines specifically with 1 of the 20 amino acids that are to be incorporated into proteins. The transfer RNA then acts as a carrier to transport its specific type of amino acid to the ribosomes, where protein molecules are forming. In the ribosomes, each specific type of transfer RNA recognizes a particular codon on the messenger RNA (described later) and thereby delivers the appropriate amino acid to the appropriate place in the chain of the newly forming protein molecule. Transfer RNA, which contains only about 80 nucleotides, is a relatively small molecule in comparison with messenger RNA. It is a folded chain of nucleotides with a cloverleaf appearance similar to that shown in Figure 3–9. At one end of the molecule is always an adenylic acid; it is to this that the transported amino acid attaches at a hydroxyl group of the ribose in the adenylic acid. Because the function of transfer RNA is to cause attachment of a specific amino acid to a forming protein chain, it is essential that each type of transfer RNA also have specificity for a particular codon in the Forming protein Table 3–1 RNA Codons for Amino Acids and for Start and Stop Amino Acid RNA Codons Alanine Arginine Asparagine Aspartic acid Cysteine Glutamic acid Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine Start (CI) Stop (CT) GCU CGU AAU GAU UGU GAA CAA GGU CAU AUU CUU AAA AUG UUU CCU UCU ACU UGG UAU GUU AUG UAA GCC CGC AAC GAC UGC GAG CAG GGC CAC AUC CUC AAG GCA CGA GCG CGG GGA GGG AUA CUA UUC CCC UCC ACC AGA AGG CUG UUA UUG CCA UCA ACA CCG UCG ACG AGC AGU UAC GUC GUA GUG UAG UGA CI, chain-initiating; CT, chain-terminating. messenger RNA. The specific code in the transfer RNA that allows it to recognize a specific codon is again a triplet of nucleotide bases and is called an anticodon. This is located approximately in the middle of the transfer RNA molecule (at the bottom of the cloverleaf configuration shown in Figure 3–9). During formation of the protein molecule, the anticodon bases combine loosely by hydrogen bonding with the codon Alanine Cysteine Histidine Alanine Phenylalanine Serine Proline Transfer RNA Start codon GGG AUG GCC UGU CAU GCC UUU UCC CCC AAA CAG GAC UAU Ribosome Messenger RNA movement Ribosome Figure 3–9 A messenger RNA strand is moving through two ribosomes. As each “codon” passes through, an amino acid is added to the growing protein chain, which is shown in the right-hand ribosome. The transfer RNA molecule transports each specific amino acid to the newly forming protein. Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction bases of the messenger RNA. In this way, the respective amino acids are lined up one after another along the messenger RNA chain, thus establishing the appropriate sequence of amino acids in the newly forming protein molecule. Ribosomal RNA The third type of RNA in the cell is ribosomal RNA; it constitutes about 60 per cent of the ribosome. The remainder of the ribosome is protein, containing about 75 types of proteins that are both structural proteins and enzymes needed in the manufacture of protein molecules. The ribosome is the physical structure in the cytoplasm on which protein molecules are actually synthesized. However, it always functions in association with the other two types of RNA as well: transfer RNA transports amino acids to the ribosome for incorporation into the developing protein molecule, whereas messenger RNA provides the information necessary for sequencing the amino acids in proper order for each specific type of protein to be manufactured. Thus, the ribosome acts as a manufacturing plant in which the protein molecules are formed. Formation of Ribosomes in the Nucleolus. The DNA genes for formation of ribosomal RNA are located in five pairs of chromosomes in the nucleus, and each of these chromosomes contains many duplicates of these particular genes because of the large amounts of ribosomal RNA required for cellular function. As the ribosomal RNA forms, it collects in the nucleolus, a specialized structure lying adjacent to the chromosomes.When large amounts of ribosomal RNA are being synthesized, as occurs in cells that manufacture large amounts of protein, the nucleolus is a large structure, whereas in cells that synthesize little protein, the nucleolus may not even be seen. Ribosomal RNA is specially processed in the nucleolus, where it binds with “ribosomal proteins” to form granular condensation products that are primordial subunits of ribosomes. These subunits are then released from the nucleolus and transported through the large pores of the nuclear envelope to almost all parts of the cytoplasm. After the subunits enter the cytoplasm, they are assembled to form mature, functional ribosomes. Therefore, proteins are formed in the cytoplasm of the cell, but not in the cell nucleus, because the nucleus does not contain mature ribosomes. Formation of Proteins on the Ribosomes—The Process of “Translation” When a molecule of messenger RNA comes in contact with a ribosome, it travels through the ribosome, beginning at a predetermined end of the RNA molecule specified by an appropriate sequence of RNA 33 bases called the “chain-initiating” codon. Then, as shown in Figure 3–9, while the messenger RNA travels through the ribosome, a protein molecule is formed— a process called translation. Thus, the ribosome reads the codons of the messenger RNA in much the same way that a tape is “read” as it passes through the playback head of a tape recorder. Then, when a “stop” (or “chain-terminating”) codon slips past the ribosome, the end of a protein molecule is signaled and the protein molecule is freed into the cytoplasm. Polyribosomes. A single messenger RNA molecule can form protein molecules in several ribosomes at the same time because the initial end of the RNA strand can pass to a successive ribosome as it leaves the first, as shown at the bottom left in Figure 3–9 and in Figure 3–10. The protein molecules are in different stages of development in each ribosome. As a result, clusters of ribosomes frequently occur, 3 to 10 ribosomes being attached to a single messenger RNA at the same time. These clusters are called polyribosomes. It is especially important to note that a messenger RNA can cause the formation of a protein molecule in any ribosome; that is, there is no specificity of ribosomes for given types of protein. The ribosome is simply the physical manufacturing plant in which the chemical reactions take place. Many Ribosomes Attach to the Endoplasmic Reticulum. In Chapter 2, it was noted that many ribosomes become attached to the endoplasmic reticulum. This occurs because the initial ends of many forming protein molecules have amino acid sequences that immediately attach to specific receptor sites on the endoplasmic reticulum; this causes these molecules to penetrate the reticulum wall and enter the endoplasmic reticulum matrix. This gives a granular appearance to those portions of the reticulum where proteins are being formed and entering the matrix of the reticulum. Figure 3–10 shows the functional relation of messenger RNA to the ribosomes and the manner in which the ribosomes attach to the membrane of the endoplasmic reticulum. Note the process of translation occurring in several ribosomes at the same time in response to the same strand of messenger RNA. Note also the newly forming polypeptide (protein) chains passing through the endoplasmic reticulum membrane into the endoplasmic matrix. Yet it should be noted that except in glandular cells in which large amounts of protein-containing secretory vesicles are formed, most proteins synthesized by the ribosomes are released directly into the cytosol instead of into the endoplasmic reticulum. These proteins are enzymes and internal structural proteins of the cell. Chemical Steps in Protein Synthesis. Some of the chemical events that occur in synthesis of a protein molecule are shown in Figure 3–11. This figure shows representative reactions for three separate amino acids, AA1, AA2, and AA20. The stages of the reactions are the following: (1) Each amino acid is activated by a chemical 34 Unit I Transfer RNA Introduction to Physiology: The Cell and General Physiology Messenger RNA Small Ribosome subunit Figure 3–10 Amino acid Amino acid Activated amino acid Large subunit Polypeptide chain AA1 + ATP AA2 + ATP AMP AA1 + tRNA1 AA1 AA20 + ATP AMP AA2 + tRNA2 AMP AA20 + tRNA20 tRNA2 + tRNA20 + AA2 AA20 ¸ Ô Ô ˝ Ô Ô ˛ RNA-amino acyl complex tRNA1 + Physical structure of the ribosomes, as well as their functional relation to messenger RNA, transfer RNA, and the endoplasmic reticulum during the formation of protein molecules. (Courtesy of Dr. Don W. Fawcett, Montana.) Messenger RNA GCC UGU AAU CAU CGU AUG GUU GCC UGU AAU CAU CGU AUG GUU tRNA20 AA20 AA9 AA13 AA3 GTP tRNA13 tRNA3 AA5 GTP GTP AA2 tRNA5 AA1 AA1 AA5 AA3 tRNA2 tRNA1 Protein chain tRNA9 Complex between tRNA, messenger RNA, and amino acid GTP GTP GTP GTP AA9 Figure 3–11 AA2 AA13 AA20 Chemical events in the formation of a protein molecule. process in which ATP combines with the amino acid to form an adenosine monophosphate complex with the amino acid, giving up two high-energy phosphate bonds in the process. (2) The activated amino acid, having an excess of energy, then combines with its specific transfer RNA to form an amino acid–tRNA complex and, at the same time, releases the adenosine monophosphate. (3) The transfer RNA carrying the amino acid complex then comes in contact with the messenger RNA molecule in the ribosome, where the anticodon of the transfer RNA attaches temporarily to its specific codon of the messenger RNA, thus lining up the amino acid in appropriate sequence to form a protein molecule. Then, under the influence of the enzyme peptidyl transferase (one of the proteins in the ribosome), peptide bonds are formed between the successive amino acids, thus adding progressively to the protein chain. These chemical events require energy from two additional high-energy phosphate bonds, making a total of four high-energy bonds used for each amino acid added to the protein chain. Thus, the synthesis of proteins is one of the most energy-consuming processes of the cell. Peptide Linkage. The successive amino acids in the protein chain combine with one another according to the typical reaction: NH2 O R C C OH + H NH2 O R C C H R N C H R N C COOH COOH + H2O Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction 35 In this chemical reaction, a hydroxyl radical (OH–) is removed from the COOH portion of the first amino acid, and a hydrogen (H+) of the NH2 portion of the other amino acid is removed. These combine to form water, and the two reactive sites left on the two successive amino acids bond with each other, resulting in a single molecule. This process is called peptide linkage. As each additional amino acid is added, an additional peptide linkage is formed. There are basically two methods by which the biochemical activities in the cell are controlled. One of these is genetic regulation, in which the degree of activation of the genes themselves is controlled, and the other is enzyme regulation, in which the activity levels of already formed enzymes in the cell are controlled. Synthesis of Other Substances in the Cell The “Operon” of the Cell and Its Control of Biochemical Synthesis—Function of the Promoter. Synthesis of a cellular Genetic Regulation biochemical product usually requires a series of reactions, and each of these reactions is catalyzed by a special protein enzyme. Formation of all the enzymes needed for the synthetic process often is controlled by a sequence of genes located one after the other on the same chromosomal DNA strand. This area of the DNA strand is called an operon, and the genes responsible for forming the respective enzymes are called structural genes. In Figure 3–12, three respective structural genes are shown in an operon, and it is demonstrated that they control the formation of three respective enzymes that in turn cause synthesis of a specific intracellular product. Note in the figure the segment on the DNA strand called the promoter. This is a group of nucleotides that has specific affinity for RNA polymerase, as already discussed. The polymerase must bind with this promoter before it can begin traveling along the DNA strand to synthesize RNA. Therefore, the promoter is an essential element for activating the operon. Many thousand protein enzymes formed in the manner just described control essentially all the other chemical reactions that take place in cells. These enzymes promote synthesis of lipids, glycogen, purines, pyrimidines, and hundreds of other substances. We discuss many of these synthetic processes in relation to carbohydrate, lipid, and protein metabolism in Chapters 67 through 69. It is by means of all these substances that the many functions of the cells are performed. Control of Gene Function and Biochemical Activity in Cells From our discussion thus far, it is clear that the genes control both the physical and the chemical functions of the cells. However, the degree of activation of respective genes must be controlled as well; otherwise, some parts of the cell might overgrow or some chemical reactions might overact until they kill the cell. Each cell has powerful internal feedback control mechanisms that keep the various functional operations of the cell in step with one another. For each gene (more than 30,000 genes in all), there is at least one such feedback mechanism. Control of the Operon by a “Repressor Protein”—The “Repressor Operator.” Also note in Figure 3–12 an addi- tional band of nucleotides lying in the middle of the promoter. This area is called a repressor operator because a “regulatory” protein can bind here and prevent attachment of RNA polymerase to the promoter, thereby blocking transcription of the genes of Activator operator Repressor operator Operon ¸ Ô Ô Ô ˝ Ô Ô Ô ˛ Promoter Figure 3–12 Function of an operon to control synthesis of a non protein intracellular product, such as an intracellular metabolic chemical. Note that the synthesized product exerts negative feedback to inhibit the function of the operon, in this way automatically controlling the concentration of the product itself. Structural Gene A Structural Gene B Enzyme A Enzyme B Structural Gene C Enzyme C Inhibition of the operator Substrates (Negative feedback) Synthesized product 36 Unit I Introduction to Physiology: The Cell and General Physiology this operon. Such a negative regulatory protein is called a repressor protein. Control of the Operon by an “Activator Protein”—The “Activator Operator.” Note in Figure 3–12 another operator, called the activator operator, that lies adjacent to but ahead of the promoter. When a regulatory protein binds to this operator, it helps attract the RNA polymerase to the promoter, in this way activating the operon. Therefore, a regulatory protein of this type is called an activator protein. Negative Feedback Control of the Operon. Finally, note in Figure 3–12 that the presence of a critical amount of a synthesized product in the cell can cause negative feedback inhibition of the operon that is responsible for its synthesis. It can do this either by causing a regulatory repressor protein to bind at the repressor operator or by causing a regulatory activator protein to break its bond with the activator operator. In either case, the operon becomes inhibited. Therefore, once the required synthesized product has become abundant enough for proper cell function, the operon becomes dormant. Conversely, when the synthesized product becomes degraded in the cell and its concentration decreases, the operon once again becomes active. In this way, the desired concentration of the product is controlled automatically. Other Mechanisms for Control of Transcription by the Operon. Variations in the basic mechanism for control of the operon have been discovered with rapidity in the past 2 decades. Without giving details, let us list some of them: 1. An operon frequently is controlled by a regulatory gene located elsewhere in the genetic complex of the nucleus. That is, the regulatory gene causes the formation of a regulatory protein that in turn acts either as an activator or as a repressor substance to control the operon. 2. Occasionally, many different operons are controlled at the same time by the same regulatory protein. In some instances, the same regulatory protein functions as an activator for one operon and as a repressor for another operon. When multiple operons are controlled simultaneously in this manner, all the operons that function together are called a regulon. 3. Some operons are controlled not at the starting point of transcription on the DNA strand but farther along the strand. Sometimes the control is not even at the DNA strand itself but during the processing of the RNA molecules in the nucleus before they are released into the cytoplasm; rarely, control might occur at the level of protein formation in the cytoplasm during RNA translation by the ribosomes. 4. In nucleated cells, the nuclear DNA is packaged in specific structural units, the chromosomes. Within each chromosome, the DNA is wound around small proteins called histones, which in turn are held tightly together in a compacted state by still other proteins. As long as the DNA is in this compacted state, it cannot function to form RNA. However, multiple control mechanisms are beginning to be discovered that can cause selected areas of chromosomes to become decompacted one part at a time so that partial RNA transcription can occur. Even then, some specific “transcriptor factor” controls the actual rate of transcription by the separate operon in the chromosome. Thus, still higher orders of control are used for establishing proper cell function. In addition, signals from outside the cell, such as some of the body’s hormones, can activate specific chromosomal areas and specific transcription factors, thus controlling the chemical machinery for function of the cell. Because there are more than 30,000 different genes in each human cell, the large number of ways in which genetic activity can be controlled is not surprising. The gene control systems are especially important for controlling intracellular concentrations of amino acids, amino acid derivatives, and intermediate substrates and products of carbohydrate, lipid, and protein metabolism. Control of Intracellular Function by Enzyme Regulation In addition to control of cell function by genetic regulation, some cell activities are controlled by intracellular inhibitors or activators that act directly on specific intracellular enzymes. Thus, enzyme regulation represents a second category of mechanisms by which cellular biochemical functions can be controlled. Enzyme Inhibition. Some chemical substances formed in the cell have direct feedback effects in inhibiting the specific enzyme systems that synthesize them. Almost always the synthesized product acts on the first enzyme in a sequence, rather than on the subsequent enzymes, usually binding directly with the enzyme and causing an allosteric conformational change that inactivates it. One can readily recognize the importance of inactivating the first enzyme: this prevents buildup of intermediary products that are not used. Enzyme inhibition is another example of negative feedback control; it is responsible for controlling intracellular concentrations of multiple amino acids, purines, pyrimidines, vitamins, and other substances. Enzyme Activation. Enzymes that are normally inactive often can be activated when needed. An example of this occurs when most of the ATP has been depleted in a cell. In this case, a considerable amount of cyclic adenosine monophosphate (cAMP) begins to be formed as a breakdown product of the ATP; the presence of this cAMP, in turn, immediately activates the glycogen-splitting enzyme phosphorylase, liberating glucose molecules that are rapidly metabolized and their energy used for replenishment of the ATP stores. Thus, cAMP acts as an enzyme activator for the Chapter 3 37 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction enzyme phosphorylase and thereby helps control intracellular ATP concentration. Another interesting instance of both enzyme inhibition and enzyme activation occurs in the formation of the purines and pyrimidines. These substances are needed by the cell in approximately equal quantities for formation of DNA and RNA. When purines are formed, they inhibit the enzymes that are required for formation of additional purines. However, they activate the enzymes for formation of pyrimidines. Conversely, the pyrimidines inhibit their own enzymes but activate the purine enzymes. In this way, there is continual cross-feed between the synthesizing systems for these two substances, resulting in almost exactly equal amounts of the two substances in the cells at all times. Chromosome Centromere Nuclear membrane Nucleolus Aster Centriole A B C D E F G H Summary. In summary, there are two principal methods by which cells control proper proportions and proper quantities of different cellular constituents: (1) the mechanism of genetic regulation and (2) the mechanism of enzyme regulation. The genes can be either activated or inhibited, and likewise, the enzyme systems can be either activated or inhibited. These regulatory mechanisms most often function as feedback control systems that continually monitor the cell’s biochemical composition and make corrections as needed. But on occasion, substances from without the cell (especially some of the hormones discussed throughout this text) also control the intracellular biochemical reactions by activating or inhibiting one or more of the intracellular control systems. Figure 3–13 The DNA-Genetic System Also Controls Cell Reproduction Cell reproduction is another example of the ubiquitous role that the DNA-genetic system plays in all life processes. The genes and their regulatory mechanisms determine the growth characteristics of the cells and also when or whether these cells will divide to form new cells. In this way, the all-important genetic system controls each stage in the development of the human being, from the single-cell fertilized ovum to the whole functioning body. Thus, if there is any central theme to life, it is the DNA-genetic system. Life Cycle of the Cell. The life cycle of a cell is the period from cell reproduction to the next cell reproduction. When mammalian cells are not inhibited and are reproducing as rapidly as they can, this life cycle may be as little as 10 to 30 hours. It is terminated by a series of distinct physical events called mitosis that cause division of the cell into two new daughter cells. The events of mitosis are shown in Figure 3–13 and are described later. The actual stage of mitosis, however, lasts for only about 30 minutes, so that more than 95 per cent of the life cycle of even rapidly reproducing cells is represented by the interval between mitosis, called interphase. Stages of cell reproduction. A, B, and C, Prophase. D, Prometaphase. E, Metaphase. F, Anaphase. G and H, Telophase. (From Margaret C. Gladbach, Estate of Mary E. and Dan Todd, Kansas.) Except in special conditions of rapid cellular reproduction, inhibitory factors almost always slow or stop the uninhibited life cycle of the cell. Therefore, different cells of the body actually have life cycle periods that vary from as little as 10 hours for highly stimulated bone marrow cells to an entire lifetime of the human body for most nerve cells. Cell Reproduction Begins with Replication of DNA As is true of almost all other important events in the cell, reproduction begins in the nucleus itself. The first step is replication (duplication) of all DNA in the chromosomes. Only after this has occurred can mitosis take place. The DNA begins to be duplicated some 5 to 10 hours before mitosis, and this is completed in 4 to 8 hours. The net result is two exact replicas of all DNA. These replicas become the DNA in the two new 38 Unit I Introduction to Physiology: The Cell and General Physiology daughter cells that will be formed at mitosis. After replication of the DNA, there is another period of 1 to 2 hours before mitosis begins abruptly. Even during this period, preliminary changes are beginning to take place that will lead to the mitotic process. Chemical and Physical Events of DNA Replication. DNA is replicated in much the same way that RNA is transcribed in response to DNA, except for a few important differences: 1. Both strands of the DNA in each chromosome are replicated, not simply one of them. 2. Both entire strands of the DNA helix are replicated from end to end, rather than small portions of them, as occurs in the transcription of RNA. 3. The principal enzymes for replicating DNA are a complex of multiple enzymes called DNA polymerase, which is comparable to RNA polymerase. It attaches to and moves along the DNA template strand while another enzyme, DNA ligase, causes bonding of successive DNA nucleotides to one another, using high-energy phosphate bonds to energize these attachments. 4. Formation of each new DNA strand occurs simultaneously in hundreds of segments along each of the two strands of the helix until the entire strand is replicated. Then the ends of the subunits are joined together by the DNA ligase enzyme. 5. Each newly formed strand of DNA remains attached by loose hydrogen bonding to the original DNA strand that was used as its template. Therefore, two DNA helixes are coiled together. 6. Because the DNA helixes in each chromosome are approximately 6 centimeters in length and have millions of helix turns, it would be impossible for the two newly formed DNA helixes to uncoil from each other were it not for some special mechanism. This is achieved by enzymes that periodically cut each helix along its entire length, rotate each segment enough to cause separation, and then resplice the helix. Thus, the two new helixes become uncoiled. DNA Repair, DNA “Proofreading,” and “Mutation.” During the hour or so between DNA replication and the beginning of mitosis, there is a period of very active repair and “proofreading” of the DNA strands. That is, wherever inappropriate DNA nucleotides have been matched up with the nucleotides of the original template strand, special enzymes cut out the defective areas and replace these with appropriate complementary nucleotides. This is achieved by the same DNA polymerases and DNA ligases that are used in replication. This repair process is referred to as DNA proofreading. Because of repair and proofreading, the transcription process rarely makes a mistake. But when a mistake is made, this is called a mutation. The mutation causes formation of some abnormal protein in the cell rather than a needed protein, often leading to abnormal cellular function and sometimes even cell death. Yet, given that there are 30,000 or more genes in the human genome and that the period from one human generation to another is about 30 years, one would expect as many as 10 or many more mutations in the passage of the genome from parent to child. As a further protection, however, each human genome is represented by two separate sets of chromosomes with almost identical genes. Therefore, one functional gene of each pair is almost always available to the child despite mutations. Chromosomes and Their Replication The DNA helixes of the nucleus are packaged in chromosomes. The human cell contains 46 chromosomes arranged in 23 pairs. Most of the genes in the two chromosomes of each pair are identical or almost identical to each other, so it is usually stated that the different genes also exist in pairs, although occasionally this is not the case. In addition to DNA in the chromosome, there is a large amount of protein in the chromosome, composed mainly of many small molecules of electropositively charged histones. The histones are organized into vast numbers of small, bobbin-like cores. Small segments of each DNA helix are coiled sequentially around one core after another. The histone cores play an important role in the regulation of DNA activity because as long as the DNA is packaged tightly, it cannot function as a template for either the formation of RNA or the replication of new DNA. Further, some of the regulatory proteins have been shown to decondense the histone packaging of the DNA and to allow small segments at a time to form RNA. Several nonhistone proteins are also major components of chromosomes, functioning both as chromosomal structural proteins and, in connection with the genetic regulatory machinery, as activators, inhibitors, and enzymes. Replication of the chromosomes in their entirety occurs during the next few minutes after replication of the DNA helixes has been completed; the new DNA helixes collect new protein molecules as needed. The two newly formed chromosomes remain attached to each other (until time for mitosis) at a point called the centromere located near their center. These duplicated but still attached chromosomes are called chromatids. Cell Mitosis The actual process by which the cell splits into two new cells is called mitosis. Once each chromosome has been replicated to form the two chromatids, in many cells, mitosis follows automatically within 1 or 2 hours. Mitotic Apparatus: Function of the Centrioles. One of the first events of mitosis takes place in the cytoplasm, occurring during the latter part of interphase in or Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction around the small structures called centrioles. As shown in Figure 3–13, two pairs of centrioles lie close to each other near one pole of the nucleus. (These centrioles, like the DNA and chromosomes, were also replicated during interphase, usually shortly before replication of the DNA.) Each centriole is a small cylindrical body about 0.4 micrometer long and about 0.15 micrometer in diameter, consisting mainly of nine parallel tubular structures arranged in the form of a cylinder. The two centrioles of each pair lie at right angles to each other. Each pair of centrioles, along with attached pericentriolar material, is called a centrosome. Shortly before mitosis is to take place, the two pairs of centrioles begin to move apart from each other. This is caused by polymerization of protein microtubules growing between the respective centriole pairs and actually pushing them apart. At the same time, other microtubules grow radially away from each of the centriole pairs, forming a spiny star, called the aster, in each end of the cell. Some of the spines of the aster penetrate the nuclear membrane and help separate the two sets of chromatids during mitosis. The complex of microtubules extending between the two new centriole pairs is called the spindle, and the entire set of microtubules plus the two pairs of centrioles is called the mitotic apparatus. Prophase. The first stage of mitosis, called prophase, is shown in Figure 3–13A, B, and C. While the spindle is forming, the chromosomes of the nucleus (which in interphase consist of loosely coiled strands) become condensed into well-defined chromosomes. Prometaphase. During this stage (see Figure 3–13D), the growing microtubular spines of the aster fragment the nuclear envelope. At the same time, multiple microtubules from the aster attach to the chromatids at the centromeres, where the paired chromatids are still bound to each other; the tubules then pull one chromatid of each pair toward one cellular pole and its partner toward the opposite pole. Metaphase. During metaphase (see Figure 3–13E), the two asters of the mitotic apparatus are pushed farther apart. This is believed to occur because the microtubular spines from the two asters, where they interdigitate with each other to form the mitotic spindle, actually push each other away. There is reason to believe that minute contractile protein molecules called “motor molecules,” perhaps composed of the muscle protein actin, extend between the respective spines and, using a stepping action as in muscle, actively slide the spines in a reverse direction along each other. Simultaneously, the chromatids are pulled tightly by their attached microtubules to the very center of the cell, lining up to form the equatorial plate of the mitotic spindle. Anaphase. During this phase (see Figure 3–13F), the two chromatids of each chromosome are pulled apart at the centromere. All 46 pairs of chromatids are separated, forming two separate sets of 46 daughter 39 chromosomes. One of these sets is pulled toward one mitotic aster and the other toward the other aster as the two respective poles of the dividing cell are pushed still farther apart. Telophase. In telophase (see Figure 3–13G and H), the two sets of daughter chromosomes are pushed completely apart. Then the mitotic apparatus dissolutes, and a new nuclear membrane develops around each set of chromosomes. This membrane is formed from portions of the endoplasmic reticulum that are already present in the cytoplasm. Shortly thereafter, the cell pinches in two, midway between the two nuclei. This is caused by formation of a contractile ring of microfilaments composed of actin and probably myosin (the two contractile proteins of muscle) at the juncture of the newly developing cells that pinches them off from each other. Control of Cell Growth and Cell Reproduction We know that certain cells grow and reproduce all the time, such as the blood-forming cells of the bone marrow, the germinal layers of the skin, and the epithelium of the gut. Many other cells, however, such as smooth muscle cells, may not reproduce for many years. A few cells, such as the neurons and most striated muscle cells, do not reproduce during the entire life of a person, except during the original period of fetal life. In certain tissues, an insufficiency of some types of cells causes these to grow and reproduce rapidly until appropriate numbers of them are again available. For instance, in some young animals, seven eighths of the liver can be removed surgically, and the cells of the remaining one eighth will grow and divide until the liver mass returns almost to normal. The same occurs for many glandular cells and most cells of the bone marrow, subcutaneous tissue, intestinal epithelium, and almost any other tissue except highly differentiated cells such as nerve and muscle cells. We know little about the mechanisms that maintain proper numbers of the different types of cells in the body. However, experiments have shown at least three ways in which growth can be controlled. First, growth often is controlled by growth factors that come from other parts of the body. Some of these circulate in the blood, but others originate in adjacent tissues. For instance, the epithelial cells of some glands, such as the pancreas, fail to grow without a growth factor from the sublying connective tissue of the gland. Second, most normal cells stop growing when they have run out of space for growth. This occurs when cells are grown in tissue culture; the cells grow until they contact a solid object, and then growth stops. Third, cells grown in tissue culture often stop growing when minute amounts of their own secretions are allowed to collect in the culture medium. This, too, could provide a means for negative feedback control of growth. 40 Unit I Introduction to Physiology: The Cell and General Physiology Regulation of Cell Size. Cell size is determined almost entirely by the amount of functioning DNA in the nucleus. If replication of the DNA does not occur, the cell grows to a certain size and thereafter remains at that size. Conversely, it is possible, by use of the chemical colchicine, to prevent formation of the mitotic spindle and therefore to prevent mitosis, even though replication of the DNA continues. In this event, the nucleus contains far greater quantities of DNA than it normally does, and the cell grows proportionately larger. It is assumed that this results simply from increased production of RNA and cell proteins, which in turn cause the cell to grow larger. Cell Differentiation A special characteristic of cell growth and cell division is cell differentiation, which refers to changes in physical and functional properties of cells as they proliferate in the embryo to form the different bodily structures and organs. The description of an especially interesting experiment that helps explain these processes follows. When the nucleus from an intestinal mucosal cell of a frog is surgically implanted into a frog ovum from which the original ovum nucleus was removed, the result is often the formation of a normal frog. This demonstrates that even the intestinal mucosal cell, which is a well-differentiated cell, carries all the necessary genetic information for development of all structures required in the frog’s body. Therefore, it has become clear that differentiation results not from loss of genes but from selective repression of different genetic operons. In fact, electron micrographs suggest that some segments of DNA helixes wound around histone cores become so condensed that they no longer uncoil to form RNA molecules. One explanation for this is as follows: It has been supposed that the cellular genome begins at a certain stage of cell differentiation to produce a regulatory protein that forever after represses a select group of genes. Therefore, the repressed genes never function again. Regardless of the mechanism, mature human cells produce a maximum of about 8000 to 10,000 proteins rather than the potential 30,000 or more if all genes were active. Embryological experiments show that certain cells in an embryo control differentiation of adjacent cells. For instance, the primordial chorda-mesoderm is called the primary organizer of the embryo because it forms a focus around which the rest of the embryo develops. It differentiates into a mesodermal axis that contains segmentally arranged somites and, as a result of inductions in the surrounding tissues, causes formation of essentially all the organs of the body. Another instance of induction occurs when the developing eye vesicles come in contact with the ectoderm of the head and cause the ectoderm to thicken into a lens plate that folds inward to form the lens of the eye. Therefore, a large share of the embryo develops as a result of such inductions, one part of the body affecting another part, and this part affecting still other parts. Thus, although our understanding of cell differentiation is still hazy, we know many control mechanisms by which differentiation could occur. Apoptosis—Programmed Cell Death The 100 trillion cells of the body are members of a highly organized community in which the total number of cells is regulated not only by controlling the rate of cell division but also by controlling the rate of cell death. When cells are no longer needed or become a threat to the organism, they undergo a suicidal programmed cell death, or apoptosis. This process involves a specific proteolytic cascade that causes the cell to shrink and condense, to disassemble its cytoskeleton, and to alter its cell surface so that a neighboring phagocytic cell, such as a macrophage, can attach to the cell membrane and digest the cell. In contrast to programmed death, cells that die as a result of an acute injury usually swell and burst due to loss of cell membrane integrity, a process called cell necrosis. Necrotic cells may spill their contents, causing inflammation and injury to neighboring cells. Apoptosis, however, is an orderly cell death that results in disassembly and phagocytosis of the cell before any leakage of its contents occurs, and neighboring cells usually remain healthy. Apoptosis is initiated by activation of a family of proteases called caspases. These are enzymes that are synthesized and stored in the cell as inactive procaspases. The mechanisms of activation of caspases are complex, but once activated, the enzymes cleave and activate other procaspases, triggering a cascade that rapidly breaks down proteins within the cell. The cell thus dismantles itself, and its remains are rapidly digested by neighboring phagocytic cells. A tremendous amount of apoptosis occurs in tissues that are being remodeled during development. Even in adult humans, billions of cells die each hour in tissues such as the intestine and bone marrow and are replaced by new cells. Programmed cell death, however, is precisely balanced with the formation of new cells in healthy adults. Otherwise, the body’s tissues would shrink or grow excessively. Recent studies suggest that abnormalities of apoptosis may play a key role in neurodegenerative diseases such as Alzheimer’s disease, as well as in cancer and autoimmune disorders. Some drugs that have been used successfully for chemotherapy appear to induce apoptosis in cancer cells. Cancer Cancer is caused in all or almost all instances by mutation or by some other abnormal activation of cellular genes that control cell growth and cell mitosis. The Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction abnormal genes are called oncogenes. As many as 100 different oncogenes have been discovered. Also present in all cells are antioncogenes, which suppress the activation of specific oncogenes. Therefore, loss of or inactivation of antioncogenes can allow activation of oncogenes that lead to cancer. Only a minute fraction of the cells that mutate in the body ever lead to cancer. There are several reasons for this. First, most mutated cells have less survival capability than normal cells and simply die. Second, only a few of the mutated cells that do survive become cancerous, because even most mutated cells still have normal feedback controls that prevent excessive growth. Third, those cells that are potentially cancerous are often, if not usually, destroyed by the body’s immune system before they grow into a cancer. This occurs in the following way: Most mutated cells form abnormal proteins within their cell bodies because of their altered genes, and these proteins activate the body’s immune system, causing it to form antibodies or sensitized lymphocytes that react against the cancerous cells, destroying them. In support of this is the fact that in people whose immune systems have been suppressed, such as in those taking immunosuppressant drugs after kidney or heart transplantation, the probability of a cancer’s developing is multiplied as much as fivefold. Fourth, usually several different activated oncogenes are required simultaneously to cause a cancer. For instance, one such gene might promote rapid reproduction of a cell line, but no cancer occurs because there is not a simultaneous mutant gene to form the needed blood vessels. But what is it that causes the altered genes? Considering that many trillions of new cells are formed each year in humans, a better question might be, Why is it that all of us do not develop millions or billions of mutant cancerous cells? The answer is the incredible precision with which DNA chromosomal strands are replicated in each cell before mitosis can take place, and also the proofreading process that cuts and repairs any abnormal DNA strand before the mitotic process is allowed to proceed. Yet, despite all these inherited cellular precautions, probably one newly formed cell in every few million still has significant mutant characteristics. Thus, chance alone is all that is required for mutations to take place, so we can suppose that a large number of cancers are merely the result of an unlucky occurrence. However, the probability of mutations can be increased manyfold when a person is exposed to certain chemical, physical, or biological factors, including the following: 1. It is well known that ionizing radiation, such as x-rays, gamma rays, and particle radiation from radioactive substances, and even ultraviolet light can predispose individuals to cancer. Ions formed in tissue cells under the influence of such radiation are highly reactive and can rupture DNA strands, thus causing many mutations. 41 2. Chemical substances of certain types also have a high propensity for causing mutations. It was discovered long ago that various aniline dye derivatives are likely to cause cancer, so that workers in chemical plants producing such substances, if unprotected, have a special predisposition to cancer. Chemical substances that can cause mutation are called carcinogens. The carcinogens that currently cause the greatest number of deaths are those in cigarette smoke. They cause about one quarter of all cancer deaths. 3. Physical irritants also can lead to cancer, such as continued abrasion of the linings of the intestinal tract by some types of food. The damage to the tissues leads to rapid mitotic replacement of the cells. The more rapid the mitosis, the greater the chance for mutation. 4. In many families, there is a strong hereditary tendency to cancer. This results from the fact that most cancers require not one mutation but two or more mutations before cancer occurs. In those families that are particularly predisposed to cancer, it is presumed that one or more cancerous genes are already mutated in the inherited genome. Therefore, far fewer additional mutations must take place in such family members before a cancer begins to grow. 5. In laboratory animals, certain types of viruses can cause some kinds of cancer, including leukemia. This usually results in one of two ways. In the case of DNA viruses, the DNA strand of the virus can insert itself directly into one of the chromosomes and thereby cause a mutation that leads to cancer. In the case of RNA viruses, some of these carry with them an enzyme called reverse transcriptase that causes DNA to be transcribed from the RNA. The transcribed DNA then inserts itself into the animal cell genome, leading to cancer. Invasive Characteristic of the Cancer Cell. The major differences between the cancer cell and the normal cell are the following: (1) The cancer cell does not respect usual cellular growth limits; the reason for this is that these cells presumably do not require all the same growth factors that are necessary to cause growth of normal cells. (2) Cancer cells often are far less adhesive to one another than are normal cells. Therefore, they have a tendency to wander through the tissues, to enter the blood stream, and to be transported all through the body, where they form nidi for numerous new cancerous growths. (3) Some cancers also produce angiogenic factors that cause many new blood vessels to grow into the cancer, thus supplying the nutrients required for cancer growth. Why Do Cancer Cells Kill? The answer to this question usually is simple. Cancer tissue competes with normal tissues for nutrients. Because cancer cells continue to proliferate indefinitely, their number multiplying day by day, cancer cells soon demand essentially all the 42 Unit I Introduction to Physiology: The Cell and General Physiology nutrition available to the body or to an essential part of the body. As a result, normal tissues gradually suffer nutritive death. References Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell. New York: Garland Science, 2002. Aranda A, Pascal A: Nuclear hormone receptors and gene expression. Physiol Rev 81:1269, 2001. Balmain A, Gray J, Ponder B: The genetics and genomics of cancer. Nat Genet 33(Suppl):238, 2003. Bowen ID, Bowen SM, Jones AH: Mitosis and Apoptosis: Matters of Life and Death. London: Chapman & Hall, 1998. Burke W: Genomics as a probe for disease biology. N Engl J Med 349:969, 2003. Caplen NJ, Mousses S: Short interfering RNA (siRNA)mediated RNA interference (RNAi) in human cells. Ann N Y Acad Sci 1002:56, 2003. Cooke MS, Evans MD, Dizdaroglu M, Lunec J: Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195, 2003. Cullen BR: Nuclear RNA export. J Cell Sci 116:587, 2003. Fedier A, Fink D: Mutations in DNA mismatch repair genes: implications for DNA damage signaling and drug sensitivity. Int J Oncol 24:1039, 2004. Hahn S: Structure and mechanism of the RNA polymerase II transcription machinery. Nat Struct Mol Biol 11:394, 2004. Hall JG: Genomic imprinting: nature and clinical relevance. Annu Rev Med 48:35, 1997. Jockusch BM, Hüttelmaier S, Illenberger S: From the nucleus toward the cell periphery: a guided tour for mRNAs. News Physiol Sci 18:7, 2003. Kazazian HH Jr: Mobile elements: drivers of genome evolution. Science 303:1626, 2004. Lewin B: Genes IV. Oxford: Oxford University Press, 2000. Nabel GJ: Genetic, cellular and immune approaches to disease therapy: past and future. Nat Med 10:135, 2004. Pollard TD, Earnshaw WC: Cell Biology. Philadelphia: Elsevier Science, 2002. U N I Membrane Physiology, Nerve, and Muscle 4. Transport of Substances Through the Cell Membrane 5. Membrane Potentials and Action Potentials 6. Contraction of Skeletal Muscle 7. Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling 8. Contraction and Excitation of Smooth Muscle T II C H A P T E R 4 Transport of Substances Through the Cell Membrane Figure 4–1 gives the approximate concentrations of important electrolytes and other substances in the extracellular fluid and intracellular fluid. Note that the extracellular fluid contains a large amount of sodium but only a small amount of potassium. Exactly the opposite is true of the intracellular fluid. Also, the extracellular fluid contains a large amount of chloride ions, whereas the intracellular fluid contains very little. But the concentrations of phosphates and proteins in the intracellular fluid are considerably greater than those in the extracellular fluid. These differences are extremely important to the life of the cell. The purpose of this chapter is to explain how the differences are brought about by the transport mechanisms of the cell membranes. The Lipid Barrier of the Cell Membrane, and Cell Membrane Transport Proteins The structure of the membrane covering the outside of every cell of the body is discussed in Chapter 2 and illustrated in Figures 2–3 and 4–2. This membrane consists almost entirely of a lipid bilayer, but it also contains large numbers of protein molecules in the lipid, many of which penetrate all the way through the membrane, as shown in Figure 4–2. The lipid bilayer is not miscible with either the extracellular fluid or the intracellular fluid. Therefore, it constitutes a barrier against movement of water molecules and water-soluble substances between the extracellular and intracellular fluid compartments. However, as demonstrated in Figure 4–2 by the leftmost arrow, a few substances can penetrate this lipid bilayer, diffusing directly through the lipid substance itself; this is true mainly of lipid-soluble substances, as described later. The protein molecules in the membrane have entirely different properties for transporting substances. Their molecular structures interrupt the continuity of the lipid bilayer, constituting an alternative pathway through the cell membrane. Most of these penetrating proteins, therefore, can function as transport proteins. Different proteins function differently. Some have watery spaces all the way through the molecule and allow free movement of water as well as selected ions or molecules; these are called channel proteins. Others, called carrier proteins, bind with molecules or ions that are to be transported; conformational changes in the protein molecules then move the substances through the interstices of the protein to the other side of the membrane. Both the channel proteins and the carrier proteins are usually highly selective in the types of molecules or ions that are allowed to cross the membrane. “Diffusion” Versus “Active Transport.” Transport through the cell membrane, either directly through the lipid bilayer or through the proteins, occurs by one of two basic processes: diffusion or active transport. Although there are many variations of these basic mechanisms, diffusion means random molecular movement of substances molecule by molecule, either through intermolecular spaces in the membrane or in combination with a carrier 45 46 Unit II EXTRACELLULAR FLUID Membrane Physiology, Nerve, and Muscle INTRACELLULAR FLUID Na+ --------------- 142 mEq/ L --------- 10 mEq/L K+ ----------------- 4 mEq/ L ------------ 140 mEq/L Ca++ -------------- 2.4 mEq/ L ---------- 0.0001 mEq/L Mg++ -------------- 1.2 mEq/ L ---------- 58 mEq/L Cl – ---------------- 103 mEq/ L --------- 4 mEq/L HCO3– ----------- 28 mEq/ L ----------- 10 mEq/L Phosphates----- 4 mEq/ L -------------75 mEq/L SO4– ------------- 1 mEq/L ------------- 2 mEq/L Glucose --------- 90 mg/dl ------------ 0 to 20 mg/dl Amino acids ---- 30 mg/dl ------------ 200 mg/dl ? Cholesterol Phospholipids Neutral fat 0.5 g/dl-------------- 2 to 95 g/dl PO2 --------------- 35 mm Hg --------- 20 mm Hg ? PCO2 ------------- 46 mm Hg --------- 50 mm Hg ? pH ----------------- 7.4 ------------------- 7.0 Proteins ---------- 2 g/dl ---------------- 16 g/dl (5 mEq/ L) (40 mEq/ L) Figure 4–1 Chemical compositions of extracellular and intracellular fluids. Channel protein Carrier proteins Energy Simple diffusion Facilitated diffusion Diffusion Active transport Figure 4–2 Transport pathways through the cell membrane, and the basic mechanisms of transport. protein. The energy that causes diffusion is the energy of the normal kinetic motion of matter. By contrast, active transport means movement of ions or other substances across the membrane in combination with a carrier protein in such a way that the carrier protein causes the substance to move against an energy gradient, such as from a low-concentration state to a high-concentration state. This movement requires an additional source of energy besides kinetic energy. Following is a more detailed explanation of Figure 4–3 Diffusion of a fluid molecule during a thousandth of a second. the basic physics and physical chemistry of these two processes. Diffusion All molecules and ions in the body fluids, including water molecules and dissolved substances, are in constant motion, each particle moving its own separate way. Motion of these particles is what physicists call “heat”—the greater the motion, the higher the temperature—and the motion never ceases under any condition except at absolute zero temperature. When a moving molecule, A, approaches a stationary molecule, B, the electrostatic and other nuclear forces of molecule A repel molecule B, transferring some of the energy of motion of molecule A to molecule B. Consequently, molecule B gains kinetic energy of motion, while molecule A slows down, losing some of its kinetic energy. Thus, as shown in Figure 4–3, a single molecule in a solution bounces among the other molecules first in one direction, then another, then another, and so forth, randomly bouncing thousands of times each second. This continual movement of molecules among one another in liquids or in gases is called diffusion. Ions diffuse in the same manner as whole molecules, and even suspended colloid particles diffuse in a similar manner, except that the colloids diffuse far less rapidly than molecular substances because of their large size. Diffusion Through the Cell Membrane Diffusion through the cell membrane is divided into two subtypes called simple diffusion and facilitated diffusion. Simple diffusion means that kinetic movement of molecules or ions occurs through a membrane opening or through intermolecular spaces without any interaction with carrier proteins in the membrane. The rate of diffusion is determined by the amount of Chapter 4 47 Transport of Substances Through the Cell Membrane substance available, the velocity of kinetic motion, and the number and sizes of openings in the membrane through which the molecules or ions can move. Facilitated diffusion requires interaction of a carrier protein. The carrier protein aids passage of the molecules or ions through the membrane by binding chemically with them and shuttling them through the membrane in this form. Simple diffusion can occur through the cell membrane by two pathways: (1) through the interstices of the lipid bilayer if the diffusing substance is lipid soluble, and (2) through watery channels that penetrate all the way through some of the large transport proteins, as shown to the left in Figure 4–2. Diffusion of Lipid-Soluble Substances Through the Lipid Bilayer. One of the most important factors that determines how rapidly a substance diffuses through the lipid bilayer is the lipid solubility of the substance. For instance, the lipid solubilities of oxygen, nitrogen, carbon dioxide, and alcohols are high, so that all these can dissolve directly in the lipid bilayer and diffuse through the cell membrane in the same manner that diffusion of water solutes occurs in a watery solution. For obvious reasons, the rate of diffusion of each of these substances through the membrane is directly proportional to its lipid solubility. Especially large amounts of oxygen can be transported in this way; therefore, oxygen can be delivered to the interior of the cell almost as though the cell membrane did not exist. Diffusion of Water and Other Lipid-Insoluble Molecules Through Protein Channels. Even though water is highly insoluble in the membrane lipids, it readily passes through channels in protein molecules that penetrate all the way through the membrane. The rapidity with which water molecules can move through most cell membranes is astounding. As an example, the total amount of water that diffuses in each direction through the red cell membrane during each second is about 100 times as great as the volume of the red cell itself. Other lipid-insoluble molecules can pass through the protein pore channels in the same way as water molecules if they are water soluble and small enough. However, as they become larger, their penetration falls off rapidly. For instance, the diameter of the urea molecule is only 20 per cent greater than that of water, yet its penetration through the cell membrane pores is about 1000 times less than that of water. Even so, given the astonishing rate of water penetration, this amount of urea penetration still allows rapid transport of urea through the membrane within minutes. Diffusion Through Protein Channels, and “Gating” of These Channels Computerized three-dimensional reconstructions of protein channels have demonstrated tubular pathways all the way from the extracellular to the intracellular fluid. Therefore, substances can move by simple diffusion directly along these channels from one side of the membrane to the other. The protein channels are distinguished by two important characteristics: (1) they are often selectively permeable to certain substances, and (2) many of the channels can be opened or closed by gates. Selective Permeability of Protein Channels. Many of the protein channels are highly selective for transport of one or more specific ions or molecules. This results from the characteristics of the channel itself, such as its diameter, its shape, and the nature of the electrical charges and chemical bonds along its inside surfaces. To give an example, one of the most important of the protein channels, the so-called sodium channel, is only 0.3 by 0.5 nanometer in diameter, but more important, the inner surfaces of this channel are strongly negatively charged, as shown by the negative signs inside the channel proteins in the top panel of Figure 4–4. These strong negative charges can pull small dehydrated sodium ions into these channels, actually pulling the sodium ions away from their hydrating water molecules. Once in the channel, the sodium ions diffuse in either direction according to the usual laws of diffusion. Thus, the sodium channel is specifically selective for passage of sodium ions. Conversely, another set of protein channels is selective for potassium transport, shown in the lower panel of Figure 4–4. These channels are slightly smaller than the sodium channels, only 0.3 by 0.3 nanometer, but they are not negatively charged, and their chemical bonds are different. Therefore, no strong attractive force is pulling ions into the channels, and the potassium ions are not pulled away from the water Outside Gate closed Na+ Na+ – – – – – – – – – – – – Gate open – – – – Inside Outside Inside Gate closed Gate open K+ K+ Figure 4–4 Transport of sodium and potassium ions through protein channels. Also shown are conformational changes in the protein molecules to open or close “gates” guarding the channels. Unit II Membrane Physiology, Nerve, and Muscle molecules that hydrate them. The hydrated form of the potassium ion is considerably smaller than the hydrated form of sodium because the sodium ion attracts far more water molecules than does potassium. Therefore, the smaller hydrated potassium ions can pass easily through this small channel, whereas the larger hydrated sodium ions are rejected, thus providing selective permeability for a specific ion. Gating of Protein Channels. Gating of protein channels provides a means of controlling ion permeability of the channels. This is shown in both panels of Figure 4–4 for selective gating of sodium and potassium ions. It is believed that some of the gates are actual gatelike extensions of the transport protein molecule, which can close the opening of the channel or can be lifted away from the opening by a conformational change in the shape of the protein molecule itself. The opening and closing of gates are controlled in two principal ways: 1. Voltage gating. In this instance, the molecular conformation of the gate or of its chemical bonds responds to the electrical potential across the cell membrane. For instance, in the top panel of Figure 4–4, when there is a strong negative charge on the inside of the cell membrane, this presumably could cause the outside sodium gates to remain tightly closed; conversely, when the inside of the membrane loses its negative charge, these gates would open suddenly and allow tremendous quantities of sodium to pass inward through the sodium pores. This is the basic mechanism for eliciting action potentials in nerves that are responsible for nerve signals. In the bottom panel of Figure 4–4, the potassium gates are on the intracellular ends of the potassium channels, and they open when the inside of the cell membrane becomes positively charged. The opening of these gates is partly responsible for terminating the action potential, as is discussed more fully in Chapter 5. 2. Chemical (ligand) gating. Some protein channel gates are opened by the binding of a chemical substance (a ligand) with the protein; this causes a conformational or chemical bonding change in the protein molecule that opens or closes the gate. This is called chemical gating or ligand gating. One of the most important instances of chemical gating is the effect of acetylcholine on the so-called acetylcholine channel. Acetylcholine opens the gate of this channel, providing a negatively charged pore about 0.65 nanometer in diameter that allows uncharged molecules or positive ions smaller than this diameter to pass through. This gate is exceedingly important for the transmission of nerve signals from one nerve cell to another (see Chapter 45) and from nerve cells to muscle cells to cause muscle contraction (see Chapter 7). Open sodium channel 3 Picoamperes 48 0 3 0 0 2 A 4 6 Milliseconds 8 10 Recorder To recorder Membrane “patch” B Figure 4–5 A, Record of current flow through a single voltage-gated sodium channel, demonstrating the “all or none” principle for opening and closing of the channel. B, The “patch-clamp” method for recording current flow through a single protein channel. To the left, recording is performed from a “patch” of a living cell membrane. To the right, recording is from a membrane patch that has been torn away from the cell. Open-State Versus Closed-State of Gated Channels. Figure 4–5A shows an especially interesting characteristic of most voltage-gated channels. This figure shows two recordings of electrical current flowing through a single sodium channel when there was an approximate 25-millivolt potential gradient across the membrane. Note that the channel conducts current either “all or none.” That is, the gate of the channel snaps open and then snaps closed, each open state lasting for only a fraction of a millisecond up to several milliseconds. This demonstrates the rapidity with 49 Transport of Substances Through the Cell Membrane which changes can occur during the opening and closing of the protein molecular gates. At one voltage potential, the channel may remain closed all the time or almost all the time, whereas at another voltage level, it may remain open either all or most of the time. At in-between voltages, as shown in the figure, the gates tend to snap open and closed intermittently, giving an average current flow somewhere between the minimum and the maximum. Patch-Clamp Method for Recording Ion Current Flow Through Single Channels. One might wonder how it is technically possible to record ion current flow through single protein channels as shown in Figure 4–5A. This has been achieved by using the “patch-clamp” method illustrated in Figure 4–5B. Very simply, a micropipette, having a tip diameter of only 1 or 2 micrometers, is abutted against the outside of a cell membrane. Then suction is applied inside the pipette to pull the membrane against the tip of the pipette. This creates a seal where the edges of the pipette touch the cell membrane. The result is a minute membrane “patch” at the tip of the pipette through which electrical current flow can be recorded. Alternatively, as shown to the right in Figure 4–5B, the small cell membrane patch at the end of the pipette can be torn away from the cell. The pipette with its sealed patch is then inserted into a free solution. This allows the concentrations of ions both inside the micropipette and in the outside solution to be altered as desired. Also, the voltage between the two sides of the membrane can be set at will—that is, “clamped” to a given voltage. It has been possible to make such patches small enough so that only a single channel protein is found in the membrane patch being studied. By varying the concentrations of different ions, as well as the voltage across the membrane, one can determine the transport characteristics of the single channel and also its gating properties. Simple diffusion Facilitated diffusion Rate of diffusion Chapter 4 Vmax Concentration of substance Figure 4–6 Effect of concentration of a substance on rate of diffusion through a membrane by simple diffusion and facilitated diffusion. This shows that facilitated diffusion approaches a maximum rate called the Vmax. Transported molecule Binding point Carrier protein and conformational change Facilitated Diffusion Facilitated diffusion is also called carrier-mediated diffusion because a substance transported in this manner diffuses through the membrane using a specific carrier protein to help. That is, the carrier facilitates diffusion of the substance to the other side. Facilitated diffusion differs from simple diffusion in the following important way: Although the rate of simple diffusion through an open channel increases proportionately with the concentration of the diffusing substance, in facilitated diffusion the rate of diffusion approaches a maximum, called Vmax, as the concentration of the diffusing substance increases.This difference between simple diffusion and facilitated diffusion is demonstrated in Figure 4–6. The figure shows that as the concentration of the diffusing substance increases, the rate of simple diffusion continues to increase proportionately, but in the case of facilitated diffusion, the rate of diffusion cannot rise greater than the Vmax level. What is it that limits the rate of facilitated diffusion? A probable answer is the mechanism illustrated in Figure 4–7. This figure shows a carrier protein with a Release of binding Figure 4–7 Postulated mechanism for facilitated diffusion. pore large enough to transport a specific molecule partway through. It also shows a binding “receptor” on the inside of the protein carrier. The molecule to be transported enters the pore and becomes bound. Then, in a fraction of a second, a conformational or chemical change occurs in the carrier protein, so that the pore now opens to the opposite side of the membrane. Because the binding force of the receptor is weak, the thermal motion of the attached molecule causes it to break away and to be released on the opposite side of 50 Unit II Membrane Physiology, Nerve, and Muscle the membrane. The rate at which molecules can be transported by this mechanism can never be greater than the rate at which the carrier protein molecule can undergo change back and forth between its two states. Note specifically, though, that this mechanism allows the transported molecule to move—that is, to “diffuse”—in either direction through the membrane. Among the most important substances that cross cell membranes by facilitated diffusion are glucose and most of the amino acids. In the case of glucose, the carrier molecule has been discovered, and it has a molecular weight of about 45,000; it can also transport several other monosaccharides that have structures similar to that of glucose, including galactose. Also, insulin can increase the rate of facilitated diffusion of glucose as much as 10-fold to 20-fold. This is the principal mechanism by which insulin controls glucose use in the body, as discussed in Chapter 78. Factors That Affect Net Rate of Diffusion By now it is evident that many substances can diffuse through the cell membrane. What is usually important is the net rate of diffusion of a substance in the desired direction. This net rate is determined by several factors. Effect of Concentration Difference on Net Diffusion Through a Membrane. Figure 4–8A shows a cell membrane with a substance in high concentration on the outside and low concentration on the inside. The rate at which the substance diffuses inward is proportional to the concentration of molecules on the outside, because this concentration determines how many molecules strike the outside of the membrane each second. Conversely, the rate at which molecules diffuse outward is proportional to their concentration inside the membrane. Therefore, the rate of net diffusion into the cell is proportional to the concentration on the outside minus the concentration on the inside, or: Net diffusion µ (Co - Ci) in which Co is concentration outside and Ci is concentration inside. Effect of Membrane Electrical Potential on Diffusion of Ions— The “Nernst Potential.” If an electrical potential is applied across the membrane, as shown in Figure 4–8B, the electrical charges of the ions cause them to move through the membrane even though no concentration difference exists to cause movement. Thus, in the left panel of Figure 4–8B, the concentration of negative ions is the same on both sides of the membrane, but a positive charge has been applied to the right side of the membrane and a negative charge to the left, creating an electrical gradient across the membrane. The positive charge attracts the negative ions, whereas the negative charge repels them. Therefore, net diffusion occurs from left to right.After much time, large quantities of negative ions have moved to the Outside Inside Co Ci Membrane A - - - - – - - - - - - - - + – - - - - Piston P1 - + - - - - - - - - - - - B P2 C Figure 4–8 Effect of concentration difference (A), electrical potential difference affecting negative ions (B), and pressure difference (C) to cause diffusion of molecules and ions through a cell membrane. right, creating the condition shown in the right panel of Figure 4–8B, in which a concentration difference of the ions has developed in the direction opposite to the electrical potential difference. The concentration difference now tends to move the ions to the left, while the electrical difference tends to move them to the right. When the concentration difference rises high enough, the two effects balance each other. At normal body temperature (37°C), the electrical difference that will balance a given concentration difference of univalent ions—such as sodium (Na+) ions—can be determined from the following formula, called the Nernst equation: EMF (in millivolts) = ± 61 log C1 C2 in which EMF is the electromotive force (voltage) between side 1 and side 2 of the membrane, C1 is the concentration on side 1, and C2 is the concentration on side 2. This equation is extremely important in understanding the transmission of nerve impulses and is discussed in much greater detail in Chapter 5. Effect of a Pressure Difference Across the Membrane. At times, considerable pressure difference develops Chapter 4 51 Transport of Substances Through the Cell Membrane between the two sides of a diffusible membrane. This occurs, for instance, at the blood capillary membrane in all tissues of the body. The pressure is about 20 mm Hg greater inside the capillary than outside. Pressure actually means the sum of all the forces of the different molecules striking a unit surface area at a given instant. Therefore, when the pressure is higher on one side of a membrane than on the other, this means that the sum of all the forces of the molecules striking the channels on that side of the membrane is greater than on the other side. In most instances, this is caused by greater numbers of molecules striking the membrane per second on one side than on the other side. The result is that increased amounts of energy are available to cause net movement of molecules from the high-pressure side toward the low-pressure side. This effect is demonstrated in Figure 4–8C, which shows a piston developing high pressure on one side of a “pore,” thereby causing more molecules to strike the pore on this side and, therefore, more molecules to “diffuse” to the other side. Osmosis Across Selectively Permeable Membranes— “Net Diffusion” of Water By far the most abundant substance that diffuses through the cell membrane is water. Enough water ordinarily diffuses in each direction through the red cell membrane per second to equal about 100 times the volume of the cell itself. Yet, normally, the amount that diffuses in the two directions is balanced so precisely that zero net movement of water occurs. Therefore, the volume of the cell remains constant. However, under certain conditions, a concentration difference for water can develop across a membrane, just as concentration differences for other substances can occur. When this happens, net movement of water does occur across the cell membrane, causing the cell either to swell or to shrink, depending on the direction of the water movement. This process of net movement of water caused by a concentration difference of water is called osmosis. To give an example of osmosis, let us assume the conditions shown in Figure 4–9, with pure water on one side of the cell membrane and a solution of sodium chloride on the other side. Water molecules pass through the cell membrane with ease, whereas sodium and chloride ions pass through only with difficulty. Therefore, sodium chloride solution is actually a mixture of permeant water molecules and nonpermeant sodium and chloride ions, and the membrane is said to be selectively permeable to water but much less so to sodium and chloride ions. Yet the presence of the sodium and chloride has displaced some of the water molecules on the side of the membrane where these ions are present and, therefore, has reduced the concentration of water molecules to less than that of pure water. As a result, in the example of Figure 4–9, more water molecules strike the channels on the left side, Water NaCl solution Osmosis Figure 4–9 Osmosis at a cell membrane when a sodium chloride solution is placed on one side of the membrane and water is placed on the other side. where there is pure water, than on the right side, where the water concentration has been reduced. Thus, net movement of water occurs from left to right—that is, osmosis occurs from the pure water into the sodium chloride solution. Osmotic Pressure If in Figure 4–9 pressure were applied to the sodium chloride solution, osmosis of water into this solution would be slowed, stopped, or even reversed. The exact amount of pressure required to stop osmosis is called the osmotic pressure of the sodium chloride solution. The principle of a pressure difference opposing osmosis is demonstrated in Figure 4–10, which shows a selectively permeable membrane separating two columns of fluid, one containing pure water and the other containing a solution of water and any solute that will not penetrate the membrane. Osmosis of water from chamber B into chamber A causes the levels of the fluid columns to become farther and farther apart, until eventually a pressure difference develops between the two sides of the membrane great enough to oppose the osmotic effect. The pressure difference across the membrane at this point is equal to the osmotic pressure of the solution that contains the nondiffusible solute. Importance of Number of Osmotic Particles (Molar Concentration) in Determining Osmotic Pressure. The osmotic pres- sure exerted by particles in a solution, whether they are molecules or ions, is determined by the number of particles per unit volume of fluid, not by the mass of the particles. The reason for this is that each particle in a solution, regardless of its mass, exerts, on average, the same amount of pressure against the membrane. That is, large particles, which have greater mass (m) than small particles, move at slower velocities (v). The small particles move at higher velocities in such a way 52 Unit II Membrane Physiology, Nerve, and Muscle osmolality of the extracellular and intracellular fluids is about 300 milliosmoles per kilogram of water. A B Nondiffusible solute Semipermeable membrane Water Relation of Osmolality to Osmotic Pressure. At normal body temperature, 37°C, a concentration of 1 osmole per liter will cause 19,300 mm Hg osmotic pressure in the solution. Likewise, 1 milliosmole per liter concentration is equivalent to 19.3 mm Hg osmotic pressure. Multiplying this value by the 300 milliosmolar concentration of the body fluids gives a total calculated osmotic pressure of the body fluids of 5790 mm Hg. The measured value for this, however, averages only about 5500 mm Hg. The reason for this difference is that many of the ions in the body fluids, such as sodium and chloride ions, are highly attracted to one another; consequently, they cannot move entirely unrestrained in the fluids and create their full osmotic pressure potential. Therefore, on average, the actual osmotic pressure of the body fluids is about 0.93 times the calculated value. The Term “Osmolarity.” Because of the difficulty of meas- Figure 4–10 Demonstration of osmotic pressure caused by osmosis at a semipermeable membrane. that their average kinetic energies (k), determined by the equation k= mv 2 2 are the same for each small particle as for each large particle. Consequently, the factor that determines the osmotic pressure of a solution is the concentration of the solution in terms of number of particles (which is the same as its molar concentration if it is a nondissociated molecule), not in terms of mass of the solute. “Osmolality”—The Osmole. To express the concentration of a solution in terms of numbers of particles, the unit called the osmole is used in place of grams. One osmole is 1 gram molecular weight of osmotically active solute. Thus, 180 grams of glucose, which is 1 gram molecular weight of glucose, is equal to 1 osmole of glucose because glucose does not dissociate into ions. Conversely, if a solute dissociates into two ions, 1 gram molecular weight of the solute will become 2 osmoles because the number of osmotically active particles is now twice as great as is the case for the nondissociated solute. Therefore, when fully dissociated, 1 gram molecular weight of sodium chloride, 58.5 grams, is equal to 2 osmoles. Thus, a solution that has 1 osmole of solute dissolved in each kilogram of water is said to have an osmolality of 1 osmole per kilogram, and a solution that has 1/1000 osmole dissolved per kilogram has an osmolality of 1 milliosmole per kilogram. The normal uring kilograms of water in a solution, which is required to determine osmolality, osmolarity, which is the osmolar concentration expressed as osmoles per liter of solution rather than osmoles per kilogram of water, is used instead. Although, strictly speaking, it is osmoles per kilogram of water (osmolality) that determines osmotic pressure, for dilute solutions such as those in the body, the quantitative differences between osmolarity and osmolality are less than 1 per cent. Because it is far more practical to measure osmolarity than osmolality, this is the usual practice in almost all physiologic studies. “Active Transport” of Substances Through Membranes At times, a large concentration of a substance is required in the intracellular fluid even though the extracellular fluid contains only a small concentration. This is true, for instance, for potassium ions. Conversely, it is important to keep the concentrations of other ions very low inside the cell even though their concentrations in the extracellular fluid are great. This is especially true for sodium ions. Neither of these two effects could occur by simple diffusion, because simple diffusion eventually equilibrates concentrations on the two sides of the membrane. Instead, some energy source must cause excess movement of potassium ions to the inside of cells and excess movement of sodium ions to the outside of cells. When a cell membrane moves molecules or ions “uphill” against a concentration gradient (or “uphill” against an electrical or pressure gradient), the process is called active transport. Different substances that are actively transported through at least some cell membranes include sodium ions, potassium ions, calcium ions, iron ions, hydrogen ions, chloride ions, iodide ions, urate ions, several different sugars, and most of the amino acids. Chapter 4 53 Transport of Substances Through the Cell Membrane Primary Active Transport and Secondary Active Transport. Active transport is divided into two types according to the source of the energy used to cause the transport: primary active transport and secondary active transport. In primary active transport, the energy is derived directly from breakdown of adenosine triphosphate (ATP) or of some other high-energy phosphate compound. In secondary active transport, the energy is derived secondarily from energy that has been stored in the form of ionic concentration differences of secondary molecular or ionic substances between the two sides of a cell membrane, created originally by primary active transport. In both instances, transport depends on carrier proteins that penetrate through the cell membrane, as is true for facilitated diffusion. However, in active transport, the carrier protein functions differently from the carrier in facilitated diffusion because it is capable of imparting energy to the transported substance to move it against the electrochemical gradient. Following are some examples of primary active transport and secondary active transport, with more detailed explanations of their principles of function. Primary Active Transport Sodium-Potassium Pump Among the substances that are transported by primary active transport are sodium, potassium, calcium, hydrogen, chloride, and a few other ions. The active transport mechanism that has been studied in greatest detail is the sodium-potassium (Na+-K+) pump, a transport process that pumps sodium ions outward through the cell membrane of all cells and at the same time pumps potassium ions from the outside to the inside. This pump is responsible for maintaining the sodium and potassium concentration differences across the cell membrane, as well as for establishing a negative electrical voltage inside the cells. Indeed, Chapter 5 shows that this pump is also the basis of nerve function, transmitting nerve signals throughout the nervous system. Figure 4–11 shows the basic physical components of the Na+-K+ pump. The carrier protein is a complex of two separate globular proteins: a larger one called the a subunit, with a molecular weight of about 100,000, and a smaller one called the b subunit, with a molecular weight of about 55,000. Although the function of the smaller protein is not known (except that it might anchor the protein complex in the lipid membrane), the larger protein has three specific features that are important for the functioning of the pump: 1. It has three receptor sites for binding sodium ions on the portion of the protein that protrudes to the inside of the cell. 2. It has two receptor sites for potassium ions on the outside. 3. The inside portion of this protein near the sodium binding sites has ATPase activity. To put the pump into perspective: When two potassium ions bind on the outside of the carrier protein 3Na+ Outside 2K+ ATPase ATP Inside 3Na+ 2K+ ADP + Pi Figure 4–11 Postulated mechanism of the sodium-potassium pump. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, phosphate ion. and three sodium ions bind on the inside, the ATPase function of the protein becomes activated. This then cleaves one molecule of ATP, splitting it to adenosine diphosphate (ADP) and liberating a high-energy phosphate bond of energy. This liberated energy is then believed to cause a chemical and conformational change in the protein carrier molecule, extruding the three sodium ions to the outside and the two potassium ions to the inside. As with other enzymes, the Na+-K+ ATPase pump can run in reverse. If the electrochemical gradients for Na+ and K+ are experimentally increased enough so that the energy stored in their gradients is greater than the chemical energy of ATP hydrolysis, these ions will move down their concentration gradients and the Na+K+ pump will synthesize ATP from ADP and phosphate. The phosphorylated form of the Na+-K+ pump, therefore, can either donate its phosphate to ADP to produce ATP or use the energy to change its conformation and pump Na+ out of the cell and K+ into the cell. The relative concentrations of ATP, ADP, and phosphate, as well as the electrochemical gradients for Na+ and K+, determine the direction of the enzyme reaction. For some cells, such as electrically active nerve cells, 60 to 70 per cent of the cells’ energy requirement may be devoted to pumping Na+ out of the cell and K+ into the cell. Importance of the Na+-K+ Pump for Controlling Cell Volume. One of the most important functions of the Na+-K+ pump is to control the volume of each cell. Without function of this pump, most cells of the body would swell until they burst. The mechanism for controlling the volume is as follows: Inside the cell are large numbers of proteins and other organic molecules that cannot escape from the cell. Most of these are negatively charged and therefore attract large numbers of potassium, sodium, and other positive ions as well. All these molecules and ions then cause osmosis of water to the interior of the cell. Unless this is checked, the 54 Unit II Membrane Physiology, Nerve, and Muscle cell will swell indefinitely until it bursts. The normal mechanism for preventing this is the Na+-K+ pump. Note again that this device pumps three Na+ ions to the outside of the cell for every two K+ ions pumped to the interior. Also, the membrane is far less permeable to sodium ions than to potassium ions, so that once the sodium ions are on the outside, they have a strong tendency to stay there. Thus, this represents a net loss of ions out of the cell, which initiates osmosis of water out of the cell as well. If a cell begins to swell for any reason, this automatically activates the Na+-K+ pump, moving still more ions to the exterior and carrying water with them. Therefore, the Na+-K+ pump performs a continual surveillance role in maintaining normal cell volume. Electrogenic Nature of the Na+-K+ Pump. The fact that the Na+-K+ pump moves three Na+ ions to the exterior for every two K+ ions to the interior means that a net of one positive charge is moved from the interior of the cell to the exterior for each cycle of the pump. This creates positivity outside the cell but leaves a deficit of positive ions inside the cell; that is, it causes negativity on the inside. Therefore, the Na+-K+ pump is said to be electrogenic because it creates an electrical potential across the cell membrane. As discussed in Chapter 5, this electrical potential is a basic requirement in nerve and muscle fibers for transmitting nerve and muscle signals. Primary Active Transport of Calcium Ions Another important primary active transport mechanism is the calcium pump. Calcium ions are normally maintained at extremely low concentration in the intracellular cytosol of virtually all cells in the body, at a concentration about 10,000 times less than that in the extracellular fluid. This is achieved mainly by two primary active transport calcium pumps. One is in the cell membrane and pumps calcium to the outside of the cell. The other pumps calcium ions into one or more of the intracellular vesicular organelles of the cell, such as the sarcoplasmic reticulum of muscle cells and the mitochondria in all cells. In each of these instances, the carrier protein penetrates the membrane and functions as an enzyme ATPase, having the same capability to cleave ATP as the ATPase of the sodium carrier protein. The difference is that this protein has a highly specific binding site for calcium instead of for sodium. Primary Active Transport of Hydrogen Ions At two places in the body, primary active transport of hydrogen ions is very important: (1) in the gastric glands of the stomach, and (2) in the late distal tubules and cortical collecting ducts of the kidneys. In the gastric glands, the deep-lying parietal cells have the most potent primary active mechanism for transporting hydrogen ions of any part of the body. This is the basis for secreting hydrochloric acid in the stomach digestive secretions. At the secretory ends of the gastric gland parietal cells, the hydrogen ion concentration is increased as much as a millionfold and then released into the stomach along with chloride ions to form hydrochloric acid. In the renal tubules are special intercalated cells in the late distal tubules and cortical collecting ducts that also transport hydrogen ions by primary active transport. In this case, large amounts of hydrogen ions are secreted from the blood into the urine for the purpose of eliminating excess hydrogen ions from the body fluids. The hydrogen ions can be secreted into the urine against a concentration gradient of about 900-fold. Energetics of Primary Active Transport The amount of energy required to transport a substance actively through a membrane is determined by how much the substance is concentrated during transport. Compared with the energy required to concentrate a substance 10-fold, to concentrate it 100-fold requires twice as much energy, and to concentrate it 1000-fold requires three times as much energy. In other words, the energy required is proportional to the logarithm of the degree that the substance is concentrated, as expressed by the following formula: Energy (in calories per osmole) = 1400 log C1 C2 Thus, in terms of calories, the amount of energy required to concentrate 1 osmole of substance 10-fold is about 1400 calories; or to concentrate it 100-fold, 2800 calories. One can see that the energy expenditure for concentrating substances in cells or for removing substances from cells against a concentration gradient can be tremendous. Some cells, such as those lining the renal tubules and many glandular cells, expend as much as 90 per cent of their energy for this purpose alone. Secondary Active Transport— Co-Transport and Counter-Transport When sodium ions are transported out of cells by primary active transport, a large concentration gradient of sodium ions across the cell membrane usually develops—high concentration outside the cell and very low concentration inside. This gradient represents a storehouse of energy because the excess sodium outside the cell membrane is always attempting to diffuse to the interior. Under appropriate conditions, this diffusion energy of sodium can pull other substances along with the sodium through the cell membrane.This phenomenon is called co-transport; it is one form of secondary active transport. For sodium to pull another substance along with it, a coupling mechanism is required. This is achieved by means of still another carrier protein in the cell membrane. The carrier in this instance serves as an attachment point for both the sodium ion and the substance to be co-transported. Once they both are attached, the energy gradient of the sodium ion causes both the sodium ion and the other substance to be transported together to the interior of the cell. Chapter 4 Transport of Substances Through the Cell Membrane In counter-transport, sodium ions again attempt to diffuse to the interior of the cell because of their large concentration gradient. However, this time, the substance to be transported is on the inside of the cell and must be transported to the outside. Therefore, the sodium ion binds to the carrier protein where it projects to the exterior surface of the membrane, while the substance to be counter-transported binds to the interior projection of the carrier protein. Once both have bound, a conformational change occurs, and energy released by the sodium ion moving to the interior causes the other substance to move to the exterior. Co-Transport of Glucose and Amino Acids Along with Sodium Ions Glucose and many amino acids are transported into most cells against large concentration gradients; the mechanism of this is entirely by co-transport, as shown in Figure 4–12. Note that the transport carrier protein has two binding sites on its exterior side, one for sodium and one for glucose. Also, the concentration of sodium ions is very high on the outside and very low inside, which provides energy for the transport. A special property of the transport protein is that a conformational change to allow sodium movement to the interior will not occur until a glucose molecule also attaches. When they both become attached, the conformational change takes place automatically, and the sodium and glucose are transported to the inside of the cell at the same time. Hence, this is a sodium-glucose co-transport mechanism. Sodium co-transport of the amino acids occurs in the same manner as for glucose, except that it uses a different set of transport proteins. Five amino acid transport proteins have been identified, each of which is responsible for transporting one subset of amino acids with specific molecular characteristics. Sodium co-transport of glucose and amino acids occurs especially through the epithelial cells of the intestinal tract and the renal tubules of the kidneys to promote absorption of these substances into the blood, as is discussed in later chapters. Na+ Glucose Na-binding site Glucose-binding site Na+ Glucose Figure 4–12 Postulated mechanism for sodium co-transport of glucose. 55 Other important co-transport mechanisms in at least some cells include co-transport of chloride ions, iodine ions, iron ions, and urate ions. Sodium Counter-Transport of Calcium and Hydrogen Ions Two especially important counter-transport mechanisms (transport in a direction opposite to the primary ion) are sodium-calcium counter-transport and sodium-hydrogen counter-transport. Sodium-calcium counter-transport occurs through all or almost all cell membranes, with sodium ions moving to the interior and calcium ions to the exterior, both bound to the same transport protein in a countertransport mode. This is in addition to primary active transport of calcium that occurs in some cells. Sodium-hydrogen counter-transport occurs in several tissues. An especially important example is in the proximal tubules of the kidneys, where sodium ions move from the lumen of the tubule to the interior of the tubular cell, while hydrogen ions are countertransported into the tubule lumen. As a mechanism for concentrating hydrogen ions, counter-transport is not nearly as powerful as the primary active transport of hydrogen ions that occurs in the more distal renal tubules, but it can transport extremely large numbers of hydrogen ions, thus making it a key to hydrogen ion control in the body fluids, as discussed in detail in Chapter 30. Active Transport Through Cellular Sheets At many places in the body, substances must be transported all the way through a cellular sheet instead of simply through the cell membrane. Transport of this type occurs through the (1) intestinal epithelium, (2) epithelium of the renal tubules, (3) epithelium of all exocrine glands, (4) epithelium of the gallbladder, and (5) membrane of the choroid plexus of the brain and other membranes. The basic mechanism for transport of a substance through a cellular sheet is (1) active transport through the cell membrane on one side of the transporting cells in the sheet, and then (2) either simple diffusion or facilitated diffusion through the membrane on the opposite side of the cell. Figure 4–13 shows a mechanism for transport of sodium ions through the epithelial sheet of the intestines, gallbladder, and renal tubules. This figure shows that the epithelial cells are connected together tightly at the luminal pole by means of junctions called “kisses.” The brush border on the luminal surfaces of the cells is permeable to both sodium ions and water. Therefore, sodium and water diffuse readily from the lumen into the interior of the cell. Then, at the basal and lateral membranes of the cells, sodium ions are actively transported into the extracellular fluid of the surrounding connective tissue and blood vessels. This creates a high sodium ion concentration gradient across these membranes, which in turn causes osmosis 56 Unit II Na+ Active transport Osmosis Active transport Na+ Osmosis Active transport Lumen Na+ Na+ References Basement membrane Na+ and H2O Connective tissue Brush border Membrane Physiology, Nerve, and Muscle Osmosis Diffusion Figure 4–13 Basic mechanism of active transport across a layer of cells. of water as well. Thus, active transport of sodium ions at the basolateral sides of the epithelial cells results in transport not only of sodium ions but also of water. These are the mechanisms by which almost all the nutrients, ions, and other substances are absorbed into the blood from the intestine; they are also the way the same substances are reabsorbed from the glomerular filtrate by the renal tubules. Throughout this text are numerous examples of the different types of transport discussed in this chapter. Agre P, Kozono D: Aquaporin water channels: molecular mechanisms for human diseases. FEBS Lett 555:72, 2003. Benos DJ, Stanton BA: Functional domains within the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels. J Physiol 520:631, 1999. Caplan MJ: Ion pump sorting in polarized renal epithelial cells. Kidney Int 60:427, 2001. Decoursey TE: Voltage-gated proton channels and other proton transfer pathways. Physiol Rev 83:475, 2003. De Weer P: A century of thinking about cell membranes. Annu Rev Physiol 62:919, 2000. Dolphin AC: G protein modulation of voltage-gated calcium channels. Pharmacol Rev 55:607, 2003. Jentsch TJ, Stein V, Weinreich F, Zdebik AA: Molecular structure and physiological function of chloride channels. Physiol Rev 82:503, 2002. Kaupp UB, Seifert R: Cyclic nucleotide-gated ion channels. Physiol Rev 82:769, 2002. Kellenberger S, Schild L: Epithelial sodium channel/ degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev 82:735, 2002. MacKinnon R: Potassium channels. FEBS Lett 555:62, 2003. Peres A, Giovannardi S, Bossi E, Fesce R: Electrophysiological insights into the mechanism of ion-coupled cotransporters. News Physiol Sci 19:80, 2004. Philipson KD, Nicoll DA, Ottolia M, et al: The Na+/Ca2+ exchange molecule: an overview. Ann N Y Acad Sci 976:1, 2002. Rossier BC, Pradervand S, Schild L, Hummler E: Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu Rev Physiol 64:877, 2002. Russell JM: Sodium-potassium-chloride cotransport. Physiol Rev 80:211, 2000. C H A P T E R 5 Membrane Potentials and Action Potentials Electrical potentials exist across the membranes of virtually all cells of the body. In addition, some cells, such as nerve and muscle cells, are capable of generating rapidly changing electrochemical impulses at their membranes, and these impulses are used to transmit signals along the nerve or muscle membranes. In still other types of cells, such as glandular cells, macrophages, and ciliated cells, local changes in membrane potentials also activate many of the cells’ functions. The present discussion is concerned with membrane potentials generated both at rest and during action by nerve and muscle cells. Basic Physics of Membrane Potentials Membrane Potentials Caused by Diffusion “Diffusion Potential” Caused by an Ion Concentration Difference on the Two Sides of the Membrane. In Figure 5–1A, the potassium concentration is great inside a nerve fiber membrane but very low outside the membrane. Let us assume that the membrane in this instance is permeable to the potassium ions but not to any other ions. Because of the large potassium concentration gradient from inside toward outside, there is a strong tendency for extra numbers of potassium ions to diffuse outward through the membrane. As they do so, they carry positive electrical charges to the outside, thus creating electropositivity outside the membrane and electronegativity inside because of negative anions that remain behind and do not diffuse outward with the potassium. Within a millisecond or so, the potential difference between the inside and outside, called the diffusion potential, becomes great enough to block further net potassium diffusion to the exterior, despite the high potassium ion concentration gradient. In the normal mammalian nerve fiber, the potential difference required is about 94 millivolts, with negativity inside the fiber membrane. Figure 5–1B shows the same phenomenon as in Figure 5–1A, but this time with high concentration of sodium ions outside the membrane and low sodium inside. These ions are also positively charged. This time, the membrane is highly permeable to the sodium ions but impermeable to all other ions. Diffusion of the positively charged sodium ions to the inside creates a membrane potential of opposite polarity to that in Figure 5–1A, with negativity outside and positivity inside. Again, the membrane potential rises high enough within milliseconds to block further net diffusion of sodium ions to the inside; however, this time, in the mammalian nerve fiber, the potential is about 61 millivolts positive inside the fiber. Thus, in both parts of Figure 5–1, we see that a concentration difference of ions across a selectively permeable membrane can, under appropriate conditions, create a membrane potential. In later sections of this chapter, we show that many of the rapid changes in membrane potentials observed during nerve and muscle impulse transmission result from the occurrence of such rapidly changing diffusion potentials. 57 58 Unit II Membrane Physiology, Nerve, and Muscle DIFFUSION POTENTIALS Nerve fiber (Anions)– Nerve fiber + – – + + – – + (Anions)– (Anions) + – – + + – + – + + – + – + – + + – + – + + + + + K Na K Na – + + – + – + – + + – + – + – + + + – – + (– 94 mV) (+ 61 mV) + – + – + + – + – + – + + – – + + (Anions)– A – – – – – – – – – – B Figure 5–1 A, Establishment of a “diffusion” potential across a nerve fiber membrane, caused by diffusion of potassium ions from inside the cell to outside through a membrane that is selectively permeable only to potassium. B, Establishment of a “diffusion potential” when the nerve fiber membrane is permeable only to sodium ions. Note that the internal membrane potential is negative when potassium ions diffuse and positive when sodium ions diffuse because of opposite concentration gradients of these two ions. Relation of the Diffusion Potential to the Concentration Difference—The Nernst Potential. The diffusion potential level across a membrane that exactly opposes the net diffusion of a particular ion through the membrane is called the Nernst potential for that ion, a term that was introduced in Chapter 4. The magnitude of this Nernst potential is determined by the ratio of the concentrations of that specific ion on the two sides of the membrane. The greater this ratio, the greater the tendency for the ion to diffuse in one direction, and therefore the greater the Nernst potential required to prevent additional net diffusion. The following equation, called the Nernst equation, can be used to calculate the Nernst potential for any univalent ion at normal body temperature of 98.6°F (37°C): EMF (millivolts) = ± 61 log Concentration inside Concentration outside where EMF is electromotive force. When using this formula, it is usually assumed that the potential in the extracellular fluid outside the membrane remains at zero potential, and the Nernst potential is the potential inside the membrane. Also, the sign of the potential is positive (+) if the ion diffusing from inside to outside is a negative ion, and it is negative (–) if the ion is positive. Thus, when the concentration of positive potassium ions on the inside is 10 times that on the outside, the log of 10 is 1, so that the Nernst potential calculates to be –61 millivolts inside the membrane. three factors: (1) the polarity of the electrical charge of each ion, (2) the permeability of the membrane (P) to each ion, and (3) the concentrations (C) of the respective ions on the inside (i) and outside (o) of the membrane. Thus, the following formula, called the Goldman equation, or the Goldman-Hodgkin-Katz equation, gives the calculated membrane potential on the inside of the membrane when two univalent positive ions, sodium (Na+) and potassium (K+), and one univalent negative ion, chloride (Cl–), are involved. EMF (millivolts) C Na +i PNa + + C K +i PK + + CCl - o PCl = -61 ◊ log C Na + o PNa + + C K - o PK + + CCl -i PCl Let us study the importance and the meaning of this equation. First, sodium, potassium, and chloride ions are the most important ions involved in the development of membrane potentials in nerve and muscle fibers, as well as in the neuronal cells in the nervous system. The concentration gradient of each of these ions across the membrane helps determine the voltage of the membrane potential. Second, the degree of importance of each of the ions in determining the voltage is proportional to the membrane permeability for that particular ion.That is, if the membrane has zero permeability to both potassium and chloride ions, the membrane potential becomes entirely dominated by the concentration gradient of sodium ions alone, and the resulting potential will be equal to the Nernst potential for sodium. The same holds for each of the other two ions if the membrane should become selectively permeable for either one of them alone. Third, a positive ion concentration gradient from inside the membrane to the outside causes electronegativity inside the membrane. The reason for this is that excess positive ions diffuse to the outside when their concentration is higher inside than outside.This carries positive charges to the outside but leaves the nondiffusible negative anions on the inside, thus creating electronegativity on the inside. The opposite effect occurs when there is a gradient for a negative ion. That is, a chloride ion gradient from the outside to the inside causes negativity inside the cell because excess negatively charged chloride ions diffuse to the inside, while leaving the nondiffusible positive ions on the outside. Fourth, as explained later, the permeability of the sodium and potassium channels undergoes rapid changes during transmission of a nerve impulse, whereas the permeability of the chloride channels does not change greatly during this process. Therefore, rapid changes in sodium and potassium permeability are primarily responsible for signal transmission in nerves, which is the subject of most of the remainder of this chapter. Calculation of the Diffusion Potential When the Membrane Is Permeable to Several Different Ions Measuring the Membrane Potential When a membrane is permeable to several different ions, the diffusion potential that develops depends on The method for measuring the membrane potential is simple in theory but often difficult in practice because Chapter 5 59 Membrane Potentials and Action Potentials Nerve fiber –+–+–+–+–+–+–+– +–++––+–+––++–+ –+–+–+–+–+–+–+– +–++––+–+––++–+ –+–+–+–+–+–+–+– +–++––+–+––++–+ –+–+–+–+–+–+–+– +–++––+–+––++–+ –+–+–+–+–+–+–+– +–++––+–+––++–+ 0 + I KC +++++++++++ –––––––––– +++++ ––––– Silver–silver chloride electrode – – – – – – – – – (– 90 – – – – – – – + + + + + + + + + mV) + + + + + + + + Electrical potential (millivolts) — 0 –90 Figure 5–2 Measurement of the membrane potential of the nerve fiber using a microelectrode. of the small size of most of the fibers. Figure 5–2 shows a small pipette filled with an electrolyte solution. The pipette is impaled through the cell membrane to the interior of the fiber. Then another electrode, called the “indifferent electrode,” is placed in the extracellular fluid, and the potential difference between the inside and outside of the fiber is measured using an appropriate voltmeter. This voltmeter is a highly sophisticated electronic apparatus that is capable of measuring very small voltages despite extremely high resistance to electrical flow through the tip of the micropipette, which has a lumen diameter usually less than 1 micrometer and a resistance more than a million ohms. For recording rapid changes in the membrane potential during transmission of nerve impulses, the microelectrode is connected to an oscilloscope, as explained later in the chapter. The lower part of Figure 5–3 shows the electrical potential that is measured at each point in or near the nerve fiber membrane, beginning at the left side of the figure and passing to the right. As long as the electrode is outside the nerve membrane, the recorded potential is zero, which is the potential of the extracellular fluid. Then, as the recording electrode passes through the voltage change area at the cell membrane (called the electrical dipole layer), the potential decreases abruptly to –90 millivolts. Moving across the center of the fiber, the potential remains at a steady –90-millivolt level but reverses back to zero the instant it passes through the membrane on the opposite side of the fiber. To create a negative potential inside the membrane, only enough positive ions to develop the electrical dipole layer at the membrane itself must be transported outward. All the remaining ions inside the nerve fiber can be both positive and negative, as shown in the upper panel of Figure 5–3. Therefore, an incredibly small number of ions needs to be transferred through the membrane to establish the normal “resting potential” of –90 millivolts inside the nerve fiber; this means that only about 1/3,000,000 to 1/100,000,000 of the total positive charges inside the fiber needs to be transferred. Also, an Figure 5–3 Distribution of positively and negatively charged ions in the extracellular fluid surrounding a nerve fiber and in the fluid inside the fiber; note the alignment of negative charges along the inside surface of the membrane and positive charges along the outside surface. The lower panel displays the abrupt changes in membrane potential that occur at the membranes on the two sides of the fiber. equally small number of positive ions moving from outside to inside the fiber can reverse the potential from –90 millivolts to as much as +35 millivolts within as little as 1/10,000 of a second. Rapid shifting of ions in this manner causes the nerve signals discussed in subsequent sections of this chapter. Resting Membrane Potential of Nerves The resting membrane potential of large nerve fibers when not transmitting nerve signals is about –90 millivolts. That is, the potential inside the fiber is 90 millivolts more negative than the potential in the extracellular fluid on the outside of the fiber. In the next few paragraphs, we explain all the factors that determine the level of this resting potential, but before doing so, we must describe the transport properties of the resting nerve membrane for sodium and potassium. Active Transport of Sodium and Potassium Ions Through the Membrane—The Sodium-Potassium (Na+-K+) Pump. First, let us recall from Chapter 4 that all cell membranes of the body have a powerful Na+-K+ that continually pumps sodium ions to the outside of the cell and potassium ions to the inside, as illustrated on the left-hand side in Figure 5–4. Further, note that this is an electrogenic pump because more positive charges are pumped to the outside than to the inside (three Na+ ions to the outside for each two K+ ions to the inside), leaving a net deficit of positive ions on the inside; this causes a negative potential inside the cell membrane. 60 Unit II Membrane Physiology, Nerve, and Muscle Outside 3Na+ 2K+ Na+ K+ K+ 4 mEq/L K+ 140 mEq/L (–94 mV) (-94 mV) ATP Na+ K+ + + Na -K pump Na+ ADP K+ K+ -Na+ "leak" channels A Na+ K+ 142 mEq/L 4 mEq/L Na+ 14 mEq/L K+ 140 mEq/L (+61 mV) (–94 mV) Figure 5–4 Functional characteristics of the Na+-K+ pump and of the K+-Na+ “leak” channels. ADP, adenosine diphosphate; ATP, adenosine triphosphate. (–86 mV) B + + Diffusion The Na+-K+ also causes large concentration gradients for sodium and potassium across the resting nerve membrane. These gradients are the following: Na+ Na+ (outside): 142 mEq/L Na+ (inside): 14 mEq/L + K (outside): 4 mEq/L K+ (inside): 140 mEq/L Na K + pump + 4 mEq/L + + + + (Anions)- + K+ + outside /Na = 0.1 + /K outside = 35.0 Leakage of Potassium and Sodium Through the Nerve Membrane. The right side of Figure 5–4 shows a channel protein in the nerve membrane through which potassium and sodium ions can leak, called a potassiumsodium (K+-Na+) “leak” channel. The emphasis is on potassium leakage because, on average, the channels are far more permeable to potassium than to sodium, normally about 100 times as permeable. As discussed later, this differential in permeability is exceedingly important in determining the level of the normal resting membrane potential. Origin of the Normal Resting Membrane Potential Figure 5–5 shows the important factors in the establishment of the normal resting membrane potential of –90 millivolts. They are as follows. Contribution of the Potassium Diffusion Potential. In Figure 5–5A, we make the assumption that the only movement of ions through the membrane is diffusion of potassium ions, as demonstrated by the open channels between the potassium symbols (K+) inside and outside the membrane. Because of the high ratio of potassium ions inside to outside, 35:1, the Nernst - Na+ 14 mEq/L Diffusion The ratios of these two respective ions from the inside to the outside are + inside + inside + pump + 142 mEq/L + + + - K+ 140 mEq/L (–90 mV) (Anions)- - + + + + + + + + + + + + + + + + + + + C Figure 5–5 Establishment of resting membrane potentials in nerve fibers under three conditions: A, when the membrane potential is caused entirely by potassium diffusion alone; B, when the membrane potential is caused by diffusion of both sodium and potassium ions; and C, when the membrane potential is caused by diffusion of both sodium and potassium ions plus pumping of both these ions by the Na+-K+ pump. potential corresponding to this ratio is –94 millivolts because the logarithm of 35 is 1.54, and this times –61 millivolts is –94 millivolts. Therefore, if potassium ions were the only factor causing the resting potential, the resting potential inside the fiber would be equal to –94 millivolts, as shown in the figure. Contribution of Sodium Diffusion Through the Nerve Membrane. Figure 5–5B shows the addition of slight permeability of the nerve membrane to sodium ions, caused by the minute diffusion of sodium ions through the K+-Na+ 61 Membrane Potentials and Action Potentials leak channels. The ratio of sodium ions from inside to outside the membrane is 0.1, and this gives a calculated Nernst potential for the inside of the membrane of +61 millivolts. But also shown in Figure 5–5B is the Nernst potential for potassium diffusion of –94 millivolts. How do these interact with each other, and what will be the summated potential? This can be answered by using the Goldman equation described previously. Intuitively, one can see that if the membrane is highly permeable to potassium but only slightly permeable to sodium, it is logical that the diffusion of potassium contributes far more to the membrane potential than does the diffusion of sodium. In the normal nerve fiber, the permeability of the membrane to potassium is about 100 times as great as its permeability to sodium. Using this value in the Goldman equation gives a potential inside the membrane of –86 millivolts, which is near the potassium potential shown in the figure. 0 — I KC +++++ ––––– –––– ++++ ++++ –––– –––––– ++++++ +35 D ep on Millivolts io n 0 rizati Nerve signals are transmitted by action potentials, which are rapid changes in the membrane potential that spread rapidly along the nerve fiber membrane. Each action potential begins with a sudden change from the normal resting negative membrane potential to a positive potential and then ends with an almost equally rapid change back to the negative potential. To conduct a nerve signal, the action potential moves along the nerve fiber until it comes to the fiber’s end. The upper panel of Figure 5–6 shows the changes that occur at the membrane during the action potential, with transfer of positive charges to the interior of the fiber at its onset and return of positive charges to the exterior at its end. The lower panel shows graphically the successive changes in membrane potential over a few 10,000ths of a second, illustrating the –––– ++++ R e p ola Nerve Action Potential ++++ –––– Silver–silver chloride electrode Overshoot Contribution of the Na+-K+ Pump. In Figure 5–5C, the Na+-K+ pump is shown to provide an additional contribution to the resting potential. In this figure, there is continuous pumping of three sodium ions to the outside for each two potassium ions pumped to the inside of the membrane. The fact that more sodium ions are being pumped to the outside than potassium to the inside causes continual loss of positive charges from inside the membrane; this creates an additional degree of negativity (about –4 millivolts additional) on the inside beyond that which can be accounted for by diffusion alone. Therefore, as shown in Figure 5–5C, the net membrane potential with all these factors operative at the same time is about –90 millivolts. In summary, the diffusion potentials alone caused by potassium and sodium diffusion would give a membrane potential of about –86 millivolts, almost all of this being determined by potassium diffusion. Then, an additional –4 millivolts is contributed to the membrane potential by the continuously acting electrogenic Na+-K+ pump, giving a net membrane potential of –90 millivolts. + o l a ri z a t Chapter 5 –90 Resting 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Milliseconds Figure 5–6 Typical action potential recorded by the method shown in the upper panel of the figure. explosive onset of the action potential and the almost equally rapid recovery. The successive stages of the action potential are as follows. Resting Stage. This is the resting membrane potential before the action potential begins. The membrane is said to be “polarized” during this stage because of the –90 millivolts negative membrane potential that is present. Depolarization Stage. At this time, the membrane sud- denly becomes very permeable to sodium ions, allowing tremendous numbers of positively charged sodium ions to diffuse to the interior of the axon. The normal “polarized” state of –90 millivolts is immediately neutralized by the inflowing positively charged sodium ions, with the potential rising rapidly in the positive direction. This is called depolarization. In large nerve fibers, the great excess of positive sodium ions moving to the inside causes the membrane potential to actually “overshoot” beyond the zero level and to become somewhat positive. In some smaller fibers, as well as in 62 Unit II Membrane Physiology, Nerve, and Muscle many central nervous system neurons, the potential merely approaches the zero level and does not overshoot to the positive state. Repolarization Stage. Within a few 10,000ths of a second after the membrane becomes highly permeable to sodium ions, the sodium channels begin to close and the potassium channels open more than normal. Then, rapid diffusion of potassium ions to the exterior re-establishes the normal negative resting membrane potential. This is called repolarization of the membrane. To explain more fully the factors that cause both depolarization and repolarization, we need to describe the special characteristics of two other types of transport channels through the nerve membrane: the voltage-gated sodium and potassium channels. Voltage-Gated Sodium and Potassium Channels The necessary actor in causing both depolarization and repolarization of the nerve membrane during the action potential is the voltage-gated sodium channel. A voltage-gated potassium channel also plays an important role in increasing the rapidity of repolarization of the membrane. These two voltage-gated channels are in addition to the Na+-K+ pump and the K+-Na+ leak channels. Voltage-Gated Sodium Channel—Activation and Inactivation of the Channel The upper panel of Figure 5–7 shows the voltage-gated sodium channel in three separate states. This channel has two gates—one near the outside of the channel called the activation gate, and another near the inside called the inactivation gate. The upper left of the figure depicts the state of these two gates in the normal resting membrane when the membrane potential is –90 millivolts. In this state, the activation gate is closed, which prevents any entry of sodium ions to the interior of the fiber through these sodium channels. Activation of the Sodium Channel. When the membrane potential becomes less negative than during the resting state, rising from –90 millivolts toward zero, it finally reaches a voltage—usually somewhere between –70 and –50 millivolts—that causes a sudden conformational change in the activation gate, flipping it all the way to the open position. This is called the activated state; during this state, sodium ions can pour inward through the channel, increasing the sodium permeability of the membrane as much as 500- to 5000-fold. Inactivation of the Sodium Channel. The upper right panel of Figure 5–7 shows a third state of the sodium channel. The same increase in voltage that opens the activation gate also closes the inactivation gate. The inactivation gate, however, closes a few 10,000ths of a second after the activation gate opens. That is, the Activation gate Na+ Inactivation gate Resting (-90 mV) Inside Resting (-90 mV) K+ Na+ Na+ Activated (-90 to +35 mV) Inactivated (+35 to -90 mV, delayed) K+ Slow activation (+35 to -90 mV) Figure 5–7 Characteristics of the voltage-gated sodium (top) and potassium (bottom) channels, showing successive activation and inactivation of the sodium channels and delayed activation of the potassium channels when the membrane potential is changed from the normal resting negative value to a positive value. conformational change that flips the inactivation gate to the closed state is a slower process than the conformational change that opens the activation gate. Therefore, after the sodium channel has remained open for a few 10,000ths of a second, the inactivation gate closes, and sodium ions no longer can pour to the inside of the membrane. At this point, the membrane potential begins to recover back toward the resting membrane state, which is the repolarization process. Another important characteristic of the sodium channel inactivation process is that the inactivation gate will not reopen until the membrane potential returns to or near the original resting membrane potential level. Therefore, it usually is not possible for the sodium channels to open again without the nerve fiber’s first repolarizing. Voltage-Gated Potassium Channel and Its Activation The lower panel of Figure 5–7 shows the voltage-gated potassium channel in two states: during the resting state (left) and toward the end of the action potential (right). During the resting state, the gate of the potassium channel is closed, and potassium ions are prevented from passing through this channel to the exterior. When the membrane potential rises from –90 millivolts toward zero, this voltage change causes a conformational opening of the gate and allows increased potassium diffusion outward through the channel. However, because of the slight delay in opening of the potassium channels, for the most part, Membrane Potentials and Action Potentials Chapter 5 they open just at the same time that the sodium channels are beginning to close because of inactivation. Thus, the decrease in sodium entry to the cell and the simultaneous increase in potassium exit from the cell combine to speed the repolarization process, leading to full recovery of the resting membrane potential within another few 10,000ths of a second. Research Method for Measuring the Effect of Voltage on Opening and Closing of the Voltage-Gated Channels—The “Voltage Clamp.” The original research that led to quantitative understanding of the sodium and potassium channels was so ingenious that it led to Nobel Prizes for the scientists responsible, Hodgkin and Huxley. The essence of these studies is shown in Figures 5–8 and 5–9. Amplifier Electrode in fluid Voltage electrode Current electrode Figure 5–8 “Voltage clamp” method for studying flow of ions through specific channels. Activation 30 20 10 0 –90 mV ac In Conductance (mmho/cm2 ) Na+ channel K+ channel ti v at +10 mV Membrane potential 0 1 2 Time (milliseconds) –90 mV 3 Figure 5–9 Typical changes in conductance of sodium and potassium ion channels when the membrane potential is suddenly increased from the normal resting value of –90 millivolts to a positive value of +10 millivolts for 2 milliseconds. This figure shows that the sodium channels open (activate) and then close (inactivate) before the end of the 2 milliseconds, whereas the potassium channels only open (activate), and the rate of opening is much slower than that of the sodium channels. 63 Figure 5–8 shows an experimental apparatus called a voltage clamp, which is used to measure flow of ions through the different channels. In using this apparatus, two electrodes are inserted into the nerve fiber. One of these is to measure the voltage of the membrane potential, and the other is to conduct electrical current into or out of the nerve fiber. This apparatus is used in the following way: The investigator decides which voltage he or she wants to establish inside the nerve fiber. The electronic portion of the apparatus is then adjusted to the desired voltage, and this automatically injects either positive or negative electricity through the current electrode at whatever rate is required to hold the voltage, as measured by the voltage electrode, at the level set by the operator. When the membrane potential is suddenly increased by this voltage clamp from –90 millivolts to zero, the voltage-gated sodium and potassium channels open, and sodium and potassium ions begin to pour through the channels. To counterbalance the effect of these ion movements on the desired setting of the intracellular voltage, electrical current is injected automatically through the current electrode of the voltage clamp to maintain the intracellular voltage at the required steady zero level. To achieve this, the current injected must be equal to but of opposite polarity to the net current flow through the membrane channels. To measure how much current flow is occurring at each instant, the current electrode is connected to an oscilloscope that records the current flow, as demonstrated on the screen of the oscilloscope in Figure 5–8. Finally, the investigator adjusts the concentrations of the ions to other than normal levels both inside and outside the nerve fiber and repeats the study. This can be done easily when using large nerve fibers removed from some crustaceans, especially the giant squid axon, which in some cases is as large as 1 millimeter in diameter. When sodium is the only permeant ion in the solutions inside and outside the squid axon, the voltage clamp measures current flow only through the sodium channels. When potassium is the only permeant ion, current flow only through the potassium channels is measured. Another means for studying the flow of ions through an individual type of channel is to block one type of channel at a time. For instance, the sodium channels can be blocked by a toxin called tetrodotoxin by applying it to the outside of the cell membrane where the sodium activation gates are located. Conversely, tetraethylammonium ion blocks the potassium channels when it is applied to the interior of the nerve fiber. Figure 5–9 shows typical changes in conductance of the voltage-gated sodium and potassium channels when the membrane potential is suddenly changed by use of the voltage clamp from –90 millivolts to +10 millivolts and then, 2 milliseconds later, back to –90 millivolts. Note the sudden opening of the sodium channels (the activation stage) within a small fraction of a millisecond after the membrane potential is increased to the positive value. However, during the next millisecond or so, the sodium channels automatically close (the inactivation stage). Note the opening (activation) of the potassium channels. These open slowly and reach their full open state only after the sodium channels have almost completely closed. Further, once the potassium channels open, they remain open for the entire duration of the positive membrane potential and do not close again until after the membrane potential is decreased back to a negative value. 64 Unit II Membrane Physiology, Nerve, and Muscle Summary of the Events That Cause the Action Potential Figure 5–10 shows in summary form the sequential events that occur during and shortly after the action potential. The bottom of the figure shows the changes in membrane conductance for sodium and potassium ions. During the resting state, before the action potential begins, the conductance for potassium ions is 50 to 100 times as great as the conductance for sodium ions. This is caused by much greater leakage of potassium ions than sodium ions through the leak channels. However, at the onset of the action potential, the sodium channels instantaneously become activated and allow up to a 5000-fold increase in sodium conductance. Then the inactivation process closes the sodium channels within another fraction of a millisecond. The onset of the action potential also causes voltage gating of the potassium channels, causing them to begin opening more slowly a fraction of a millisecond after the sodium channels open. At the end of the action potential, the return of the membrane potential to the negative state causes the potassium channels to close back to their original status, but again, only after an additional millisecond or more delay. The middle portion of Figure 5–10 shows the ratio of sodium conductance to potassium conductance at each instant during the action potential, and above this is the action potential itself. During the early portion of the action potential, the ratio of sodium to potassium conductance increases more than 1000-fold. Therefore, far more sodium ions flow to the interior of the fiber than do potassium ions to the exterior. This is what causes the membrane potential to become positive at the action potential onset. Then the sodium channels begin to close and the potassium channels to open, so that the ratio of conductance shifts far in favor of high potassium conductance but low sodium conductance. This allows very rapid loss of potassium ions to the exterior but virtually zero flow of sodium ions to the interior. Consequently, the action potential quickly returns to its baseline level. Roles of Other Ions During the Action Potential + 60 + 40 + 20 Overshoot Na+ conductance K+ conductance 100 0 –20 –40 –60 –80 –100 10 1 0.1 Positive afterpotential 0.01 0.001 100 Action potential Ratio of conductances Na+ K+ 10 Conductance (mmho/cm2 ) Membrane potential (mV) Thus far, we have considered only the roles of sodium and potassium ions in the generation of the action potential. At least two other types of ions must be considered: negative anions and calcium ions. 1 0.1 0.01 0.005 0 0.5 1.0 Milliseconds 1.5 Figure 5–10 Changes in sodium and potassium conductance during the course of the action potential. Sodium conductance increases several thousand-fold during the early stages of the action potential, whereas potassium conductance increases only about 30-fold during the latter stages of the action potential and for a short period thereafter. (These curves were constructed from theory presented in papers by Hodgkin and Huxley but transposed from squid axon to apply to the membrane potentials of large mammalian nerve fibers.) Impermeant Negatively Charged Ions (Anions) Inside the Nerve Axon. Inside the axon are many negatively charged ions that cannot go through the membrane channels. They include the anions of protein molecules and of many organic phosphate compounds, sulfate compounds, and so forth. Because these ions cannot leave the interior of the axon, any deficit of positive ions inside the membrane leaves an excess of these impermeant negative anions. Therefore, these impermeant negative ions are responsible for the negative charge inside the fiber when there is a net deficit of positively charged potassium ions and other positive ions. Calcium Ions. The membranes of almost all cells of the body have a calcium pump similar to the sodium pump, and calcium serves along with (or instead of) sodium in some cells to cause most of the action potential. Like the sodium pump, the calcium pump pumps calcium ions from the interior to the exterior of the cell membrane (or into the endoplasmic reticulum of the cell), creating a calcium ion gradient of about 10,000-fold. This leaves an internal cell concentration of calcium ions of about 10–7 molar, in contrast to an external concentration of about 10–3 molar. In addition, there are voltage-gated calcium channels. These channels are slightly permeable to sodium ions as well as to calcium ions; when they open, both calcium and sodium ions flow to the interior of the fiber. Therefore, these channels are also called Ca++-Na+ channels. The calcium channels are slow to become activated, requiring 10 to 20 times as long for activation as the sodium channels. Therefore, they are called slow channels, in contrast to the sodium channels, which are called fast channels. Calcium channels are numerous in both cardiac muscle and smooth muscle. In fact, in some types of smooth muscle, the fast sodium channels are hardly Chapter 5 Membrane Potentials and Action Potentials present, so that the action potentials are caused almost entirely by activation of slow calcium channels. Increased Permeability of the Sodium Channels When There Is a Deficit of Calcium Ions. The concentration of calcium ions in the extracellular fluid also has a profound effect on the voltage level at which the sodium channels become activated. When there is a deficit of calcium ions, the sodium channels become activated (opened) by very little increase of the membrane potential from its normal, very negative level. Therefore, the nerve fiber becomes highly excitable, sometimes discharging repetitively without provocation rather than remaining in the resting state. In fact, the calcium ion concentration needs to fall only 50 per cent below normal before spontaneous discharge occurs in some peripheral nerves, often causing muscle “tetany.” This is sometimes lethal because of tetanic contraction of the respiratory muscles. The probable way in which calcium ions affect the sodium channels is as follows: These ions appear to bind to the exterior surfaces of the sodium channel protein molecule. The positive charges of these calcium ions in turn alter the electrical state of the channel protein itself, in this way altering the voltage level required to open the sodium gate. Initiation of the Action Potential fiber from –90 millivolts up to about –65 millivolts usually causes the explosive development of an action potential. This level of –65 millivolts is said to be the threshold for stimulation. Propagation of the Action Potential In the preceding paragraphs, we discussed the action potential as it occurs at one spot on the membrane. However, an action potential elicited at any one point on an excitable membrane usually excites adjacent portions of the membrane, resulting in propagation of the action potential along the membrane. This mechanism is demonstrated in Figure 5–11. Figure 5–11A shows a normal resting nerve fiber, and Figure 5–11B shows a nerve fiber that has been excited in its midportion—that is, the midportion suddenly develops increased permeability to sodium. The arrows show a “local circuit” of current flow from the depolarized areas of the membrane to the adjacent resting membrane areas. That is, positive electrical charges are carried by the inward-diffusing sodium ions through the depolarized membrane and then for several millimeters in both directions along the core of the axon. These positive charges increase the voltage for a distance of 1 to 3 millimeters inside the large myelinated Up to this point, we have explained the changing sodium and potassium permeability of the membrane, as well as the development of the action potential itself, but we have not explained what initiates the action potential. The answer is quite simple. +++++++++++++++++++++++ ––––––––––––––––––––––– A Positive-Feedback Vicious Cycle Opens the Sodium Channels. First, as long as the membrane of the nerve fiber remains undisturbed, no action potential occurs in the normal nerve. However, if any event causes enough initial rise in the membrane potential from –90 millivolts toward the zero level, the rising voltage itself causes many voltage-gated sodium channels to begin opening. This allows rapid inflow of sodium ions, which causes a further rise in the membrane potential, thus opening still more voltage-gated sodium channels and allowing more streaming of sodium ions to the interior of the fiber. This process is a positive-feedback vicious cycle that, once the feedback is strong enough, continues until all the voltage-gated sodium channels have become activated (opened). Then, within another fraction of a millisecond, the rising membrane potential causes closure of the sodium channels as well as opening of potassium channels, and the action potential soon terminates. ––––––––––––––––––––––– +++++++++++++++++++++++ A ++++++++++++––+++++++++ ––––––––––––++––––––––– ––––––––––––++––––––––– + + + +++ + + +++ +– – + + + + + +++ + B ++++++++++––––++++++++ ––– –––– –– – + +++–––––––– ––––––––––++++–––––––– ++++++++++––––++++++++ C ++––––––––––––––––––++ – – + + +++ + + + + + + + + + + + + + – – Threshold for Initiation of the Action Potential. An action potential will not occur until the initial rise in membrane potential is great enough to create the vicious cycle described in the preceding paragraph. This occurs when the number of Na+ ions entering the fiber becomes greater than the number of K+ ions leaving the fiber. A sudden rise in membrane potential of 15 to 30 millivolts usually is required. Therefore, a sudden increase in the membrane potential in a large nerve 65 – – + + +++ + + + + + + + + + + + + + – – ++––––––––––––––––––++ D Figure 5–11 Propagation of action potentials in both directions along a conductive fiber. Unit II Membrane Physiology, Nerve, and Muscle fiber to above the threshold voltage value for initiating an action potential. Therefore, the sodium channels in these new areas immediately open, as shown in Figure 5–11C and D, and the explosive action potential spreads. These newly depolarized areas produce still more local circuits of current flow farther along the membrane, causing progressively more and more depolarization. Thus, the depolarization process travels along the entire length of the fiber. This transmission of the depolarization process along a nerve or muscle fiber is called a nerve or muscle impulse. Direction of Propagation. As demonstrated in Figure 5–11, an excitable membrane has no single direction of propagation, but the action potential travels in all directions away from the stimulus—even along all branches of a nerve fiber—until the entire membrane has become depolarized. All-or-Nothing Principle. Once an action potential has been elicited at any point on the membrane of a normal fiber, the depolarization process travels over the entire membrane if conditions are right, or it does not travel at all if conditions are not right. This is called the all-or-nothing principle, and it applies to all normal excitable tissues. Occasionally, the action potential reaches a point on the membrane at which it does not generate sufficient voltage to stimulate the next area of the membrane. When this occurs, the spread of depolarization stops. Therefore, for continued propagation of an impulse to occur, the ratio of action potential to threshold for excitation must at all times be greater than 1. This “greater than 1” requirement is called the safety factor for propagation. Re-establishing Sodium and Potassium Ionic Gradients After Action Potentials Are Completed—Importance of Energy Metabolism The transmission of each action potential along a nerve fiber reduces very slightly the concentration differences of sodium and potassium inside and outside the membrane, because sodium ions diffuse to the inside during depolarization and potassium ions diffuse to the outside during repolarization. For a single action potential, this effect is so minute that it cannot be measured. Indeed, 100,000 to 50 million impulses can be transmitted by large nerve fibers before the concentration differences reach the point that action potential conduction ceases. Even so, with time, it becomes necessary to re-establish the sodium and potassium membrane concentration differences. This is achieved by action of the Na+-K+ pump in the same way as described previously in the chapter for the original establishment of the resting potential.That is, sodium ions that have diffused to the interior of the cell during the action potentials and potassium ions that have diffused to the exterior must be returned to Heat production 66 At rest 0 100 200 300 Impulses per second Figure 5–12 Heat production in a nerve fiber at rest and at progressively increasing rates of stimulation. their original state by the Na+-K+ pump. Because this pump requires energy for operation, this “recharging” of the nerve fiber is an active metabolic process, using energy derived from the adenosine triphosphate (ATP) energy system of the cell. Figure 5–12 shows that the nerve fiber produces excess heat during recharging, which is a measure of energy expenditure when the nerve impulse frequency increases. A special feature of the Na+-K+ ATPase pump is that its degree of activity is strongly stimulated when excess sodium ions accumulate inside the cell membrane. In fact, the pumping activity increases approximately in proportion to the third power of this intracellular sodium concentration. That is, as the internal sodium concentration rises from 10 to 20 mEq/L, the activity of the pump does not merely double but increases about eightfold. Therefore, it is easy to understand how the “recharging” process of the nerve fiber can be set rapidly into motion whenever the concentration differences of sodium and potassium ions across the membrane begin to “run down.” Plateau in Some Action Potentials In some instances, the excited membrane does not repolarize immediately after depolarization; instead, the potential remains on a plateau near the peak of the spike potential for many milliseconds, and only then does repolarization begin. Such a plateau is shown in Figure 5–13; one can readily see that the plateau greatly prolongs the period of depolarization. This type of action potential occurs in heart muscle fibers, where the plateau lasts for as long as 0.2 to 0.3 second and causes contraction of heart muscle to last for this same long period. The cause of the plateau is a combination of several factors. First, in heart muscle, two types of channels Chapter 5 +60 Plateau +60 +20 +40 0 +20 Millivolts Millivolts +40 67 Membrane Potentials and Action Potentials –20 –40 Rhythmical action Potassium conductance potentials Threshold 0 – 20 –60 – 40 –80 – 60 –100 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Seconds Figure 5–13 Action potential (in millivolts) from a Purkinje fiber of the heart, showing a “plateau.” enter into the depolarization process: (1) the usual voltage-activated sodium channels, called fast channels, and (2) voltage-activated calcium-sodium channels, which are slow to open and therefore are called slow channels. Opening of fast channels causes the spike portion of the action potential, whereas the slow, prolonged opening of the slow calcium-sodium channels mainly allows calcium ions to enter the fiber, which is largely responsible for the plateau portion of the action potential as well. A second factor that may be partly responsible for the plateau is that the voltage-gated potassium channels are slower than usual to open, often not opening very much until the end of the plateau. This delays the return of the membrane potential toward its normal negative value of –80 to –90 millivolts. RHYTHMICITY OF SOME EXCITABLE TISSUES— REPETITIVE DISCHARGE Repetitive self-induced discharges occur normally in the heart, in most smooth muscle, and in many of the neurons of the central nervous system. These rhythmical discharges cause (1) the rhythmical beat of the heart, (2) rhythmical peristalsis of the intestines, and (3) such neuronal events as the rhythmical control of breathing. Also, almost all other excitable tissues can discharge repetitively if the threshold for stimulation of the tissue cells is reduced low enough. For instance, even large nerve fibers and skeletal muscle fibers, which normally are highly stable, discharge repetitively when they are placed in a solution that contains the drug veratrine or when the calcium ion concentration falls 1 2 Seconds 3 Hyperpolarization Figure 5–14 Rhythmical action potentials (in millivolts) similar to those recorded in the rhythmical control center of the heart. Note their relationship to potassium conductance and to the state of hyperpolarization. below a critical value, both of which increase sodium permeability of the membrane. Re-excitation Process Necessary for Spontaneous Rhythmicity. For spontaneous rhythmicity to occur, the membrane even in its natural state must be permeable enough to sodium ions (or to calcium and sodium ions through the slow calcium-sodium channels) to allow automatic membrane depolarization. Thus, Figure 5–14 shows that the “resting” membrane potential in the rhythmical control center of the heart is only –60 to –70 millivolts. This is not enough negative voltage to keep the sodium and calcium channels totally closed. Therefore, the following sequence occurs: (1) some sodium and calcium ions flow inward; (2) this increases the membrane voltage in the positive direction, which further increases membrane permeability; (3) still more ions flow inward; and (4) the permeability increases more, and so on, until an action potential is generated. Then, at the end of the action potential, the membrane repolarizes. After another delay of milliseconds or seconds, spontaneous excitability causes depolarization again, and a new action potential occurs spontaneously. This cycle continues over and over and causes self-induced rhythmical excitation of the excitable tissue. Why does the membrane of the heart control center not depolarize immediately after it has become repolarized, rather than delaying for nearly a second before the onset of the next action potential? The answer can be found by observing the curve labeled “potassium conductance” in Figure 5–14. This shows that toward the end of each action potential, and continuing for a short period thereafter, the membrane becomes excessively permeable to potassium ions. The excessive outflow of potassium ions carries tremendous numbers of positive charges to the outside of the 68 Unit II Membrane Physiology, Nerve, and Muscle Axon Myelin sheath Schwann cell cytoplasm Schwann cell nucleus Node of Ranvier A Figure 5–15 Unmyelinated axons Cross section of a small nerve trunk containing both myelinated and unmyelinated fibers. Schwann cell nucleus Schwann cell cytoplasm membrane, leaving inside the fiber considerably more negativity than would otherwise occur. This continues for nearly a second after the preceding action potential is over, thus drawing the membrane potential nearer to the potassium Nernst potential.This is a state called hyperpolarization, also shown in Figure 5–14.As long as this state exists, self–re-excitation will not occur. But the excess potassium conductance (and the state of hyperpolarization) gradually disappears, as shown after each action potential is completed in the figure, thereby allowing the membrane potential again to increase up to the threshold for excitation. Then, suddenly, a new action potential results, and the process occurs again and again. Special Characteristics of Signal Transmission in Nerve Trunks Myelinated and Unmyelinated Nerve Fibers. Figure 5–15 shows a cross section of a typical small nerve, revealing many large nerve fibers that constitute most of the cross-sectional area. However, a more careful look reveals many more very small fibers lying between the large ones. The large fibers are myelinated, and the small ones are unmyelinated. The average nerve trunk contains about twice as many unmyelinated fibers as myelinated fibers. Figure 5–16 shows a typical myelinated fiber. The central core of the fiber is the axon, and the membrane of the axon is the membrane that actually conducts the action potential. The axon is filled in its center with axoplasm, which is a viscid intracellular fluid. Surrounding the axon is a myelin sheath that is often much thicker than the axon itself. About once every 1 to 3 millimeters along the length of the myelin sheath is a node of Ranvier. B Figure 5–16 Function of the Schwann cell to insulate nerve fibers. A, Wrapping of a Schwann cell membrane around a large axon to form the myelin sheath of the myelinated nerve fiber. B, Partial wrapping of the membrane and cytoplasm of a Schwann cell around multiple unmyelinated nerve fibers (shown in cross section). (A, Modified from Leeson TS, Leeson R: Histology. Philadelphia: WB Saunders, 1979.) The myelin sheath is deposited around the axon by Schwann cells in the following manner: The membrane of a Schwann cell first envelops the axon. Then the Schwann cell rotates around the axon many times, laying down multiple layers of Schwann cell membrane containing the lipid substance sphingomyelin. This substance is an excellent electrical insulator that decreases ion flow through the membrane about 5000-fold. At the juncture between each two successive Schwann cells along the axon, a small uninsulated area only 2 to 3 micrometers in length remains where ions still can flow with ease through the axon membrane between the extracellular fluid and the intracellular fluid inside the axon. This area is called the node of Ranvier. “Saltatory” Conduction in Myelinated Fibers from Node to Node. Even though almost no ions can flow through the thick myelin sheaths of myelinated nerves, they can flow with ease through the nodes of Ranvier. Therefore, action potentials occur only at the nodes. Yet the action potentials are conducted from node to node, as shown in Figure 5–17; this is called saltatory conduction. That is, electrical current flows through the surrounding extracellular fluid outside the myelin sheath as well as through the axoplasm inside the axon from node to node, exciting successive nodes one after another. Thus, Chapter 5 Myelin sheath Axoplasm 69 Membrane Potentials and Action Potentials Node of Ranvier +60 Action potentials +40 Millivolts +20 0 -20 -40 Acute subthreshold potentials Threshold -60 A 1 2 3 0 Figure 5–17 Saltatory conduction along a myelinated axon. Flow of electrical current from node to node is illustrated by the arrows. the nerve impulse jumps down the fiber, which is the origin of the term “saltatory.” Saltatory conduction is of value for two reasons. First, by causing the depolarization process to jump long intervals along the axis of the nerve fiber, this mechanism increases the velocity of nerve transmission in myelinated fibers as much as 5- to 50-fold. Second, saltatory conduction conserves energy for the axon because only the nodes depolarize, allowing perhaps 100 times less loss of ions than would otherwise be necessary, and therefore requiring little metabolism for reestablishing the sodium and potassium concentration differences across the membrane after a series of nerve impulses. Still another feature of saltatory conduction in large myelinated fibers is the following: The excellent insulation afforded by the myelin membrane and the 50fold decrease in membrane capacitance allow repolarization to occur with very little transfer of ions. Velocity of Conduction in Nerve Fibers. The velocity of con- duction in nerve fibers varies from as little as 0.25 m/sec in very small unmyelinated fibers to as great as 100 m/ sec (the length of a football field in 1 second) in very large myelinated fibers. Excitation—The Process of Eliciting the Action Potential Basically, any factor that causes sodium ions to begin to diffuse inward through the membrane in sufficient numbers can set off automatic regenerative opening of the sodium channels. This can result from mechanical disturbance of the membrane, chemical effects on the membrane, or passage of electricity through the membrane. All these are used at different points in the body to elicit nerve or muscle action potentials: mechanical pressure to excite sensory nerve endings in the skin, chemical neurotransmitters to transmit signals from one neuron to the next in the brain, and electrical current to transmit signals between successive muscle cells in the heart and intestine. For the purpose of understanding the excitation process, let us begin by discussing the principles of electrical stimulation. B 1 C 2 3 Milliseconds D 4 Figure 5–18 Effect of stimuli of increasing voltages to elicit an action potential. Note development of “acute subthreshold potentials” when the stimuli are below the threshold value required for eliciting an action potential. Excitation of a Nerve Fiber by a Negatively Charged Metal Electrode. The usual means for exciting a nerve or muscle in the experimental laboratory is to apply electricity to the nerve or muscle surface through two small electrodes, one of which is negatively charged and the other positively charged. When this is done, the excitable membrane becomes stimulated at the negative electrode. The cause of this effect is the following: Remember that the action potential is initiated by the opening of voltage-gated sodium channels. Further, these channels are opened by a decrease in the normal resting electrical voltage across the membrane. That is, negative current from the electrode decreases the voltage on the outside of the membrane to a negative value nearer to the voltage of the negative potential inside the fiber. This decreases the electrical voltage across the membrane and allows the sodium channels to open, resulting in an action potential. Conversely, at the positive electrode, the injection of positive charges on the outside of the nerve membrane heightens the voltage difference across the membrane rather than lessening it. This causes a state of hyperpolarization, which actually decreases the excitability of the fiber rather than causing an action potential. Threshold for Excitation, and “Acute Local Potentials.” A weak negative electrical stimulus may not be able to excite a fiber. However, when the voltage of the stimulus is increased, there comes a point at which excitation does take place. Figure 5–18 shows the effects of successively applied stimuli of progressing strength. A very weak stimulus at point A causes the membrane potential to change from –90 to –85 millivolts, but this is not a sufficient change for the automatic regenerative processes of the action potential to develop. At point B, the stimulus is greater, but again, the intensity is still not enough. The stimulus does, however, disturb the membrane potential locally for as long as 1 millisecond or more after both of these weak stimuli. These local potential changes are called acute local potentials, and when they fail to elicit an action potential, they are called acute subthreshold potentials. 70 Membrane Physiology, Nerve, and Muscle Unit II decrease excitability. For instance, a high extracellular fluid calcium ion concentration decreases membrane permeability to sodium ions and simultaneously reduces excitability. Therefore, calcium ions are said to be a “stabilizer.” At point C in Figure 5–18, the stimulus is even stronger. Now the local potential has barely reached the level required to elicit an action potential, called the threshold level, but this occurs only after a short “latent period.” At point D, the stimulus is still stronger, the acute local potential is also stronger, and the action potential occurs after less of a latent period. Thus, this figure shows that even a very weak stimulus causes a local potential change at the membrane, but the intensity of the local potential must rise to a threshold level before the action potential is set off. Local Anesthetics. Among the most important stabilizers are the many substances used clinically as local anesthetics, including procaine and tetracaine. Most of these act directly on the activation gates of the sodium channels, making it much more difficult for these gates to open, thereby reducing membrane excitability. When excitability has been reduced so low that the ratio of action potential strength to excitability threshold (called the “safety factor”) is reduced below 1.0, nerve impulses fail to pass along the anesthetized nerves. “Refractory Period” After an Action Potential, During Which a New Stimulus Cannot Be Elicited A new action potential cannot occur in an excitable fiber as long as the membrane is still depolarized from the preceding action potential. The reason for this is that shortly after the action potential is initiated, the sodium channels (or calcium channels, or both) become inactivated, and no amount of excitatory signal applied to these channels at this point will open the inactivation gates. The only condition that will allow them to reopen is for the membrane potential to return to or near the original resting membrane potential level. Then, within another small fraction of a second, the inactivation gates of the channels open, and a new action potential can be initiated. The period during which a second action potential cannot be elicited, even with a strong stimulus, is called the absolute refractory period. This period for large myelinated nerve fibers is about 1/2500 second. Therefore, one can readily calculate that such a fiber can transmit a maximum of about 2500 impulses per second. Recording Membrane Potentials and Action Potentials Cathode Ray Oscilloscope. Earlier in this chapter, we noted that the membrane potential changes extremely rapidly during the course of an action potential. Indeed, most of the action potential complex of large nerve fibers takes place in less than 1/1000 second. In some figures of this chapter, an electrical meter has been shown recording these potential changes. However, it must be understood that any meter capable of recording most action potentials must be capable of responding extremely rapidly. For practical purposes, the only common type of meter that is capable of responding accurately to the rapid membrane potential changes is the cathode ray oscilloscope. Figure 5–19 shows the basic components of a cathode ray oscilloscope.The cathode ray tube itself is composed basically of an electron gun and a fluorescent screen against which electrons are fired. Where the electrons hit the screen surface, the fluorescent material glows. If the electron beam is moved across the screen, the spot Inhibition of Excitability— “Stabilizers” and Local Anesthetics In contrast to the factors that increase nerve excitability, still others, called membrane-stabilizing factors, can Recorded action potential Horizontal plates Electron gun Electron beam Plugs Stimulus artifact Vertical plates Electronic sweep circuit Electronic amplifier Electrical stimulator Nerve Figure 5–19 Cathode ray oscilloscope for recording transient action potentials. Chapter 5 Membrane Potentials and Action Potentials of glowing light also moves and draws a fluorescent line on the screen. In addition to the electron gun and fluorescent surface, the cathode ray tube is provided with two sets of electrically charged plates—one set positioned on the two sides of the electron beam, and the other set positioned above and below. Appropriate electronic control circuits change the voltage on these plates so that the electron beam can be bent up or down in response to electrical signals coming from recording electrodes on nerves. The beam of electrons also is swept horizontally across the screen at a constant time rate by an internal electronic circuit of the oscilloscope. This gives the record shown on the face of the cathode ray tube in the figure, giving a time base horizontally and voltage changes from the nerve electrodes shown vertically. Note at the left end of the record a small stimulus artifact caused by the electrical stimulus used to elicit the nerve action potential. Then further to the right is the recorded action potential itself. References Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell. New York: Garland Science, 2002. Grillner S: The motor infrastructure: from ion channels to neuronal networks. Nat Rev Neurosci 4:573, 2003. 71 Hodgkin AL: The Conduction of the Nervous Impulse. Springfield, IL: Charles C Thomas, 1963. Hodgkin AL, Huxley AF: Quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol (Lond) 117:500, 1952. Kleber AG, Rudy Y: Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev 84:431, 2004. Lu Z: Mechanism of rectification in inward-rectifier K+ channels. Annu Rev Physiol 66:103, 2004. Matthews GG: Cellular Physiology of Nerve and Muscle. Malden, MA: Blackwell Science, 1998. Perez-Reyes E: Molecular physiology of low-voltageactivated T-type calcium channels. Physiol Rev 83:117, 2003. Poliak S, Peles E: The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci 12:968, 2003. Pollard TD, Earnshaw WC: Cell Biology. Philadelphia: Elsevier Science, 2002. Ruff RL: Neurophysiology of the neuromuscular junction: overview. Ann N Y Acad Sci 998:1, 2003. Xu-Friedman MA, Regehr WG: Structural contributions to short-term synaptic plasticity. Physiol Rev 84:69, 2004. C H A P T E R Contraction of Skeletal Muscle About 40 per cent of the body is skeletal muscle, and perhaps another 10 per cent is smooth and cardiac muscle. Some of the same basic principles of contraction apply to all these different types of muscle. In this chapter, function of skeletal muscle is considered mainly; the specialized functions of smooth muscle are discussed in Chapter 8, and cardiac muscle is discussed in Chapter 9. Physiologic Anatomy of Skeletal Muscle Skeletal Muscle Fiber Figure 6–1 shows the organization of skeletal muscle, demonstrating that all skeletal muscles are composed of numerous fibers ranging from 10 to 80 micrometers in diameter. Each of these fibers is made up of successively smaller subunits, also shown in Figure 6–1 and described in subsequent paragraphs. In most skeletal muscles, each fiber extends the entire length of the muscle. Except for about 2 per cent of the fibers, each fiber is usually innervated by only one nerve ending, located near the middle of the fiber. Sarcolemma. The sarcolemma is the cell membrane of the muscle fiber. The sarcolemma consists of a true cell membrane, called the plasma membrane, and an outer coat made up of a thin layer of polysaccharide material that contains numerous thin collagen fibrils. At each end of the muscle fiber, this surface layer of the sarcolemma fuses with a tendon fiber, and the tendon fibers in turn collect into bundles to form the muscle tendons that then insert into the bones. Myofibrils; Actin and Myosin Filaments. Each muscle fiber contains several hundred to several thousand myofibrils, which are demonstrated by the many small open dots in the cross-sectional view of Figure 6–1C. Each myofibril (Figure 6–1D and E) is composed of about 1500 adjacent myosin filaments and 3000 actin filaments, which are large polymerized protein molecules that are responsible for the actual muscle contraction.These can be seen in longitudinal view in the electron micrograph of Figure 6–2 and are represented diagrammatically in Figure 6–1, parts E through L. The thick filaments in the diagrams are myosin, and the thin filaments are actin. Note in Figure 6–1E that the myosin and actin filaments partially interdigitate and thus cause the myofibrils to have alternate light and dark bands, as illustrated in Figure 6–2. The light bands contain only actin filaments and are called I bands because they are isotropic to polarized light. The dark bands contain myosin filaments, as well as the ends of the actin filaments where they overlap the myosin, and are called A bands because they are anisotropic to polarized light. Note also the small projections from the sides of the myosin filaments in Figure 6–1E and L. These are cross-bridges. It is the interaction between these cross-bridges and the actin filaments that causes contraction. Figure 6–1E also shows that the ends of the actin filaments are attached to a so-called Z disc. From this disc, these filaments extend in both directions to 72 6 73 Contraction of Skeletal Muscle Chapter 6 SKELETAL MUSCLE Muscle A Muscle fasciculus B C H band Z disc A band Muscle fiber I band Myofibril Z Sarcomere Z D G-Actin molecules H J Myofilaments F-Actin filament K Figure 6–1 Organization of skeletal muscle, from the gross to the molecular level. F, G, H, and I are cross sections at the levels indicated. (Drawing by Sylvia Colard Keene. Modified from Fawcett DW: Bloom and Fawcett: A Textbook of Histology. Philadelphia: WB Saunders, 1986.) L E Myosin filament Myosin molecule M N F G interdigitate with the myosin filaments. The Z disc, which itself is composed of filamentous proteins different from the actin and myosin filaments, passes crosswise across the myofibril and also crosswise from myofibril to myofibril, attaching the myofibrils to one another all the way across the muscle fiber. Therefore, the entire muscle fiber has light and dark bands, as do the individual myofibrils.These bands give skeletal and cardiac muscle their striated appearance. The portion of the myofibril (or of the whole muscle fiber) that lies between two successive Z discs is called a sarcomere. When the muscle fiber is contracted, as shown at the bottom of Figure 6–4, the length of the sarcomere is about 2 micrometers. At this length, the actin filaments completely overlap the myosin filaments, and the tips of the actin filaments are just H I Light meromyosin Heavy meromyosin beginning to overlap one another. We will see later that, at this length, the muscle is capable of generating its greatest force of contraction. What Keeps the Myosin and Actin Filaments in Place? Titin Filamentous Molecules. The side-by-side rela- tionship between the myosin and actin filaments is difficult to maintain. This is achieved by a large number of filamentous molecules of a protein called titin. Each titin molecule has a molecular weight of about 3 million, which makes it one of the largest protein molecules in the body. Also, because it is filamentous, it is very springy. These springy titin molecules act as a framework that holds the myosin and actin filaments in place so that the contractile machinery of the sarcomere will work. There is reason to believe that the 74 Unit II Membrane Physiology, Nerve, and Muscle Figure 6–2 Electron micrograph of muscle myofibrils showing the detailed organization of actin and myosin filaments. Note the mitochondria lying between the myofibrils. (From Fawcett DW: The Cell. Philadelphia: WB Saunders, 1981.) titin molecule itself acts as template for initial formation of portions of the contractile filaments of the sarcomere, especially the myosin filaments. Sarcoplasm. The many myofibrils of each muscle fiber are suspended side by side in the muscle fiber. The spaces between the myofibrils are filled with intracellular fluid called sarcoplasm, containing large quantities of potassium, magnesium, and phosphate, plus multiple protein enzymes. Also present are tremendous numbers of mitochondria that lie parallel to the myofibrils. These supply the contracting myofibrils with large amounts of energy in the form of adenosine triphosphate (ATP) formed by the mitochondria. Sarcoplasmic Reticulum. Also in the sarcoplasm sur- rounding the myofibrils of each muscle fiber is an extensive reticulum (Figure 6–3), called the sarcoplasmic reticulum. This reticulum has a special organization that is extremely important in controlling muscle contraction, as discussed in Chapter 7.The very rapidly contracting types of muscle fibers have especially extensive sarcoplasmic reticula. General Mechanism of Muscle Contraction The initiation and execution of muscle contraction occur in the following sequential steps. 1. An action potential travels along a motor nerve to its endings on muscle fibers. 2. At each ending, the nerve secretes a small amount of the neurotransmitter substance acetylcholine. 3. The acetylcholine acts on a local area of the muscle fiber membrane to open multiple “acetylcholinegated” channels through protein molecules floating in the membrane. Figure 6–3 Sarcoplasmic reticulum in the extracellular spaces between the myofibrils, showing a longitudinal system paralleling the myofibrils. Also shown in cross section are T tubules (arrows) that lead to the exterior of the fiber membrane and are important for conducting the electrical signal into the center of the muscle fiber. (From Fawcett DW: The Cell. Philadelphia: WB Saunders, 1981.) 4. Opening of the acetylcholine-gated channels allows large quantities of sodium ions to diffuse to the interior of the muscle fiber membrane. This initiates an action potential at the membrane. 5. The action potential travels along the muscle fiber membrane in the same way that action potentials travel along nerve fiber membranes. 6. The action potential depolarizes the muscle membrane, and much of the action potential electricity flows through the center of the muscle fiber. Here it causes the sarcoplasmic reticulum to release large quantities of calcium ions that have been stored within this reticulum. 7. The calcium ions initiate attractive forces between the actin and myosin filaments, causing them to slide alongside each other, which is the contractile process. 8. After a fraction of a second, the calcium ions are pumped back into the sarcoplasmic reticulum by a Ca++ membrane pump, and they remain stored in the reticulum until a new muscle action potential comes along; this removal of calcium ions from the myofibrils causes the muscle contraction to cease. We now describe the molecular machinery of the muscle contractile process. Molecular Mechanism of Muscle Contraction Sliding Filament Mechanism of Muscle Contraction. Figure 6–4 demonstrates the basic mechanism of muscle contraction. It shows the relaxed state of a sarcomere (top) and the contracted state (bottom). In the relaxed state, the ends of the actin filaments extending from two successive Z discs barely begin to overlap one another. Conversely, in the contracted state, these actin filaments have been pulled inward among the myosin Chapter 6 I A I Z Head A Z Tail Two heavy chains Relaxed I A Z 75 Contraction of Skeletal Muscle I Light chains Z B Actin filaments Contracted Figure 6–4 Relaxed and contracted states of a myofibril showing (top) sliding of the actin filaments (pink) into the spaces between the myosin filaments (red), and (bottom) pulling of the Z membranes toward each other. filaments, so that their ends overlap one another to their maximum extent. Also, the Z discs have been pulled by the actin filaments up to the ends of the myosin filaments. Thus, muscle contraction occurs by a sliding filament mechanism. But what causes the actin filaments to slide inward among the myosin filaments? This is caused by forces generated by interaction of the cross-bridges from the myosin filaments with the actin filaments. Under resting conditions, these forces are inactive, but when an action potential travels along the muscle fiber, this causes the sarcoplasmic reticulum to release large quantities of calcium ions that rapidly surround the myofibrils. The calcium ions in turn activate the forces between the myosin and actin filaments, and contraction begins. But energy is needed for the contractile process to proceed. This energy comes from highenergy bonds in the ATP molecule, which is degraded to adenosine diphosphate (ADP) to liberate the energy. In the next few sections, we describe what is known about the details of these molecular processes of contraction. Molecular Characteristics of the Contractile Filaments Myosin Filament. The myosin filament is composed of multiple myosin molecules, each having a molecular weight of about 480,000. Figure 6–5A shows an individual molecule; Figure 6–5B shows the organization of many molecules to form a myosin filament, as well as interaction of this filament on one side with the ends of two actin filaments. The myosin molecule (see Figure 6–5A) is composed of six polypeptide chains—two heavy chains, each with a molecular weight of about 200,000, and four light chains with molecular weights of about 20,000 each. Cross-bridges Hinges Body Myosin filament Figure 6–5 A, Myosin molecule. B, Combination of many myosin molecules to form a myosin filament. Also shown are thousands of myosin cross-bridges and interaction between the heads of the crossbridges with adjacent actin filaments. The two heavy chains wrap spirally around each other to form a double helix, which is called the tail of the myosin molecule. One end of each of these chains is folded bilaterally into a globular polypeptide structure called a myosin head. Thus, there are two free heads at one end of the double-helix myosin molecule. The four light chains are also part of the myosin head, two to each head. These light chains help control the function of the head during muscle contraction. The myosin filament is made up of 200 or more individual myosin molecules. The central portion of one of these filaments is shown in Figure 6–5B, displaying the tails of the myosin molecules bundled together to form the body of the filament, while many heads of the molecules hang outward to the sides of the body. Also, part of the body of each myosin molecule hangs to the side along with the head, thus providing an arm that extends the head outward from the body, as shown in the figure. The protruding arms and heads together are called cross-bridges. Each cross-bridge is flexible at two points called hinges—one where the arm leaves the body of the myosin filament, and the other where the head attaches to the arm. The hinged arms allow the heads either to be extended far outward from the body of the myosin filament or to be brought close to the body. The hinged heads in turn participate in the actual contraction process, as discussed in the following sections. The total length of each myosin filament is uniform, almost exactly 1.6 micrometers. Note, however, that there are no cross-bridge heads in the very center of the myosin filament for a distance of about 0.2 micrometer because the hinged arms extend away from the center. 76 Unit II Membrane Physiology, Nerve, and Muscle Now, to complete the picture, the myosin filament itself is twisted so that each successive pair of crossbridges is axially displaced from the previous pair by 120 degrees. This ensures that the cross-bridges extend in all directions around the filament. ATPase Activity of the Myosin Head. Another feature of the myosin head that is essential for muscle contraction is that it functions as an ATPase enzyme. As explained later, this property allows the head to cleave ATP and to use the energy derived from the ATP’s high-energy phosphate bond to energize the contraction process. Actin Filament. The actin filament is also complex. It is composed of three protein components: actin, tropomyosin, and troponin. The backbone of the actin filament is a doublestranded F-actin protein molecule, represented by the two lighter-colored strands in Figure 6–6. The two strands are wound in a helix in the same manner as the myosin molecule. Each strand of the double F-actin helix is composed of polymerized G-actin molecules, each having a molecular weight of about 42,000. Attached to each one of the G-actin molecules is one molecule of ADP. It is believed that these ADP molecules are the active sites on the actin filaments with which the crossbridges of the myosin filaments interact to cause muscle contraction. The active sites on the two F-actin strands of the double helix are staggered, giving one active site on the overall actin filament about every 2.7 nanometers. Each actin filament is about 1 micrometer long. The bases of the actin filaments are inserted strongly into the Z discs; the ends of the filaments protrude in both directions to lie in the spaces between the myosin molecules, as shown in Figure 6–4. Tropomyosin Molecules. The actin filament also con- tains another protein, tropomyosin. Each molecule of tropomyosin has a molecular weight of 70,000 and a length of 40 nanometers. These molecules are wrapped spirally around the sides of the F-actin helix. In the resting state, the tropomyosin molecules lie on top of the active sites of the actin strands, so that attraction Active sites F-actin Troponin complex Tropomyosin Figure 6–6 Actin filament, composed of two helical strands of F-actin molecules and two strands of tropomyosin molecules that fit in the grooves between the actin strands. Attached to one end of each tropomyosin molecule is a troponin complex that initiates contraction. cannot occur between the actin and myosin filaments to cause contraction. Troponin and Its Role in Muscle Contraction. Attached intermittently along the sides of the tropomyosin molecules are still other protein molecules called troponin. These are actually complexes of three loosely bound protein subunits, each of which plays a specific role in controlling muscle contraction. One of the subunits (troponin I) has a strong affinity for actin, another (troponin T) for tropomyosin, and a third (troponin C) for calcium ions. This complex is believed to attach the tropomyosin to the actin. The strong affinity of the troponin for calcium ions is believed to initiate the contraction process, as explained in the next section. Interaction of One Myosin Filament, Two Actin Filaments, and Calcium Ions to Cause Contraction Inhibition of the Actin Filament by the Troponin-Tropomyosin Complex; Activation by Calcium Ions. A pure actin filament without the presence of the troponin-tropomyosin complex (but in the presence of magnesium ions and ATP) binds instantly and strongly with the heads of the myosin molecules. Then, if the troponintropomyosin complex is added to the actin filament, the binding between myosin and actin does not take place. Therefore, it is believed that the active sites on the normal actin filament of the relaxed muscle are inhibited or physically covered by the troponintropomyosin complex. Consequently, the sites cannot attach to the heads of the myosin filaments to cause contraction. Before contraction can take place, the inhibitory effect of the troponin-tropomyosin complex must itself be inhibited. This brings us to the role of the calcium ions. In the presence of large amounts of calcium ions, the inhibitory effect of the troponin-tropomyosin on the actin filaments is itself inhibited. The mechanism of this is not known, but one suggestion is the following: When calcium ions combine with troponin C, each molecule of which can bind strongly with up to four calcium ions, the troponin complex supposedly undergoes a conformational change that in some way tugs on the tropomyosin molecule and moves it deeper into the groove between the two actin strands. This “uncovers” the active sites of the actin, thus allowing these to attract the myosin cross-bridge heads and cause contraction to proceed. Although this is a hypothetical mechanism, it does emphasize that the normal relation between the troponin-tropomyosin complex and actin is altered by calcium ions, producing a new condition that leads to contraction. Interaction Between the “Activated” Actin Filament and the Myosin Cross-Bridges—The “Walk-Along” Theory of Contraction. As soon as the actin filament becomes activated by the calcium ions, the heads of the cross-bridges from the myosin filaments become attracted to the active sites of the actin filament, and this, in some way, causes contraction to occur. Although the precise Chapter 6 Movement Active sites Hinges Contraction of Skeletal Muscle Actin filament Power stroke Myosin filament Figure 6–7 “Walk-along” mechanism for contraction of the muscle. manner by which this interaction between the crossbridges and the actin causes contraction is still partly theoretical, one hypothesis for which considerable evidence exists is the “walk-along” theory (or “ratchet” theory) of contraction. Figure 6–7 demonstrates this postulated walk-along mechanism for contraction.The figure shows the heads of two cross-bridges attaching to and disengaging from active sites of an actin filament. It is postulated that when a head attaches to an active site, this attachment simultaneously causes profound changes in the intramolecular forces between the head and arm of its cross-bridge. The new alignment of forces causes the head to tilt toward the arm and to drag the actin filament along with it. This tilt of the head is called the power stroke. Then, immediately after tilting, the head automatically breaks away from the active site. Next, the head returns to its extended direction. In this position, it combines with a new active site farther down along the actin filament; then the head tilts again to cause a new power stroke, and the actin filament moves another step. Thus, the heads of the crossbridges bend back and forth and step by step walk along the actin filament, pulling the ends of two successive actin filaments toward the center of the myosin filament. Each one of the cross-bridges is believed to operate independently of all others, each attaching and pulling in a continuous repeated cycle. Therefore, the greater the number of cross-bridges in contact with the actin filament at any given time, the greater, theoretically, the force of contraction. ATP as the Source of Energy for Contraction—Chemical Events in the Motion of the Myosin Heads. When a muscle con- tracts, work is performed and energy is required. Large amounts of ATP are cleaved to form ADP during the contraction process; the greater the amount of work performed by the muscle, the greater the amount of ATP that is cleaved, which is called the Fenn effect. The following sequence of events is believed to be the means by which this occurs: 1. Before contraction begins, the heads of the crossbridges bind with ATP. The ATPase activity of the myosin head immediately cleaves the ATP but leaves the cleavage products, ADP plus phosphate 77 ion, bound to the head. In this state, the conformation of the head is such that it extends perpendicularly toward the actin filament but is not yet attached to the actin. 2. When the troponin-tropomyosin complex binds with calcium ions, active sites on the actin filament are uncovered, and the myosin heads then bind with these, as shown in Figure 6–7. 3. The bond between the head of the cross-bridge and the active site of the actin filament causes a conformational change in the head, prompting the head to tilt toward the arm of the cross-bridge. This provides the power stroke for pulling the actin filament. The energy that activates the power stroke is the energy already stored, like a “cocked” spring, by the conformational change that occurred in the head when the ATP molecule was cleaved earlier. 4. Once the head of the cross-bridge tilts, this allows release of the ADP and phosphate ion that were previously attached to the head. At the site of release of the ADP, a new molecule of ATP binds. This binding of new ATP causes detachment of the head from the actin. 5. After the head has detached from the actin, the new molecule of ATP is cleaved to begin the next cycle, leading to a new power stroke. That is, the energy again “cocks” the head back to its perpendicular condition, ready to begin the new power stroke cycle. 6. When the cocked head (with its stored energy derived from the cleaved ATP) binds with a new active site on the actin filament, it becomes uncocked and once again provides a new power stroke. Thus, the process proceeds again and again until the actin filaments pull the Z membrane up against the ends of the myosin filaments or until the load on the muscle becomes too great for further pulling to occur. Effect of Amount of Actin and Myosin Filament Overlap on Tension Developed by the Contracting Muscle Figure 6–8 shows the effect of sarcomere length and amount of myosin-actin filament overlap on the active tension developed by a contracting muscle fiber.To the right, shown in black, are different degrees of overlap of the myosin and actin filaments at different sarcomere lengths. At point D on the diagram, the actin filament has pulled all the way out to the end of the myosin filament, with no actin-myosin overlap. At this point, the tension developed by the activated muscle is zero. Then, as the sarcomere shortens and the actin filament begins to overlap the myosin filament, the tension increases progressively until the sarcomere length decreases to about 2.2 micrometers. At this point, the actin filament has already overlapped all the cross-bridges of the myosin filament but has not yet reached the center of the myosin filament. With 78 Unit II Membrane Physiology, Nerve, and Muscle Normal range of contraction D B C C Tension developed (per cent) B A A 50 D 0 0 Tension during contraction Tension of muscle 100 Increase in tension during contraction Tension before contraction D 0 1/2 normal 1 2 3 4 Length of sarcomere (micrometers) Figure 6–8 Length-tension diagram for a single fully contracted sarcomere, showing maximum strength of contraction when the sarcomere is 2.0 to 2.2 micrometers in length. At the upper right are the relative positions of the actin and myosin filaments at different sarcomere lengths from point A to point D. (Modified from Gordon AM, Huxley AF, Julian FJ: The length-tension diagram of single vertebrate striated muscle fibers. J Physiol 171:28P, 1964.) further shortening, the sarcomere maintains full tension until point B is reached, at a sarcomere length of about 2 micrometers. At this point, the ends of the two actin filaments begin to overlap each other in addition to overlapping the myosin filaments. As the sarcomere length falls from 2 micrometers down to about 1.65 micrometers, at point A, the strength of contraction decreases rapidly. At this point, the two Z discs of the sarcomere abut the ends of the myosin filaments. Then, as contraction proceeds to still shorter sarcomere lengths, the ends of the myosin filaments are crumpled and, as shown in the figure, the strength of contraction approaches zero, but the entire muscle has now contracted to its shortest length. Effect of Muscle Length on Force of Contraction in the Whole Intact Muscle. The top curve of Figure 6–9 is similar to that in Figure 6–8, but the curve in Figure 6–9 depicts tension of the intact, whole muscle rather than of a single muscle fiber. The whole muscle has a large amount of connective tissue in it; also, the sarcomeres in different parts of the muscle do not always contract the same amount. Therefore, the curve has somewhat different dimensions from those shown for the individual muscle fiber, but it exhibits the same general form for the slope in the normal range of contraction, as noted in Figure 6–9. Note in Figure 6–9 that when the muscle is at its normal resting length, which is at a sarcomere length of about 2 micrometers, it contracts upon activation with the approximate maximum force of contraction. However, the increase in tension that occurs during contraction, called active tension, decreases as the Normal Length 2x normal Figure 6–9 Relation of muscle length to tension in the muscle both before and during muscle contraction. muscle is stretched beyond its normal length—that is, to a sarcomere length greater than about 2.2 micrometers. This is demonstrated by the decreased length of the arrow in the figure at greater than normal muscle length. Relation of Velocity of Contraction to Load A skeletal muscle contracts extremely rapidly when it contracts against no load—to a state of full contraction in about 0.1 second for the average muscle. When loads are applied, the velocity of contraction becomes progressively less as the load increases, as shown in Figure 6–10. That is, when the load has been increased to equal the maximum force that the muscle can exert, the velocity of contraction becomes zero and no contraction results, despite activation of the muscle fiber. This decreasing velocity of contraction with load is caused by the fact that a load on a contracting muscle is a reverse force that opposes the contractile force caused by muscle contraction. Therefore, the net force that is available to cause velocity of shortening is correspondingly reduced. Energetics of Muscle Contraction Work Output During Muscle Contraction When a muscle contracts against a load, it performs work. This means that energy is transferred from the muscle to the external load to lift an object to a greater height or to overcome resistance to movement. In mathematical terms, work is defined by the following equation: Velocity of contraction (cm/sec) Chapter 6 Contraction of Skeletal Muscle 30 20 10 0 0 1 2 3 Load-opposing contraction (kg) 4 Figure 6–10 Relation of load to velocity of contraction in a skeletal muscle with a cross section of 1 square centimeter and a length of 8 centimeters. W=L¥D in which W is the work output, L is the load, and D is the distance of movement against the load. The energy required to perform the work is derived from the chemical reactions in the muscle cells during contraction, as described in the following sections. Sources of Energy for Muscle Contraction We have already seen that muscle contraction depends on energy supplied by ATP. Most of this energy is required to actuate the walk-along mechanism by which the cross-bridges pull the actin filaments, but small amounts are required for (1) pumping calcium ions from the sarcoplasm into the sarcoplasmic reticulum after the contraction is over, and (2) pumping sodium and potassium ions through the muscle fiber membrane to maintain appropriate ionic environment for propagation of muscle fiber action potentials. The concentration of ATP in the muscle fiber, about 4 millimolar, is sufficient to maintain full contraction for only 1 to 2 seconds at most.The ATP is split to form ADP, which transfers energy from the ATP molecule to the contracting machinery of the muscle fiber. Then, as described in Chapter 2, the ADP is rephosphorylated to form new ATP within another fraction of a second, which allows the muscle to continue its contraction. There are several sources of the energy for this rephosphorylation. The first source of energy that is used to reconstitute the ATP is the substance phosphocreatine, which carries a high-energy phosphate bond similar to the bonds of ATP. The high-energy phosphate bond of phosphocreatine has a slightly higher amount of free 79 energy than that of each ATP bond, as is discussed more fully in Chapters 67 and 72. Therefore, phosphocreatine is instantly cleaved, and its released energy causes bonding of a new phosphate ion to ADP to reconstitute the ATP. However, the total amount of phosphocreatine in the muscle fiber is also very little— only about five times as great as the ATP. Therefore, the combined energy of both the stored ATP and the phosphocreatine in the muscle is capable of causing maximal muscle contraction for only 5 to 8 seconds. The second important source of energy, which is used to reconstitute both ATP and phosphocreatine, is “glycolysis” of glycogen previously stored in the muscle cells. Rapid enzymatic breakdown of the glycogen to pyruvic acid and lactic acid liberates energy that is used to convert ADP to ATP; the ATP can then be used directly to energize additional muscle contraction and also to re-form the stores of phosphocreatine. The importance of this glycolysis mechanism is twofold. First, the glycolytic reactions can occur even in the absence of oxygen, so that muscle contraction can be sustained for many seconds and sometimes up to more than a minute, even when oxygen delivery from the blood is not available. Second, the rate of formation of ATP by the glycolytic process is about 2.5 times as rapid as ATP formation in response to cellular foodstuffs reacting with oxygen. However, so many end products of glycolysis accumulate in the muscle cells that glycolysis also loses its capability to sustain maximum muscle contraction after about 1 minute. The third and final source of energy is oxidative metabolism. This means combining oxygen with the end products of glycolysis and with various other cellular foodstuffs to liberate ATP. More than 95 per cent of all energy used by the muscles for sustained, longterm contraction is derived from this source. The foodstuffs that are consumed are carbohydrates, fats, and protein. For extremely long-term maximal muscle activity—over a period of many hours—by far the greatest proportion of energy comes from fats, but for periods of 2 to 4 hours, as much as one half of the energy can come from stored carbohydrates. The detailed mechanisms of these energetic processes are discussed in Chapters 67 through 72. In addition, the importance of the different mechanisms of energy release during performance of different sports is discussed in Chapter 84 on sports physiology. Efficiency of Muscle Contraction. The efficiency of an engine or a motor is calculated as the percentage of energy input that is converted into work instead of heat. The percentage of the input energy to muscle (the chemical energy in nutrients) that can be converted into work, even under the best conditions, is less than 25 per cent, with the remainder becoming heat. The reason for this low efficiency is that about one half of the energy in foodstuffs is lost during the formation of ATP, and even then, only 40 to 45 per cent of the energy in the ATP itself can later be converted into work. 80 Unit II Membrane Physiology, Nerve, and Muscle Many features of muscle contraction can be demonstrated by eliciting single muscle twitches. This can be accomplished by instantaneous electrical excitation of the nerve to a muscle or by passing a short electrical stimulus through the muscle itself, giving rise to a single, sudden contraction lasting for a fraction of a second. quadriceps muscle, a half million times as large as the stapedius. Further, the fibers may be as small as 10 micrometers in diameter or as large as 80 micrometers. Finally, the energetics of muscle contraction vary considerably from one muscle to another. Therefore, it is no wonder that the mechanical characteristics of muscle contraction differ among muscles. Figure 6–12 shows records of isometric contractions of three types of skeletal muscle: an ocular muscle, which has a duration of isometric contraction of less than 1/40 second; the gastrocnemius muscle, which has a duration of contraction of about 1/15 second; and the soleus muscle, which has a duration of contraction of about 1/3 second. It is interesting that these durations of contraction are adapted to the functions of the respective muscles. Ocular movements must be extremely rapid to maintain fixation of the eyes on specific objects to provide accuracy of vision. The gastrocnemius muscle must contract moderately rapidly to provide sufficient velocity of limb movement for running and jumping, and the soleus muscle is concerned principally with slow contraction for continual, long-term support of the body against gravity. Isometric Versus Isotonic Contraction. Muscle contraction is Fast Versus Slow Muscle Fibers. As we discuss more fully in said to be isometric when the muscle does not shorten during contraction and isotonic when it does shorten but the tension on the muscle remains constant throughout the contraction. Systems for recording the two types of muscle contraction are shown in Figure 6–11. In the isometric system, the muscle contracts against a force transducer without decreasing the muscle length, as shown on the right in Figure 6–11. In the isotonic system, the muscle shortens against a fixed load; this is illustrated on the left in the figure, showing a muscle lifting a pan of weights. The characteristics of isotonic contraction depend on the load against which the muscle contracts, as well as the inertia of the load. However, the isometric system records strictly changes in force of muscle contraction itself. Therefore, the isometric system is most often used when comparing the functional characteristics of different muscle types. Chapter 84 on sports physiology, every muscle of the body is composed of a mixture of so-called fast and slow muscle fibers, with still other fibers gradated between these two extremes. The muscles that react rapidly are composed mainly of “fast” fibers with only small numbers of the slow variety. Conversely, the muscles that respond slowly but with prolonged contraction are composed mainly of “slow” fibers. The differences between these two types of fibers are as follows. Maximum efficiency can be realized only when the muscle contracts at a moderate velocity. If the muscle contracts slowly or without any movement, small amounts of maintenance heat are released during contraction, even though little or no work is performed, thereby decreasing the conversion efficiency to as little as zero. Conversely, if contraction is too rapid, large proportions of the energy are used to overcome viscous friction within the muscle itself, and this, too, reduces the efficiency of contraction. Ordinarily, maximum efficiency is developed when the velocity of contraction is about 30 per cent of maximum. Characteristics of Whole Muscle Contraction Fast Fibers. (1) Large fibers for great strength of con- traction. (2) Extensive sarcoplasmic reticulum for rapid release of calcium ions to initiate contraction. (3) Large amounts of glycolytic enzymes for rapid release of energy by the glycolytic process. (4) Less extensive blood supply because oxidative metabolism is of Characteristics of Isometric Twitches Recorded from Different Muscles. The human body has many sizes of skeletal muscles—from the very small stapedius muscle in the middle ear, measuring only a few millimeters long and a millimeter or so in diameter, up to the very large Kymograph Stimulating electrodes Muscle Weights Electronic force transducer Force of contraction Stimulating electrodes Duration of depolarization Soleus Gastrocnemius Ocular muscle 0 40 80 120 160 200 Milliseconds To electronic recorder ISOTONIC SYSTEM ISOMETRIC SYSTEM Figure 6–11 Isotonic and isometric systems for recording muscle contractions. Figure 6–12 Duration of isometric contractions for different types of mammalian skeletal muscles, showing a latent period between the action potential (depolarization) and muscle contraction. Chapter 6 81 Contraction of Skeletal Muscle Slow Fibers. (1) Smaller fibers. (2) Also innervated by smaller nerve fibers. (3) More extensive blood vessel system and capillaries to supply extra amounts of oxygen. (4) Greatly increased numbers of mitochondria, also to support high levels of oxidative metabolism. (5) Fibers contain large amounts of myoglobin, an ironcontaining protein similar to hemoglobin in red blood cells. Myoglobin combines with oxygen and stores it until needed; this also greatly speeds oxygen transport to the mitochondria. The myoglobin gives the slow muscle a reddish appearance and the name red muscle, whereas a deficit of red myoglobin in fast muscle gives it the name white muscle. Mechanics of Skeletal Muscle Contraction Motor Unit. Each motoneuron that leaves the spinal cord innervates multiple muscle fibers, the number depending on the type of muscle. All the muscle fibers innervated by a single nerve fiber are called a motor unit. In general, small muscles that react rapidly and whose control must be exact have more nerve fibers for fewer muscle fibers (for instance, as few as two or three muscle fibers per motor unit in some of the laryngeal muscles). Conversely, large muscles that do not require fine control, such as the soleus muscle, may have several hundred muscle fibers in a motor unit. An average figure for all the muscles of the body is questionable, but a good guess would be about 80 to 100 muscle fibers to a motor unit. The muscle fibers in each motor unit are not all bunched together in the muscle but overlap other motor units in microbundles of 3 to 15 fibers. This interdigitation allows the separate motor units to contract in support of one another rather than entirely as individual segments. Muscle Contractions of Different Force—Force Summation. Summation means the adding together of individual twitch contractions to increase the intensity of overall muscle contraction. Summation occurs in two ways: (1) by increasing the number of motor units contracting simultaneously, which is called multiple fiber summation, and (2) by increasing the frequency of contraction, which is called frequency summation and can lead to tetanization. Multiple Fiber Summation. When the central nervous system sends a weak signal to contract a muscle, the smaller motor units of the muscle may be stimulated in preference to the larger motor units. Then, as the strength of the signal increases, larger and larger motor units begin to be excited as well, with the largest motor units often having as much as 50 times the contractile force of the smallest units. This is called the size principle. It is important, because it allows the gradations of muscle force during weak contraction to occur in small steps, whereas the steps become progressively greater when large amounts of force are required. The cause of this size principle is that the smaller motor units are driven by small motor nerve fibers, and the small motoneurons in the spinal cord are more excitable than the larger ones, so they naturally are excited first. Strength of muscle contraction secondary importance. (5) Fewer mitochondria, also because oxidative metabolism is secondary. Tetanization 5 10 15 20 25 30 35 40 45 50 55 Rate of stimulation (times per second) Figure 6–13 Frequency summation and tetanization. Another important feature of multiple fiber summation is that the different motor units are driven asynchronously by the spinal cord, so that contraction alternates among motor units one after the other, thus providing smooth contraction even at low frequencies of nerve signals. Frequency Summation and Tetanization. Figure 6–13 shows the principles of frequency summation and tetanization. To the left are displayed individual twitch contractions occurring one after another at low frequency of stimulation. Then, as the frequency increases, there comes a point where each new contraction occurs before the preceding one is over. As a result, the second contraction is added partially to the first, so that the total strength of contraction rises progressively with increasing frequency. When the frequency reaches a critical level, the successive contractions eventually become so rapid that they fuse together, and the whole muscle contraction appears to be completely smooth and continuous, as shown in the figure. This is called tetanization. At a slightly higher frequency, the strength of contraction reaches its maximum, so that any additional increase in frequency beyond that point has no further effect in increasing contractile force. This occurs because enough calcium ions are maintained in the muscle sarcoplasm, even between action potentials, so that full contractile state is sustained without allowing any relaxation between the action potentials. Maximum Strength of Contraction. The maximum strength of tetanic contraction of a muscle operating at a normal muscle length averages between 3 and 4 kilograms per square centimeter of muscle, or 50 pounds per square inch. Because a quadriceps muscle can have as much as 16 square inches of muscle belly, as much as 800 pounds of tension may be applied to the patellar tendon. Thus, one can readily understand how it is possible for muscles to pull their tendons out of their insertions in bone. Changes in Muscle Strength at the Onset of Contraction—The Staircase Effect (Treppe). When a muscle begins to con- tract after a long period of rest, its initial strength of 82 Unit II Membrane Physiology, Nerve, and Muscle contraction may be as little as one half its strength 10 to 50 muscle twitches later. That is, the strength of contraction increases to a plateau, a phenomenon called the staircase effect, or treppe. Although all the possible causes of the staircase effect are not known, it is believed to be caused primarily by increasing calcium ions in the cytosol because of the release of more and more ions from the sarcoplasmic reticulum with each successive muscle action potential and failure of the sarcoplasm to recapture the ions immediately. Skeletal Muscle Tone. Even when muscles are at rest, a certain amount of tautness usually remains. This is called muscle tone. Because normal skeletal muscle fibers do not contract without an action potential to stimulate the fibers, skeletal muscle tone results entirely from a low rate of nerve impulses coming from the spinal cord. These, in turn, are controlled partly by signals transmitted from the brain to the appropriate spinal cord anterior motoneurons and partly by signals that originate in muscle spindles located in the muscle itself. Both of these are discussed in relation to muscle spindle and spinal cord function in Chapter 54. Muscle Fatigue. Prolonged and strong contraction of a muscle leads to the well-known state of muscle fatigue. Studies in athletes have shown that muscle fatigue increases in almost direct proportion to the rate of depletion of muscle glycogen. Therefore, fatigue results mainly from inability of the contractile and metabolic processes of the muscle fibers to continue supplying the same work output. However, experiments have also shown that transmission of the nerve signal through the neuromuscular junction, which is discussed in Chapter 7, can diminish at least a small amount after intense prolonged muscle activity, thus further diminishing muscle contraction. Interruption of blood flow through a contracting muscle leads to almost complete muscle fatigue within 1 or 2 minutes because of the loss of nutrient supply, especially loss of oxygen. Lever Systems of the Body. Muscles operate by applying tension to their points of insertion into bones, and the bones in turn form various types of lever systems. Figure 6–14 shows the lever system activated by the biceps muscle to lift the forearm. If we assume that a large biceps muscle has a cross-sectional area of 6 square inches, the maximum force of contraction would be about 300 pounds. When the forearm is at right angles with the upper arm, the tendon attachment of the biceps is about 2 inches anterior to the fulcrum at the elbow, and the total length of the forearm lever is about 14 inches. Therefore, the amount of lifting power of the biceps at the hand would be only one seventh of the 300 pounds of muscle force, or about 43 pounds. When the arm is fully extended, the attachment of the biceps is much less than 2 inches anterior to the fulcrum, and the force with which the hand can be brought forward is also much less than 43 pounds. In short, an analysis of the lever systems of the body depends on knowledge of (1) the point of muscle insertion, (2) its distance from the fulcrum of the lever, (3) the length of the lever arm, and (4) the position of the lever. Many types of movement are required in the body, some of which need great strength and others of which need large distances of movement. For this reason, there are many different types of muscle; some are long and contract a long distance, and some are short but have large cross-sectional areas and can provide extreme strength of contraction over short distances. The study of different types of muscles, lever systems, and their movements is called kinesiology and is an important scientific component of human physioanatomy. “Positioning” of a Body Part by Contraction of Agonist and Antagonist Muscles on Opposite Sides of a Joint—“Coactivation” of Antagonist Muscles. Virtually all body movements are caused by simultaneous contraction of agonist and antagonist muscles on opposite sides of joints. This is called coactivation of the agonist and antagonist muscles, and it is controlled by the motor control centers of the brain and spinal cord. The position of each separate part of the body, such as an arm or a leg, is determined by the relative degrees of contraction of the agonist and antagonist sets of muscles. For instance, let us assume that an arm or a leg is to be placed in a midrange position. To achieve this, agonist and antagonist muscles are excited about equally. Remember that an elongated muscle contracts with more force than a shortened muscle, which was demonstrated in Figure 6–9, showing maximum strength of contraction at full functional muscle length and almost no strength of contraction at half normal length. Therefore, the elongated muscle on one side of a joint can contract with far greater force than the shorter muscle on the opposite side. As an arm or leg moves toward its midposition, the strength of the longer muscle decreases, whereas the strength of the shorter muscle increases until the two strengths equal each other. At this point, movement of the arm or leg stops. Thus, by varying the ratios of the degree of activation of the agonist and antagonist muscles, the nervous system directs the positioning of the arm or leg. We learn in Chapter 54 that the motor nervous system has additional important mechanisms to compensate for different muscle loads when directing this positioning process. Remodeling of Muscle to Match Function Figure 6–14 Lever system activated by the biceps muscle. All the muscles of the body are continually being remodeled to match the functions that are required of Chapter 6 Contraction of Skeletal Muscle them. Their diameters are altered, their lengths are altered, their strengths are altered, their vascular supplies are altered, and even the types of muscle fibers are altered at least slightly. This remodeling process is often quite rapid, within a few weeks. Indeed, experiments in animals have shown that muscle contractile proteins in some smaller, more active muscles can be replaced in as little as 2 weeks. Muscle Hypertrophy and Muscle Atrophy. When the total mass of a muscle increases, this is called muscle hypertrophy. When it decreases, the process is called muscle atrophy. Virtually all muscle hypertrophy results from an increase in the number of actin and myosin filaments in each muscle fiber, causing enlargement of the individual muscle fibers; this is called simply fiber hypertrophy. Hypertrophy occurs to a much greater extent when the muscle is loaded during the contractile process. Only a few strong contractions each day are required to cause significant hypertrophy within 6 to 10 weeks. The manner in which forceful contraction leads to hypertrophy is not known. It is known, however, that the rate of synthesis of muscle contractile proteins is far greater when hypertrophy is developing, leading also to progressively greater numbers of both actin and myosin filaments in the myofibrils, often increasing as much as 50 per cent. In turn, some of the myofibrils themselves have been observed to split within hypertrophying muscle to form new myofibrils, but how important this is in usual muscle hypertrophy is still unknown. Along with the increasing size of myofibrils, the enzyme systems that provide energy also increase. This is especially true of the enzymes for glycolysis, allowing rapid supply of energy during short-term forceful muscle contraction. When a muscle remains unused for many weeks, the rate of decay of the contractile proteins is more rapid than the rate of replacement. Therefore, muscle atrophy occurs. Adjustment of Muscle Length. Another type of hyper- trophy occurs when muscles are stretched to greater than normal length. This causes new sarcomeres to be added at the ends of the muscle fibers, where they attach to the tendons. In fact, new sarcomeres can be added as rapidly as several per minute in newly developing muscle, illustrating the rapidity of this type of hypertrophy. Conversely, when a muscle continually remains shortened to less than its normal length, sarcomeres at the ends of the muscle fibers can actually disappear. It is by these processes that muscles are continually remodeled to have the appropriate length for proper muscle contraction. Hyperplasia of Muscle Fibers. Under rare conditions of extreme muscle force generation, the actual number of muscle fibers has been observed to increase (but only by a few percentage points), in addition to the fiber hypertrophy process. This increase in fiber number is called fiber hyperplasia. When it does occur, the mechanism is linear splitting of previously enlarged fibers. Effects of Muscle Denervation. When a muscle loses its nerve supply, it no longer receives the contractile signals that are required to maintain normal muscle size. Therefore, atrophy begins almost immediately. After 83 about 2 months, degenerative changes also begin to appear in the muscle fibers themselves. If the nerve supply to the muscle grows back rapidly, full return of function can occur in as little as 3 months, but from that time onward, the capability of functional return becomes less and less, with no further return of function after 1 to 2 years. In the final stage of denervation atrophy, most of the muscle fibers are destroyed and replaced by fibrous and fatty tissue. The fibers that do remain are composed of a long cell membrane with a lineup of muscle cell nuclei but with few or no contractile properties and little or no capability of regenerating myofibrils if a nerve does regrow. The fibrous tissue that replaces the muscle fibers during denervation atrophy also has a tendency to continue shortening for many months, which is called contracture. Therefore, one of the most important problems in the practice of physical therapy is to keep atrophying muscles from developing debilitating and disfiguring contractures. This is achieved by daily stretching of the muscles or use of appliances that keep the muscles stretched during the atrophying process. Recovery of Muscle Contraction in Poliomyelitis: Development of Macromotor Units. When some but not all nerve fibers to a muscle are destroyed, as commonly occurs in poliomyelitis, the remaining nerve fibers branch off to form new axons that then innervate many of the paralyzed muscle fibers. This causes large motor units called macromotor units, which can contain as many as five times the normal number of muscle fibers for each motoneuron coming from the spinal cord. This decreases the fineness of control one has over the muscles but does allow the muscles to regain varying degrees of strength. Rigor Mortis Several hours after death, all the muscles of the body go into a state of contracture called “rigor mortis”; that is, the muscles contract and become rigid, even without action potentials. This rigidity results from loss of all the ATP, which is required to cause separation of the crossbridges from the actin filaments during the relaxation process. The muscles remain in rigor until the muscle proteins deteriorate about 15 to 25 hours later, which presumably results from autolysis caused by enzymes released from lysosomes. All these events occur more rapidly at higher temperatures. References Berchtold MW, Brinkmeier H, Muntener M: Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. Physiol Rev 80:1215, 2000. Brooks SV: Current topics for teaching skeletal muscle physiology. Adv Physiol Educ 27:171, 2003. Clausen T: Na+-K+ pump regulation and skeletal muscle contractility. Physiol Rev 83:1269, 2003. Glass DJ: Molecular mechanisms modulating muscle mass. Trends Mol Med 8:344, 2003. Glass DJ: Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol 5:87, 2003. Gordon AM, Homsher E, Regnier M: Regulation of contraction in striated muscle. Physiol Rev 80:853, 2000. 84 Unit II Membrane Physiology, Nerve, and Muscle Gordon AM, Regnier M, Homsher E: Skeletal and cardiac muscle contractile activation: tropomyosin “rocks and rolls.” News Physiol Sci 16:49, 2001. Huxley AF, Gordon AM: Striation patterns in active and passive shortening of muscle. Nature (Lond) 193:280, 1962. Huxley HE: A personal view of muscle and motility mechanisms. Annu Rev Physiol 58:1, 1996. Jurkat-Rott K, Lerche H, Lehmann-Horn F: Skeletal muscle channelopathies. J Neurol 249:1493, 2002. Kjær M: Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. Physiol Rev 84:649, 2004. MacIntosh BR: Role of calcium sensitivity modulation in skeletal muscle performance. News Physiol Sci 18:222, 2003. Matthews GG: Cellular Physiology of Nerve and Muscle. Malden, MA: Blackwell Science, 1998. Sieck GC, Regnier M: Plasticity and energetic demands of contraction in skeletal and cardiac muscle. J Appl Physiol 90:1158, 2001. Stamler JS, Meissner G: Physiology of nitric oxide in skeletal muscle. Physiol Rev 81:209, 2001. Szent-Gyorgyi AG: Regulation of contraction by calcium binding myosins. Biophys Chem 59:357, 1996. C H A P T E R 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling Transmission of Impulses from Nerve Endings to Skeletal Muscle Fibers: The Neuromuscular Junction The skeletal muscle fibers are innervated by large, myelinated nerve fibers that originate from large motoneurons in the anterior horns of the spinal cord. As pointed out in Chapter 6, each nerve fiber, after entering the muscle belly, normally branches and stimulates from three to several hundred skeletal muscle fibers. Each nerve ending makes a junction, called the neuromuscular junction, with the muscle fiber near its midpoint. The action potential initiated in the muscle fiber by the nerve signal travels in both directions toward the muscle fiber ends. With the exception of about 2 per cent of the muscle fibers, there is only one such junction per muscle fiber. Physiologic Anatomy of the Neuromuscular Junction—The Motor End Plate. Figure 7–1A and B shows the neuromuscular junction from a large, myelinated nerve fiber to a skeletal muscle fiber. The nerve fiber forms a complex of branching nerve terminals that invaginate into the surface of the muscle fiber but lie outside the muscle fiber plasma membrane. The entire structure is called the motor end plate. It is covered by one or more Schwann cells that insulate it from the surrounding fluids. Figure 7–1C shows an electron micrographic sketch of the junction between a single axon terminal and the muscle fiber membrane. The invaginated membrane is called the synaptic gutter or synaptic trough, and the space between the terminal and the fiber membrane is called the synaptic space or synaptic cleft. This space is 20 to 30 nanometers wide. At the bottom of the gutter are numerous smaller folds of the muscle membrane called subneural clefts, which greatly increase the surface area at which the synaptic transmitter can act. In the axon terminal are many mitochondria that supply adenosine triphosphate (ATP), the energy source that is used for synthesis of an excitatory transmitter acetylcholine. The acetylcholine in turn excites the muscle fiber membrane. Acetylcholine is synthesized in the cytoplasm of the terminal, but it is absorbed rapidly into many small synaptic vesicles, about 300,000 of which are normally in the terminals of a single end plate. In the synaptic space are large quantities of the enzyme acetylcholinesterase, which destroys acetylcholine a few milliseconds after it has been released from the synaptic vesicles. Secretion of Acetylcholine by the Nerve Terminals When a nerve impulse reaches the neuromuscular junction, about 125 vesicles of acetylcholine are released from the terminals into the synaptic space. Some of the details of this mechanism can be seen in Figure 7–2, which shows an expanded view of a synaptic space with the neural membrane above and the muscle membrane and its subneural clefts below. 85 86 Unit II Myelin sheath Membrane Physiology, Nerve, and Muscle Axon Terminal nerve branches Teloglial cell Muscle nuclei Myofibrils A B Axon terminal in synaptic trough Synaptic vesicles Figure 7–1 C Different views of the motor end plate. A, Longitudinal section through the end plate. B, Surface view of the end plate. C, Electron micrographic appearance of the contact point between a single axon terminal and the muscle fiber membrane. (Redrawn from Fawcett DW, as modified from Couteaux R, in Bloom W, Fawcett DW: A Textbook of Histology. Philadelphia: WB Saunders, 1986.) Subneural clefts On the inside surface of the neural membrane are linear dense bars, shown in cross section in Figure 7–2. To each side of each dense bar are protein particles that penetrate the neural membrane; these are voltagegated calcium channels. When an action potential spreads over the terminal, these channels open and allow calcium ions to diffuse from the synaptic space to the interior of the nerve terminal. The calcium ions, in turn, are believed to exert an attractive influence on the acetylcholine vesicles, drawing them to the neural membrane adjacent to the dense bars. The vesicles then fuse with the neural membrane and empty their acetylcholine into the synaptic space by the process of exocytosis. Although some of the aforementioned details are speculative, it is known that the effective stimulus for causing acetylcholine release from the vesicles is entry of calcium ions and that acetylcholine from the vesicles is then emptied through the neural membrane adjacent to the dense bars. Effect of Acetylcholine on the Postsynaptic Muscle Fiber Membrane to Open Ion Channels. Figure 7–2 also shows many very small acetylcholine receptors in the muscle fiber membrane; these are acetylcholine-gated ion channels, and they are located almost entirely near the mouths of the subneural clefts lying immediately below the dense bar areas, where the acetylcholine is emptied into the synaptic space. Each receptor is a protein complex that has a total molecular weight of 275,000. The complex is composed Neural Release sites membrane Vesicles Dense bar Calcium channels Basal lamina and acetylcholinesterase Acetylcholine receptors Subneural cleft Muscle membrane Figure 7–2 Release of acetylcholine from synaptic vesicles at the neural membrane of the neuromuscular junction. Note the proximity of the release sites in the neural membrane to the acetylcholine receptors in the muscle membrane, at the mouths of the subneural clefts. Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling of five subunit proteins, two alpha proteins and one each of beta, delta, and gamma proteins. These protein molecules penetrate all the way through the membrane, lying side by side in a circle to form a tubular channel, illustrated in Figure 7–3. The channel remains constricted, as shown in section A of the figure, until two acetylcholine molecules attach respectively to the two alpha subunit proteins. This causes a conformational change that opens the channel, as shown in section B of the figure. The opened acetylcholine channel has a diameter of about 0.65 nanometer, which is large enough to allow the important positive ions—sodium (Na+), potassium (K+), and calcium (Ca++)—to move easily through the opening. Conversely, negative ions, such as chloride ions, do not pass through because of strong negative charges in the mouth of the channel that repel these negative ions. 87 In practice, far more sodium ions flow through the acetylcholine channels than any other ions, for two reasons. First, there are only two positive ions in large concentration: sodium ions in the extracellular fluid, and potassium ions in the intracellular fluid. Second, the very negative potential on the inside of the muscle membrane, –80 to –90 millivolts, pulls the positively charged sodium ions to the inside of the fiber, while simultaneously preventing efflux of the positively charged potassium ions when they attempt to pass outward. As shown in Figure 7–3B, the principal effect of opening the acetylcholine-gated channels is to allow large numbers of sodium ions to pour to the inside of the fiber, carrying with them large numbers of positive charges. This creates a local positive potential change inside the muscle fiber membrane, called the end plate potential. In turn, this end plate potential initiates an action potential that spreads along the muscle membrane and thus causes muscle contraction. Destruction of the Released Acetylcholine by Acetylcholinesterase. The acetylcholine, once released into – – – – – – A Na+ Ach – – – – – – B Figure 7–3 Acetylcholine channel. A, Closed state. B, After acetylcholine (Ach) has become attached and a conformational change has opened the channel, allowing sodium ions to enter the muscle fiber and excite contraction. Note the negative charges at the channel mouth that prevent passage of negative ions such as chloride ions. the synaptic space, continues to activate the acetylcholine receptors as long as the acetylcholine persists in the space. However, it is removed rapidly by two means: (1) Most of the acetylcholine is destroyed by the enzyme acetylcholinesterase, which is attached mainly to the spongy layer of fine connective tissue that fills the synaptic space between the presynaptic nerve terminal and the postsynaptic muscle membrane. (2) A small amount of acetylcholine diffuses out of the synaptic space and is then no longer available to act on the muscle fiber membrane. The short time that the acetylcholine remains in the synaptic space—a few milliseconds at most—normally is sufficient to excite the muscle fiber. Then the rapid removal of the acetylcholine prevents continued muscle re-excitation after the muscle fiber has recovered from its initial action potential. End Plate Potential and Excitation of the Skeletal Muscle Fiber. The sudden insurgence of sodium ions into the muscle fiber when the acetylcholine channels open causes the electrical potential inside the fiber at the local area of the end plate to increase in the positive direction as much as 50 to 75 millivolts, creating a local potential called the end plate potential. Recall from Chapter 5 that a sudden increase in nerve membrane potential of more than 20 to 30 millivolts is normally sufficient to initiate more and more sodium channel opening, thus initiating an action potential at the muscle fiber membrane. Figure 7–4 shows the principle of an end plate potential initiating the action potential. This figure shows three separate end plate potentials. End plate potentials A and C are too weak to elicit an action potential, but they do produce weak local end plate voltage changes, as recorded in the figure. By contrast, end plate potential B is much stronger and causes enough sodium channels to open so that the selfregenerative effect of more and more sodium ions 88 Unit II Membrane Physiology, Nerve, and Muscle +60 +40 Millivolts +20 0 – 20 – 40 – 60 – 80 A –100 0 B 15 30 C 45 60 75 Milliseconds Figure 7–4 End plate potentials (in millivolts). A, Weakened end plate potential recorded in a curarized muscle, too weak to elicit an action potential. B, Normal end plate potential eliciting a muscle action potential. C, Weakened end plate potential caused by botulinum toxin that decreases end plate release of acetylcholine, again too weak to elicit a muscle action potential. flowing to the interior of the fiber initiates an action potential. The weakness of the end plate potential at point A was caused by poisoning of the muscle fiber with curare, a drug that blocks the gating action of acetylcholine on the acetylcholine channels by competing for the acetylcholine receptor sites. The weakness of the end plate potential at point C resulted from the effect of botulinum toxin, a bacterial poison that decreases the quantity of acetylcholine release by the nerve terminals. Safety Factor for Transmission at the Neuromuscular Junction; Fatigue of the Junction. Ordinarily, each impulse that arrives at the neuromuscular junction causes about three times as much end plate potential as that required to stimulate the muscle fiber. Therefore, the normal neuromuscular junction is said to have a high safety factor. However, stimulation of the nerve fiber at rates greater than 100 times per second for several minutes often diminishes the number of acetylcholine vesicles so much that impulses fail to pass into the muscle fiber. This is called fatigue of the neuromuscular junction, and it is the same effect that causes fatigue of synapses in the central nervous system when the synapses are overexcited. Under normal functioning conditions, measurable fatigue of the neuromuscular junction occurs rarely, and even then only at the most exhausting levels of muscle activity. Molecular Biology of Acetylcholine Formation and Release Because the neuromuscular junction is large enough to be studied easily, it is one of the few synapses of the nervous system for which most of the details of chemical transmission have been worked out. The formation and release of acetylcholine at this junction occur in the following stages: 1. Small vesicles, about 40 nanometers in size, are formed by the Golgi apparatus in the cell body of the motoneuron in the spinal cord. These vesicles are then transported by axoplasm that “streams” through the core of the axon from the central cell body in the spinal cord all the way to the neuromuscular junction at the tips of the peripheral nerve fibers. About 300,000 of these small vesicles collect in the nerve terminals of a single skeletal muscle end plate. 2. Acetylcholine is synthesized in the cytosol of the nerve fiber terminal but is immediately transported through the membranes of the vesicles to their interior, where it is stored in highly concentrated form, about 10,000 molecules of acetylcholine in each vesicle. 3. When an action potential arrives at the nerve terminal, it opens many calcium channels in the membrane of the nerve terminal because this terminal has an abundance of voltage-gated calcium channels. As a result, the calcium ion concentration inside the terminal membrane increases about 100-fold, which in turn increases the rate of fusion of the acetylcholine vesicles with the terminal membrane about 10,000-fold. This fusion makes many of the vesicles rupture, allowing exocytosis of acetylcholine into the synaptic space. About 125 vesicles usually rupture with each action potential. Then, after a few milliseconds, the acetylcholine is split by acetylcholinesterase into acetate ion and choline, and the choline is reabsorbed actively into the neural terminal to be reused to form new acetylcholine. This sequence of events occurs within a period of 5 to 10 milliseconds. 4. The number of vesicles available in the nerve ending is sufficient to allow transmission of only a few thousand nerve-to-muscle impulses. Therefore, for continued function of the neuromuscular junction, new vesicles need to be re-formed rapidly. Within a few seconds after each action potential is over, “coated pits” appear in the terminal nerve membrane, caused by contractile proteins in the nerve ending, especially the protein clathrin, which is attached to the membrane in the areas of the original vesicles. Within about 20 seconds, the proteins contract and cause the pits to break away to the interior of the membrane, thus forming new vesicles. Within another few seconds, acetylcholine is transported to the interior of these vesicles, and they are then ready for a new cycle of acetylcholine release. Drugs That Enhance or Block Transmission at the Neuromuscular Junction Drugs That Stimulate the Muscle Fiber by Acetylcholine-Like Action. Many compounds, including methacholine, car- bachol, and nicotine, have the same effect on the muscle fiber as does acetylcholine. The difference between Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling these drugs and acetylcholine is that the drugs are not destroyed by cholinesterase or are destroyed so slowly that their action often persists for many minutes to several hours. The drugs work by causing localized areas of depolarization of the muscle fiber membrane at the motor end plate where the acetylcholine receptors are located. Then, every time the muscle fiber recovers from a previous contraction, these depolarized areas, by virtue of leaking ions, initiate a new action potential, thereby causing a state of muscle spasm. Drugs That Stimulate the Neuromuscular Junction by Inactivating Acetylcholinesterase. Three particularly well- known drugs, neostigmine, physostigmine, and diisopropyl fluorophosphate, inactivate the acetylcholinesterase in the synapses so that it no longer hydrolyzes acetylcholine. Therefore, with each successive nerve impulse, additional acetylcholine accumulates and stimulates the muscle fiber repetitively. This causes muscle spasm when even a few nerve impulses reach the muscle. Unfortunately, it also can cause death due to laryngeal spasm, which smothers the person. Neostigmine and physostigmine combine with acetylcholinesterase to inactivate the acetylcholinesterase for up to several hours, after which these drugs are displaced from the acetylcholinesterase so that the esterase once again becomes active. Conversely, diisopropyl fluorophosphate, which has military potential as a powerful “nerve” gas poison, inactivates acetylcholinesterase for weeks, which makes this a particularly lethal poison. Drugs That Block Transmission at the Neuromuscular Junction. A group of drugs known as curariform drugs can prevent passage of impulses from the nerve ending into the muscle. For instance, D-tubocurarine blocks the action of acetylcholine on the muscle fiber acetylcholine receptors, thus preventing sufficient increase in permeability of the muscle membrane channels to initiate an action potential. Myasthenia Gravis Myasthenia gravis, which occurs in about 1 in every 20,000 persons, causes muscle paralysis because of inability of the neuromuscular junctions to transmit enough signals from the nerve fibers to the muscle fibers. Pathologically, antibodies that attack the acetylcholine-gated sodium ion transport proteins have been demonstrated in the blood of most patients with myasthenia gravis. Therefore, it is believed that myasthenia gravis is an autoimmune disease in which the patients have developed immunity against their own acetylcholine-activated ion channels. Regardless of the cause, the end plate potentials that occur in the muscle fibers are mostly too weak to stimulate the muscle fibers. If the disease is intense enough, the patient dies of paralysis—in particular, paralysis of the respiratory muscles. The disease usually can be ameliorated for several hours by administering neostigmine or some other anticholinesterase drug, which allows larger than normal amounts of acetylcholine to accumulate in the synaptic space. Within minutes, some of these paralyzed people can begin to function almost normally, until a new dose of neostigmine is required a few hours later. 89 Muscle Action Potential Almost everything discussed in Chapter 5 regarding initiation and conduction of action potentials in nerve fibers applies equally to skeletal muscle fibers, except for quantitative differences. Some of the quantitative aspects of muscle potentials are the following: 1. Resting membrane potential: about –80 to –90 millivolts in skeletal fibers—the same as in large myelinated nerve fibers. 2. Duration of action potential: 1 to 5 milliseconds in skeletal muscle—about five times as long as in large myelinated nerves. 3. Velocity of conduction: 3 to 5 m/sec—about 1/13 the velocity of conduction in the large myelinated nerve fibers that excite skeletal muscle. Spread of the Action Potential to the Interior of the Muscle Fiber by Way of “Transverse Tubules” The skeletal muscle fiber is so large that action potentials spreading along its surface membrane cause almost no current flow deep within the fiber. Yet, to cause maximum muscle contraction, current must penetrate deeply into the muscle fiber to the vicinity of the separate myofibrils. This is achieved by transmission of action potentials along transverse tubules (T tubules) that penetrate all the way through the muscle fiber from one side of the fiber to the other, as illustrated in Figure 7–5. The T tubule action potentials cause release of calcium ions inside the muscle fiber in the immediate vicinity of the myofibrils, and these calcium ions then cause contraction. This overall process is called excitation-contraction coupling. Excitation-Contraction Coupling Transverse Tubule–Sarcoplasmic Reticulum System Figure 7–5 shows myofibrils surrounded by the T tubule–sarcoplasmic reticulum system. The T tubules are very small and run transverse to the myofibrils. They begin at the cell membrane and penetrate all the way from one side of the muscle fiber to the opposite side. Not shown in the figure is the fact that these tubules branch among themselves so that they form entire planes of T tubules interlacing among all the separate myofibrils. Also, where the T tubules originate from the cell membrane, they are open to the exterior of the muscle fiber. Therefore, they communicate with the extracellular fluid surrounding the muscle fiber, and they themselves contain extracellular fluid in their lumens. In other words, the T tubules are actually internal extensions of the cell membrane. Therefore, when an action potential spreads over a muscle fiber 90 Unit II Membrane Physiology, Nerve, and Muscle Myofibrils Sarcolemma Terminal cisternae Triad of the reticulum Z line Transverse tubule Mitochondrion A band Sarcoplasmic reticulum Transverse tubule I band Sarcotubules membrane, a potential change also spreads along the T tubules to the deep interior of the muscle fiber. The electrical currents surrounding these T tubules then elicit the muscle contraction. Figure 7–5 also shows a sarcoplasmic reticulum, in yellow. This is composed of two major parts: (1) large chambers called terminal cisternae that abut the T tubules, and (2) long longitudinal tubules that surround all surfaces of the actual contracting myofibrils. Release of Calcium Ions by the Sarcoplasmic Reticulum One of the special features of the sarcoplasmic reticulum is that within its vesicular tubules is an excess of calcium ions in high concentration, and many of these ions are released from each vesicle when an action potential occurs in the adjacent T tubule. Figure 7–6 shows that the action potential of the T tubule causes current flow into the sarcoplasmic reticular cisternae where they abut the T tubule. This in turn causes rapid opening of large numbers of calcium channels through the membranes of the cisternae as well as their attached longitudinal tubules. These channels remain open for a few milliseconds; during this time, enough calcium ions are released into the Figure 7–5 Transverse (T) tubule–sarcoplasmic reticulum system. Note that the T tubules communicate with the outside of the cell membrane, and deep in the muscle fiber, each T tubule lies adjacent to the ends of longitudinal sarcoplasmic reticulum tubules that surround all sides of the actual myofibrils that contract. This illustration was drawn from frog muscle, which has one T tubule per sarcomere, located at the Z line. A similar arrangement is found in mammalian heart muscle, but mammalian skeletal muscle has two T tubules per sarcomere, located at the A-I band junctions. (Redrawn from Bloom W, Fawcett DW: A Textbook of Histology. Philadelphia: WB Saunders, 1986. Modified after Peachey LD: J Cell Biol 25:209, 1965. Drawn by Sylvia Colard Keene.) sarcoplasm surrounding the myofibrils to cause contraction, as discussed in Chapter 6. Calcium Pump for Removing Calcium Ions from the Myofibrillar Fluid After Contraction Occurs. Once the calcium ions have been released from the sarcoplasmic tubules and have diffused among the myofibrils, muscle contraction continues as long as the calcium ions remain in high concentration. However, a continually active calcium pump located in the walls of the sarcoplasmic reticulum pumps calcium ions away from the myofibrils back into the sarcoplasmic tubules. This pump can concentrate the calcium ions about 10,000-fold inside the tubules. In addition, inside the reticulum is a protein called calsequestrin that can bind up to 40 times more calcium. Excitatory “Pulse” of Calcium Ions. The normal resting state concentration (less than 10-7 molar) of calcium ions in the cytosol that bathes the myofibrils is too little to elicit contraction. Therefore, the troponintropomyosin complex keeps the actin filaments inhibited and maintains a relaxed state of the muscle. Conversely, full excitation of the T tubule and sarcoplasmic reticulum system causes enough release of calcium ions to increase the concentration in the myofibrillar fluid to as high as 2 ¥ 10-4 molar Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling 91 Action potential Sarcolemma Calcium pump Ca Ca ATP required Figure 7–6 Excitation-contraction coupling in the muscle, showing (1) an action potential that causes release of calcium ions from the sarcoplasmic reticulum and then (2) reuptake of the calcium ions by a calcium pump. concentration, a 500-fold increase, which is about 10 times the level required to cause maximum muscle contraction. Immediately thereafter, the calcium pump depletes the calcium ions again. The total duration of this calcium “pulse” in the usual skeletal muscle fiber lasts about 1/20 of a second, although it may last several times as long in some fibers and several times less in others. (In heart muscle, the calcium pulse lasts about 1/3 of a second because of the long duration of the cardiac action potential.) During this calcium pulse, muscle contraction occurs. If the contraction is to continue without interruption for long intervals, a series of calcium pulses must be initiated by a continuous series of repetitive action potentials, as discussed in Chapter 6. References Also see references for Chapters 5 and 6. Allman BL, Rice CL: Neuromuscular fatigue and aging: central and peripheral factors. Muscle Nerve 25:785, 2002. Amonof MJ: Electromyography in Clinical Practice. New York: Churchill Livingstone, 1998. Brown RH Jr: Dystrophin-associated proteins and the muscular dystrophies. Annu Rev Med 48:457, 1997. Chaudhuri A, Behan PO: Fatigue in neurological disorders. Lancet 363:978, 2004. Engel AG, Ohno K, Shen XM, Sine SM: Congenital myasthenic syndromes: multiple molecular targets at the neuromuscular junction. Ann N Y Acad Sci 998:138, 2003. Haouzi P, Chenuel B, Huszczuk A: Sensing vascular distension in skeletal muscle by slow conducting afferent fibers: Ca++ Ca++ Actin filaments Myosin filaments neurophysiological basis and implication for respiratory control. J Appl Physiol 96:407, 2004. Hoch W: Molecular dissection of neuromuscular junction formation. Trends Neurosci 26:335, 2003. Keesey JC: Clinical evaluation and management of myasthenia gravis. Muscle Nerve 29:484, 2004. Lee C: Conformation, action, and mechanism of action of neuromuscular blocking muscle relaxants. Pharmacol Ther 98:143, 2003. Leite JF, Rodrigues-Pinguet N, Lester HA: Insights into channel function via channel dysfunction. J Clin Invest 111:436, 2003. Payne AM, Delbono O: Neurogenesis of excitationcontraction uncoupling in aging skeletal muscle. Exerc Sport Sci Rev 32:36, 2004. Pette D: Historical perspectives: plasticity of mammalian skeletal muscle. J Appl Physiol 90:1119, 2001. Rekling JC, Funk GD, Bayliss DA, et al: Synaptic control of motoneuronal excitability. Physiol Rev 80:767, 2000. Schiaffino S, Serrano A: Calcineurin signaling and neural control of skeletal muscle fiber type and size. Trends Pharmacol Sci 23:569, 2002. Tang W, Sencer S, Hamilton SL: Calmodulin modulation of proteins involved in excitation-contraction coupling. Front Biosci 7:583, 2002. Toyoshima C, Nomura H, Sugita Y: Structural basis of ion pumping by Ca2+-ATPase of sarcoplasmic reticulum. FEBS Lett 555:106, 2003. Van der Kloot W, Molgo J: Quantal acetylcholine release at the vertebrate neuromuscular junction. Physiol Rev 74:899, 1994. Vincent A: Unraveling the pathogenesis of myasthenia gravis. Nat Rev Immunol 10:797, 2002. Vincent A, McConville J, Farrugia ME, et al: Antibodies in myasthenia gravis and related disorders. Ann N Y Acad Sci 998:324, 2003. C H A P T E R Contraction and Excitation of Smooth Muscle Contraction of Smooth Muscle In Chapters 6 and 7, the discussion was concerned with skeletal muscle. We now turn to smooth muscle, which is composed of far smaller fibers— usually 1 to 5 micrometers in diameter and only 20 to 500 micrometers in length. In contrast, skeletal muscle fibers are as much as 30 times greater in diameter and hundreds of times as long. Many of the same principles of contraction apply to smooth muscle as to skeletal muscle. Most important, essentially the same attractive forces between myosin and actin filaments cause contraction in smooth muscle as in skeletal muscle, but the internal physical arrangement of smooth muscle fibers is very different. Types of Smooth Muscle The smooth muscle of each organ is distinctive from that of most other organs in several ways: (1) physical dimensions, (2) organization into bundles or sheets, (3) response to different types of stimuli, (4) characteristics of innervation, and (5) function. Yet, for the sake of simplicity, smooth muscle can generally be divided into two major types, which are shown in Figure 8–1: multi-unit smooth muscle and unitary (or single-unit) smooth muscle. Multi-Unit Smooth Muscle. This type of smooth muscle is composed of discrete, separate smooth muscle fibers. Each fiber operates independently of the others and often is innervated by a single nerve ending, as occurs for skeletal muscle fibers. Further, the outer surfaces of these fibers, like those of skeletal muscle fibers, are covered by a thin layer of basement membrane–like substance, a mixture of fine collagen and glycoprotein that helps insulate the separate fibers from one another. The most important characteristic of multi-unit smooth muscle fibers is that each fiber can contract independently of the others, and their control is exerted mainly by nerve signals. In contrast, a major share of control of unitary smooth muscle is exerted by non-nervous stimuli. Some examples of multi-unit smooth muscle are the ciliary muscle of the eye, the iris muscle of the eye, and the piloerector muscles that cause erection of the hairs when stimulated by the sympathetic nervous system. Unitary Smooth Muscle. The term “unitary” is confusing because it does not mean single muscle fibers. Instead, it means a mass of hundreds to thousands of smooth muscle fibers that contract together as a single unit. The fibers usually are arranged in sheets or bundles, and their cell membranes are adherent to one another at multiple points so that force generated in one muscle fiber can be transmitted to the next. In addition, the cell membranes are joined by many gap junctions through which ions can flow freely from one muscle cell to the next so that action potentials or simple ion flow without action potentials can travel 92 8 Chapter 8 93 Contraction and Excitation of Smooth Muscle Adventitia Actin filaments Dense bodies Medial muscle fibers Endothelium Small artery Multi-unit smooth muscle Unitary smooth muscle A B Myosin filaments Figure 8–1 Multi-unit (A) and unitary (B) smooth muscle. from one fiber to the next and cause the muscle fibers to contract together. This type of smooth muscle is also known as syncytial smooth muscle because of its syncytial interconnections among fibers. It is also called visceral smooth muscle because it is found in the walls of most viscera of the body, including the gut, bile ducts, ureters, uterus, and many blood vessels. Cell membrane Contractile Mechanism in Smooth Muscle Chemical Basis for Smooth Muscle Contraction Smooth muscle contains both actin and myosin filaments, having chemical characteristics similar to those of the actin and myosin filaments in skeletal muscle. It does not contain the normal troponin complex that is required in the control of skeletal muscle contraction, so the mechanism for control of contraction is different. This is discussed in detail later in this chapter. Chemical studies have shown that actin and myosin filaments derived from smooth muscle interact with each other in much the same way that they do in skeletal muscle. Further, the contractile process is activated by calcium ions, and adenosine triphosphate (ATP) is degraded to adenosine diphosphate (ADP) to provide the energy for contraction. There are, however, major differences between the physical organization of smooth muscle and that of skeletal muscle, as well as differences in excitationcontraction coupling, control of the contractile process by calcium ions, duration of contraction, and amount of energy required for contraction. Figure 8–2 Physical structure of smooth muscle. The upper left-hand fiber shows actin filaments radiating from dense bodies. The lower lefthand fiber and the right-hand diagram demonstrate the relation of myosin filaments to actin filaments. Physical Basis for Smooth Muscle Contraction Smooth muscle does not have the same striated arrangement of actin and myosin filaments as is found in skeletal muscle. Instead, electron micrographic techniques suggest the physical organization exhibited in Figure 8–2. This figure shows large numbers of actin filaments attached to so-called dense bodies. Some of these bodies are attached to the cell membrane. Others are dispersed inside the cell. Some of the membrane dense bodies of adjacent cells are bonded together by intercellular protein bridges. It is mainly through these bonds that the force of contraction is transmitted from one cell to the next. 94 Unit II Membrane Physiology, Nerve, and Muscle Interspersed among the actin filaments in the muscle fiber are myosin filaments. These have a diameter more than twice that of the actin filaments. In electron micrographs, one usually finds 5 to 10 times as many actin filaments as myosin filaments. To the right in Figure 8–2 is a postulated structure of an individual contractile unit within a smooth muscle cell, showing large numbers of actin filaments radiating from two dense bodies; the ends of these filaments overlap a myosin filament located midway between the dense bodies. This contractile unit is similar to the contractile unit of skeletal muscle, but without the regularity of the skeletal muscle structure; in fact, the dense bodies of smooth muscle serve the same role as the Z discs in skeletal muscle. There is another difference: Most of the myosin filaments have what are called “sidepolar” cross-bridges arranged so that the bridges on one side hinge in one direction and those on the other side hinge in the opposite direction. This allows the myosin to pull an actin filament in one direction on one side while simultaneously pulling another actin filament in the opposite direction on the other side. The value of this organization is that it allows smooth muscle cells to contract as much as 80 per cent of their length instead of being limited to less than 30 per cent, as occurs in skeletal muscle. Comparison of Smooth Muscle Contraction and Skeletal Muscle Contraction Although most skeletal muscles contract and relax rapidly, most smooth muscle contraction is prolonged tonic contraction, sometimes lasting hours or even days.Therefore, it is to be expected that both the physical and the chemical characteristics of smooth muscle versus skeletal muscle contraction would differ. Following are some of the differences. Slow Cycling of the Myosin Cross-Bridges. The rapidity of cycling of the myosin cross-bridges in smooth muscle—that is, their attachment to actin, then release from the actin, and reattachment for the next cycle— is much, much slower in smooth muscle than in skeletal muscle; in fact, the frequency is as little as 1/10 to 1/300 that in skeletal muscle. Yet the fraction of time that the cross-bridges remain attached to the actin filaments, which is a major factor that determines the force of contraction, is believed to be greatly increased in smooth muscle. A possible reason for the slow cycling is that the cross-bridge heads have far less ATPase activity than in skeletal muscle, so that degradation of the ATP that energizes the movements of the cross-bridge heads is greatly reduced, with corresponding slowing of the rate of cycling. Energy Required to Sustain Smooth Muscle Contraction. Only 1/10 to 1/300 as much energy is required to sustain the same tension of contraction in smooth muscle as in skeletal muscle. This, too, is believed to result from the slow attachment and detachment cycling of the crossbridges and because only one molecule of ATP is required for each cycle, regardless of its duration. This sparsity of energy utilization by smooth muscle is exceedingly important to the overall energy economy of the body, because organs such as the intestines, urinary bladder, gallbladder, and other viscera often maintain tonic muscle contraction almost indefinitely. Slowness of Onset of Contraction and Relaxation of the Total Smooth Muscle Tissue. A typical smooth muscle tissue begins to contract 50 to 100 milliseconds after it is excited, reaches full contraction about 0.5 second later, and then declines in contractile force in another 1 to 2 seconds, giving a total contraction time of 1 to 3 seconds. This is about 30 times as long as a single contraction of an average skeletal muscle fiber. But because there are so many types of smooth muscle, contraction of some types can be as short as 0.2 second or as long as 30 seconds. The slow onset of contraction of smooth muscle, as well as its prolonged contraction, is caused by the slowness of attachment and detachment of the cross-bridges with the actin filaments. In addition, the initiation of contraction in response to calcium ions is much slower than in skeletal muscle, as discussed later. Force of Muscle Contraction. Despite the relatively few myosin filaments in smooth muscle, and despite the slow cycling time of the cross-bridges, the maximum force of contraction of smooth muscle is often greater than that of skeletal muscle—as great as 4 to 6 kg/cm2 cross-sectional area for smooth muscle, in comparison with 3 to 4 kilograms for skeletal muscle. This great force of smooth muscle contraction results from the prolonged period of attachment of the myosin crossbridges to the actin filaments. “Latch” Mechanism for Prolonged Holding of Contractions of Smooth Muscle. Once smooth muscle has developed full contraction, the amount of continuing excitation usually can be reduced to far less than the initial level, yet the muscle maintains its full force of contraction. Further, the energy consumed to maintain contraction is often minuscule, sometimes as little as 1/300 the energy required for comparable sustained skeletal muscle contraction. This is called the “latch” mechanism. The importance of the latch mechanism is that it can maintain prolonged tonic contraction in smooth muscle for hours with little use of energy. Little continued excitatory signal is required from nerve fibers or hormonal sources. Stress-Relaxation of Smooth Muscle. Another impor- tant characteristic of smooth muscle, especially the visceral unitary type of smooth muscle of many hollow organs, is its ability to return to nearly its original force of contraction seconds or minutes after it has been elongated or shortened. For example, a sudden increase in fluid volume in the urinary bladder, thus stretching the smooth muscle in the bladder wall, causes an immediate large increase in pressure in the bladder. However, during the next 15 seconds to a Chapter 8 Contraction and Excitation of Smooth Muscle minute or so, despite continued stretch of the bladder wall, the pressure returns almost exactly back to the original level. Then, when the volume is increased by another step, the same effect occurs again. Conversely, when the volume is suddenly decreased, the pressure falls very low at first but then rises back in another few seconds or minutes to or near to the original level. These phenomena are called stressrelaxation and reverse stress-relaxation. Their importance is that, except for short periods of time, they allow a hollow organ to maintain about the same amount of pressure inside its lumen despite long-term, large changes in volume. Regulation of Contraction by Calcium Ions As is true for skeletal muscle, the initiating stimulus for most smooth muscle contraction is an increase in intracellular calcium ions. This increase can be caused in different types of smooth muscle by nerve stimulation of the smooth muscle fiber, hormonal stimulation, stretch of the fiber, or even change in the chemical environment of the fiber. Yet smooth muscle does not contain troponin, the regulatory protein that is activated by calcium ions to cause skeletal muscle contraction. Instead, smooth muscle contraction is activated by an entirely different mechanism, as follows. Combination of Calcium Ions with Calmodulin—Activation of Myosin Kinase and Phosphorylation of the Myosin Head. In place of troponin, smooth muscle cells contain a large amount of another regulatory protein called calmodulin. Although this protein is similar to troponin, it is different in the manner in which it initiates contraction. Calmodulin does this by activating the myosin cross-bridges. This activation and subsequent contraction occur in the following sequence: 1. The calcium ions bind with calmodulin. 2. The calmodulin-calcium combination joins with and activates myosin kinase, a phosphorylating enzyme. 3. One of the light chains of each myosin head, called the regulatory chain, becomes phosphorylated in response to this myosin kinase. When this chain is not phosphorylated, the attachment-detachment cycling of the myosin head with the actin filament does not occur. But when the regulatory chain is phosphorylated, the head has the capability of binding repetitively with the actin filament and proceeding through the entire cycling process of intermittent “pulls,” the same as occurs for skeletal muscle, thus causing muscle contraction. Cessation of Contraction—Role of Myosin Phosphatase. When the calcium ion concentration falls below a critical level, the aforementioned processes automatically reverse, except for the phosphorylation of the myosin head. Reversal of this requires another enzyme, 95 myosin phosphatase, located in the fluids of the smooth muscle cell, which splits the phosphate from the regulatory light chain. Then the cycling stops and contraction ceases. The time required for relaxation of muscle contraction, therefore, is determined to a great extent by the amount of active myosin phosphatase in the cell. Possible Mechanism for Regulation of the Latch Phenomenon Because of the importance of the latch phenomenon in smooth muscle, and because this phenomenon allows long-term maintenance of tone in many smooth muscle organs without much expenditure of energy, many attempts have been made to explain it. Among the many mechanisms that have been postulated, one of the simplest is the following. When the myosin kinase and myosin phosphatase enzymes are both strongly activated, the cycling frequency of the myosin heads and the velocity of contraction are great. Then, as the activation of the enzymes decreases, the cycling frequency decreases, but at the same time, the deactivation of these enzymes allows the myosin heads to remain attached to the actin filament for a longer and longer proportion of the cycling period. Therefore, the number of heads attached to the actin filament at any given time remains large. Because the number of heads attached to the actin determines the static force of contraction, tension is maintained, or “latched”; yet little energy is used by the muscle, because ATP is not degraded to ADP except on the rare occasion when a head detaches. Nervous and Hormonal Control of Smooth Muscle Contraction Although skeletal muscle fibers are stimulated exclusively by the nervous system, smooth muscle can be stimulated to contract by multiple types of signals: by nervous signals, by hormonal stimulation, by stretch of the muscle, and in several other ways. The principal reason for the difference is that the smooth muscle membrane contains many types of receptor proteins that can initiate the contractile process. Still other receptor proteins inhibit smooth muscle contraction, which is another difference from skeletal muscle. Therefore, in this section, we discuss nervous control of smooth muscle contraction, followed by hormonal control and other means of control. Neuromuscular Junctions of Smooth Muscle Physiologic Anatomy of Smooth Muscle Neuromuscular Junctions. Neuromuscular junctions of the highly struc- tured type found on skeletal muscle fibers do not occur in smooth muscle. Instead, the autonomic nerve fibers that innervate smooth muscle generally branch 96 Unit II Membrane Physiology, Nerve, and Muscle Varicosities Visceral Multi-unit Figure 8–3 Innervation of smooth muscle. diffusely on top of a sheet of muscle fibers, as shown in Figure 8–3. In most instances, these fibers do not make direct contact with the smooth muscle fiber cell membranes but instead form so-called diffuse junctions that secrete their transmitter substance into the matrix coating of the smooth muscle often a few nanometers to a few micrometers away from the muscle cells; the transmitter substance then diffuses to the cells. Furthermore, where there are many layers of muscle cells, the nerve fibers often innervate only the outer layer, and muscle excitation travels from this outer layer to the inner layers by action potential conduction in the muscle mass or by additional diffusion of the transmitter substance. The axons that innervate smooth muscle fibers do not have typical branching end feet of the type in the motor end plate on skeletal muscle fibers. Instead, most of the fine terminal axons have multiple varicosities distributed along their axes. At these points the Schwann cells that envelop the axons are interrupted so that transmitter substance can be secreted through the walls of the varicosities. In the varicosities are vesicles similar to those in the skeletal muscle end plate that contain transmitter substance. But, in contrast to the vesicles of skeletal muscle junctions, which always contain acetylcholine, the vesicles of the autonomic nerve fiber endings contain acetylcholine in some fibers and norepinephrine in others—and occasionally other substances as well. In a few instances, particularly in the multi-unit type of smooth muscle, the varicosities are separated from the muscle cell membrane by as little as 20 to 30 nanometers—the same width as the synaptic cleft that occurs in the skeletal muscle junction. These are called contact junctions, and they function in much the same way as the skeletal muscle neuromuscular junction; the rapidity of contraction of these smooth muscle fibers is considerably faster than that of fibers stimulated by the diffuse junctions. Excitatory and Inhibitory Transmitter Substances Secreted at the Smooth Muscle Neuromuscular Junction. The most important transmitter substances secreted by the autonomic nerves innervating smooth muscle are acetylcholine and norepinephrine, but they are never secreted by the same nerve fibers. Acetylcholine is an excitatory transmitter substance for smooth muscle fibers in some organs but an inhibitory transmitter for smooth muscle in other organs. When acetylcholine excites a muscle fiber, norepinephrine ordinarily inhibits it. Conversely, when acetylcholine inhibits a fiber, norepinephrine usually excites it. But why these different responses? The answer is that both acetylcholine and norepinephrine excite or inhibit smooth muscle by first binding with a receptor protein on the surface of the muscle cell membrane. Some of the receptor proteins are excitatory receptors, whereas others are inhibitory receptors. Thus, the type of receptor determines whether the smooth muscle is inhibited or excited and also determines which of the two transmitters, acetylcholine or norepinephrine, is effective in causing the excitation or inhibition. These receptors are discussed in more detail in Chapter 60 in relation to function of the autonomic nervous system. Membrane Potentials and Action Potentials in Smooth Muscle Membrane Potentials in Smooth Muscle. The quantitative voltage of the membrane potential of smooth muscle depends on the momentary condition of the muscle. In the normal resting state, the intracellular potential is usually about -50 to -60 millivolts, which is about 30 millivolts less negative than in skeletal muscle. Action Potentials in Unitary Smooth Muscle. Action poten- tials occur in unitary smooth muscle (such as visceral muscle) in the same way that they occur in skeletal muscle. They do not normally occur in many, if not most, multi-unit types of smooth muscle, as discussed in a subsequent section. The action potentials of visceral smooth muscle occur in one of two forms: (1) spike potentials or (2) action potentials with plateaus. Spike Potentials. Typical spike action potentials, such as those seen in skeletal muscle, occur in most types of unitary smooth muscle. The duration of this type of action potential is 10 to 50 milliseconds, as shown in Figure 8–4A. Such action potentials can be elicited in many ways, for example, by electrical stimulation, by the action of hormones on the smooth muscle, by the action of transmitter substances from nerve fibers, by stretch, or as a result of spontaneous generation in the muscle fiber itself, as discussed subsequently. Action Potentials with Plateaus. Figure 8–4C shows a smooth muscle action potential with a plateau. The onset of this action potential is similar to that of the typical spike potential. However, instead of rapid repolarization of the muscle fiber membrane, the repolarization is delayed for several hundred to as much as 1000 milliseconds (1 second). The importance of the plateau is that it can account for the prolonged Chapter 8 Contraction and Excitation of Smooth Muscle 97 ions act directly on the smooth muscle contractile mechanism to cause contraction. Thus, the calcium performs two tasks at once. 0 Slow Wave Potentials in Unitary Smooth Muscle, and Spontaneous Generation of Action Potentials. Some smooth Millivolts +20 –40 Slow waves –60 0 A 100 0 Milliseconds 50 B 10 20 30 Seconds Millivolts 0 – 25 – 50 0 C 0.1 0.2 0.3 0.4 Seconds Figure 8–4 A, Typical smooth muscle action potential (spike potential) elicited by an external stimulus. B, Repetitive spike potentials, elicited by slow rhythmical electrical waves that occur spontaneously in the smooth muscle of the intestinal wall. C, Action potential with a plateau, recorded from a smooth muscle fiber of the uterus. contraction that occurs in some types of smooth muscle, such as the ureter, the uterus under some conditions, and certain types of vascular smooth muscle. (Also, this is the type of action potential seen in cardiac muscle fibers that have a prolonged period of contraction, as discussed in Chapters 9 and 10.) Importance of Calcium Channels in Generating the Smooth Muscle Action Potential. The smooth muscle cell membrane has far more voltage-gated calcium channels than does skeletal muscle but few voltagegated sodium channels. Therefore, sodium participates little in the generation of the action potential in most smooth muscle. Instead, flow of calcium ions to the interior of the fiber is mainly responsible for the action potential. This occurs in the same self-regenerative way as occurs for the sodium channels in nerve fibers and in skeletal muscle fibers. However, the calcium channels open many times more slowly than do sodium channels, and they also remain open much longer. This accounts in large measure for the prolonged plateau action potentials of some smooth muscle fibers. Another important feature of calcium ion entry into the cells during the action potential is that the calcium muscle is self-excitatory. That is, action potentials arise within the smooth muscle cells themselves without an extrinsic stimulus. This often is associated with a basic slow wave rhythm of the membrane potential. A typical slow wave in a visceral smooth muscle of the gut is shown in Figure 8–4B. The slow wave itself is not the action potential. That is, it is not a selfregenerative process that spreads progressively over the membranes of the muscle fibers. Instead, it is a local property of the smooth muscle fibers that make up the muscle mass. The cause of the slow wave rhythm is unknown. One suggestion is that the slow waves are caused by waxing and waning of the pumping of positive ions (presumably sodium ions) outward through the muscle fiber membrane; that is, the membrane potential becomes more negative when sodium is pumped rapidly and less negative when the sodium pump becomes less active. Another suggestion is that the conductances of the ion channels increase and decrease rhythmically. The importance of the slow waves is that, when they are strong enough, they can initiate action potentials. The slow waves themselves cannot cause muscle contraction, but when the peak of the negative slow wave potential inside the cell membrane rises in the positive direction from -60 to about -35 millivolts (the approximate threshold for eliciting action potentials in most visceral smooth muscle), an action potential develops and spreads over the muscle mass. Then contraction does occur. Figure 8–4B demonstrates this effect, showing that at each peak of the slow wave, one or more action potentials occur. These repetitive sequences of action potentials elicit rhythmical contraction of the smooth muscle mass. Therefore, the slow waves are called pacemaker waves. In Chapter 62, we see that this type of pacemaker activity controls the rhythmical contractions of the gut. Excitation of Visceral Smooth Muscle by Muscle Stretch. When visceral (unitary) smooth muscle is stretched sufficiently, spontaneous action potentials usually are generated. They result from a combination of (1) the normal slow wave potentials and (2) decrease in overall negativity of the membrane potential caused by the stretch itself. This response to stretch allows the gut wall, when excessively stretched, to contract automatically and rhythmically. For instance, when the gut is overfilled by intestinal contents, local automatic contractions often set up peristaltic waves that move the contents away from the overfilled intestine, usually in the direction of the anus. Depolarization of Multi-Unit Smooth Muscle Without Action Potentials The smooth muscle fibers of multi-unit smooth muscle (such as the muscle of the iris of the eye or the 98 Unit II Membrane Physiology, Nerve, and Muscle piloerector muscle of each hair) normally contract mainly in response to nerve stimuli. The nerve endings secrete acetylcholine in the case of some multi-unit smooth muscles and norepinephrine in the case of others. In both instances, the transmitter substances cause depolarization of the smooth muscle membrane, and this in turn elicits contraction. Action potentials usually do not develop; the reason is that the fibers are too small to generate an action potential. (When action potentials are elicited in visceral unitary smooth muscle, 30 to 40 smooth muscle fibers must depolarize simultaneously before a self-propagating action potential ensues.) Yet, in small smooth muscle cells, even without an action potential, the local depolarization (called the junctional potential) caused by the nerve transmitter substance itself spreads “electrotonically” over the entire fiber and is all that is needed to cause muscle contraction. Effect of Local Tissue Factors and Hormones to Cause Smooth Muscle Contraction Without Action Potentials Probably half of all smooth muscle contraction is initiated by stimulatory factors acting directly on the smooth muscle contractile machinery and without action potentials. Two types of non-nervous and non–action potential stimulating factors often involved are (1) local tissue chemical factors and (2) various hormones. Smooth Muscle Contraction in Response to Local Tissue Chemical Factors. In Chapter 17, we discuss control of contraction of the arterioles, meta-arterioles, and precapillary sphincters. The smallest of these vessels have little or no nervous supply. Yet the smooth muscle is highly contractile, responding rapidly to changes in local chemical conditions in the surrounding interstitial fluid. In the normal resting state, many of these small blood vessels remain contracted. But when extra blood flow to the tissue is needed, multiple factors can relax the vessel wall, thus allowing for increased flow. In this way, a powerful local feedback control system controls the blood flow to the local tissue area. Some of the specific control factors are as follows: 1. Lack of oxygen in the local tissues causes smooth muscle relaxation and, therefore, vasodilatation. 2. Excess carbon dioxide causes vasodilatation. 3. Increased hydrogen ion concentration causes vasodilatation. Adenosine, lactic acid, increased potassium ions, diminished calcium ion concentration, and increased body temperature can all cause local vasodilatation. Effects of Hormones on Smooth Muscle Contraction. Most circulating hormones in the blood affect smooth muscle contraction to some degree, and some have profound effects. Among the more important of these are norepinephrine, epinephrine, acetylcholine, angiotensin, endothelin, vasopressin, oxytocin, serotonin, and histamine. A hormone causes contraction of a smooth muscle when the muscle cell membrane contains hormonegated excitatory receptors for the respective hormone. Conversely, the hormone causes inhibition if the membrane contains inhibitory receptors for the hormone rather than excitatory receptors. Mechanisms of Smooth Muscle Excitation or Inhibition by Hormones or Local Tissue Factors. Some hormone receptors in the smooth muscle membrane open sodium or calcium ion channels and depolarize the membrane, the same as after nerve stimulation. Sometimes action potentials result, or action potentials that are already occurring may be enhanced. In other cases, depolarization occurs without action potentials, and this depolarization allows calcium ion entry into the cell, which promotes the contraction. Inhibition, in contrast, occurs when the hormone (or other tissue factor) closes the sodium and calcium channels to prevent entry of these positive ions; inhibition also occurs if the normally closed potassium channels are opened, allowing positive potassium ions to diffuse out of the cell. Both of these actions increase the degree of negativity inside the muscle cell, a state called hyperpolarization, which strongly inhibits muscle contraction. Sometimes smooth muscle contraction or inhibition is initiated by hormones without directly causing any change in the membrane potential. In these instances, the hormone may activate a membrane receptor that does not open any ion channels but instead causes an internal change in the muscle fiber, such as release of calcium ions from the intracellular sarcoplasmic reticulum; the calcium then induces contraction. To inhibit contraction, other receptor mechanisms are known to activate the enzyme adenylate cyclase or guanylate cyclase in the cell membrane; the portions of the receptors that protrude to the interior of the cells are coupled to these enzymes, causing the formation of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), so-called second messengers. The cAMP or cGMP has many effects, one of which is to change the degree of phosphorylation of several enzymes that indirectly inhibit contraction. The pump that moves calcium ions from the sarcoplasm into the sarcoplasmic reticulum is activated, as well as the cell membrane pump that moves calcium ions out of the cell itself; these effects reduce the calcium ion concentration in the sarcoplasm, thereby inhibiting contraction. Smooth muscles have considerable diversity in how they initiate contraction or relaxation in response to different hormones, neurotransmitters, and other substances. In some instances, the same substance may cause either relaxation or contraction of smooth muscles in different locations. For example, norepinephrine inhibits contraction of smooth muscle in the intestine but stimulates contraction of smooth muscle in blood vessels. Chapter 8 99 Contraction and Excitation of Smooth Muscle Source of Calcium Ions That Cause Contraction (1) Through the Cell Membrane and (2) from the Sarcoplasmic Reticulum Although the contractile process in smooth muscle, as in skeletal muscle, is activated by calcium ions, the source of the calcium ions differs; the difference is that the sarcoplasmic reticulum, which provides virtually all the calcium ions for skeletal muscle contraction, is only slightly developed in most smooth muscle. Instead, almost all the calcium ions that cause contraction enter the muscle cell from the extracellular fluid at the time of the action potential or other stimulus. That is, the concentration of calcium ions in the extracellular fluid is greater than 10-3 molar, in comparison with less than 10-7 molar inside the smooth muscle cell; this causes rapid diffusion of the calcium ions into the cell from the extracellular fluid when the calcium pores open. The time required for this diffusion to occur averages 200 to 300 milliseconds and is called the latent period before contraction begins. This latent period is about 50 times as great for smooth muscle as for skeletal muscle contraction. Role of the Smooth Muscle Sarcoplasmic Reticulum. Figure 8–5 shows a few slightly developed sarcoplasmic tubules that lie near the cell membrane in some larger smooth muscle cells. Small invaginations of the cell membrane, called caveolae, abut the surfaces of these tubules. The caveolae suggest a rudimentary analog of the transverse tubule system of skeletal muscle. When an action potential is transmitted into the caveolae, this is believed to excite calcium ion release from the abutting sarcoplasmic tubules in the same way that action potentials in skeletal muscle transverse tubules cause release of calcium ions from the skeletal muscle longitudinal sarcoplasmic tubules. In general, the more extensive the sarcoplasmic reticulum in the smooth muscle fiber, the more rapidly it contracts. Effect on Smooth Muscle Contraction Caused by Changing of Extracellular Calcium Ion Concentration. Although chang- ing the extracellular fluid calcium ion concentration from normal has little effect on the force of contraction of skeletal muscle, this is not true for most smooth muscle. When the extracellular fluid calcium ion concentration falls to about 1/3 to 1/10 normal, smooth muscle contraction usually ceases. Therefore, the force of contraction of smooth muscle usually is highly dependent on extracellular fluid calcium ion concentration. A Calcium Pump Is Required to Cause Smooth Muscle Relaxation. To cause relaxation of smooth muscle after it has contracted, the calcium ions must be removed from the intracellular fluids. This removal is achieved by a calcium pump that pumps calcium ions out Caveolae Sarcoplasmic reticulum Figure 8–5 Sarcoplasmic tubules in a large smooth muscle fiber showing their relation to invaginations in the cell membrane called caveolae. of the smooth muscle fiber back into the extracellular fluid, or into a sarcoplasmic reticulum, if it is present. This pump is slow-acting in comparison with the fast-acting sarcoplasmic reticulum pump in skeletal muscle. Therefore, a single smooth muscle contraction often lasts for seconds rather than hundredths to tenths of a second, as occurs for skeletal muscle. References Also see references for Chapters 5 and 6. Blaustein MP, Lederer WJ: Sodium/calcium exchange: its physiological implications. Physiol Rev 79:763, 1999. Davis MJ, Hill MA: Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 79:387, 1999. Harnett KM, Biancani P: Calcium-dependent and calciumindependent contractions in smooth muscles. Am J Med 115(Suppl 3A):24S, 2003. Horowitz A, Menice CB, Laporte R, Morgan KG: Mechanisms of smooth muscle contraction. Physiol Rev 76:967, 1996. Kamm KE, Stull JT: Regulation of smooth muscle contractile elements by second messengers. Annu Rev Physiol 51:299, 1989. Kuriyama H, Kitamura K, Itoh T, Inoue R: Physiological features of visceral smooth muscle cells, with special reference to receptors and ion channels. Physiol Rev 78:811, 1998. Lee CH, Poburko D, Kuo KH, et al: Ca2+ oscillations, gradients, and homeostasis in vascular smooth muscle. Am J Physiol Heart Circ Physiol 282:H1571, 2002. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA: Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 93:280, 2003. 100 Unit II Membrane Physiology, Nerve, and Muscle Somlyo AP, Somlyo AV: Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 83:1325, 2003. Stephens NL: Airway smooth muscle. Lung 179:333, 2001. Walker JS, Wingard CJ, Murphy RA: Energetics of crossbridge phosphorylation and contraction in vascular smooth muscle. Hypertension 23:1106, 1994. Webb RC: Smooth muscle contraction and relaxation. Adv Physiol Educ 27:201, 2003. U N I The Heart 9. Heart Muscle; The Heart as a Pump and Function of the Heart Valves 10. Rhythmical Excitation of the Heart 11. The Normal Electrocardiogram 12. Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis 13. Cardiac Arrhythmias and Their Electrocardiographic Interpretation T III C H A P T E R 9 Heart Muscle; The Heart as a Pump and Function of the Heart Valves With this chapter we begin discussion of the heart and circulatory system. The heart, shown in Figure 9–1, is actually two separate pumps: a right heart that pumps blood through the lungs, and a left heart that pumps blood through the peripheral organs. In turn, each of these hearts is a pulsatile two-chamber pump composed of an atrium and a ventricle. Each atrium is a weak primer pump for the ventricle, helping to move blood into the ventricle. The ventricles then supply the main pumping force that propels the blood either (1) through the pulmonary circulation by the right ventricle or (2) through the peripheral circulation by the left ventricle. Special mechanisms in the heart cause a continuing succession of heart contractions called cardiac rhythmicity, transmitting action potentials throughout the heart muscle to cause the heart’s rhythmical beat. This rhythmical control system is explained in Chapter 10. In this chapter, we explain how the heart operates as a pump, beginning with the special features of heart muscle itself. Physiology of Cardiac Muscle The heart is composed of three major types of cardiac muscle: atrial muscle, ventricular muscle, and specialized excitatory and conductive muscle fibers. The atrial and ventricular types of muscle contract in much the same way as skeletal muscle, except that the duration of contraction is much longer. Conversely, the specialized excitatory and conductive fibers contract only feebly because they contain few contractile fibrils; instead, they exhibit either automatic rhythmical electrical discharge in the form of action potentials or conduction of the action potentials through the heart, providing an excitatory system that controls the rhythmical beating of the heart. Physiologic Anatomy of Cardiac Muscle Figure 9–2 shows a typical histological picture of cardiac muscle, demonstrating cardiac muscle fibers arranged in a latticework, with the fibers dividing, recombining, and then spreading again. One also notes immediately from this figure that cardiac muscle is striated in the same manner as in typical skeletal muscle. Further, cardiac muscle has typical myofibrils that contain actin and myosin filaments almost identical to those found in skeletal muscle; these filaments lie side by side and slide along one another during contraction in the same manner as occurs in skeletal muscle (see Chapter 6). But in other ways, cardiac muscle is quite different from skeletal muscle, as we shall see. Cardiac Muscle as a Syncytium. The dark areas crossing the cardiac muscle fibers in Figure 9–2 are called intercalated discs; they are actually cell membranes that separate individual cardiac muscle cells from one another. That is, cardiac muscle fibers are made up of many individual cells connected in series and in parallel with one another. 103 104 Unit III The Heart HEAD AND UPPER EXTREMITY Plateau Aorta Pulmonary artery Superior vena cava Right atrium Pulmonary vein Pulmonary valve Left atrium Tricuspid valve Mitral valve Right ventricle Aortic valve Left ventricle Inferior vena cava Millivolts Lungs +20 0 – 20 – 40 – 60 – 80 –100 Purkinje fiber Plateau +20 0 – 20 – 40 – 60 – 80 –100 Ventricular muscle 0 1 2 3 4 Seconds TRUNK AND LOWER EXTREMITY Figure 9–1 Structure of the heart, and course of blood flow through the heart chambers and heart valves. Figure 9–2 “Syncytial,” interconnecting nature of cardiac muscle fibers. At each intercalated disc the cell membranes fuse with one another in such a way that they form permeable “communicating” junctions (gap junctions) that allow almost totally free diffusion of ions. Therefore, from a functional point of view, ions move with ease in the intracellular fluid along the longitudinal axes of the cardiac muscle fibers, so that action potentials travel easily from one cardiac muscle cell to the next, past the intercalated discs. Thus, cardiac muscle is a syncytium of many heart muscle cells in which the cardiac cells are so interconnected that when one of these cells becomes excited, the action potential spreads to all of them, spreading from cell to cell throughout the latticework interconnections. Figure 9–3 Rhythmical action potentials (in millivolts) from a Purkinje fiber and from a ventricular muscle fiber, recorded by means of microelectrodes. The heart actually is composed of two syncytiums: the atrial syncytium that constitutes the walls of the two atria, and the ventricular syncytium that constitutes the walls of the two ventricles. The atria are separated from the ventricles by fibrous tissue that surrounds the atrioventricular (A-V) valvular openings between the atria and ventricles. Normally, potentials are not conducted from the atrial syncytium into the ventricular syncytium directly through this fibrous tissue. Instead, they are conducted only by way of a specialized conductive system called the A-V bundle, a bundle of conductive fibers several millimeters in diameter that is discussed in detail in Chapter 10. This division of the muscle of the heart into two functional syncytiums allows the atria to contract a short time ahead of ventricular contraction, which is important for effectiveness of heart pumping. Action Potentials in Cardiac Muscle The action potential recorded in a ventricular muscle fiber, shown in Figure 9–3, averages about 105 millivolts, which means that the intracellular potential rises from a very negative value, about -85 millivolts, between beats to a slightly positive value, about +20 millivolts, during each beat. After the initial spike, the membrane remains depolarized for about 0.2 second, exhibiting a plateau as shown in the figure, followed at the end of the plateau by abrupt repolarization. The presence of this plateau in the action potential causes ventricular contraction to last as much as 15 times as long in cardiac muscle as in skeletal muscle. Chapter 9 105 Heart Muscle; The Heart as a Pump and Function of the Heart Valves What Causes the Long Action Potential and the Plateau? At this point, we must ask the questions: Why is the action potential of cardiac muscle so long, and why does it have a plateau, whereas that of skeletal muscle does not? The basic biophysical answers to these questions were presented in Chapter 5, but they merit summarizing here as well. At least two major differences between the membrane properties of cardiac and skeletal muscle account for the prolonged action potential and the plateau in cardiac muscle. First, the action potential of skeletal muscle is caused almost entirely by sudden opening of large numbers of so-called fast sodium channels that allow tremendous numbers of sodium ions to enter the skeletal muscle fiber from the extracellular fluid. These channels are called “fast” channels because they remain open for only a few thousandths of a second and then abruptly close. At the end of this closure, repolarization occurs, and the action potential is over within another thousandth of a second or so. In cardiac muscle, the action potential is caused by opening of two types of channels: (1) the same fast sodium channels as those in skeletal muscle and (2) another entirely different population of slow calcium channels, which are also called calcium-sodium channels. This second population of channels differs from the fast sodium channels in that they are slower to open and, even more important, remain open for several tenths of a second. During this time, a large quantity of both calcium and sodium ions flows through these channels to the interior of the cardiac muscle fiber, and this maintains a prolonged period of depolarization, causing the plateau in the action potential. Further, the calcium ions that enter during this plateau phase activate the muscle contractile process, while the calcium ions that cause skeletal muscle contraction are derived from the intracellular sarcoplasmic reticulum. The second major functional difference between cardiac muscle and skeletal muscle that helps account for both the prolonged action potential and its plateau is this: Immediately after the onset of the action potential, the permeability of the cardiac muscle membrane for potassium ions decreases about fivefold, an effect that does not occur in skeletal muscle. This decreased potassium permeability may result from the excess calcium influx through the calcium channels just noted. Regardless of the cause, the decreased potassium permeability greatly decreases the outflux of positively charged potassium ions during the action potential plateau and thereby prevents early return of the action potential voltage to its resting level. When the slow calcium-sodium channels do close at the end of 0.2 to 0.3 second and the influx of calcium and sodium ions ceases, the membrane permeability for potassium ions also increases rapidly; this rapid loss of potassium from the fiber immediately returns the membrane potential to its resting level, thus ending the action potential. Velocity of Signal Conduction in Cardiac Muscle. The velocity of conduction of the excitatory action potential signal along both atrial and ventricular muscle fibers is about 0.3 to 0.5 m/sec, or about 1/250 the velocity in very large nerve fibers and about 1/10 the velocity in skeletal muscle fibers. The velocity of conduction in the specialized heart conductive system—in the Purkinje fibers—is as great as 4 m/sec in most parts of the system, which allows reasonably rapid conduction of the excitatory signal to the different parts of the heart, as explained in Chapter 10. Refractory Period of Cardiac Muscle. Cardiac muscle, like all excitable tissue, is refractory to restimulation during the action potential. Therefore, the refractory period of the heart is the interval of time, as shown to the left in Figure 9–4, during which a normal cardiac impulse cannot re-excite an already excited area of cardiac muscle. The normal refractory period of the ventricle is 0.25 to 0.30 second, which is about the duration of the prolonged plateau action potential. There is an additional relative refractory period of Refractory period Force of ventricular heart muscle contraction, showing also duration of the refractory period and relative refractory period, plus the effect of premature contraction. Note that premature contractions do not cause wave summation, as occurs in skeletal muscle. Force of contraction Figure 9–4 Relative refractory period Early premature contraction 0 1 2 Seconds Later premature contraction 3 106 Unit III about 0.05 second during which the muscle is more difficult than normal to excite but nevertheless can be excited by a very strong excitatory signal, as demonstrated by the early “premature” contraction in the second example of Figure 9–4. The refractory period of atrial muscle is much shorter than that for the ventricles (about 0.15 second for the atria compared with 0.25 to 0.30 second for the ventricles). Excitation-Contraction Coupling—Function of Calcium Ions and the Transverse Tubules The term “excitation-contraction coupling” refers to the mechanism by which the action potential causes the myofibrils of muscle to contract. This was discussed for skeletal muscle in Chapter 7. Once again, there are differences in this mechanism in cardiac muscle that have important effects on the characteristics of cardiac muscle contraction. As is true for skeletal muscle, when an action potential passes over the cardiac muscle membrane, the action potential spreads to the interior of the cardiac muscle fiber along the membranes of the transverse (T) tubules. The T tubule action potentials in turn act on the membranes of the longitudinal sarcoplasmic tubules to cause release of calcium ions into the muscle sarcoplasm from the sarcoplasmic reticulum. In another few thousandths of a second, these calcium ions diffuse into the myofibrils and catalyze the chemical reactions that promote sliding of the actin and myosin filaments along one another; this produces the muscle contraction. Thus far, this mechanism of excitation-contraction coupling is the same as that for skeletal muscle, but there is a second effect that is quite different. In addition to the calcium ions that are released into the sarcoplasm from the cisternae of the sarcoplasmic reticulum, a large quantity of extra calcium ions also diffuses into the sarcoplasm from the T tubules themselves at the time of the action potential. Indeed, without this extra calcium from the T tubules, the strength of cardiac muscle contraction would be reduced considerably because the sarcoplasmic reticulum of cardiac muscle is less well developed than that of skeletal muscle and does not store enough calcium to provide full contraction. Conversely, the T tubules of cardiac muscle have a diameter 5 times as great as that of the skeletal muscle tubules, which means a volume 25 times as great. Also, inside the T tubules is a large quantity of mucopolysaccharides that are electronegatively charged and bind an abundant store of calcium ions, keeping these always available for diffusion to the interior of the cardiac muscle fiber when a T tubule action potential appears. The strength of contraction of cardiac muscle depends to a great extent on the concentration of calcium ions in the extracellular fluids. The reason for this is that the openings of the T tubules pass directly through the cardiac muscle cell membrane into the extracellular spaces surrounding the cells, allowing the same extracellular fluid that is in the cardiac muscle interstitium to percolate through the T tubules as well. Consequently, the quantity of calcium ions in the T The Heart tubule system—that is, the availability of calcium ions to cause cardiac muscle contraction—depends to a great extent on the extracellular fluid calcium ion concentration. (By way of contrast, the strength of skeletal muscle contraction is hardly affected by moderate changes in extracellular fluid calcium concentration because skeletal muscle contraction is caused almost entirely by calcium ions released from the sarcoplasmic reticulum inside the skeletal muscle fiber itself.) At the end of the plateau of the cardiac action potential, the influx of calcium ions to the interior of the muscle fiber is suddenly cut off, and the calcium ions in the sarcoplasm are rapidly pumped back out of the muscle fibers into both the sarcoplasmic reticulum and the T tubule–extracellular fluid space. As a result, the contraction ceases until a new action potential comes along. Duration of Contraction. Cardiac muscle begins to contract a few milliseconds after the action potential begins and continues to contract until a few milliseconds after the action potential ends. Therefore, the duration of contraction of cardiac muscle is mainly a function of the duration of the action potential, including the plateau— about 0.2 second in atrial muscle and 0.3 second in ventricular muscle. The Cardiac Cycle The cardiac events that occur from the beginning of one heartbeat to the beginning of the next are called the cardiac cycle. Each cycle is initiated by spontaneous generation of an action potential in the sinus node, as explained in Chapter 10. This node is located in the superior lateral wall of the right atrium near the opening of the superior vena cava, and the action potential travels from here rapidly through both atria and then through the A-V bundle into the ventricles. Because of this special arrangement of the conducting system from the atria into the ventricles, there is a delay of more than 0.1 second during passage of the cardiac impulse from the atria into the ventricles. This allows the atria to contract ahead of ventricular contraction, thereby pumping blood into the ventricles before the strong ventricular contraction begins. Thus, the atria act as primer pumps for the ventricles, and the ventricles in turn provide the major source of power for moving blood through the body’s vascular system. Diastole and Systole The cardiac cycle consists of a period of relaxation called diastole, during which the heart fills with blood, followed by a period of contraction called systole. Figure 9–5 shows the different events during the cardiac cycle for the left side of the heart.The top three curves show the pressure changes in the aorta, left ventricle, and left atrium, respectively. The fourth curve depicts the changes in left ventricular volume, the fifth Chapter 9 Heart Muscle; The Heart as a Pump and Function of the Heart Valves 107 Isovolumic relaxation Isovolumic contraction Volume (ml) Pressure (mm Hg) 120 100 Ejection Rapid inflow Diastasis Atrial systole Aortic valve closes Aortic valve opens Aortic pressure 80 60 40 A-V valve opens A-V valve closes 20 a c v 0 130 Atrial pressure Ventricular pressure Ventricular volume 90 R 50 P Q 1st 2nd 3rd T Electrocardiogram S Phonocardiogram Systole Diastole Systole Figure 9–5 Events of the cardiac cycle for left ventricular function, showing changes in left atrial pressure, left ventricular pressure, aortic pressure, ventricular volume, the electrocardiogram, and the phonocardiogram. the electrocardiogram, and the sixth a phonocardiogram, which is a recording of the sounds produced by the heart—mainly by the heart valves—as it pumps. It is especially important that the reader study in detail this figure and understand the causes of all the events shown. Relationship of the Electrocardiogram to the Cardiac Cycle The electrocardiogram in Figure 9–5 shows the P, Q, R, S, and T waves, which are discussed in Chapters 11, 12, and 13. They are electrical voltages generated by the heart and recorded by the electrocardiograph from the surface of the body. The P wave is caused by spread of depolarization through the atria, and this is followed by atrial contraction, which causes a slight rise in the atrial pressure curve immediately after the electrocardiographic P wave. About 0.16 second after the onset of the P wave, the QRS waves appear as a result of electrical depolarization of the ventricles, which initiates contraction of the ventricles and causes the ventricular pressure to begin rising, as also shown in the figure. Therefore, the QRS complex begins slightly before the onset of ventricular systole. Finally, one observes the ventricular T wave in the electrocardiogram. This represents the stage of repolarization of the ventricles when the ventricular muscle fibers begin to relax. Therefore, the T wave occurs slightly before the end of ventricular contraction. Function of the Atria as Primer Pumps Blood normally flows continually from the great veins into the atria; about 80 per cent of the blood flows directly through the atria into the ventricles even before the atria contract. Then, atrial contraction usually causes an additional 20 per cent filling of the ventricles. Therefore, the atria simply function as 108 Unit III primer pumps that increase the ventricular pumping effectiveness as much as 20 per cent. However, the heart can continue to operate under most conditions even without this extra 20 per cent effectiveness because it normally has the capability of pumping 300 to 400 per cent more blood than is required by the resting body. Therefore, when the atria fail to function, the difference is unlikely to be noticed unless a person exercises; then acute signs of heart failure occasionally develop, especially shortness of breath. Pressure Changes in the Atria—The a, c, and v Waves. In the atrial pressure curve of Figure 9–5, three minor pressure elevations, called the a, c, and v atrial pressure waves, are noted. The a wave is caused by atrial contraction. Ordinarily, the right atrial pressure increases 4 to 6 mm Hg during atrial contraction, and the left atrial pressure increases about 7 to 8 mm Hg. The c wave occurs when the ventricles begin to contract; it is caused partly by slight backflow of blood into the atria at the onset of ventricular contraction but mainly by bulging of the A-V valves backward toward the atria because of increasing pressure in the ventricles. The v wave occurs toward the end of ventricular contraction; it results from slow flow of blood into the atria from the veins while the A-V valves are closed during ventricular contraction. Then, when ventricular contraction is over, the A-V valves open, allowing this stored atrial blood to flow rapidly into the ventricles and causing the v wave to disappear. Function of the Ventricles as Pumps Filling of the Ventricles. During ventricular systole, large amounts of blood accumulate in the right and left atria because of the closed A-V valves. Therefore, as soon as systole is over and the ventricular pressures fall again to their low diastolic values, the moderately increased pressures that have developed in the atria during ventricular systole immediately push the A-V valves open and allow blood to flow rapidly into the ventricles, as shown by the rise of the left ventricular volume curve in Figure 9–5. This is called the period of rapid filling of the ventricles. The period of rapid filling lasts for about the first third of diastole. During the middle third of diastole, only a small amount of blood normally flows into the ventricles; this is blood that continues to empty into the atria from the veins and passes through the atria directly into the ventricles. During the last third of diastole, the atria contract and give an additional thrust to the inflow of blood into the ventricles; this accounts for about 20 per cent of the filling of the ventricles during each heart cycle. Emptying of the Ventricles During Systole Period of Isovolumic (Isometric) Contraction. Immediately after ventricular contraction begins, the ventricular pressure rises abruptly, as shown in Figure 9–5, The Heart causing the A-V valves to close. Then an additional 0.02 to 0.03 second is required for the ventricle to build up sufficient pressure to push the semilunar (aortic and pulmonary) valves open against the pressures in the aorta and pulmonary artery. Therefore, during this period, contraction is occurring in the ventricles, but there is no emptying. This is called the period of isovolumic or isometric contraction, meaning that tension is increasing in the muscle but little or no shortening of the muscle fibers is occurring. Period of Ejection. When the left ventricular pressure rises slightly above 80 mm Hg (and the right ventricular pressure slightly above 8 mm Hg), the ventricular pressures push the semilunar valves open. Immediately, blood begins to pour out of the ventricles, with about 70 per cent of the blood emptying occurring during the first third of the period of ejection and the remaining 30 per cent emptying during the next two thirds. Therefore, the first third is called the period of rapid ejection, and the last two thirds, the period of slow ejection. Period of Isovolumic (Isometric) Relaxation. At the end of systole, ventricular relaxation begins suddenly, allowing both the right and left intraventricular pressures to decrease rapidly. The elevated pressures in the distended large arteries that have just been filled with blood from the contracted ventricles immediately push blood back toward the ventricles, which snaps the aortic and pulmonary valves closed. For another 0.03 to 0.06 second, the ventricular muscle continues to relax, even though the ventricular volume does not change, giving rise to the period of isovolumic or isometric relaxation. During this period, the intraventricular pressures decrease rapidly back to their low diastolic levels. Then the A-V valves open to begin a new cycle of ventricular pumping. End-Diastolic Volume, End-Systolic Volume, and Stroke Volume Output. During diastole, normal filling of the ventricles increases the volume of each ventricle to about 110 to 120 milliliters. This volume is called the end-diastolic volume. Then, as the ventricles empty during systole, the volume decreases about 70 milliliters, which is called the stroke volume output. The remaining volume in each ventricle, about 40 to 50 milliliters, is called the end-systolic volume. The fraction of the end-diastolic volume that is ejected is called the ejection fraction— usually equal to about 60 per cent. When the heart contracts strongly, the end-systolic volume can be decreased to as little as 10 to 20 milliliters. Conversely, when large amounts of blood flow into the ventricles during diastole, the ventricular enddiastolic volumes can become as great as 150 to 180 milliliters in the healthy heart. By both increasing the end-diastolic volume and decreasing the end-systolic volume, the stroke volume output can be increased to more than double normal. Chapter 9 Heart Muscle; The Heart as a Pump and Function of the Heart Valves Function of the Valves 109 Aortic and Pulmonary Artery Valves. The aortic and pul- Atrioventricular Valves. The A-V valves (the tricuspid and mitral valves) prevent backflow of blood from the ventricles to the atria during systole, and the semilunar valves (the aortic and pulmonary artery valves) prevent backflow from the aorta and pulmonary arteries into the ventricles during diastole. These valves, shown in Figure 9–6 for the left ventricle, close and open passively. That is, they close when a backward pressure gradient pushes blood backward, and they open when a forward pressure gradient forces blood in the forward direction. For anatomical reasons, the thin, filmy A-V valves require almost no backflow to cause closure, whereas the much heavier semilunar valves require rather rapid backflow for a few milliseconds. Function of the Papillary Muscles. Figure 9–6 also shows papillary muscles that attach to the vanes of the A-V valves by the chordae tendineae. The papillary muscles contract when the ventricular walls contract, but contrary to what might be expected, they do not help the valves to close. Instead, they pull the vanes of the valves inward toward the ventricles to prevent their bulging too far backward toward the atria during ventricular contraction. If a chorda tendinea becomes ruptured or if one of the papillary muscles becomes paralyzed, the valve bulges far backward during ventricular contraction, sometimes so far that it leaks severely and results in severe or even lethal cardiac incapacity. MITRAL VALVE Cusp Chordae tendineae Papillary muscles Cusp AORTIC VALVE monary artery semilunar valves function quite differently from the A-V valves. First, the high pressures in the arteries at the end of systole cause the semilunar valves to snap to the closed position, in contrast to the much softer closure of the A-V valves. Second, because of smaller openings, the velocity of blood ejection through the aortic and pulmonary valves is far greater than that through the much larger A-V valves. Also, because of the rapid closure and rapid ejection, the edges of the aortic and pulmonary valves are subjected to much greater mechanical abrasion than are the A-V valves. Finally, the A-V valves are supported by the chordae tendineae, which is not true for the semilunar valves. It is obvious from the anatomy of the aortic and pulmonary valves (as shown for the aortic valve at the bottom of Figure 9–6) that they must be constructed with an especially strong yet very pliable fibrous tissue base to withstand the extra physical stresses. Aortic Pressure Curve When the left ventricle contracts, the ventricular pressure increases rapidly until the aortic valve opens. Then, after the valve opens, the pressure in the ventricle rises much less rapidly, as shown in Figure 9–5, because blood immediately flows out of the ventricle into the aorta and then into the systemic distribution arteries. The entry of blood into the arteries causes the walls of these arteries to stretch and the pressure to increase to about 120 mm Hg. Next, at the end of systole, after the left ventricle stops ejecting blood and the aortic valve closes, the elastic walls of the arteries maintain a high pressure in the arteries, even during diastole. A so-called incisura occurs in the aortic pressure curve when the aortic valve closes. This is caused by a short period of backward flow of blood immediately before closure of the valve, followed by sudden cessation of the backflow. After the aortic valve has closed, the pressure in the aorta decreases slowly throughout diastole because the blood stored in the distended elastic arteries flows continually through the peripheral vessels back to the veins. Before the ventricle contracts again, the aortic pressure usually has fallen to about 80 mm Hg (diastolic pressure), which is two thirds the maximal pressure of 120 mm Hg (systolic pressure) that occurs in the aorta during ventricular contraction. The pressure curves in the right ventricle and pulmonary artery are similar to those in the aorta, except that the pressures are only about one sixth as great, as discussed in Chapter 14. Relationship of the Heart Sounds to Heart Pumping Figure 9–6 Mitral and aortic valves (the left ventricular valves). When listening to the heart with a stethoscope, one does not hear the opening of the valves because this is a Unit III relatively slow process that normally makes no noise. However, when the valves close, the vanes of the valves and the surrounding fluids vibrate under the influence of sudden pressure changes, giving off sound that travels in all directions through the chest. When the ventricles contract, one first hears a sound caused by closure of the A-V valves. The vibration is low in pitch and relatively long-lasting and is known as the first heart sound. When the aortic and pulmonary valves close at the end of systole, one hears a rapid snap because these valves close rapidly, and the surroundings vibrate for a short period. This sound is called the second heart sound. The precise causes of the heart sounds are discussed more fully in Chapter 23, in relation to listening to the sounds with the stethoscope. The Heart 300 Intraventricular pressure (mm Hg) 110 Systolic pressure 250 200 Isovolumic relaxation Period of ejection 150 Isovolumic contraction III 100 EW IV 50 I II Diastolic pressure 0 0 Work Output of the Heart The stroke work output of the heart is the amount of energy that the heart converts to work during each heartbeat while pumping blood into the arteries. Minute work output is the total amount of energy converted to work in 1 minute; this is equal to the stroke work output times the heart rate per minute. Work output of the heart is in two forms. First, by far the major proportion is used to move the blood from the low-pressure veins to the high-pressure arteries. This is called volume-pressure work or external work. Second, a minor proportion of the energy is used to accelerate the blood to its velocity of ejection through the aortic and pulmonary valves. This is the kinetic energy of blood flow component of the work output. Right ventricular external work output is normally about one sixth the work output of the left ventricle because of the sixfold difference in systolic pressures that the two ventricles pump. The additional work output of each ventricle required to create kinetic energy of blood flow is proportional to the mass of blood ejected times the square of velocity of ejection. Ordinarily, the work output of the left ventricle required to create kinetic energy of blood flow is only about 1 per cent of the total work output of the ventricle and therefore is ignored in the calculation of the total stroke work output. But in certain abnormal conditions, such as aortic stenosis, in which blood flows with great velocity through the stenosed valve, more than 50 per cent of the total work output may be required to create kinetic energy of blood flow. Graphical Analysis of Ventricular Pumping Figure 9–7 shows a diagram that is especially useful in explaining the pumping mechanics of the left ventricle. The most important components of the diagram are the two curves labeled “diastolic pressure” and “systolic pressure.” These curves are volume-pressure curves. The diastolic pressure curve is determined by filling the heart with progressively greater volumes of blood and then measuring the diastolic pressure immediately before ventricular contraction occurs, which is the enddiastolic pressure of the ventricle. The systolic pressure curve is determined by recording the systolic pressure achieved during ventricular contraction at each volume of filling. 50 Period of filling 100 150 200 250 Left ventricular volume (ml) Figure 9–7 Relationship between left ventricular volume and intraventricular pressure during diastole and systole. Also shown by the heavy red lines is the “volume-pressure diagram,” demonstrating changes in intraventricular volume and pressure during the normal cardiac cycle. EW, net external work. Until the volume of the noncontracting ventricle rises above about 150 milliliters, the “diastolic” pressure does not increase greatly. Therefore, up to this volume, blood can flow easily into the ventricle from the atrium. Above 150 milliliters, the ventricular diastolic pressure increases rapidly, partly because of fibrous tissue in the heart that will stretch no more and partly because the pericardium that surrounds the heart becomes filled nearly to its limit. During ventricular contraction, the “systolic” pressure increases even at low ventricular volumes and reaches a maximum at a ventricular volume of 150 to 170 milliliters. Then, as the volume increases still further, the systolic pressure actually decreases under some conditions, as demonstrated by the falling systolic pressure curve in Figure 9–7, because at these great volumes, the actin and myosin filaments of the cardiac muscle fibers are pulled apart far enough that the strength of each cardiac fiber contraction becomes less than optimal. Note especially in the figure that the maximum systolic pressure for the normal left ventricle is between 250 and 300 mm Hg, but this varies widely with each person’s heart strength and degree of heart stimulation by cardiac nerves. For the normal right ventricle, the maximum systolic pressure is between 60 and 80 mm Hg. “Volume-Pressure Diagram” During the Cardiac Cycle; Cardiac Work Output. The red lines in Figure 9–7 form a loop called the volume-pressure diagram of the cardiac cycle for normal function of the left ventricle. It is divided into four phases. Phase I: Period of filling. This phase in the volumepressure diagram begins at a ventricular volume of about 45 milliliters and a diastolic pressure near 0 mm Hg. Forty-five milliliters is the amount of Chapter 9 Heart Muscle; The Heart as a Pump and Function of the Heart Valves blood that remains in the ventricle after the previous heartbeat and is called the end-systolic volume. As venous blood flows into the ventricle from the left atrium, the ventricular volume normally increases to about 115 milliliters, called the end-diastolic volume, an increase of 70 milliliters. Therefore, the volume-pressure diagram during phase I extends along the line labeled “I,” with the volume increasing to 115 milliliters and the diastolic pressure rising to about 5 mm Hg. Phase II: Period of isovolumic contraction. During isovolumic contraction, the volume of the ventricle does not change because all valves are closed. However, the pressure inside the ventricle increases to equal the pressure in the aorta, at a pressure value of about 80 mm Hg, as depicted by the arrow end of the line labeled “II.” Phase III: Period of ejection. During ejection, the systolic pressure rises even higher because of still more contraction of the ventricle. At the same time, the volume of the ventricle decreases because the aortic valve has now opened and blood flows out of the ventricle into the aorta. Therefore, the curve labeled “III” traces the changes in volume and systolic pressure during this period of ejection. Phase IV: Period of isovolumic relaxation. At the end of the period of ejection, the aortic valve closes, and the ventricular pressure falls back to the diastolic pressure level. The line labeled “IV” traces this decrease in intraventricular pressure without any change in volume. Thus, the ventricle returns to its starting point, with about 45 milliliters of blood left in the ventricle and at an atrial pressure near 0 mm Hg. Readers well trained in the basic principles of physics should recognize that the area subtended by this functional volume-pressure diagram (the tan shaded area, labeled EW) represents the net external work output of the ventricle during its contraction cycle. In experimental studies of cardiac contraction, this diagram is used for calculating cardiac work output. When the heart pumps large quantities of blood, the area of the work diagram becomes much larger. That is, it extends far to the right because the ventricle fills with more blood during diastole, it rises much higher because the ventricle contracts with greater pressure, and it usually extends farther to the left because the ventricle contracts to a smaller volume—especially if the ventricle is stimulated to increased activity by the sympathetic nervous system. Concepts of Preload and Afterload. In assessing the contrac- tile properties of muscle, it is important to specify the degree of tension on the muscle when it begins to contract, which is called the preload, and to specify the load against which the muscle exerts its contractile force, which is called the afterload. For cardiac contraction, the preload is usually considered to be the end-diastolic pressure when the ventricle has become filled. The afterload of the ventricle is the pressure in the artery leading from the ventricle. In Figure 9–7, this corresponds to the systolic pressure described by the phase III curve of the volume-pressure diagram. (Sometimes the afterload is loosely considered to be the resistance in the circulation rather than the pressure.) 111 The importance of the concepts of preload and afterload is that in many abnormal functional states of the heart or circulation, the pressure during filling of the ventricle (the preload), the arterial pressure against which the ventricle must contract (the afterload), or both are severely altered from normal. Chemical Energy Required for Cardiac Contraction: Oxygen Utilization by the Heart Heart muscle, like skeletal muscle, uses chemical energy to provide the work of contraction. This energy is derived mainly from oxidative metabolism of fatty acids and, to a lesser extent, of other nutrients, especially lactate and glucose. Therefore, the rate of oxygen consumption by the heart is an excellent measure of the chemical energy liberated while the heart performs its work. The different chemical reactions that liberate this energy are discussed in Chapters 67 and 68. Efficiency of Cardiac Contraction. During heart muscle contraction, most of the expended chemical energy is converted into heat and a much smaller portion into work output. The ratio of work output to total chemical energy expenditure is called the efficiency of cardiac contraction, or simply efficiency of the heart. Maximum efficiency of the normal heart is between 20 and 25 per cent. In heart failure, this can decrease to as low as 5 to 10 per cent. Regulation of Heart Pumping When a person is at rest, the heart pumps only 4 to 6 liters of blood each minute. During severe exercise, the heart may be required to pump four to seven times this amount. The basic means by which the volume pumped by the heart is regulated are (1) intrinsic cardiac regulation of pumping in response to changes in volume of blood flowing into the heart and (2) control of heart rate and strength of heart pumping by the autonomic nervous system. Intrinsic Regulation of Heart Pumping—The Frank-Starling Mechanism In Chapter 20, we will learn that under most conditions, the amount of blood pumped by the heart each minute is determined almost entirely by the rate of blood flow into the heart from the veins, which is called venous return. That is, each peripheral tissue of the body controls its own local blood flow, and all the local tissue flows combine and return by way of the veins to the right atrium. The heart, in turn, automatically pumps this incoming blood into the arteries, so that it can flow around the circuit again. This intrinsic ability of the heart to adapt to increasing volumes of inflowing blood is called the FrankStarling mechanism of the heart, in honor of Frank and 112 Unit III Starling, two great physiologists of a century ago. Basically, the Frank-Starling mechanism means that the greater the heart muscle is stretched during filling, the greater is the force of contraction and the greater the quantity of blood pumped into the aorta. Or, stated another way: Within physiologic limits, the heart pumps all the blood that returns to it by the way of the veins. What Is the Explanation of the Frank-Starling Mechanism? When an extra amount of blood flows into the ventricles, the cardiac muscle itself is stretched to greater length. This in turn causes the muscle to contract with increased force because the actin and myosin filaments are brought to a more nearly optimal degree of overlap for force generation. Therefore, the ventricle, because of its increased pumping, automatically pumps the extra blood into the arteries. This ability of stretched muscle, up to an optimal length, to contract with increased work output is characteristic of all striated muscle, as explained in Chapter 6, and is not simply a characteristic of cardiac muscle. In addition to the important effect of lengthening the heart muscle, still another factor increases heart pumping when its volume is increased. Stretch of the right atrial wall directly increases the heart rate by 10 to 20 per cent; this, too, helps increase the amount of blood pumped each minute, although its contribution is much less than that of the Frank-Starling mechanism. The Heart work output for that side increases until it reaches the limit of the ventricle’s pumping ability. Figure 9–9 shows another type of ventricular function curve called the ventricular volume output curve. The two curves of this figure represent function of the two ventricles of the human heart based on data extrapolated from lower animals. As the right and left atrial pressures increase, the respective ventricular volume outputs per minute also increase. Thus, ventricular function curves are another way of expressing the Frank-Starling mechanism of the heart. That is, as the ventricles fill in response to higher atrial pressures, each ventricular volume and strength of cardiac muscle contraction increase, causing the heart to pump increased quantities of blood into the arteries. Control of the Heart by the Sympathetic and Parasympathetic Nerves The pumping effectiveness of the heart also is controlled by the sympathetic and parasympathetic (vagus) nerves, which abundantly supply the heart, as shown in Figure 9–10. For given levels of input atrial pressure, the amount of blood pumped each minute (cardiac output) often can be increased more than 100 per cent by sympathetic stimulation. By contrast, the output can be decreased to as low as zero or almost zero by vagal (parasympathetic) stimulation. Mechanisms of Excitation of the Heart by the Sympathetic Nerves. Strong sympathetic stimulation can increase One of the best ways to express the functional ability of the ventricles to pump blood is by ventricular function curves, as shown in Figures 9–8 and 9–9. Figure 9–8 shows a type of ventricular function curve called the stroke work output curve. Note that as the atrial pressure for each side of the heart increases, the stroke the heart rate in young adult humans from the normal rate of 70 beats per minute up to 180 to 200 and, rarely, even 250 beats per minute. Also, sympathetic stimulation increases the force of heart contraction to as much as double normal, thereby increasing the volume of blood pumped and increasing the ejection pressure. Left ventricular stroke work (gram meters) Right ventricular stroke work (gram meters) 40 4 30 3 20 2 10 1 0 0 0 10 20 Left mean atrial pressure (mm Hg) 0 10 20 Right mean atrial pressure (mm Hg) Ventricular output (L /min) Ventricular Function Curves 15 Right ventricle 10 Left ventricle 5 0 –4 0 +4 +8 +12 Atrial pressure (mm Hg) +16 Figure 9–8 Left and right ventricular function curves recorded from dogs, depicting ventricular stroke work output as a function of left and right mean atrial pressures. (Curves reconstructed from data in Sarnoff SJ: Myocardial contractility as described by ventricular function curves. Physiol Rev 35:107, 1955.) Figure 9–9 Approximate normal right and left ventricular volume output curves for the normal resting human heart as extrapolated from data obtained in dogs and data from human beings. Chapter 9 Heart Muscle; The Heart as a Pump and Function of the Heart Valves 113 Sympathetic chains Sympathetic nerves A-V node Sympathetic nerves Figure 9–10 20 Cardiac output (L/min) S-A node Maximum sympathetic stimulation 25 Vagi 15 Normal sympathetic stimulation 10 Zero sympathetic stimulation (Parasympathetic stimulation) 5 0 –4 Cardiac sympathetic and parasympathetic nerves. (The vagus nerves to the heart are parasympathetic nerves.) Thus, sympathetic stimulation often can increase the maximum cardiac output as much as twofold to threefold, in addition to the increased output caused by the Frank-Starling mechanism already discussed. Conversely, inhibition of the sympathetic nerves to the heart can decrease cardiac pumping to a moderate extent in the following way: Under normal conditions, the sympathetic nerve fibers to the heart discharge continuously at a slow rate that maintains pumping at about 30 per cent above that with no sympathetic stimulation. Therefore, when the activity of the sympathetic nervous system is depressed below normal, this decreases both heart rate and strength of ventricular muscle contraction, thereby decreasing the level of cardiac pumping as much as 30 per cent below normal. Parasympathetic (Vagal) Stimulation of the Heart. Strong stimulation of the parasympathetic nerve fibers in the vagus nerves to the heart can stop the heartbeat for a few seconds, but then the heart usually “escapes” and beats at a rate of 20 to 40 beats per minute as long as the parasympathetic stimulation continues. In addition, strong vagal stimulation can decrease the strength of heart muscle contraction by 20 to 30 per cent. The vagal fibers are distributed mainly to the atria and not much to the ventricles, where the power contraction of the heart occurs. This explains the effect of vagal stimulation mainly to decrease heart rate rather than to decrease greatly the strength of heart contraction. Nevertheless, the great decrease in heart rate combined with a slight decrease in heart contraction strength can decrease ventricular pumping 50 per cent or more. Effect of Sympathetic or Parasympathetic Stimulation on the Cardiac Function Curve. Figure 9–11 shows four cardiac 0 +4 +8 Right atrial pressure (mm Hg) Figure 9–11 Effect on the cardiac output curve of different degrees of sympathetic or parasympathetic stimulation. function curves. They are similar to the ventricular function curves of Figure 9–9. However, they represent function of the entire heart rather than of a single ventricle; they show the relation between right atrial pressure at the input of the right heart and cardiac output from the left ventricle into the aorta. The curves of Figure 9–11 demonstrate that at any given right atrial pressure, the cardiac output increases during increased sympathetic stimulation and decreases during increased parasympathetic stimulation. These changes in output caused by nerve stimulation result both from changes in heart rate and from changes in contractile strength of the heart because both change in response to the nerve stimulation. Effect of Potassium and Calcium Ions on Heart Function In the discussion of membrane potentials in Chapter 5, it was pointed out that potassium ions have a marked effect on membrane potentials, and in Chapter 6 it was noted that calcium ions play an especially important role in activating the muscle contractile process. Therefore, it is to be expected that the concentration of each of these two ions in the extracellular fluids should also have important effects on cardiac pumping. Effect of Potassium Ions. Excess potassium in the extra- cellular fluids causes the heart to become dilated and Unit III flaccid and also slows the heart rate. Large quantities also can block conduction of the cardiac impulse from the atria to the ventricles through the A-V bundle. Elevation of potassium concentration to only 8 to 12 mEq/L—two to three times the normal value—can cause such weakness of the heart and abnormal rhythm that this can cause death. These effects result partially from the fact that a high potassium concentration in the extracellular fluids decreases the resting membrane potential in the cardiac muscle fibers, as explained in Chapter 5. As the membrane potential decreases, the intensity of the action potential also decreases, which makes contraction of the heart progressively weaker. The Heart Normal range Cardiac output (L/min) 114 5 4 3 2 1 0 0 50 100 150 200 Arterial pressure (mm Hg) 250 Effect of Calcium Ions. An excess of calcium ions causes effects almost exactly opposite to those of potassium ions, causing the heart to go toward spastic contraction. This is caused by a direct effect of calcium ions to initiate the cardiac contractile process, as explained earlier in the chapter. Conversely, deficiency of calcium ions causes cardiac flaccidity, similar to the effect of high potassium. Fortunately, however, calcium ion levels in the blood normally are regulated within a very narrow range. Therefore, cardiac effects of abnormal calcium concentrations are seldom of clinical concern. Effect of Temperature on Heart Function Increased body temperature, as occurs when one has fever, causes a greatly increased heart rate, sometimes to as fast as double normal. Decreased temperature causes a greatly decreased heart rate, falling to as low as a few beats per minute when a person is near death from hypothermia in the body temperature range of 60° to 70°F. These effects presumably result from the fact that heat increases the permeability of the cardiac muscle membrane to ions that control heart rate, resulting in acceleration of the self-excitation process. Contractile strength of the heart often is enhanced temporarily by a moderate increase in temperature, as occurs during body exercise, but prolonged elevation of temperature exhausts the metabolic systems of the heart and eventually causes weakness. Therefore, optimal function of the heart depends greatly on proper control of body temperature by the temperature control mechanisms explained in Chapter 73. Increasing the Arterial Pressure Load (up to a Limit) Does Not Decrease the Cardiac Output Note in Figure 9–12 that increasing the arterial pressure in the aorta does not decrease the cardiac output until the mean arterial pressure rises above about 160 mm Hg. In other words, during normal function of Figure 9–12 Constancy of cardiac output up to a pressure level of 160 mm Hg. Only when the arterial pressure rises above this normal limit does the increasing pressure load cause the cardiac output to fall significantly. the heart at normal systolic arterial pressures (80 to 140 mm Hg), the cardiac output is determined almost entirely by the ease of blood flow through the body’s tissues, which in turn controls venous return of blood to the heart. This is the principal subject of Chapter 20. References Bers DM: Cardiac excitation-contraction coupling. Nature 415:198, 2002. Brette F, Orchard C:T-tubule function in mammalian cardiac myocytes. Circ Res 92:1182, 2003. Brutsaert DL: Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Physiol Rev 83:59, 2003. Clancy CE, Kass RS: Defective cardiac ion channels: from mutations to clinical syndromes. J Clin Invest 110:1075, 2002. Fozzard HA: Cardiac sodium and calcium channels: a history of excitatory currents. Cardiovasc Res 55:1, 2002. Fuchs F, Smith SH: Calcium, cross-bridges, and the FrankStarling relationship. News Physiol Sci 16:5, 2001. Guyton AC: Determination of cardiac output by equating venous return curves with cardiac response curves. Physiol Rev 35:123, 1955. Guyton AC, Jones CE, Coleman TG: Circulatory Physiology: Cardiac Output and Its Regulation, 2nd ed. Philadelphia: WB Saunders, 1973. Herring N, Danson EJ, Paterson DJ: Cholinergic control of heart rate by nitric oxide is site specific. News Physiol Sci 17:202, 2002. Korzick DH: Regulation of cardiac excitation-contraction coupling: a cellular update. Adv Physiol Educ 27:192, 2003. Olson EN: A decade of discoveries in cardiac biology. Nat Med 10:467, 2004. Page E, Fozzard HA, Solaro JR: Handbook of Physiology, sec 2: The Cardiovascular System, vol 1: The Heart. New York: Oxford University Press, 2002. Chapter 9 Heart Muscle; The Heart as a Pump and Function of the Heart Valves Rudy Y: From genome to physiome: integrative models of cardiac excitation. Ann Biomed Eng 28:945, 2000. Sarnoff SJ: Myocardial contractility as described by ventricular function curves. Physiol Rev 35:107, 1955. Starling EH: The Linacre Lecture on the Law of the Heart. London: Longmans Green, 1918. 115 Sussman MA, Anversa P: Myocardial aging and senescence: where have the stem cells gone? Annu Rev Physiol 66:29, 2004. Zucker IH, Schultz HD, Li YF, et al: The origin of sympathetic outflow in heart failure: the roles of angiotensin II and nitric oxide. Prog Biophys Mol Biol 84:217, 2004. C H A P T E R 1 Rhythmical Excitation of the Heart The heart is endowed with a special system for (1) generating rhythmical electrical impulses to cause rhythmical contraction of the heart muscle and (2) conducting these impulses rapidly through the heart.When this system functions normally, the atria contract about one sixth of a second ahead of ventricular contraction, which allows filling of the ventricles before they pump the blood through the lungs and peripheral circulation. Another special importance of the system is that it allows all portions of the ventricles to contract almost simultaneously, which is essential for most effective pressure generation in the ventricular chambers. This rhythmical and conductive system of the heart is susceptible to damage by heart disease, especially by ischemia of the heart tissues resulting from poor coronary blood flow. The result is often a bizarre heart rhythm or abnormal sequence of contraction of the heart chambers, and the pumping effectiveness of the heart often is affected severely, even to the extent of causing death. Specialized Excitatory and Conductive System of the Heart Figure 10–1 shows the specialized excitatory and conductive system of the heart that controls cardiac contractions. The figure shows the sinus node (also called sinoatrial or S-A node), in which the normal rhythmical impulse is generated; the internodal pathways that conduct the impulse from the sinus node to the atrioventricular (A-V) node; the A-V node, in which the impulse from the atria is delayed before passing into the ventricles; the A-V bundle, which conducts the impulse from the atria into the ventricles; and the left and right bundle branches of Purkinje fibers, which conduct the cardiac impulse to all parts of the ventricles. Sinus (Sinoatrial) Node The sinus node (also called sinoatrial node) is a small, flattened, ellipsoid strip of specialized cardiac muscle about 3 millimeters wide, 15 millimeters long, and 1 millimeter thick. It is located in the superior posterolateral wall of the right atrium immediately below and slightly lateral to the opening of the superior vena cava. The fibers of this node have almost no contractile muscle filaments and are each only 3 to 5 micrometers in diameter, in contrast to a diameter of 10 to 15 micrometers for the surrounding atrial muscle fibers. However, the sinus nodal fibers connect directly with the atrial muscle fibers, so that any action potential that begins in the sinus node spreads immediately into the atrial muscle wall. Automatic Electrical Rhythmicity of the Sinus Fibers Some cardiac fibers have the capability of self-excitation, a process that can cause automatic rhythmical discharge and contraction. This is especially true of 116 0 Rhythmical Excitation of the Heart Chapter 10 A-V node Sinus node A-V bundle Left bundle branch Internodal pathways Right bundle branch Figure 10–1 Sinus node, and the Purkinje system of the heart, showing also the A-V node, atrial internodal pathways, and ventricular bundle branches. Sinus nodal fiber Ventricular muscle fiber Threshold for discharge +20 Millivolts 0 – 40 “Resting potential” – 80 0 1 2 Seconds 3 Figure 10–2 Rhythmical discharge of a sinus nodal fiber. Also, the sinus nodal action potential is compared with that of a ventricular muscle fiber. 117 fiber for three heartbeats and, by comparison, a single ventricular muscle fiber action potential. Note that the “resting membrane potential” of the sinus nodal fiber between discharges has a negativity of about -55 to -60 millivolts, in comparison with -85 to -90 millivolts for the ventricular muscle fiber. The cause of this lesser negativity is that the cell membranes of the sinus fibers are naturally leaky to sodium and calcium ions, and positive charges of the entering sodium and calcium ions neutralize much of the intracellular negativity. Before attempting to explain the rhythmicity of the sinus nodal fibers, first recall from the discussions of Chapters 5 and 9 that cardiac muscle has three types of membrane ion channels that play important roles in causing the voltage changes of the action potential. They are (1) fast sodium channels, (2) slow sodiumcalcium channels, and (3) potassium channels. Opening of the fast sodium channels for a few 10,000ths of a second is responsible for the rapid upstroke spike of the action potential observed in ventricular muscle, because of rapid influx of positive sodium ions to the interior of the fiber. Then the “plateau” of the ventricular action potential is caused primarily by slower opening of the slow sodium-calcium channels, which lasts for about 0.3 second. Finally, opening of potassium channels allows diffusion of large amounts of positive potassium ions in the outward direction through the fiber membrane and returns the membrane potential to its resting level. But there is a difference in the function of these channels in the sinus nodal fiber because the “resting” potential is much less negative—only -55 millivolts in the nodal fiber instead of the -90 millivolts in the ventricular muscle fiber. At this level of -55 millivolts, the fast sodium channels mainly have already become “inactivated,” which means that they have become blocked. The cause of this is that any time the membrane potential remains less negative than about -55 millivolts for more than a few milliseconds, the inactivation gates on the inside of the cell membrane that close the fast sodium channels become closed and remain so. Therefore, only the slow sodium-calcium channels can open (i.e., can become “activated”) and thereby cause the action potential. As a result, the atrial nodal action potential is slower to develop than the action potential of the ventricular muscle. Also, after the action potential does occur, return of the potential to its negative state occurs slowly as well, rather than the abrupt return that occurs for the ventricular fiber. Self-Excitation of Sinus Nodal Fibers. Because of the the fibers of the heart’s specialized conducting system, including the fibers of the sinus node. For this reason, the sinus node ordinarily controls the rate of beat of the entire heart, as discussed in detail later in this chapter. First, let us describe this automatic rhythmicity. Mechanism of Sinus Nodal Rhythmicity. Figure 10–2 shows action potentials recorded from inside a sinus nodal high sodium ion concentration in the extracellular fluid outside the nodal fiber, as well as a moderate number of already open sodium channels, positive sodium ions from outside the fibers normally tend to leak to the inside. Therefore, between heartbeats, influx of positively charged sodium ions causes a slow rise in the resting membrane potential in the positive direction. Thus, as shown in Figure 10–2, the “resting” potential gradually rises between each two heartbeats. When the potential reaches a threshold voltage of 118 Unit III about -40 millivolts, the sodium-calcium channels become “activated,” thus causing the action potential. Therefore, basically, the inherent leakiness of the sinus nodal fibers to sodium and calcium ions causes their self-excitation. Why does this leakiness to sodium and calcium ions not cause the sinus nodal fibers to remain depolarized all the time? The answer is that two events occur during the course of the action potential to prevent this. First, the sodium-calcium channels become inactivated (i.e., they close) within about 100 to 150 milliseconds after opening, and second, at about the same time, greatly increased numbers of potassium channels open. Therefore, influx of positive calcium and sodium ions through the sodium-calcium channels ceases, while at the same time large quantities of positive potassium ions diffuse out of the fiber. Both of these effects reduce the intracellular potential back to its negative resting level and therefore terminate the action potential. Furthermore, the potassium channels remain open for another few tenths of a second, temporarily continuing movement of positive charges out of the cell, with resultant excess negativity inside the fiber; this is called hyperpolarization. The hyperpolarization state initially carries the “resting” membrane potential down to about -55 to -60 millivolts at the termination of the action potential. Last, we must explain why this new state of hyperpolarization is not maintained forever. The reason is that during the next few tenths of a second after the action potential is over, progressively more and more potassium channels close. The inward-leaking sodium and calcium ions once again overbalance the outward flux of potassium ions, and this causes the “resting” potential to drift upward once more, finally reaching the threshold level for discharge at a potential of about -40 millivolts. Then the entire process begins again: self-excitation to cause the action potential, recovery from the action potential, hyperpolarization after the action potential is over, drift of the “resting” potential to threshold, and finally re-excitation to elicit another cycle. This process continues indefinitely throughout a person’s life. Internodal Pathways and Transmission of the Cardiac Impulse Through the Atria The ends of the sinus nodal fibers connect directly with surrounding atrial muscle fibers. Therefore, action potentials originating in the sinus node travel outward into these atrial muscle fibers. In this way, the action potential spreads through the entire atrial muscle mass and, eventually, to the A-V node. The velocity of conduction in most atrial muscle is about 0.3 m/sec, but conduction is more rapid, about 1 m/sec, in several small bands of atrial fibers. One of these, called the anterior interatrial band, passes through the anterior walls of the atria to the left atrium. In addition, three The Heart Internodal pathways Transitional fibers A-V node (0.03) Atrioventricular fibrous tissue (0.12) Penetrating portion of A-V bundle Distal portion of A-V bundle Left bundle branch Right bundle branch (0.16) Ventricular septum Figure 10–3 Organization of the A-V node. The numbers represent the interval of time from the origin of the impulse in the sinus node. The values have been extrapolated to human beings. other small bands curve through the anterior, lateral, and posterior atrial walls and terminate in the A-V node; shown in Figures 10–1 and 10–3, these are called, respectively, the anterior, middle, and posterior internodal pathways. The cause of more rapid velocity of conduction in these bands is the presence of specialized conduction fibers. These fibers are similar to even more rapidly conducting “Purkinje fibers” of the ventricles, which will be discussed. Atrioventricular Node, and Delay of Impulse Conduction from the Atria to the Ventricles The atrial conductive system is organized so that the cardiac impulse does not travel from the atria into the ventricles too rapidly; this delay allows time for the atria to empty their blood into the ventricles before ventricular contraction begins. It is primarily the A-V node and its adjacent conductive fibers that delay this transmission into the ventricles. The A-V node is located in the posterior wall of the right atrium immediately behind the tricuspid valve, as shown in Figure 10–1. And Figure 10–3 shows diagrammatically the different parts of this node, plus its connections with the entering atrial internodal pathway fibers and the exiting A-V bundle. The figure also shows the approximate intervals of time in Chapter 10 Rhythmical Excitation of the Heart fractions of a second between initial onset of the cardiac impulse in the sinus node and its subsequent appearance in the A-V nodal system. Note that the impulse, after traveling through the internodal pathways, reaches the A-V node about 0.03 second after its origin in the sinus node. Then there is a delay of another 0.09 second in the A-V node itself before the impulse enters the penetrating portion of the A-V bundle, where it passes into the ventricles.A final delay of another 0.04 second occurs mainly in this penetrating A-V bundle, which is composed of multiple small fascicles passing through the fibrous tissue separating the atria from the ventricles. Thus, the total delay in the A-V nodal and A-V bundle system is about 0.13 second. This, in addition to the initial conduction delay of 0.03 second from the sinus node to the A-V node, makes a total delay of 0.16 second before the excitatory signal finally reaches the contracting muscle of the ventricles. Cause of the Slow Conduction. The slow conduction in the transitional, nodal, and penetrating A-V bundle fibers is caused mainly by diminished numbers of gap junctions between successive cells in the conducting pathways, so that there is great resistance to conduction of excitatory ions from one conducting fiber to the next. Therefore, it is easy to see why each succeeding cell is slow to be excited. Rapid Transmission in the Ventricular Purkinje System Special Purkinje fibers lead from the A-V node through the A-V bundle into the ventricles. Except for the initial portion of these fibers where they penetrate the A-V fibrous barrier, they have functional characteristics that are quite the opposite of those of the A-V nodal fibers. They are very large fibers, even larger than the normal ventricular muscle fibers, and they transmit action potentials at a velocity of 1.5 to 4.0 m/sec, a velocity about 6 times that in the usual ventricular muscle and 150 times that in some of the A-V nodal fibers. This allows almost instantaneous transmission of the cardiac impulse throughout the entire remainder of the ventricular muscle. The rapid transmission of action potentials by Purkinje fibers is believed to be caused by a very high level of permeability of the gap junctions at the intercalated discs between the successive cells that make up the Purkinje fibers. Therefore, ions are transmitted easily from one cell to the next, thus enhancing the velocity of transmission. The Purkinje fibers also have very few myofibrils, which means that they contract little or not at all during the course of impulse transmission. One-Way Conduction Through the A-V Bundle. A special characteristic of the A-V bundle is the inability, except in abnormal states, of action potentials to travel backward from the ventricles to the atria. This prevents 119 re-entry of cardiac impulses by this route from the ventricles to the atria, allowing only forward conduction from the atria to the ventricles. Furthermore, it should be recalled that everywhere, except at the A-V bundle, the atrial muscle is separated from the ventricular muscle by a continuous fibrous barrier, a portion of which is shown in Figure 10–3. This barrier normally acts as an insulator to prevent passage of the cardiac impulse between atrial and ventricular muscle through any other route besides forward conduction through the A-V bundle itself. (In rare instances, an abnormal muscle bridge does penetrate the fibrous barrier elsewhere besides at the A-V bundle. Under such conditions, the cardiac impulse can re-enter the atria from the ventricles and cause a serious cardiac arrhythmia.) Distribution of the Purkinje Fibers in the Ventricles—The Left and Right Bundle Branches. After penetrating the fibrous tissue between the atrial and ventricular muscle, the distal portion of the A-V bundle passes downward in the ventricular septum for 5 to 15 millimeters toward the apex of the heart, as shown in Figures 10–1 and 10–3. Then the bundle divides into left and right bundle branches that lie beneath the endocardium on the two respective sides of the ventricular septum. Each branch spreads downward toward the apex of the ventricle, progressively dividing into smaller branches. These branches in turn course sidewise around each ventricular chamber and back toward the base of the heart. The ends of the Purkinje fibers penetrate about one third the way into the muscle mass and finally become continuous with the cardiac muscle fibers. From the time the cardiac impulse enters the bundle branches in the ventricular septum until it reaches the terminations of the Purkinje fibers, the total elapsed time averages only 0.03 second. Therefore, once the cardiac impulse enters the ventricular Purkinje conductive system, it spreads almost immediately to the entire ventricular muscle mass. Transmission of the Cardiac Impulse in the Ventricular Muscle Once the impulse reaches the ends of the Purkinje fibers, it is transmitted through the ventricular muscle mass by the ventricular muscle fibers themselves. The velocity of transmission is now only 0.3 to 0.5 m/sec, one sixth that in the Purkinje fibers. The cardiac muscle wraps around the heart in a double spiral, with fibrous septa between the spiraling layers; therefore, the cardiac impulse does not necessarily travel directly outward toward the surface of the heart but instead angulates toward the surface along the directions of the spirals. Because of this, transmission from the endocardial surface to the epicardial surface of the ventricle requires as much as another 0.03 second, approximately equal to the time required for transmission through the entire ventricular portion 120 Unit III of the Purkinje system. Thus, the total time for transmission of the cardiac impulse from the initial bundle branches to the last of the ventricular muscle fibers in the normal heart is about 0.06 second. Summary of the Spread of the Cardiac Impulse Through the Heart Figure 10–4 shows in summary form the transmission of the cardiac impulse through the human heart. The numbers on the figure represent the intervals of time, in fractions of a second, that lapse between the origin of the cardiac impulse in the sinus node and its appearance at each respective point in the heart. Note that the impulse spreads at moderate velocity through the atria but is delayed more than 0.1 second in the A-V nodal region before appearing in the ventricular septal A-V bundle. Once it has entered this bundle, it spreads very rapidly through the Purkinje fibers to the entire endocardial surfaces of the ventricles.Then the impulse once again spreads slightly less rapidly through the ventricular muscle to the epicardial surfaces. It is extremely important that the student learn in detail the course of the cardiac impulse through the heart and the precise times of its appearance in each separate part of the heart, because a thorough quantitative knowledge of this process is essential to the understanding of electrocardiography, to be discussed in Chapters 11 through 13. .07 .04 .06 S-A .03 .07 .09 .22 .19 A-V .03 .05 .07 .18 .17 Control of Excitation and Conduction in the Heart The Sinus Node as the Pacemaker of the Heart In the discussion thus far of the genesis and transmission of the cardiac impulse through the heart, we have noted that the impulse normally arises in the sinus node. In some abnormal conditions, this is not the case. A few other parts of the heart can exhibit intrinsic rhythmical excitation in the same way that the sinus nodal fibers do; this is particularly true of the A-V nodal and Purkinje fibers. The A-V nodal fibers, when not stimulated from some outside source, discharge at an intrinsic rhythmical rate of 40 to 60 times per minute, and the Purkinje fibers discharge at a rate somewhere between 15 and 40 times per minute. These rates are in contrast to the normal rate of the sinus node of 70 to 80 times per minute. The question we must ask is: Why does the sinus node rather than the A-V node or the Purkinje fibers control the heart’s rhythmicity? The answer derives from the fact that the discharge rate of the sinus node is considerably faster than the natural self-excitatory discharge rate of either the A-V node or the Purkinje fibers. Each time the sinus node discharges, its impulse is conducted into both the A-V node and the Purkinje fibers, also discharging their excitable membranes. But the sinus node discharges again before either the A-V node or the Purkinje fibers can reach their own thresholds for self-excitation. Therefore, the new impulse from the sinus node discharges both the A-V node and the Purkinje fibers before self-excitation can occur in either of these. Thus, the sinus node controls the beat of the heart because its rate of rhythmical discharge is faster than that of any other part of the heart. Therefore, the sinus node is virtually always the pacemaker of the normal heart. Abnormal Pacemakers—“Ectopic” Pacemaker. Occasionally .16 .00 The Heart .21 .17 .19 .18 .21 .20 Figure 10–4 Transmission of the cardiac impulse through the heart, showing the time of appearance (in fractions of a second after initial appearance at the sinoatrial node) in different parts of the heart. some other part of the heart develops a rhythmical discharge rate that is more rapid than that of the sinus node. For instance, this sometimes occurs in the A-V node or in the Purkinje fibers when one of these becomes abnormal. In either case, the pacemaker of the heart shifts from the sinus node to the A-V node or to the excited Purkinje fibers. Under rarer conditions, a place in the atrial or ventricular muscle develops excessive excitability and becomes the pacemaker. A pacemaker elsewhere than the sinus node is called an “ectopic” pacemaker. An ectopic pacemaker causes an abnormal sequence of contraction of the different parts of the heart and can cause significant debility of heart pumping. Another cause of shift of the pacemaker is blockage of transmission of the cardiac impulse from the sinus node to the other parts of the heart. The new pacemaker then occurs most frequently at the A-V node or Chapter 10 Rhythmical Excitation of the Heart in the penetrating portion of the A-V bundle on the way to the ventricles. When A-V block occurs—that is, when the cardiac impulse fails to pass from the atria into the ventricles through the A-V nodal and bundle system—the atria continue to beat at the normal rate of rhythm of the sinus node, while a new pacemaker usually develops in the Purkinje system of the ventricles and drives the ventricular muscle at a new rate somewhere between 15 and 40 beats per minute. After sudden A-V bundle block, the Purkinje system does not begin to emit its intrinsic rhythmical impulses until 5 to 20 seconds later because, before the blockage, the Purkinje fibers had been “overdriven” by the rapid sinus impulses and, consequently, are in a suppressed state. During these 5 to 20 seconds, the ventricles fail to pump blood, and the person faints after the first 4 to 5 seconds because of lack of blood flow to the brain. This delayed pickup of the heartbeat is called Stokes-Adams syndrome. If the delay period is too long, it can lead to death. Role of the Purkinje System in Causing Synchronous Contraction of the Ventricular Muscle It is clear from our description of the Purkinje system that normally the cardiac impulse arrives at almost all portions of the ventricles within a narrow span of time, exciting the first ventricular muscle fiber only 0.03 to 0.06 second ahead of excitation of the last ventricular muscle fiber. This causes all portions of the ventricular muscle in both ventricles to begin contracting at almost the same time and then to continue contracting for about another 0.3 second. Effective pumping by the two ventricular chambers requires this synchronous type of contraction. If the cardiac impulse should travel through the ventricles slowly, much of the ventricular mass would contract before contraction of the remainder, in which case the overall pumping effect would be greatly depressed. Indeed, in some types of cardiac debilities, several of which are discussed in Chapters 12 and 13, slow transmission does occur, and the pumping effectiveness of the ventricles is decreased as much as 20 to 30 per cent. Control of Heart Rhythmicity and Impulse Conduction by the Cardiac Nerves: The Sympathetic and Parasympathetic Nerves The heart is supplied with both sympathetic and parasympathetic nerves, as shown in Figure 9-10 of Chapter 9. The parasympathetic nerves (the vagi) are distributed mainly to the S-A and A-V nodes, to a lesser extent to the muscle of the two atria, and very little directly to the ventricular muscle. The sympathetic nerves, conversely, are distributed to all parts of the heart, with strong representation to the ventricular muscle as well as to all the other areas. 121 Parasympathetic (Vagal) Stimulation Can Slow or Even Block Cardiac Rhythm and Conduction—“Ventricular Escape.” Stimulation of the parasympathetic nerves to the heart (the vagi) causes the hormone acetylcholine to be released at the vagal endings. This hormone has two major effects on the heart. First, it decreases the rate of rhythm of the sinus node, and second, it decreases the excitability of the A-V junctional fibers between the atrial musculature and the A-V node, thereby slowing transmission of the cardiac impulse into the ventricles. Weak to moderate vagal stimulation slows the rate of heart pumping, often to as little as one half normal. And strong stimulation of the vagi can stop completely the rhythmical excitation by the sinus node or block completely transmission of the cardiac impulse from the atria into the ventricles through the A-V mode. In either case, rhythmical excitatory signals are no longer transmitted into the ventricles. The ventricles stop beating for 5 to 20 seconds, but then some point in the Purkinje fibers, usually in the ventricular septal portion of the A-V bundle, develops a rhythm of its own and causes ventricular contraction at a rate of 15 to 40 beats per minute. This phenomenon is called ventricular escape. Mechanism of the Vagal Effects. The acetylcholine released at the vagal nerve endings greatly increases the permeability of the fiber membranes to potassium ions, which allows rapid leakage of potassium out of the conductive fibers. This causes increased negativity inside the fibers, an effect called hyperpolarization, which makes this excitable tissue much less excitable, as explained in Chapter 5. In the sinus node, the state of hyperpolarization decreases the “resting” membrane potential of the sinus nodal fibers to a level considerably more negative than usual, to -65 to -75 millivolts rather than the normal level of -55 to -60 millivolts. Therefore, the initial rise of the sinus nodal membrane potential caused by inward sodium and calcium leakage requires much longer to reach the threshold potential for excitation. This greatly slows the rate of rhythmicity of these nodal fibers. If the vagal stimulation is strong enough, it is possible to stop entirely the rhythmical self-excitation of this node. In the A-V node, a state of hyperpolarization caused by vagal stimulation makes it difficult for the small atrial fibers entering the node to generate enough electricity to excite the nodal fibers. Therefore, the safety factor for transmission of the cardiac impulse through the transitional fibers into the A-V nodal fibers decreases. A moderate decrease simply delays conduction of the impulse, but a large decrease blocks conduction entirely. Effect of Sympathetic Stimulation on Cardiac Rhythm and Conduction. Sympathetic stimulation causes essentially the opposite effects on the heart to those caused by vagal stimulation, as follows: First, it increases the rate of sinus nodal discharge. Second, it increases the rate of conduction as well as the level of excitability in all 122 Unit III portions of the heart. Third, it increases greatly the force of contraction of all the cardiac musculature, both atrial and ventricular, as discussed in Chapter 9. In short, sympathetic stimulation increases the overall activity of the heart. Maximal stimulation can almost triple the frequency of heartbeat and can increase the strength of heart contraction as much as twofold. Mechanism of the Sympathetic Effect. Stimulation of the sympathetic nerves releases the hormone norepinephrine at the sympathetic nerve endings. The precise mechanism by which this hormone acts on cardiac muscle fibers is somewhat unclear, but the belief is that it increases the permeability of the fiber membrane to sodium and calcium ions. In the sinus node, an increase of sodium-calcium permeability causes a more positive resting potential and also causes increased rate of upward drift of the diastolic membrane potential toward the threshold level for selfexcitation, thus accelerating self-excitation and, therefore, increasing the heart rate. In the A-V node and A-V bundles, increased sodium-calcium permeability makes it easier for the action potential to excite each succeeding portion of the conducting fiber bundles, thereby decreasing the conduction time from the atria to the ventricles. The increase in permeability to calcium ions is at least partially responsible for the increase in contractile strength of the cardiac muscle under the influence of sympathetic stimulation, because calcium ions play a powerful role in exciting the contractile process of the myofibrils. References Blatter LA, Kockskamper J, Sheehan KA, et al: Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes. J Physiol 546:19, 2003. Ferrier GR, Howlett SE: Cardiac excitation-contraction coupling: role of membrane potential in regulation of contraction.Am J Physiol Heart Circ Physiol 280:H1928, 2001. The Heart Gentlesk PJ, Markwood TT, Atwood JE: Chronotropic incompetence in a young adult: case report and literature review. Chest 125:297, 2004. Huikuri HV, Castellanos A, Myerburg RJ: Sudden death due to cardiac arrhythmias. N Engl J Med 345:1473, 2001. Hume JR, Duan D, Collier ML, et al: Anion transport in heart. Physiol Rev 80:31, 2000. James TN: Structure and function of the sinus node, AV node and His bundle of the human heart: part I—structure. Prog Cardiovasc Dis 45:235, 2002. James TN: Structure and function of the sinus node, AV node and His bundle of the human heart: part II—function. Prog Cardiovasc Dis 45:327, 2003. Kaupp UB, Seifert R: Molecular diversity of pacemaker ion channels. Annu Rev Physiol 63:235, 2001. Kléber AG, Rudy Y: Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev 84:431, 2004. Leclercq C, Hare JM: Ventricular resynchronization: current state of the art. Circulation 109:296, 2004. Mazgalev TN, Ho SY, Anderson RH: Anatomicelectrophysiological correlations concerning the pathways for atrioventricular conduction. Circulation 103:2660, 2001. Page E, Fozzard HA, Solaro JR: Handbook of Physiology, sec 2: The Cardiovascular System, vol 1: The Heart. New York: Oxford University Press, 2002. Petrashevskaya NN, Koch SE, Bodi I, Schwartz A: Calcium cycling, historic overview and perspectives: role for autonomic nervous system regulation. J Mol Cell Cardiol 34:885, 2002. Priori SG: Inherited arrhythmogenic diseases: the complexity beyond monogenic disorders. Circ Res 94:140, 2004. Roden DM, Balser JR, George AL Jr, Anderson ME: Cardiac ion channels. Annu Rev Physiol 64:431, 2002. Schram G, Pourrier M, Melnyk P, Nattel S: Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ Res 90:939, 2002. Surawicz B: Electrophysiologic Basis of ECG and Cardiac Arrhythmias. Baltimore: Williams & Wilkins, 1995. Waldo AL: Mechanisms of atrial fibrillation. J Cardiovasc Electrophysiol 14(12 Suppl):S267, 2003. Yasuma F, Hayano J: Respiratory sinus arrhythmia: why does the heartbeat synchronize with respiratory rhythm? Chest 125:683, 2004. C H A P T E R 1 1 The Normal Electrocardiogram When the cardiac impulse passes through the heart, electrical current also spreads from the heart into the adjacent tissues surrounding the heart. A small portion of the current spreads all the way to the surface of the body. If electrodes are placed on the skin on opposite sides of the heart, electrical potentials generated by the current can be recorded; the recording is known as an electrocardiogram. A normal electrocardiogram for two beats of the heart is shown in Figure 11–1. Characteristics of the Normal Electrocardiogram The normal electrocardiogram (see Figure 11–1) is composed of a P wave, a QRS complex, and a T wave. The QRS complex is often, but not always, three separate waves: the Q wave, the R wave, and the S wave. The P wave is caused by electrical potentials generated when the atria depolarize before atrial contraction begins. The QRS complex is caused by potentials generated when the ventricles depolarize before contraction, that is, as the depolarization wave spreads through the ventricles. Therefore, both the P wave and the components of the QRS complex are depolarization waves. The T wave is caused by potentials generated as the ventricles recover from the state of depolarization. This process normally occurs in ventricular muscle 0.25 to 0.35 second after depolarization, and the T wave is known as a repolarization wave. Thus, the electrocardiogram is composed of both depolarization and repolarization waves. The principles of depolarization and repolarization are discussed in Chapter 5. The distinction between depolarization waves and repolarization waves is so important in electrocardiography that further clarification is needed. Depolarization Waves Versus Repolarization Waves Figure 11–2 shows a single cardiac muscle fiber in four stages of depolarization and repolarization, the color red designating depolarization. During depolarization, the normal negative potential inside the fiber reverses and becomes slightly positive inside and negative outside. In Figure 11–2A, depolarization, demonstrated by red positive charges inside and red negative charges outside, is traveling from left to right. The first half of the fiber has already depolarized, while the remaining half is still polarized. Therefore, the left electrode on the outside of the fiber is in an area of negativity, and the right electrode is in an area of positivity; this causes the meter to record positively. To the right of the muscle fiber is shown a record of changes in potential between the two electrodes, as recorded by a high-speed recording meter. Note that when depolarization has reached the halfway mark in Figure 11–2A, the record has risen to a maximum positive value. 123 124 Unit III The Heart In Figure 11–2B, depolarization has extended over the entire muscle fiber, and the recording to the right has returned to the zero baseline because both electrodes are now in areas of equal negativity. The completed wave is a depolarization wave because it results from spread of depolarization along the muscle fiber membrane. Atria Ventricles +2 RR interval +1 Millivolts S-T segment R Relation of the Monophasic Action Potential of Ventricular Muscle to the QRS and T Waves in the Standard Electrocardiogram. The monophasic action potential of ventricular T P 0 muscle, discussed in Chapter 10, normally lasts between 0.25 and 0.35 second. The top part of Figure 11–3 shows a monophasic action potential recorded from a microelectrode inserted to the inside of a single ventricular muscle fiber. The upsweep of this action potential is caused by depolarization, and the return of the potential to the baseline is caused by repolarization. Note in the lower half of the figure a simultaneous recording of the electrocardiogram from this same ventricle, which shows the QRS waves appearing at QS Q-T interval P-R interval = 0.16 sec –1 0 Figure 11–2C shows halfway repolarization of the same muscle fiber, with positivity returning to the outside of the fiber. At this point, the left electrode is in an area of positivity, and the right electrode is in an area of negativity. This is opposite to the polarity in Figure 11–2A. Consequently, the recording, as shown to the right, becomes negative. In Figure 11–2D, the muscle fiber has completely repolarized, and both electrodes are now in areas of positivity, so that no potential difference is recorded between them. Thus, in the recording to the right, the potential returns once more to zero. This completed negative wave is a repolarization wave because it results from spread of repolarization along the muscle fiber membrane. 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Time (sec) Figure 11–1 Normal electrocardiogram. 0 – + – – – – – – – –+ + + + + + + + + + + ++ + ++– – – – – – – – – A + + ++ + ++– – – – – – – – – – – – – – – –+ + + + + + + + + ––––––– – –– – –– – – – + + ++ + ++ + + + + + + + + + B + + ++ + ++ + + + + + + + + + ––––––– – –– – –– – – – + + ++ + ++ + + – – – – – – – –––––––––+++++++ C –––––––––+++++++ + + ++ + ++ + + – – – – – – – + + ++ + ++ + + + + + + + + + –––––––––––––––– D –––––––––––––––– + + ++ + ++ + + + + + + + + + + + – Depolarization wave + – + – + – Repolarization wave Figure 11–2 0.30 second Recording the depolarization wave (A and B) and the repolarization wave (C and D) from a cardiac muscle fiber. The Normal Electrocardiogram Repolarization Depolarization Chapter 11 125 (the QRS complex), but in many other fibers, it takes as long as 0.35 second. Thus, the process of ventricular repolarization extends over a long period, about 0.15 second. For this reason, the T wave in the normal electrocardiogram is a prolonged wave, but the voltage of the T wave is considerably less than the voltage of the QRS complex, partly because of its prolonged length. Voltage and Time Calibration of the Electrocardiogram R T Q S Figure 11–3 Above, Monophasic action potential from a ventricular muscle fiber during normal cardiac function, showing rapid depolarization and then repolarization occurring slowly during the plateau stage but rapidly toward the end. Below, Electrocardiogram recorded simultaneously. the beginning of the monophasic action potential and the T wave appearing at the end. Note especially that no potential is recorded in the electrocardiogram when the ventricular muscle is either completely polarized or completely depolarized. Only when the muscle is partly polarized and partly depolarized does current flow from one part of the ventricles to another part, and therefore current also flows to the surface of the body to produce the electrocardiogram. Relationship of Atrial and Ventricular Contraction to the Waves of the Electrocardiogram Before contraction of muscle can occur, depolarization must spread through the muscle to initiate the chemical processes of contraction. Refer again to Figure 11–1; the P wave occurs at the beginning of contraction of the atria, and the QRS complex of waves occurs at the beginning of contraction of the ventricles. The ventricles remain contracted until after repolarization has occurred, that is, until after the end of the T wave. The atria repolarize about 0.15 to 0.20 second after termination of the P wave. This is also approximately when the QRS complex is being recorded in the electrocardiogram. Therefore, the atrial repolarization wave, known as the atrial T wave, is usually obscured by the much larger QRS complex. For this reason, an atrial T wave seldom is observed in the electrocardiogram. The ventricular repolarization wave is the T wave of the normal electrocardiogram. Ordinarily, ventricular muscle begins to repolarize in some fibers about 0.20 second after the beginning of the depolarization wave All recordings of electrocardiograms are made with appropriate calibration lines on the recording paper. Either these calibration lines are already ruled on the paper, as is the case when a pen recorder is used, or they are recorded on the paper at the same time that the electrocardiogram is recorded, which is the case with the photographic types of electrocardiographs. As shown in Figure 11–1, the horizontal calibration lines are arranged so that 10 of the small line divisions upward or downward in the standard electrocardiogram represent 1 millivolt, with positivity in the upward direction and negativity in the downward direction. The vertical lines on the electrocardiogram are time calibration lines. Each inch in the horizontal direction is 1 second, and each inch is usually broken into five segments by dark vertical lines; the intervals between these dark lines represent 0.20 second. The 0.20 second intervals are then broken into five smaller intervals by thin lines, each of which represents 0.04 second. Normal Voltages in the Electrocardiogram. The recorded voltages of the waves in the normal electrocardiogram depend on the manner in which the electrodes are applied to the surface of the body and how close the electrodes are to the heart. When one electrode is placed directly over the ventricles and a second electrode is placed elsewhere on the body remote from the heart, the voltage of the QRS complex may be as great as 3 to 4 millivolts. Even this voltage is small in comparison with the monophasic action potential of 110 millivolts recorded directly at the heart muscle membrane. When electrocardiograms are recorded from electrodes on the two arms or on one arm and one leg, the voltage of the QRS complex usually is 1.0 to 1.5 millivolt from the top of the R wave to the bottom of the S wave; the voltage of the P wave is between 0.1 and 0.3 millivolt; and that of the T wave is between 0.2 and 0.3 millivolt. P-Q or P-R Interval. The time between the beginning of the P wave and the beginning of the QRS complex is the interval between the beginning of electrical excitation of the atria and the beginning of excitation of the ventricles. This period is called the P-Q interval. The normal P-Q interval is about 0.16 second. (Often this interval is called the P-R interval because the Q wave is likely to be absent.) Q-T Interval. Contraction of the ventricle lasts almost from the beginning of the Q wave (or R wave, if the Q wave is absent) to the end of the T wave. This 126 Unit III The Heart interval is called the Q-T interval and ordinarily is about 0.35 second. 0 Rate of Heartbeat as Determined from the Electrocardiogram. The rate of heartbeat can be determined easily from an electrocardiogram because the heart rate is the reciprocal of the time interval between two successive heartbeats. If the interval between two beats as determined from the time calibration lines is 1 second, the heart rate is 60 beats per minute. The normal interval between two successive QRS complexes in the adult person is about 0.83 second. This is a heart rate of 60/0.83 times per minute, or 72 beats per minute. – + – Pen Recorder Many modern clinical electrocardiographs use computer-based systems and electronic display, while others use a direct pen recorder that writes the electrocardiogram with a pen directly on a moving sheet of paper. Sometimes the pen is a thin tube connected at one end to an inkwell, and its recording end is connected to a powerful electromagnet system that is capable of moving the pen back and forth at high speed. As the paper moves forward, the pen records the electrocardiogram.The movement of the pen is controlled by appropriate electronic amplifiers connected to electrocardiographic electrodes on the patient. Other pen recording systems use special paper that does not require ink in the recording stylus. One such paper turns black when it is exposed to heat; the stylus itself is made very hot by electrical current flowing through its tip. Another type turns black when electrical current flows from the tip of the stylus through the paper to an electrode at its back. This leaves a black line on the paper where the stylus touches. Flow of Current Around the Heart During the Cardiac Cycle Recording Electrical Potentials from a Partially Depolarized Mass of Syncytial Cardiac Muscle Figure 11–4 shows a syncytial mass of cardiac muscle that has been stimulated at its centralmost point. – + – 0 + + – – + + +++++ + + ++++++++ + + +++++ +–+–+–+–+–+ +++++ ++++++–––––––––––––––+–+++++ + +++++ + ++++++ –– –– –– –– –– –– –– –– –– +++++ + – – – – – – – – – +++++ + – – – – – – – – – +++++ – – – – – – – – – +++++ +++++ +––––––––––––––––– +++++ + ++++++ – – – –– –– –– –– ++++++ +++++ + + + – –+ ++++++ + +++++++++++ +++ +++++++++++ Methods for Recording Electrocardiograms Sometimes the electrical currents generated by the cardiac muscle during each beat of the heart change electrical potentials and polarities on the respective sides of the heart in less than 0.01 second. Therefore, it is essential that any apparatus for recording electrocardiograms be capable of responding rapidly to these changes in potentials. 0 Figure 11–4 Instantaneous potentials develop on the surface of a cardiac muscle mass that has been depolarized in its center. Before stimulation, all the exteriors of the muscle cells had been positive and the interiors negative. For reasons presented in Chapter 5 in the discussion of membrane potentials, as soon as an area of cardiac syncytium becomes depolarized, negative charges leak to the outsides of the depolarized muscle fibers, making this part of the surface electronegative, as represented by the negative signs in Figure 11–4. The remaining surface of the heart, which is still polarized, is represented by the positive signs. Therefore, a meter connected with its negative terminal on the area of depolarization and its positive terminal on one of the still-polarized areas, as shown to the right in the figure, records positively. Two other electrode placements and meter readings are also demonstrated in Figure 11–4. These should be studied carefully, and the reader should be able to explain the causes of the respective meter readings. Because the depolarization spreads in all directions through the heart, the potential differences shown in the figure persist for only a few thousandths of a second, and the actual voltage measurements can be accomplished only with a high-speed recording apparatus. Flow of Electrical Currents in the Chest Around the Heart Figure 11–5 shows the ventricular muscle lying within the chest. Even the lungs, although mostly filled with air, conduct electricity to a surprising extent, and fluids in other tissues surrounding the heart conduct electricity even more easily. Therefore, the heart is actually suspended in a conductive medium. When one portion of the ventricles depolarizes and therefore becomes electronegative with respect to the Chapter 11 127 The Normal Electrocardiogram +0.5 mV 0 + - + Lead I 0 - + - - + + + + B A - 0 .2 mV + ++ ---- + ++ -- - + + -+ ++ ++ -- -+ ++ + ++-+ + ++ + ++ + ++ ++ +0.3 mV + 1 .2 mV +0.7 mV 0 Figure 11–5 0 + - + - remainder, electrical current flows from the depolarized area to the polarized area in large circuitous routes, as noted in the figure. It should be recalled from the discussion of the Purkinje system in Chapter 10 that the cardiac impulse first arrives in the ventricles in the septum and shortly thereafter spreads to the inside surfaces of the remainder of the ventricles, as shown by the red areas and the negative signs in Figure 11–5. This provides electronegativity on the insides of the ventricles and electropositivity on the outer walls of the ventricles, with electrical current flowing through the fluids surrounding the ventricles along elliptical paths, as demonstrated by the curving arrows in the figure. If one algebraically averages all the lines of current flow (the elliptical lines), one finds that the average current flow occurs with negativity toward the base of the heart and with positivity toward the apex. During most of the remainder of the depolarization process, current also continues to flow in this same direction, while depolarization spreads from the endocardial surface outward through the ventricular muscle mass. Then, immediately before depolarization has completed its course through the ventricles, the average direction of current flow reverses for about 0.01 second, flowing from the ventricular apex toward the base, because the last part of the heart to become depolarized is the outer walls of the ventricles near the base of the heart. + - Lead II Flow of current in the chest around partially depolarized ventricles. + - Lead III + 1 .0 mV Figure 11–6 Conventional arrangement of electrodes for recording the standard electrocardiographic leads. Einthoven’s triangle is superimposed on the chest. Thus, in normal heart ventricles, current flows from negative to positive primarily in the direction from the base of the heart toward the apex during almost the entire cycle of depolarization, except at the very end. And if a meter is connected to electrodes on the surface of the body as shown in Figure 11–5, the electrode nearer the base will be negative, whereas the electrode nearer the apex will be positive, and the recording meter will show positive recording in the electrocardiogram. Electrocardiographic Leads Three Bipolar Limb Leads Figure 11–6 shows electrical connections between the patient’s limbs and the electrocardiograph for recording electrocardiograms from the so-called standard bipolar limb leads. The term “bipolar” means that the electrocardiogram is recorded from two electrodes 128 Unit III located on different sides of the heart, in this case, on the limbs. Thus, a “lead” is not a single wire connecting from the body but a combination of two wires and their electrodes to make a complete circuit between the body and the electrocardiograph. The electrocardiograph in each instance is represented by an electrical meter in the diagram, although the actual electrocardiograph is a high-speed recording meter with a moving paper. Lead I. In recording limb lead I, the negative terminal of the electrocardiograph is connected to the right arm and the positive terminal to the left arm. Therefore, when the point where the right arm connects to the chest is electronegative with respect to the point where the left arm connects, the electrocardiograph records positively, that is, above the zero voltage line in the electrocardiogram. When the opposite is true, the electrocardiograph records below the line. Lead II. To record limb lead II, the negative terminal of the electrocardiograph is connected to the right arm and the positive terminal to the left leg. Therefore, when the right arm is negative with respect to the left leg, the electrocardiograph records positively. Lead III. To record limb lead III, the negative terminal of the electrocardiograph is connected to the left arm and the positive terminal to the left leg. This means that the electrocardiograph records positively when the left arm is negative with respect to the left leg. The Heart Now, note that the sum of the voltages in leads I and III equals the voltage in lead II; that is, 0.5 plus 0.7 equals 1.2. Mathematically, this principle, called Einthoven’s law, holds true at any given instant while the three “standard” bipolar electrocardiograms are being recorded. Normal Electrocardiograms Recorded from the Three Standard Bipolar Limb Leads. Figure 11–7 shows recordings of the electrocardiograms in leads I, II, and III. It is obvious that the electrocardiograms in these three leads are similar to one another because they all record positive P waves and positive T waves, and the major portion of the QRS complex is also positive in each electrocardiogram. On analysis of the three electrocardiograms, it can be shown, with careful measurements and proper observance of polarities, that at any given instant the sum of the potentials in leads I and III equals the potential in lead II, thus illustrating the validity of Einthoven’s law. Because the recordings from all the bipolar limb leads are similar to one another, it does not matter greatly which lead is recorded when one wants to diagnose different cardiac arrhythmias, because diagnosis of arrhythmias depends mainly on the time relations between the different waves of the cardiac cycle. But when one wants to diagnose damage in the ventricular or atrial muscle or in the Purkinje conducting system, it does matter greatly which leads are recorded, because abnormalities of cardiac muscle contraction or cardiac impulse conduction do Einthoven’s Triangle. In Figure 11–6, the triangle, called Einthoven’s triangle, is drawn around the area of the heart. This illustrates that the two arms and the left leg form apices of a triangle surrounding the heart. The two apices at the upper part of the triangle represent the points at which the two arms connect electrically with the fluids around the heart, and the lower apex is the point at which the left leg connects with the fluids. I Einthoven’s Law. Einthoven’s law states that if the electrical potentials of any two of the three bipolar limb electrocardiographic leads are known at any given instant, the third one can be determined mathematically by simply summing the first two (but note that the positive and negative signs of the different leads must be observed when making this summation). For instance, let us assume that momentarily, as noted in Figure 11–6, the right arm is -0.2 millivolt (negative) with respect to the average potential in the body, the left arm is + 0.3 millivolt (positive), and the left leg is +1.0 millivolt (positive). Observing the meters in the figure, it can be seen that lead I records a positive potential of +0.5 millivolt, because this is the difference between the -0.2 millivolt on the right arm and the +0.3 millivolt on the left arm. Similarly, lead III records a positive potential of +0.7 millivolt, and lead II records a positive potential of +1.2 millivolts because these are the instantaneous potential differences between the respective pairs of limbs. II III Figure 11–7 Normal electrocardiograms recorded from the three standard electrocardiographic leads. 129 The Normal Electrocardiogram Chapter 11 1 2 3 456 RA V1 LA V2 V3 V4 V5 V6 5000 ohms Figure 11–9 5000 ohms Normal electrocardiograms recorded from the six standard chest leads. 0 - + + 5000 ohms aVR aVL aVF Figure 11–8 Connections of the body with the electrocardiograph for recording chest leads. LA, left arm; RA, right arm. change the patterns of the electrocardiograms markedly in some leads yet may not affect other leads. Electrocardiographic interpretation of these two types of conditions—cardiac myopathies and cardiac arrhythmias—is discussed separately in Chapters 12 and 13. Chest Leads (Precordial Leads) Often electrocardiograms are recorded with one electrode placed on the anterior surface of the chest directly over the heart at one of the points shown in Figure 11–8. This electrode is connected to the positive terminal of the electrocardiograph, and the negative electrode, called the indifferent electrode, is connected through equal electrical resistances to the right arm, left arm, and left leg all at the same time, as also shown in the figure. Usually six standard chest leads are recorded, one at a time, from the anterior chest wall, the chest electrode being placed sequentially at the six points shown in the diagram. The different recordings are known as leads V1, V2, V3, V4, V5, and V6. Figure 11–9 illustrates the electrocardiograms of the healthy heart as recorded from these six standard chest leads. Because the heart surfaces are close to the chest wall, each chest lead records mainly the Figure 11–10 Normal electrocardiograms recorded from the three augmented unipolar limb leads. electrical potential of the cardiac musculature immediately beneath the electrode. Therefore, relatively minute abnormalities in the ventricles, particularly in the anterior ventricular wall, can cause marked changes in the electrocardiograms recorded from individual chest leads. In leads V1 and V2, the QRS recordings of the normal heart are mainly negative because, as shown in Figure 11–8, the chest electrode in these leads is nearer to the base of the heart than to the apex, and the base of the heart is the direction of electronegativity during most of the ventricular depolarization process. Conversely, the QRS complexes in leads V4, V5, and V6 are mainly positive because the chest electrode in these leads is nearer the heart apex, which is the direction of electropositivity during most of depolarization. Augmented Unipolar Limb Leads Another system of leads in wide use is the augmented unipolar limb lead. In this type of recording, two of the limbs are connected through electrical resistances to the negative terminal of the electrocardiograph, 130 Unit III and the third limb is connected to the positive terminal. When the positive terminal is on the right arm, the lead is known as the aVR lead; when on the left arm, the aVL lead; and when on the left leg, the aVF lead. Normal recordings of the augmented unipolar limb leads are shown in Figure 11–10. They are all similar to the standard limb lead recordings, except that the The Heart recording from the aVR lead is inverted. (Why does this inversion occur? Study the polarity connections to the electrocardiograph to determine this.) References See references for Chapter 13. C H A P T E R 1 2 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis From the discussion in Chapter 10 of impulse transmission through the heart, it is obvious that any change in the pattern of this transmission can cause abnormal electrical potentials around the heart and, consequently, alter the shapes of the waves in the electrocardiogram. For this reason, almost all serious abnormalities of the heart muscle can be diagnosed by analyzing the contours of the different waves in the different electrocardiographic leads. Principles of Vectorial Analysis of Electrocardiograms Use of Vectors to Represent Electrical Potentials Before it is possible to understand how cardiac abnormalities affect the contours of the electrocardiogram, one must first become thoroughly familiar with the concept of vectors and vectorial analysis as applied to electrical potentials in and around the heart. Several times in Chapter 11 it was pointed out that heart current flows in a particular direction in the heart at a given instant during the cardiac cycle. A vector is an arrow that points in the direction of the electrical potential generated by the current flow, with the arrowhead in the positive direction. Also, by convention, the length of the arrow is drawn proportional to the voltage of the potential. “Resultant” Vector in the Heart at Any Given Instant. Figure 12–1 shows, by the shaded area and the negative signs, depolarization of the ventricular septum and parts of the apical endocardial walls of the two ventricles. At this instant of heart excitation, electrical current flows between the depolarized areas inside the heart and the nondepolarized areas on the outside of the heart, as indicated by the long elliptical arrows. Some current also flows inside the heart chambers directly from the depolarized areas toward the still polarized areas. Overall, considerably more current flows downward from the base of the ventricles toward the apex than in the upward direction. Therefore, the summated vector of the generated potential at this particular instant, called the instantaneous mean vector, is represented by the long black arrow drawn through the center of the ventricles in a direction from base toward apex. Furthermore, because the summated current is considerable in quantity, the potential is large, and the vector is long. Direction of a Vector Is Denoted in Terms of Degrees When a vector is exactly horizontal and directed toward the person’s left side, the vector is said to extend in the direction of 0 degrees, as shown in Figure 131 132 Unit III + + ++ + + + - + + + + + + + + + + + + + + + + + - + + + + -+ + + + ++ + + +- + + + + + + + + ++ + + + + + + The Heart - aVF III - aVL + + aVR 210∞ - -30∞ I I 0∞ aVL aVR III Figure 12–1 + 120∞ 90∞ + 60∞ II + + Mean vector through the partially depolarized ventricles. Figure 12–3 Axes of the three bipolar and three unipolar leads. -90∞ +270∞ through the center of Figure 12–2 in the +59-degree direction. This means that during most of the depolarization wave, the apex of the heart remains positive with respect to the base of the heart, as discussed later in the chapter. -100∞ 0∞ 180∞ Axis for Each Standard Bipolar Lead and Each Unipolar Limb Lead A 120∞ 59∞ -90∞ Figure 12–2 Vectors drawn to represent potentials for several different hearts, and the “axis” of the potential (expressed in degrees) for each heart. 12–2. From this zero reference point, the scale of vectors rotates clockwise: when the vector extends from above and straight downward, it has a direction of +90 degrees; when it extends from the person’s left to right, it has a direction of +180 degrees; and when it extends straight upward, it has a direction of -90 (or +270) degrees. In a normal heart, the average direction of the vector during spread of the depolarization wave through the ventricles, called the mean QRS vector, is about +59 degrees, which is shown by vector A drawn In Chapter 11, the three standard bipolar and the three unipolar limb leads are described. Each lead is actually a pair of electrodes connected to the body on opposite sides of the heart, and the direction from negative electrode to positive electrode is called the “axis” of the lead. Lead I is recorded from two electrodes placed respectively on the two arms. Because the electrodes lie exactly in the horizontal direction, with the positive electrode to the left, the axis of lead I is 0 degrees. In recording lead II, electrodes are placed on the right arm and left leg. The right arm connects to the torso in the upper right-hand corner and the left leg connects in the lower left-hand corner. Therefore, the direction of this lead is about +60 degrees. By similar analysis, it can be seen that lead III has an axis of about +120 degrees; lead aVR, +210 degrees; aVF, +90 degrees; and aVL -30 degrees. The directions of the axes of all these leads are shown in Figure 12–3, which is known as the hexagonal reference system. The polarities of the electrodes are shown by the plus and minus signs in the figure. The reader must learn these axes and their polarities, particularly for the bipolar limb leads I, II, and III, to understand the remainder of this chapter. Chapter 12 133 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities Vectorial Analysis of Potentials Recorded in Different Leads Now that we have discussed, first, the conventions for representing potentials across the heart by means of vectors and, second, the axes of the leads, it is possible to use these together to determine the instantaneous potential that will be recorded in the electrocardiogram of each lead for a given vector in the heart, as follows. Figure 12–4 shows a partially depolarized heart; vector A represents the instantaneous mean direction of current flow in the ventricles. In this instance, the direction of the vector is +55 degrees, and the voltage of the potential, represented by the length of vector A, is 2 millivolts. In the diagram below the heart, vector A is shown again, and a line is drawn to represent the axis of lead I in the 0-degree direction. To determine how much of the voltage in vector A will be recorded in lead I, a line perpendicular to the axis of lead I is drawn from the tip of vector A to the lead I axis, and a so-called projected vector (B) is drawn along the lead I axis. The arrow of this projected vector points toward the positive end of the lead I axis, which means that the record momentarily being recorded in the electrocardiogram of lead I is positive. And the instantaneous recorded voltage will be equal to the length of B divided by the length of A times 2 millivolts, or about 1 millivolt. Figure 12–5 shows another example of vectorial analysis. In this example, vector A represents the electrical potential and its axis at a given instant during ventricular depolarization in a heart in which the left side of the heart depolarizes more rapidly than the right. In this instance, the instantaneous vector has a direction of 100 degrees, and its voltage is again 2 millivolts. To determine the potential actually recorded in lead I, we draw a perpendicular line from the tip of vector A to the lead I axis and find projected vector B. Vector B is very short and this time in the negative direction, indicating that at this particular instant, the recording in lead I will be negative (below the zero line in the electrocardiogram), and the voltage recorded will be slight, about -0.3 millivolts. This figure demonstrates that when the vector in the heart is in a direction almost perpendicular to the axis of the lead, the voltage recorded in the electrocardiogram of this lead is very low. Conversely, when the heart vector has almost exactly the same axis as the lead axis, essentially the entire voltage of the vector will be recorded. Vectorial Analysis of Potentials in the Three Standard Bipolar Limb Leads. In Figure 12–6, vector A depicts the - I B + A Figure 12–5 Determination of the projected vector B along the axis of lead I when vector A represents the instantaneous potential in the ventricles. - - A I II III - B I I D + A C - I B I + III + II + A Figure 12–4 Determination of a projected vector B along the axis of lead I when vector A represents the instantaneous potential in the ventricles. Figure 12–6 Determination of projected vectors in leads I, II, and III when vector A represents the instantaneous potential in the ventricles. 134 Unit III instantaneous electrical potential of a partially depolarized heart. To determine the potential recorded at this instant in the electrocardiogram for each one of the three standard bipolar limb leads, perpendicular lines (the dashed lines) are drawn from the tip of vector A to the three lines representing the axes of the three different standard leads, as shown in the figure. The projected vector B depicts the potential recorded at that instant in lead I, projected vector C depicts the potential in lead II, and projected vector D depicts the potential in lead III. In each of these, the record in the electrocardiogram is positive—that is, above the zero line—because the projected vectors point in the positive directions along the axes of all the leads. The potential in lead I (vector B) is about one half that of the actual potential in the heart (vector A); in lead II (vector C), it is almost equal to that in the heart; and in lead III (vector D), it is about one third that in the heart. An identical analysis can be used to determine potentials recorded in augmented limb leads, except that the respective axes of the augmented leads (see Figure 12–3) are used in place of the standard bipolar limb lead axes used for Figure 12–6. Vectorial Analysis of the Normal Electrocardiogram Vectors That Occur at Successive Intervals During Depolarization of the Ventricles—The QRS Complex When the cardiac impulse enters the ventricles through the atrioventricular bundle, the first part of the ventricles to become depolarized is the left endocardial surface of the septum. Then depolarization spreads rapidly to involve both endocardial surfaces of the septum, as demonstrated by the shaded portion of the ventricle in Figure 12–7A. Next, depolarization spreads along the endocardial surfaces of the remainder of the two ventricles, as shown in Figure 12–7B and C. Finally, it spreads through the ventricular muscle to the outside of the heart, as shown progressively in Figure 12–7C, D, and E. At each stage in Figure 12–7, parts A to E, the instantaneous mean electrical potential of the ventricles is represented by a red vector superimposed on the ventricle in each figure. Each of these vectors is then analyzed by the method described in the preceding section to determine the voltages that will be recorded at each instant in each of the three standard electrocardiographic leads. To the right in each figure is shown progressive development of the electrocardiographic QRS complex. Keep in mind that a positive vector in a lead will cause recording in the electrocardiogram above the zero line, whereas a negative vector will cause recording below the zero line. Before proceeding with further consideration of vectorial analysis, it is essential that this analysis of the successive normal vectors presented in Figure 12–7 be The Heart understood. Each of these analyses should be studied in detail by the procedure given here. A short summary of this sequence follows. In Figure 12–7A, the ventricular muscle has just begun to be depolarized, representing an instant about 0.01 second after the onset of depolarization. At this time, the vector is short because only a small portion of the ventricles—the septum—is depolarized. Therefore, all electrocardiographic voltages are low, as recorded to the right of the ventricular muscle for each of the leads. The voltage in lead II is greater than the voltages in leads I and III because the heart vector extends mainly in the same direction as the axis of lead II. In Figure 12–7B, which represents about 0.02 second after onset of depolarization, the heart vector is long because much of the ventricular muscle mass has become depolarized. Therefore, the voltages in all electrocardiographic leads have increased. In Figure 12–7C, about 0.035 second after onset of depolarization, the heart vector is becoming shorter and the recorded electrocardiographic voltages are lower because the outside of the heart apex is now electronegative, neutralizing much of the positivity on the other epicardial surfaces of the heart. Also, the axis of the vector is beginning to shift toward the left side of the chest because the left ventricle is slightly slower to depolarize than the right. Therefore, the ratio of the voltage in lead I to that in lead III is increasing. In Figure 12–7D, about 0.05 second after onset of depolarization, the heart vector points toward the base of the left ventricle, and it is short because only a minute portion of the ventricular muscle is still polarized positive. Because of the direction of the vector at this time, the voltages recorded in leads II and III are both negative—that is, below the line—whereas the voltage of lead I is still positive. In Figure 12–7E, about 0.06 second after onset of depolarization, the entire ventricular muscle mass is depolarized, so that no current flows around the heart and no electrical potential is generated. The vector becomes zero, and the voltages in all leads become zero. Thus, the QRS complexes are completed in the three standard bipolar limb leads. Sometimes the QRS complex has a slight negative depression at its beginning in one or more of the leads, which is not shown in Figure 12–7; this depression is the Q wave. When it occurs, it is caused by initial depolarization of the left side of the septum before the right side, which creates a weak vector from left to right for a fraction of a second before the usual base-to-apex vector occurs. The major positive deflection shown in Figure 12–7 is the R wave, and the final negative deflection is the S wave. Electrocardiogram During Repolarization—The T Wave After the ventricular muscle has become depolarized, about 0.15 second later, repolarization begins and − Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities − − II III − I I I II III − I + − I I + II II II + III + II + III + III III A B − II III − − II III − I I − 135 I I + − I I II II III + + II + II + III + III III C D − − II III − I I I + II III + II + III E Figure 12–7 Shaded areas of the ventricles are depolarized (–); nonshaded areas are still polarized (+). The ventricular vectors and QRS complexes 0.01 second after onset of ventricular depolarization (A); 0.02 second after onset of depolarization (B); 0.035 second after onset of depolarization (C); 0.05 second after onset of depolarization (D); and after depolarization of the ventricles is complete, 0.06 second after onset (E). proceeds until complete at about 0.35 second.This repolarization causes the T wave in the electrocardiogram. Because the septum and endocardial areas of the ventricular muscle depolarize first, it seems logical that these areas should repolarize first as well. However, this is not the usual case because the septum and other endocardial areas have a longer period of contraction than most of the external surfaces of the heart. Therefore, the greatest portion of ventricular muscle mass to repolarize first is the entire outer surface of the ventricles, especially near the apex of the heart. The endocardial areas, conversely, normally repolarize last. This sequence of repolarization is postulated to be caused by the high blood pressure inside the ventricles during contraction, which greatly reduces coronary blood flow to the endocardium, thereby slowing repolarization in the endocardial areas. Because the outer apical surfaces of the ventricles repolarize before the inner surfaces, the positive end of the overall ventricular vector during repolarization is toward the apex of the heart. As a result, the normal T wave in all three bipolar limb leads is positive, which is also the polarity of most of the normal QRS complex. In Figure 12–8, five stages of repolarization of the ventricles are denoted by progressive increase of the white areas—the repolarized areas. At each stage, the vector extends from the base of the heart toward the apex until it disappears in the last stage. At first, the vector is relatively small because the area of repolarization is small. Later, the vector becomes 136 Unit III The Heart - - II III - I I III + P + + ++ ++ + -+ + - + + + + ++ - + + + + + + SA + + + II III - - T I II + II + - I I + III I II III + II + Figure 12–9 III Figure 12–8 Generation of the T wave during repolarization of the ventricles, showing also vectorial analysis of the first stage of repolarization. The total time from the beginning of the T wave to its end is approximately 0.15 second. stronger because of greater degrees of repolarization. Finally, the vector becomes weaker again because the areas of depolarization still persisting become so slight that the total quantity of current flow decreases. These changes also demonstrate that the vector is greatest when about half the heart is in the polarized state and about half is depolarized. The changes in the electrocardiograms of the three standard limb leads during repolarization are noted under each of the ventricles, depicting the progressive stages of repolarization. Thus, over about 0.15 second, the period of time required for the whole process to take place, the T wave of the electrocardiogram is generated. Depolarization of the Atria— The P Wave Depolarization of the atria begins in the sinus node and spreads in all directions over the atria. Therefore, the point of original electronegativity in the atria is about at the point of entry of the superior vena cava where the sinus node lies, and the direction of initial depolarization is denoted by the black vector in Figure 12–9. Furthermore, the vector remains generally in this direction throughout the process of normal atrial depolarization. Because this direction is generally in the positive directions of the axes of the three standard bipolar limb leads I, II, and III, the electrocardiograms recorded from the atria during depolarization are also usually positive in all three of these leads, as shown in Figure 12–9. This record of atrial depolarization is known as the atrial P wave. Depolarization of the atria and generation of the P wave, showing the maximum vector through the atria and the resultant vectors in the three standard leads. At the right are the atrial P and T waves. SA, sinoatrial node. Repolarization of the Atria—The Atrial T Wave. Spread of depolarization through the atrial muscle is much slower than in the ventricles because the atria have no Purkinje system for fast conduction of the depolarization signal. Therefore, the musculature around the sinus node becomes depolarized a long time before the musculature in distal parts of the atria. Because of this, the area in the atria that also becomes repolarized first is the sinus nodal region, the area that had originally become depolarized first. Thus, when repolarization begins, the region around the sinus node becomes positive with respect to the rest of the atria. Therefore, the atrial repolarization vector is backward to the vector of depolarization. (Note that this is opposite to the effect that occurs in the ventricles.) Therefore, as shown to the right in Figure 12–9, the so-called atrial T wave follows about 0.15 second after the atrial P wave, but this T wave is on the opposite side of the zero reference line from the P wave; that is, it is normally negative rather than positive in the three standard bipolar limb leads. In the normal electrocardiogram, the atrial T wave appears at about the same time that the QRS complex of the ventricles appears. Therefore, it is almost always totally obscured by the large ventricular QRS complex, although in some very abnormal states, it does appear in the recorded electrocardiogram. Vectorcardiogram It has been noted in the discussion up to this point that the vector of current flow through the heart changes rapidly as the impulse spreads through the myocardium. It changes in two aspects: First, the vector increases and decreases in length because of increasing and decreasing voltage of the vector. Second, the vector changes direction because of Chapter 12 1 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities 2 4 3 4 III - -60∞ 5 5 I 1 137 I + I II 0∞ 180∞ 3 Depolarization QRS 2 120∞ Repolarization T 59∞ III + III Figure 12–10 QRS and T vectorcardiograms. Figure 12–11 Plotting the mean electrical axis of the ventricles from two electrocardiographic leads (leads I and III). changes in the average direction of the electrical potential from the heart. The so-called vectorcardiogram depicts these changes at different times during the cardiac cycle, as shown in Figure 12–10. In the large vectorcardiogram of Figure 12–10, point 5 is the zero reference point, and this point is the negative end of all the successive vectors. While the heart muscle is polarized between heartbeats, the positive end of the vector remains at the zero point because there is no vectorial electrical potential. However, as soon as current begins to flow through the ventricles at the beginning of ventricular depolarization, the positive end of the vector leaves the zero reference point. When the septum first becomes depolarized, the vector extends downward toward the apex of the ventricles, but it is relatively weak, thus generating the first portion of the ventricular vectorcardiogram, as shown by the positive end of vector 1. As more of the ventricular muscle becomes depolarized, the vector becomes stronger and stronger, usually swinging slightly to one side. Thus, vector 2 of Figure 12–10 represents the state of depolarization of the ventricles about 0.02 second after vector 1. After another 0.02 second, vector 3 represents the potential, and vector 4 occurs in another 0.01 second. Finally, the ventricles become totally depolarized, and the vector becomes zero once again, as shown at point 5. The elliptical figure generated by the positive ends of the vectors is called the QRS vectorcardiogram. Vectorcardiograms can be recorded on an oscilloscope by connecting body surface electrodes from the neck and lower abdomen to the vertical plates of the oscilloscope and connecting chest surface electrodes from each side of the heart to the horizontal plates. When the vector changes, the spot of light on the oscilloscope follows the course of the positive end of the changing vector, thus inscribing the vectorcardiogram on the oscilloscopic screen. Mean Electrical Axis of the Ventricular QRS— And Its Significance The vectorcardiogram during ventricular depolarization (the QRS vectorcardiogram) shown in Figure 12–10 is that of a normal heart. Note from this vectorcardiogram that the preponderant direction of the vectors of the ventricles during depolarization is mainly toward the apex of the heart. That is, during most of the cycle of ventricular depolarization, the direction of the electrical potential (negative to positive) is from the base of the ventricles toward the apex. This preponderant direction of the potential during depolarization is called the mean electrical axis of the ventricles. The mean electrical axis of the normal ventricles is 59 degrees. In many pathological conditions of the heart, this direction changes markedly— sometimes even to opposite poles of the heart. Determining the Electrical Axis from Standard Lead Electrocardiograms Clinically, the electrical axis of the heart usually is estimated from the standard bipolar limb lead electrocardiograms rather than from the vectorcardiogram. Figure 12–11 shows a method for doing this. After recording the standard leads, one determines the net potential and polarity of the recordings in leads I and III. In lead I of Figure 12–11, the recording is positive, and in lead III, the recording is mainly positive but negative during part of the cycle. If any part of a recording is negative, this negative potential is subtracted from the positive part of the potential to determine the net potential for that lead, as shown by the arrow to the right of the QRS complex for lead III. 138 Unit III Then each net potential for leads I and III is plotted on the axes of the respective leads, with the base of the potential at the point of intersection of the axes, as shown in Figure 12–11. If the net potential of lead I is positive, it is plotted in a positive direction along the line depicting lead I. Conversely, if this potential is negative, it is plotted in a negative direction. Also, for lead III, the net potential is placed with its base at the point of intersection, and, if positive, it is plotted in the positive direction along the line depicting lead III. If it is negative, it is plotted in the negative direction. To determine the vector of the total QRS ventricular mean electrical potential, one draws perpendicular lines (the dashed lines in the figure) from the apices of leads I and III, respectively. The point of intersection of these two perpendicular lines represents, by vectorial analysis, the apex of the mean QRS vector in the ventricles, and the point of intersection of the lead I and lead III axes represents the negative end of the mean vector. Therefore, the mean QRS vector is drawn between these two points. The approximate average potential generated by the ventricles during depolarization is represented by the length of this mean QRS vector, and the mean electrical axis is represented by the direction of the mean vector. Thus, the orientation of the mean electrical axis of the normal ventricles, as determined in Figure 12–11, is 59 degrees positive (+59 degrees). Abnormal Ventricular Conditions That Cause Axis Deviation The Heart side of the heart than on the other side, and this allows excess generation of electrical potential on that side. Second, more time is required for the depolarization wave to travel through the hypertrophied ventricle than through the normal ventricle. Consequently, the normal ventricle becomes depolarized considerably in advance of the hypertrophied ventricle, and this causes a strong vector from the normal side of the heart toward the hypertrophied side, which remains strongly positively charged. Thus, the axis deviates toward the hypertrophied ventricle. Vectorial Analysis of Left Axis Deviation Resulting from Hypertrophy of the Left Ventricle. Figure 12–12 shows the three standard bipolar limb lead electrocardiograms. Vectorial analysis demonstrates left axis deviation with mean electrical axis pointing in the -15-degree direction. This is a typical electrocardiogram caused by increased muscle mass of the left ventricle. In this instance, the axis deviation was caused by hypertension (high arterial blood pressure), which caused the left ventricle to hypertrophy so that it could pump blood against elevated systemic arterial pressure. A similar picture of left axis deviation occurs when the left ventricle hypertrophies as a result of aortic valvular stenosis, aortic valvular regurgitation, or any number of congenital heart conditions in which the left ventricle enlarges while the right ventricle remains relatively normal in size. Vectorial Analysis of Right Axis Deviation Resulting from Hypertrophy of the Right Ventricle. The electro- cardiogram of Figure 12–13 shows intense right axis deviation, to an electrical axis of 170 degrees, which is Although the mean electrical axis of the ventricles averages about 59 degrees, this axis can swing even in the normal heart from about 20 degrees to about 100 degrees. The causes of the normal variations are mainly anatomical differences in the Purkinje distribution system or in the musculature itself of different hearts. However, a number of abnormal conditions of the heart can cause axis deviation beyond the normal limits, as follows. Change in the Position of the Heart in the Chest. If the heart itself is angulated to the left, the mean electrical axis of the heart also shifts to the left. Such shift occurs (1) at the end of deep expiration, (2) when a person lies down, because the abdominal contents press upward against the diaphragm, and (3) quite frequently in stocky, fat people whose diaphragms normally press upward against the heart all the time. Likewise, angulation of the heart to the right causes the mean electrical axis of the ventricles to shift to the right. This occurs (1) at the end of deep inspiration, (2) when a person stands up, and (3) normally in tall, lanky people whose hearts hang downward. Hypertrophy of One Ventricle. When one ventricle greatly hypertrophies, the axis of the heart shifts toward the hypertrophied ventricle for two reasons. First, a far greater quantity of muscle exists on the hypertrophied I II III III - I- +I + III Figure 12–12 Left axis deviation in a hypertensive heart (hypertrophic left ventricle). Note the slightly prolonged QRS complex as well. Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities I I II II 139 III III - III III - I- +I I- +I + III + III Figure 12–14 Figure 12–13 High-voltage electrocardiogram in congenital pulmonary valve stenosis with right ventricular hypertrophy. Intense right axis deviation and a slightly prolonged QRS complex also are seen. 111 degrees to the right of the normal 59-degree mean ventricular QRS axis. The right axis deviation demonstrated in this figure was caused by hypertrophy of the right ventricle as a result of congenital pulmonary valve stenosis. Right axis deviation also can occur in other congenital heart conditions that cause hypertrophy of the right ventricle, such as tetralogy of Fallot and interventricular septal defect. Bundle Branch Block Causes Axis Deviation. Ordinarily, the lateral walls of the two ventricles depolarize at almost the same instant because both the left and the right bundle branches of the Purkinje system transmit the cardiac impulse to the two ventricular walls at almost the same instant. As a result, the potentials generated by the two ventricles (on the two opposite sides of the heart) almost neutralize each other. But if only one of the major bundle branches is blocked, the cardiac impulse spreads through the normal ventricle long before it spreads through the other. Therefore, depolarization of the two ventricles does not occur even nearly simultaneously, and the depolarization potentials do not neutralize each other.As a result, axis deviation occurs as follows. Vectorial Analysis of Left Axis Deviation in Left Bundle Branch Block. When the left bundle branch is Left axis deviation caused by left bundle branch block. Note also the greatly prolonged QRS complex. blocked, cardiac depolarization spreads through the right ventricle two to three times as rapidly as through the left ventricle. Consequently, much of the left ventricle remains polarized for as long as 0.1 second after the right ventricle has become totally depolarized. Thus, the right ventricle becomes electronegative, whereas the left ventricle remains electropositive during most of the depolarization process, and a strong vector projects from the right ventricle toward the left ventricle. In other words, there is intense left axis deviation of about -50 degrees because the positive end of the vector points toward the left ventricle. This is demonstrated in Figure 12–14, which shows typical left axis deviation resulting from left bundle branch block. Because of slowness of impulse conduction when the Purkinje system is blocked, in addition to axis deviation, the duration of the QRS complex is greatly prolonged because of extreme slowness of depolarization in the affected side of the heart. One can see this by observing the excessive widths of the QRS waves in Figure 12–14. This is discussed in greater detail later in the chapter. This extremely prolonged QRS complex differentiates bundle branch block from axis deviation caused by hypertrophy. Vectorial Analysis of Right Axis Deviation in Right Bundle Branch Block. When the right bundle branch is blocked, the left ventricle depolarizes far more rapidly than the right ventricle, so that the left side of the ventricles becomes electronegative as long as 140 Unit III 0.1 second before the right. Therefore, a strong vector develops, with its negative end toward the left ventricle and its positive end toward the right ventricle. In other words, intense right axis deviation occurs. Right axis deviation caused by right bundle branch block is demonstrated, and its vector is analyzed, in Figure 12–15, which shows an axis of about 105 degrees instead of the normal 59 degrees and a prolonged QRS complex because of slow conduction. Conditions That Cause Abnormal Voltages of the QRS Complex Increased Voltage in the Standard Bipolar Limb Leads Normally, the voltages in the three standard bipolar limb leads, as measured from the peak of the R wave to the bottom of the S wave, vary between 0.5 and 2.0 millivolts, with lead III usually recording the lowest voltage and lead II the highest. However, these relations are not invariable, even for the normal heart. In general, when the sum of the voltages of all the QRS complexes of the three standard leads is greater than 4 millivolts, the patient is considered to have a highvoltage electrocardiogram. The cause of high-voltage QRS complexes most often is increased muscle mass of the heart, which ordinarily results from hypertrophy of the muscle in response to excessive load on one part of the heart or the other. For example, the right ventricle hypertrophies when it must pump blood through a stenotic pulmonary valve, and the left ventricle hypertrophies when a person has high blood pressure. The increased quantity of muscle causes generation of increased quantities of electricity around the heart. As a result, The Heart the electrical potentials recorded in the electrocardiographic leads are considerably greater than normal, as shown in Figures 12–12 and 12–13. Decreased Voltage of the Electrocardiogram Decreased Voltage Caused by Cardiac Myopathies. One of the most common causes of decreased voltage of the QRS complex is a series of old myocardial artery infarctions with resultant diminished muscle mass. This also causes the depolarization wave to move through the ventricles slowly and prevents major portions of the heart from becoming massively depolarized all at once. Consequently, this condition causes some prolongation of the QRS complex along with the decreased voltage. Figure 12–16 shows a typical lowvoltage electrocardiogram with prolongation of the QRS complex, which is common after multiple small infarctions of the heart have caused local delays of impulse conduction and reduced voltages due to loss of muscle mass throughout the ventricles. Decreased Voltage Caused by Conditions Surrounding the Heart. One of the most important causes of decreased voltage in electrocardiographic leads is fluid in the pericardium. Because extracellular fluid conducts electrical currents with great ease, a large portion of the electricity flowing out of the heart is conducted from one part of the heart to another through the pericardial fluid. Thus, this effusion effectively “short-circuits” the electrical potentials generated by the heart, decreasing the electrocardiographic voltages that reach the outside surfaces of the body. Pleural effusion, to a lesser extent, also can “short-circuit” the electricity around the heart, so that the voltages at the III - I I- I +I II II III + III Figure 12–15 Right axis deviation caused by right bundle branch block. Note also the greatly prolonged QRS complex. III Figure 12–16 Low-voltage electrocardiogram following local damage throughout the ventricles caused by previous myocardial infarction. Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities surface of the body and in the electrocardiograms are decreased. Pulmonary emphysema can decrease the electrocardiographic potentials, but by a different method from that of pericardial effusion. In pulmonary emphysema, conduction of electrical current through the lungs is depressed considerably because of excessive quantity of air in the lungs. Also, the chest cavity enlarges, and the lungs tend to envelop the heart to a greater extent than normally. Therefore, the lungs act as an insulator to prevent spread of electrical voltage from the heart to the surface of the body, and this results in decreased electrocardiographic potentials in the various leads. 141 ventricular system, with replacement of this muscle by scar tissue, and (2) multiple small local blocks in the conduction of impulses at many points in the Purkinje system. As a result, cardiac impulse conduction becomes irregular, causing rapid shifts in voltages and axis deviations. This often causes double or even triple peaks in some of the electrocardiographic leads, such as those shown in Figure 12–14. Current of Injury The QRS complex lasts as long as depolarization continues to spread through the ventricles—that is, as long as part of the ventricles is depolarized and part is still polarized. Therefore, prolonged conduction of the impulse through the ventricles always causes a prolonged QRS complex. Such prolongation often occurs when one or both ventricles are hypertrophied or dilated, owing to the longer pathway that the impulse must then travel. The normal QRS complex lasts 0.06 to 0.08 second, whereas in hypertrophy or dilatation of the left or right ventricle, the QRS complex may be prolonged to 0.09 to 0.12 second. Many different cardiac abnormalities, especially those that damage the heart muscle itself, often cause part of the heart to remain partially or totally depolarized all the time. When this occurs, current flows between the pathologically depolarized and the normally polarized areas even between heartbeats. This is called a current of injury. Note especially that the injured part of the heart is negative, because this is the part that is depolarized and emits negative charges into the surrounding fluids, whereas the remainder of the heart is neutral or positive polarity. Some abnormalities that can cause current of injury are (1) mechanical trauma, which sometimes makes the membranes remain so permeable that full repolarization cannot take place; (2) infectious processes that damage the muscle membranes; and (3) ischemia of local areas of heart muscle caused by local coronary occlusions, which is by far the most common cause of current of injury in the heart. During ischemia, not enough nutrients from the coronary blood supply are available to the heart muscle to maintain normal membrane polarization. Prolonged QRS Complex Resulting from Purkinje System Blocks Effect of Current of Injury on the QRS Complex When the Purkinje fibers are blocked, the cardiac impulse must then be conducted by the ventricular muscle instead of by way of the Purkinje system. This decreases the velocity of impulse conduction to about one third of normal. Therefore, if complete block of one of the bundle branches occurs, the duration of the QRS complex usually is increased to 0.14 second or greater. In general, a QRS complex is considered to be abnormally long when it lasts more than 0.09 second; when it lasts more than 0.12 second, the prolongation is almost certainly caused by pathological block somewhere in the ventricular conduction system, as shown by the electrocardiograms for bundle branch block in Figures 12–14 and 12–15. In Figure 12–17, a small area in the base of the left ventricle is newly infarcted (loss of coronary blood flow). Therefore, during the T-P interval—that is, when the normal ventricular muscle is totally polarized—abnormal negative current still flows from the infarcted area at the base of the left ventricle and spreads toward the rest of the ventricles. The vector of this “current of injury,” as shown in the first heart in the figure, is in a direction of about 125 degrees, with the base of the vector, the negative end, toward the injured muscle. As shown in the lower portions of the figure, even before the QRS complex begins, this vector causes an initial record in lead I below the zero potential line, because the projected vector of the current of injury in lead I points toward the negative end of the lead I axis. In lead II, the record is above the line because the projected vector points more toward the positive terminal of the lead. In lead III, the projected vector points in the same direction as the positive terminal of lead III, so that the record is positive. Furthermore, because the vector lies almost exactly in the direction of the axis of lead III, the voltage of the current of injury in lead III is much greater than in either lead I or lead II. Prolonged and Bizarre Patterns of the QRS Complex Prolonged QRS Complex as a Result of Cardiac Hypertrophy or Dilatation Conditions That Cause Bizarre QRS Complexes Bizarre patterns of the QRS complex most frequently are caused by two conditions: (1) destruction of cardiac muscle in various areas throughout the 142 Unit III The Heart Injured area - - I II III - I I III + + II + J II Current of injury J Figure 12–17 III J As the heart then proceeds through its normal process of depolarization, the septum first becomes depolarized; then the depolarization spreads down to the apex and back toward the bases of the ventricles. The last portion of the ventricles to become totally depolarized is the base of the right ventricle, because the base of the left ventricle is already totally and permanently depolarized. By vectorial analysis, the successive stages of electrocardiogram generation by the depolarization wave traveling through the ventricles can be constructed graphically, as demonstrated in the lower part of Figure 12–17. When the heart becomes totally depolarized, at the end of the depolarization process (as noted by the next-to-last stage in Figure 12–17), all the ventricular muscle is in a negative state. Therefore, at this instant in the electrocardiogram, no current flows from the ventricles to the electrocardiographic electrodes because now both the injured heart muscle and the contracting muscle are depolarized. Next, as repolarization takes place, all of the heart finally repolarizes, except the area of permanent depolarization in the injured base of the left ventricle. Thus, repolarization causes a return of the current of injury in each lead, as noted at the far right in Figure 12–17. The J Point—The Zero Reference Potential for Analyzing Current of Injury One would think that the electrocardiograph machines for recording electrocardiograms could determine when no current is flowing around the Current of injury Effect of a current of injury on the electrocardiogram. heart. However, many stray currents exist in the body, such as currents resulting from “skin potentials” and from differences in ionic concentrations in different fluids of the body. Therefore, when two electrodes are connected between the arms or between an arm and a leg, these stray currents make it impossible for one to predetermine the exact zero reference level in the electrocardiogram. For these reasons, the following procedure must be used to determine the zero potential level: First, one notes the exact point at which the wave of depolarization just completes its passage through the heart, which occurs at the end of the QRS complex. At exactly this point, all parts of the ventricles have become depolarized, including both the damaged parts and the normal parts, so that no current is flowing around the heart. Even the current of injury disappears at this point. Therefore, the potential of the electrocardiogram at this instant is at zero voltage.This point is known as the “J point” in the electrocardiogram, as shown in Figure 12–18. Then, for analysis of the electrical axis of the injury potential caused by a current of injury, a horizontal line is drawn in the electrocardiogram for each lead at the level of the J point. This horizontal line is then the zero potential level in the electrocardiogram from which all potentials caused by currents of injury must be measured. Use of the J Point in Plotting Axis of Injury Potential. Figure 12–18 shows electrocardiograms (leads I and III) from an injured heart. Both records show injury potentials. In other words, the J point of each of these two electrocardiograms is not on the same line as the T-P segment. In the figure, a horizontal line has been drawn through the J point to represent the zero Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities voltage level in each of the two recordings. The injury potential in each lead is the difference between the voltage of the electrocardiogram immediately before onset of the P wave and the zero voltage level determined from the J point. In lead I, the recorded voltage of the injury potential is above the zero potential level and is, therefore, positive. Conversely, in lead III, the injury potential is below the zero voltage level and, therefore, is negative. At the bottom in Figure 12–18, the respective injury potentials in leads I and III are plotted on the coordinates of these leads, and the resultant vector of the injury potential for the whole ventricular muscle mass is determined by vectorial analysis as described. In this instance, the resultant vector extends from the right side of the ventricles toward the left and slightly upward, with an axis of about -30 degrees. If one places this vector for the injury potential directly over the ventricles, the negative end of the vector points toward the permanently depolarized, “injured” area of the ventricles. In the example shown in Figure 12–18, the injured area would be in the lateral wall of the right ventricle. This analysis is obviously complex. However, it is essential that the student go over it again and again until he or she understands it thoroughly. No other aspect of electrocardiographic analysis is more important. 143 Coronary Ischemia as a Cause of Injury Potential Insufficient blood flow to the cardiac muscle depresses the metabolism of the muscle for three reasons: (1) lack of oxygen, (2) excess accumulation of carbon dioxide, and (3) lack of sufficient food nutrients. Consequently, repolarization of the muscle membrane cannot occur in areas of severe myocardial ischemia. Often the heart muscle does not die because the blood flow is sufficient to maintain life of the muscle even though it is not sufficient to cause repolarization of the membranes. As long as this state exists, an injury potential continues to flow during the diastolic portion (the T-P portion) of each heart cycle. Extreme ischemia of the cardiac muscle occurs after coronary occlusion, and a strong current of injury flows from the infarcted area of the ventricles during the T-P interval between heartbeats, as shown in Figures 12–19 and 12–20. Therefore, one of the most important diagnostic features of electrocardiograms recorded after acute coronary thrombosis is the current of injury. Acute Anterior Wall Infarction. Figure 12–19 shows the electrocardiogram in the three standard bipolar limb I + - 0 0 “J” point “J” point III 0 + - 0 I II III - III - II- III +I +I + III + III V2 Figure 12–18 Figure 12–19 J point as the zero reference potential of the electrocardiograms for leads I and II. Also, the method for plotting the axis of the injury potential is shown by the lowermost panel. Current of injury in acute anterior wall infarction. Note the intense injury potential in lead V2. 144 Unit III leads and in one chest lead (lead V2 ) recorded from a patient with acute anterior wall cardiac infarction. The most important diagnostic feature of this electrocardiogram is the intense injury potential in chest lead V2. If one draws a zero horizontal potential line through the J point of this electrocardiogram, a strong negative injury potential during the T-P interval is found, which means that the chest electrode over the front of the heart is in an area of strongly negative potential. In other words, the negative end of the injury potential vector in this heart is against the anterior chest wall. This means that the current of injury is emanating from the anterior wall of the ventricles, which diagnoses this condition as anterior wall infarction. Analyzing the injury potentials in leads I and III, one finds a negative potential in lead I and a positive potential in lead III. This means that the resultant vector of the injury potential in the heart is about +150 degrees, with the negative end pointing toward the left ventricle and the positive end pointing toward the right ventricle. Thus, in this particular electrocardiogram, the current of injury is coming mainly from the left ventricle as well as from the anterior wall of the heart. Therefore, one would conclude that this anterior wall infarction almost certainly is caused by thrombosis of the anterior descending branch of the left coronary artery. Posterior Wall Infarction. Figure 12–20 shows the three standard bipolar limb leads and one chest lead (lead V2) from a patient with posterior wall infarction. The major diagnostic feature of this electrocardiogram is The Heart also in the chest lead. If a zero potential reference line is drawn through the J point of this lead, it is readily apparent that during the T-P interval, the potential of the current of injury is positive. This means that the positive end of the vector is in the direction of the anterior chest wall, and the negative end (injured end of the vector) points away from the chest wall. In other words, the current of injury is coming from the back of the heart opposite to the anterior chest wall, which is the reason this type of electrocardiogram is the basis for diagnosing posterior wall infarction. If one analyzes the injury potentials from leads II and III of Figure 12–20, it is readily apparent that the injury potential is negative in both leads. By vectorial analysis, as shown in the figure, one finds that the resultant vector of the injury potential is about -95 degrees, with the negative end pointing downward and the positive end pointing upward. Thus, because the infarct, as indicated by the chest lead, is on the posterior wall of the heart and, as indicated by the injury potentials in leads II and III, is in the apical portion of the heart, one would suspect that this infarct is near the apex on the posterior wall of the left ventricle. Infarction in Other Parts of the Heart. By the same proce- dures demonstrated in the preceding discussions of anterior and posterior wall infarctions, it is possible to determine the locus of any infarcted area emitting a current of injury, regardless of which part of the heart is involved. In making such vectorial analyses, it must be remembered that the positive end of the injury potential vector points toward the normal cardiac muscle, and the negative end points toward the injured portion of the heart that is emitting the current of injury. Recovery from Acute Coronary Thrombosis. Figure 12–21 shows a V3 chest lead from a patient with acute posterior wall infarction, demonstrating changes in the electrocardiogram from the day of the attack to 1 I II II - III V2 III - Same day + III 1 week 2 weeks 1 year + II Figure 12–21 Figure 12–20 Injury potential in acute posterior wall, apical infarction. Recovery of the myocardium after moderate posterior wall infarction, demonstrating disappearance of the injury potential that is present on the first day after the infarction and still slightly present at 1 week. Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities week later, 3 weeks later, and finally 1 year later. From this electrocardiogram, one can see that the injury potential is strong immediately after the acute attack (T-P segment displaced positively from the S-T segment). However, after about 1 week, the injury potential has diminished considerably, and after 3 weeks, it is gone. After that, the electrocardiogram does not change greatly during the next year. This is the usual recovery pattern after acute cardiac infarction of moderate degree, showing that the new collateral coronary blood flow develops enough to re-establish appropriate nutrition to most of the infarcted area. Conversely, in some patients with coronary infarction, the infarcted area never redevelops adequate coronary blood supply. Often, some of the heart muscle dies, but if the muscle does not die, it will continue to show an injury potential as long as the ischemia exists, particularly during bouts of exercise when the heart is overloaded. Old Recovered Myocardial Infarction. Figure 12–22 shows leads I and III after anterior infarction and leads I and III after posterior infarction about 1 year after the acute heart attack. The records show what might be called the “ideal” configurations of the QRS complex in these types of recovered myocardial infarction. Usually a Q wave has developed at the beginning of the QRS complex in lead I in anterior infarction because of loss of muscle mass in the anterior wall of the left ventricle, but in posterior infarction, a Q wave has developed at the beginning of the QRS complex in lead III because of loss of muscle in the posterior apical part of the ventricle. These configurations are certainly not found in all cases of old cardiac infarction. Local loss of muscle and local points of cardiac signal conduction block can cause very bizarre QRS patterns (especially prominent Q waves, for instance), decreased voltage, and QRS prolongation. Anterior Posterior Q 145 Current of Injury in Angina Pectoris. “Angina pectoris” means pain from the heart felt in the pectoral regions of the upper chest. This pain usually also radiates into the left neck area and down the left arm. The pain typically is caused by moderate ischemia of the heart. Usually, no pain is felt as long as the person is quiet, but as soon as he or she overworks the heart, the pain appears. An injury potential sometimes appears in the electrocardiogram during an attack of severe angina pectoris, because the coronary insufficiency becomes great enough to prevent adequate repolarization of some areas of the heart during diastole. Abnormalities in the T Wave Earlier in the chapter, it was pointed out that the T wave is normally positive in all the standard bipolar limb leads and that this is caused by repolarization of the apex and outer surfaces of the ventricles ahead of the intraventricular surfaces. That is, the T wave becomes abnormal when the normal sequence of repolarization does not occur. Several factors can change this sequence of repolarization. Effect of Slow Conduction of the Depolarization Wave on the Characteristics of the T Wave Referring back to Figure 12–14, note that the QRS complex is considerably prolonged. The reason for this prolongation is delayed conduction in the left ventricle resulting from left bundle branch block. This causes the left ventricle to become depolarized about 0.08 second after depolarization of the right ventricle, which gives a strong mean QRS vector to the left. However, the refractory periods of the right and left ventricular muscle masses are not greatly different from each other. Therefore, the right ventricle begins to repolarize long before the left ventricle; this causes strong positivity in the right ventricle and negativity in the left ventricle at the time that the T wave is developing. In other words, the mean axis of the T wave is now deviated to the right, which is opposite the mean electrical axis of the QRS complex in the same electrocardiogram. Thus, when conduction of the depolarization impulse through the ventricles is greatly delayed, the T wave is almost always of opposite polarity to that of the QRS complex. Q I III I III Shortened Depolarization in Portions of the Ventricular Muscle as a Cause of T Wave Abnormalities Figure 12–22 Electrocardiograms of anterior and posterior wall infarctions that occurred about 1 year previously, showing a Q wave in lead I in anterior wall infarction and a Q wave in lead III in posterior wall infarction. If the base of the ventricles should exhibit an abnormally short period of depolarization, that is, a shortened action potential, repolarization of the ventricles would not begin at the apex as it normally does. 146 Unit III T T T The Heart T T T Figure 12–23 Inverted T wave resulting from mild ischemia at the apex of the ventricles. Figure 12–24 Instead, the base of the ventricles would repolarize ahead of the apex, and the vector of repolarization would point from the apex toward the base of the heart, opposite to the standard vector of repolarization. Consequently, the T wave in all three standard leads would be negative rather than the usual positive. Thus, the simple fact that the base of the ventricles has a shortened period of depolarization is sufficient to cause marked changes in the T wave, even to the extent of changing the entire T wave polarity, as shown in Figure 12–23. Mild ischemia is by far the most common cause of shortening of depolarization of cardiac muscle, because this increases current flow through the potassium channels. When the ischemia occurs in only one area of the heart, the depolarization period of this area decreases out of proportion to that in other portions. As a result, definite changes in the T wave can take place. The ischemia might result from chronic, progressive coronary occlusion; acute coronary occlusion; or relative coronary insufficiency that occurs during exercise. One means for detecting mild coronary insufficiency is to have the patient exercise and to record the electrocardiogram, noting whether changes occur in the T waves. The changes in the T waves need not be specific, because any change in the T wave in any lead— Biphasic T wave caused by digitalis toxicity. inversion, for instance, or a biphasic wave—is often evidence enough that some portion of the ventricular muscle has a period of depolarization out of proportion to the rest of the heart, caused by mild to moderate coronary insufficiency. Effect of Digitalis on the T Wave. As discussed in Chapter 22, digitalis is a drug that can be used during coronary insufficiency to increase the strength of cardiac muscle contraction. But when overdosages of digitalis are given, depolarization duration in one part of the ventricles may be increased out of proportion to that of other parts. As a result, nonspecific changes, such as T wave inversion or biphasic T waves, may occur in one or more of the electrocardiographic leads. A biphasic T wave caused by excessive administration of digitalis is shown in Figure 12–24. Therefore, changes in the T wave during digitalis administration are often the earliest signs of digitalis toxicity. References See references for Chapter 13. C H A P T E R 1 Cardiac Arrhythmias and Their Electrocardiographic Interpretation Some of the most distressing types of heart malfunction occur not as a result of abnormal heart muscle but because of abnormal rhythm of the heart. For instance, sometimes the beat of the atria is not coordinated with the beat of the ventricles, so that the atria no longer function as primer pumps for the ventricles. The purpose of this chapter is to discuss the physiology of common cardiac arrhythmias and their effects on heart pumping, as well as their diagnosis by electrocardiography.The causes of the cardiac arrhythmias are usually one or a combination of the following abnormalities in the rhythmicity-conduction system of the heart: 1. Abnormal rhythmicity of the pacemaker 2. Shift of the pacemaker from the sinus node to another place in the heart 3. Blocks at different points in the spread of the impulse through the heart 4. Abnormal pathways of impulse transmission through the heart 5. Spontaneous generation of spurious impulses in almost any part of the heart Abnormal Sinus Rhythms Tachycardia The term “tachycardia” means fast heart rate, usually defined in an adult person as faster than 100 beats per minute. An electrocardiogram recorded from a patient with tachycardia is shown in Figure 13–1. This electrocardiogram is normal except that the heart rate, as determined from the time intervals between QRS complexes, is about 150 per minute instead of the normal 72 per minute. The general causes of tachycardia include increased body temperature, stimulation of the heart by the sympathetic nerves, or toxic conditions of the heart. The heart rate increases about 10 beats per minute for each degree Fahrenheit (18 beats per degree Celsius) increase in body temperature, up to a body temperature of about 105°F (40.5°C); beyond this, the heart rate may decrease because of progressive debility of the heart muscle as a result of the fever. Fever causes tachycardia because increased temperature increases the rate of metabolism of the sinus node, which in turn directly increases its excitability and rate of rhythm. Many factors can cause the sympathetic nervous system to excite the heart, as we discuss at multiple points in this text. For instance, when a patient loses blood and passes into a state of shock or semishock, sympathetic reflex stimulation of the heart often increases the heart rate to 150 to 180 beats per minute. Simple weakening of the myocardium usually increases the heart rate because the weakened heart does not pump blood into the arterial tree to a normal extent, and this elicits sympathetic reflexes to increase the heart rate. Bradycardia The term “bradycardia” means a slow heart rate, usually defined as fewer than 60 beats per minute. Bradycardia is shown by the electrocardiogram in Figure 13–2. Bradycardia in Athletes. The athlete’s heart is larger and considerably stronger than that of a normal person, which allows the athlete’s heart to pump a large stroke volume output per beat even during periods of rest. When the athlete is at rest, excessive quantities of blood pumped into the arterial tree with each beat initiate feedback circulatory reflexes or other effects to cause bradycardia. 147 3 148 Unit III The Heart SA block Figure 13–1 Sinus tachycardia (lead I). Figure 13–2 Heart rate Sinus bradycardia (lead III). 60 70 80 100 120 Figure 13–3 Sinus arrhythmia as recorded by a cardiotachometer. To the left is the record when the subject was breathing normally; to the right, when breathing deeply. Vagal Stimulation as a Cause of Bradycardia. Any circulatory reflex that stimulates the vagus nerves causes release of acetylcholine at the vagal endings in the heart, thus giving a parasympathetic effect. Perhaps the most striking example of this occurs in patients with carotid sinus syndrome. In these patients, the pressure receptors (baroreceptors) in the carotid sinus region of the carotid artery walls are excessively sensitive. Therefore, even mild external pressure on the neck elicits a strong baroreceptor reflex, causing intense vagal-acetylcholine effects on the heart, including extreme bradycardia. Indeed, sometimes this reflex is so powerful that it actually stops the heart for 5 to 10 seconds. Sinus Arrhythmia Figure 13–3 shows a cardiotachometer recording of the heart rate, at first during normal and then (in the second half of the record) during deep respiration. A cardiotachometer is an instrument that records by the height of successive spikes the duration of the interval between the successive QRS complexes in the electrocardiogram. Note from this record that the heart rate increased and decreased no more than 5 per cent during Figure 13–4 Sinoatrial nodal block, with A-V nodal rhythm during the block period (lead III). quiet respiration (left half of the record). Then, during deep respiration, the heart rate increased and decreased with each respiratory cycle by as much as 30 per cent. Sinus arrhythmia can result from any one of many circulatory conditions that alter the strengths of the sympathetic and parasympathetic nerve signals to the heart sinus node. In the “respiratory” type of sinus arrhythmia, as shown in Figure 13–3, this results mainly from “spillover” of signals from the medullary respiratory center into the adjacent vasomotor center during inspiratory and expiratory cycles of respiration. The spillover signals cause alternate increase and decrease in the number of impulses transmitted through the sympathetic and vagus nerves to the heart. Abnormal Rhythms That Result from Block of Heart Signals Within the Intracardiac Conduction Pathways Sinoatrial Block In rare instances, the impulse from the sinus node is blocked before it enters the atrial muscle. This phenomenon is demonstrated in Figure 13–4, which shows sudden cessation of P waves, with resultant standstill of the atria. However, the ventricles pick up a new rhythm, the impulse usually originating spontaneously in the atrioventricular (A-V) node, so that the rate of the ventricular QRS-T complex is slowed but not otherwise altered. Atrioventricular Block The only means by which impulses ordinarily can pass from the atria into the ventricles is through the A-V bundle, also known as the bundle of His. Conditions that can either decrease the rate of impulse conduction in this bundle or block the impulse entirely are as follows: 1. Ischemia of the A-V node or A-V bundle fibers often delays or blocks conduction from the atria to the ventricles. Coronary insufficiency can cause ischemia of the A-V node and bundle in the same way that it can cause ischemia of the myocardium. 2. Compression of the A-V bundle by scar tissue or by calcified portions of the heart can depress or block conduction from the atria to the ventricles. 3. Inflammation of the A-V node or A-V bundle can depress conductivity from the atria to the ventricles. Inflammation results frequently from Chapter 13 149 Cardiac Arrhythmias and Their Electrocardiographic Interpretation Dropped beat P P P P P P P P P P P Figure 13–5 Prolonged P-R interval caused by first degree A-V heart block (lead II). different types of myocarditis, caused, for example, by diphtheria or rheumatic fever. 4. Extreme stimulation of the heart by the vagus nerves in rare instances blocks impulse conduction through the A-V node. Such vagal excitation occasionally results from strong stimulation of the baroreceptors in people with carotid sinus syndrome, discussed earlier in relation to bradycardia. Figure 13–6 Second degree A-V block, showing occasional failure of the ventricles to receive the excitatory signals (lead V3). P P P P P P P P P P Incomplete Atrioventricular Heart Block Prolonged P-R (or P-Q) Interval—First Degree Block. The usual lapse of time between beginning of the P wave and beginning of the QRS complex is about 0.16 second when the heart is beating at a normal rate. This socalled P-R interval usually decreases in length with faster heartbeat and increases with slower heartbeat. In general, when the P-R interval increases to greater than 0.20 second, the P-R interval is said to be prolonged, and the patient is said to have first degree incomplete heart block. Figure 13–5 shows an electrocardiogram with prolonged P-R interval; the interval in this instance is about 0.30 second instead of the normal 0.20 or less. Thus, first degree block is defined as a delay of conduction from the atria to the ventricles but not actual blockage of conduction. The P-R interval seldom increases above 0.35 to 0.45 second because, by that time, conduction through the A-V bundle is depressed so much that conduction stops entirely. One means for determining the severity of some heart diseases—acute rheumatic heart disease, for instance—is to measure the P-R interval. Second Degree Block. When conduction through the A-V bundle is slowed enough to increase the P-R interval to 0.25 to 0.45 second, the action potential sometimes is strong enough to pass through the bundle into the ventricles and sometimes is not strong enough. In this instance, there will be an atrial P wave but no QRS-T wave, and it is said that there are “dropped beats” of the ventricles. This condition is called second degree heart block. Figure 13–6 shows P-R intervals of 0.30 second, as well as one dropped ventricular beat as a result of failure of conduction from the atria to the ventricles. At times, every other beat of the ventricles is dropped, so that a “2:1 rhythm” develops, with the atria beating twice for every single beat of the ventricles. At other times, rhythms of 3:2 or 3:1 also develop. Complete A-V Block (Third Degree Block). When the condi- tion causing poor conduction in the A-V node or A-V bundle becomes severe, complete block of the impulse Figure 13–7 Complete A-V block (lead II). from the atria into the ventricles occurs. In this instance, the ventricles spontaneously establish their own signal, usually originating in the A-V node or A-V bundle. Therefore, the P waves become dissociated from the QRS-T complexes, as shown in Figure 13–7. Note that the rate of rhythm of the atria in this electrocardiogram is about 100 beats per minute, whereas the rate of ventricular beat is less than 40 per minute. Furthermore, there is no relation between the rhythm of the P waves and that of the QRS-T complexes because the ventricles have “escaped” from control by the atria, and they are beating at their own natural rate, controlled most often by rhythmical signals generated in the A-V node or A-V bundle. Stokes-Adams Syndrome—Ventricular Escape. In some patients with A-V block, the total block comes and goes; that is, impulses are conducted from the atria into the ventricles for a period of time and then suddenly impulses are not conducted. The duration of block may be a few seconds, a few minutes, a few hours, or even weeks or longer before conduction returns. This condition occurs in hearts with borderline ischemia of the conductive system. Each time A-V conduction ceases, the ventricles often do not start their own beating until after a delay of 5 to 30 seconds. This results from the phenomenon called overdrive suppression. This means that ventricular excitability is at first in a suppressed state because the ventricles have been driven by the atria at a rate greater than their natural rate of rhythm. However, after a few seconds, some part of the Purkinje system beyond the block, usually in the distal part of the A-V node beyond the blocked point in the node, or in the A-V bundle, begins discharging rhythmically at a rate of 15 to 40 times per minute and acting as the pacemaker of the ventricles. This is called ventricular escape. 150 Unit III Because the brain cannot remain active for more than 4 to 7 seconds without blood supply, most patients faint a few seconds after complete block occurs because the heart does not pump any blood for 5 to 30 seconds, until the ventricles “escape.” After escape, however, the slowly beating ventricles usually pump enough blood to allow rapid recovery from the faint and then to sustain the person. These periodic fainting spells are known as the Stokes-Adams syndrome. Occasionally the interval of ventricular standstill at the onset of complete block is so long that it becomes detrimental to the patient’s health or even causes death. Consequently, most of these patients are provided with an artificial pacemaker, a small battery-operated electrical stimulator planted beneath the skin, with electrodes usually connected to the right ventricle. The pacemaker provides continued rhythmical impulses that take control of the ventricles. Incomplete Intraventricular Block— Electrical Alternans Most of the same factors that can cause A-V block can also block impulse conduction in the peripheral ventricular Purkinje system. Figure 13–8 shows the condition known as electrical alternans, which results from partial intraventricular block every other heartbeat. This electrocardiogram also shows tachycardia (rapid heart rate), which is probably the reason the block has occurred, because when the rate of the heart is rapid, it may be impossible for some portions of the Purkinje system to recover from the previous refractory period quickly enough to respond during every succeeding heartbeat. Also, many conditions that depress the heart, such as ischemia, myocarditis, or digitalis toxicity, can cause incomplete intraventricular block, resulting in electrical alternans. Premature Contractions A premature contraction is a contraction of the heart before the time that normal contraction would have been expected. This condition is also called extrasystole, premature beat, or ectopic beat. Causes of Premature Contractions. Most premature contractions result from ectopic foci in the heart, which emit abnormal impulses at odd times during the cardiac rhythm. Possible causes of ectopic foci are (1) local The Heart areas of ischemia; (2) small calcified plaques at different points in the heart, which press against the adjacent cardiac muscle so that some of the fibers are irritated; and (3) toxic irritation of the A-V node, Purkinje system, or myocardium caused by drugs, nicotine, or caffeine. Mechanical initiation of premature contractions is also frequent during cardiac catheterization; large numbers of premature contractions often occur when the catheter enters the right ventricle and presses against the endocardium. Premature Atrial Contractions Figure 13–9 shows a single premature atrial contraction. The P wave of this beat occurred too soon in the heart cycle; the P-R interval is shortened, indicating that the ectopic origin of the beat is in the atria near the A-V node. Also, the interval between the premature contraction and the next succeeding contraction is slightly prolonged, which is called a compensatory pause. One of the reasons for this is that the premature contraction originated in the atrium some distance from the sinus node, and the impulse had to travel through a considerable amount of atrial muscle before it discharged the sinus node. Consequently, the sinus node discharged late in the premature cycle, and this made the succeeding sinus node discharge also late in appearing. Premature atrial contractions occur frequently in otherwise healthy people. Indeed, they often occur in athletes whose hearts are in very healthy condition. Mild toxic conditions resulting from such factors as smoking, lack of sleep, ingestion of too much coffee, alcoholism, and use of various drugs can also initiate such contractions. Pulse Deficit. When the heart contracts ahead of schedule, the ventricles will not have filled with blood normally, and the stroke volume output during that contraction is depressed or almost absent. Therefore, the pulse wave passing to the peripheral arteries after a premature contraction may be so weak that it cannot be felt in the radial artery. Thus, a deficit in the number of radial pulses occurs when compared with the actual number of contractions of the heart. A-V Nodal or A-V Bundle Premature Contractions Figure 13–10 shows a premature contraction that originated in the A-V node or in the A-V bundle. The P wave is missing from the electrocardiographic record Premature beat Figure 13–8 Partial intraventricular block—“electrical alternans” (lead III). Figure 13–9 Atrial premature beat (lead I). Cardiac Arrhythmias and Their Electrocardiographic Interpretation Chapter 13 Premature beat P T P T P T PT P T Figure 13–10 A-V nodal premature contraction (lead III). II III II – + III III – + II Figure 13–11 Premature ventricular contractions (PVCs) demonstrated by the large abnormal QRS-T complexes (leads II and III). Axis of the premature contractions is plotted in accordance with the principles of vectorial analysis explained in Chapter 12; this shows the origin of the PVC to be near the base of the ventricles. of the premature contraction. Instead, the P wave is superimposed onto the QRS-T complex because the cardiac impulse traveled backward into the atria at the same time that it traveled forward into the ventricles; this P wave slightly distorts the QRS-T complex, but the P wave itself cannot be discerned as such. In general, A-V nodal premature contractions have the same significance and causes as atrial premature contractions. Premature Ventricular Contractions The electrocardiogram of Figure 13–11 shows a series of premature ventricular contractions (PVCs) alternat- 151 ing with normal contractions. PVCs cause specific effects in the electrocardiogram, as follows: 1. The QRS complex is usually considerably prolonged. The reason is that the impulse is conducted mainly through slowly conducting muscle of the ventricles rather than through the Purkinje system. 2. The QRS complex has a high voltage for the following reasons: when the normal impulse passes through the heart, it passes through both ventricles nearly simultaneously; consequently, in the normal heart, the depolarization waves of the two sides of the heart—mainly of opposite polarity to each other—partially neutralize each other in the electrocardiogram. When a PVC occurs, the impulse almost always travels in only one direction, so that there is no such neutralization effect, and one entire side or end of the ventricles is depolarized ahead of the other; this causes large electrical potentials, as shown for the PVCs in Figure 13–11. 3. After almost all PVCs, the T wave has an electrical potential polarity exactly opposite to that of the QRS complex, because the slow conduction of the impulse through the cardiac muscle causes the muscle fibers that depolarize first also to repolarize first. Some PVCs are relatively benign in their effects on overall pumping by the heart; they can result from such factors as cigarettes, coffee, lack of sleep, various mild toxic states, and even emotional irritability. Conversely, many other PVCs result from stray impulses or reentrant signals that originate around the borders of infarcted or ischemic areas of the heart. The presence of such PVCs is not to be taken lightly. Statistics show that people with significant numbers of PVCs have a much higher than normal chance of developing spontaneous lethal ventricular fibrillation, presumably initiated by one of the PVCs. This is especially true when the PVCs occur during the vulnerable period for causing fibrillation, just at the end of the T wave when the ventricles are coming out of refractoriness, as explained later in the chapter. Vector Analysis of the Origin of an Ectopic Premature Ventricular Contraction. In Chapter 12, the principles of vectorial analysis are explained. Applying these principles, one can determine from the electrocardiogram in Figure 13–11 the point of origin of the PVC as follows: Note that the potentials of the premature contractions in leads II and III are both strongly positive. Plotting these potentials on the axes of leads II and III and solving by vectorial analysis for the mean QRS vector in the heart, one finds that the vector of this premature contraction has its negative end (origin) at the base of the heart and its positive end toward the apex. Thus, the first portion of the heart to become depolarized during this premature contraction is near the base of the ventricles, which therefore is the locus of the ectopic focus. Paroxysmal Tachycardia Some abnormalities in different portions of the heart, including the atria, the Purkinje system, or the ventricles, can occasionally cause rapid rhythmical discharge of impulses that spread in all directions throughout the heart. This is believed to be caused most frequently by 152 Unit III The Heart Figure 13–12 Atrial paroxysmal tachycardia—onset in middle of record (lead I). Figure 13–13 Ventricular paroxysmal tachycardia (lead III). re-entrant circus movement feedback pathways that set up local repeated self–re-excitation. Because of the rapid rhythm in the irritable focus, this focus becomes the pacemaker of the heart. The term “paroxysmal” means that the heart rate becomes rapid in paroxysms, with the paroxysm beginning suddenly and lasting for a few seconds, a few minutes, a few hours, or much longer. Then the paroxysm usually ends as suddenly as it began, with the pacemaker of the heart instantly shifting back to the sinus node. Paroxysmal tachycardia often can be stopped by eliciting a vagal reflex. A type of vagal reflex sometimes elicited for this purpose is to press on the neck in the regions of the carotid sinuses, which may cause enough of a vagal reflex to stop the paroxysm. Various drugs may also be used. Two drugs frequently used are quinidine and lidocaine, either of which depresses the normal increase in sodium permeability of the cardiac muscle membrane during generation of the action potential, thereby often blocking the rhythmical discharge of the focal point that is causing the paroxysmal attack. lar paroxysmal tachycardia has the appearance of a series of ventricular premature beats occurring one after another without any normal beats interspersed. Ventricular paroxysmal tachycardia is usually a serious condition for two reasons. First, this type of tachycardia usually does not occur unless considerable ischemic damage is present in the ventricles. Second, ventricular tachycardia frequently initiates the lethal condition of ventricular fibrillation because of rapid repeated stimulation of the ventricular muscle, as we discuss in the next section. Sometimes intoxication from the heart treatment drug digitalis causes irritable foci that lead to ventricular tachycardia. Conversely, quinidine, which increases the refractory period and threshold for excitation of cardiac muscle, may be used to block irritable foci causing ventricular tachycardia. Ventricular Fibrillation Atrial Paroxysmal Tachycardia Figure 13–12 demonstrates in the middle of the record a sudden increase in the heart rate from about 95 to about 150 beats per minute. On close study of the electrocardiogram during the rapid heartbeat, an inverted P wave is seen before each QRS-T complex, and this P wave is partially superimposed onto the normal T wave of the preceding beat. This indicates that the origin of this paroxysmal tachycardia is in the atrium, but because the P wave is abnormal in shape, the origin is not near the sinus node. A-V Nodal Paroxysmal Tachycardia. Paroxysmal tachycardia often results from an aberrant rhythm that involves the A-V node. This usually causes almost normal QRS-T complexes but totally missing or obscured P waves. Atrial or A-V nodal paroxysmal tachycardia, both of which are called supraventricular tachycardias, usually occurs in young, otherwise healthy people, and they generally grow out of the predisposition to tachycardia after adolescence. In general, supraventricular tachycardia frightens a person tremendously and may cause weakness during the paroxysm, but only seldom does permanent harm come from the attack. Ventricular Paroxysmal Tachycardia Figure 13–13 shows a typical short paroxysm of ventricular tachycardia. The electrocardiogram of ventricu- The most serious of all cardiac arrhythmias is ventricular fibrillation, which, if not stopped within 1 to 3 minutes, is almost invariably fatal. Ventricular fibrillation results from cardiac impulses that have gone berserk within the ventricular muscle mass, stimulating first one portion of the ventricular muscle, then another portion, then another, and eventually feeding back onto itself to re-excite the same ventricular muscle over and over—never stopping. When this happens, many small portions of the ventricular muscle will be contracting at the same time, while equally as many other portions will be relaxing. Thus, there is never a coordinate contraction of all the ventricular muscle at once, which is required for a pumping cycle of the heart. Despite massive movement of stimulatory signals throughout the ventricles, the ventricular chambers neither enlarge nor contract but remain in an indeterminate stage of partial contraction, pumping either no blood or negligible amounts. Therefore, after fibrillation begins, unconsciousness occurs within 4 to 5 seconds for lack of blood flow to the brain, and irretrievable death of tissues begins to occur throughout the body within a few minutes. Multiple factors can spark the beginning of ventricular fibrillation—a person may have a normal heartbeat one moment, but 1 second later, the ventricles are in fibrillation. Especially likely to initiate fibrillation are (1) sudden electrical shock of the heart, or (2) ischemia of the heart muscle, of its specialized conducting system, or both. Chapter 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation Phenomenon of Re-entry—“Circus Movements” as the Basis for Ventricular Fibrillation 153 the refractory state, and the impulse can continue around the circle again and again. Third, the refractory period of the muscle might become greatly shortened. In this case, the impulse could also continue around and around the circle. All these conditions occur in different pathological states of the human heart, as follows: (1) A long pathway typically occurs in dilated hearts. (2) Decreased rate of conduction frequently results from (a) blockage of the Purkinje system, (b) ischemia of the muscle, (c) high blood potassium levels, or (d) many other factors. (3) A shortened refractory period commonly occurs in response to various drugs, such as epinephrine, or after repetitive electrical stimulation. Thus, in many cardiac disturbances, re-entry can cause abnormal patterns of cardiac contraction or abnormal cardiac rhythms that ignore the pace-setting effects of the sinus node. When the normal cardiac impulse in the normal heart has traveled through the extent of the ventricles, it has no place to go because all the ventricular muscle is refractory and cannot conduct the impulse farther. Therefore, that impulse dies, and the heart awaits a new action potential to begin in the atrial sinus node. Under some circumstances, however, this normal sequence of events does not occur. Therefore, let us explain more fully the background conditions that can initiate re-entry and lead to “circus movements,” which in turn cause ventricular fibrillation. Figure 13–14 shows several small cardiac muscle strips cut in the form of circles. If such a strip is stimulated at the 12 o’clock position so that the impulse travels in only one direction, the impulse spreads progressively around the circle until it returns to the 12 o’clock position. If the originally stimulated muscle fibers are still in a refractory state, the impulse then dies out because refractory muscle cannot transmit a second impulse. But there are three different conditions that can cause this impulse to continue to travel around the circle, that is, to cause “re-entry” of the impulse into muscle that has already been excited. This is called a “circus movement.” First, if the pathway around the circle is too long, by the time the impulse returns to the 12 o’clock position, the originally stimulated muscle will no longer be refractory and the impulse will continue around the circle again and again. Second, if the length of the pathway remains constant but the velocity of conduction becomes decreased enough, an increased interval of time will elapse before the impulse returns to the 12 o’clock position. By this time, the originally stimulated muscle might be out of Chain Reaction Mechanism of Fibrillation In ventricular fibrillation, one sees many separate and small contractile waves spreading at the same time in different directions over the cardiac muscle. The reentrant impulses in fibrillation are not simply a single impulse moving in a circle, as shown in Figure 13–14. Instead, they have degenerated into a series of multiple wave fronts that have the appearance of a “chain reaction.” One of the best ways to explain this process in fibrillation is to describe the initiation of fibrillation by electric shock caused by 60-cycle alternating electric current. Fibrillation Caused by 60-Cycle Alternating Current. At a central point in the ventricles of heart A in Figure 13–15, a 60-cycle electrical stimulus is applied through a stimulating electrode. The first cycle of the electrical stimulus causes a depolarization wave to spread in all directions, leaving all the muscle beneath the electrode in a refractory state. After about 0.25 second, part of this muscle begins to come out of the refractory state. Some portions come out of refractoriness before other NORMAL PATHWAY Stimulus point Dividing impulses Absolutely refractory Absolutely refractory Relatively refractory LONG PATHWAY Blocked impulse A Figure 13–14 Circus movement, showing annihilation of the impulse in the short pathway and continued propagation of the impulse in the long pathway. B Figure 13–15 A, Initiation of fibrillation in a heart when patches of refractory musculature are present. B, Continued propagation of fibrillatory impulses in the fibrillating ventricle. 154 Unit III portions. This state of events is depicted in heart A by many lighter patches, which represent excitable cardiac muscle, and dark patches, which represent still refractory muscle. Now, continuing 60-cycle stimuli from the electrode can cause impulses to travel only in certain directions through the heart but not in all directions. Thus, in heart A, certain impulses travel for short distances, until they reach refractory areas of the heart, and then are blocked. But other impulses pass between the refractory areas and continue to travel in the excitable areas. Then, several events transpire in rapid succession, all occurring simultaneously and eventuating in a state of fibrillation. First, block of the impulses in some directions but successful transmission in other directions creates one of the necessary conditions for a re-entrant signal to develop—that is, transmission of some of the depolarization waves around the heart in only some directions but not other directions. Second, the rapid stimulation of the heart causes two changes in the cardiac muscle itself, both of which predispose to circus movement: (1) The velocity of conduction through the heart muscle decreases, which allows a longer time interval for the impulses to travel around the heart. (2) The refractory period of the muscle is shortened, allowing re-entry of the impulse into previously excited heart muscle within a much shorter time than normally. Third, one of the most important features of fibrillation is the division of impulses, as demonstrated in heart A. When a depolarization wave reaches a refractory area in the heart, it travels to both sides around the refractory area. Thus, a single impulse becomes two impulses. Then, when each of these reaches another refractory area, it, too, divides to form two more impulses. In this way, many new wave fronts are continually being formed in the heart by progressive chain reactions until, finally, there are many small depolarization waves traveling in many directions at the same time. Furthermore, this irregular pattern of impulse travel causes many circuitous routes for the impulses to travel, greatly lengthening the conductive pathway, which is one of the conditions that sustains the fibrillation. It also results in a continual irregular pattern of patchy refractory areas in the heart. One can readily see when a vicious circle has been initiated: More and more impulses are formed; these cause more and more patches of refractory muscle, and the refractory patches cause more and more division of the impulses.Therefore, any time a single area of cardiac muscle comes out of refractoriness, an impulse is close at hand to re-enter the area. Heart B in Figure 13–15 demonstrates the final state that develops in fibrillation. Here one can see many impulses traveling in all directions, some dividing and increasing the number of impulses, whereas others are blocked by refractory areas. In fact, a single electric shock during this vulnerable period frequently can lead to an odd pattern of impulses spreading multidirectionally around refractory areas of muscle, which will lead to fibrillation. Electrocardiogram in Ventricular Fibrillation In ventricular fibrillation, the electrocardiogram is bizarre (Figure 13–16) and ordinarily shows no ten- The Heart Figure 13–16 Ventricular fibrillation (lead II). dency toward a regular rhythm of any type. During the first few seconds of ventricular fibrillation, relatively large masses of muscle contract simultaneously, and this causes coarse, irregular waves in the electrocardiogram. After another few seconds, the coarse contractions of the ventricles disappear, and the electrocardiogram changes into a new pattern of low-voltage, very irregular waves. Thus, no repetitive electrocardiographic pattern can be ascribed to ventricular fibrillation. Instead, the ventricular muscle contracts at as many as 30 to 50 small patches of muscle at a time, and electrocardiographic potentials change constantly and spasmodically because the electrical currents in the heart flow first in one direction and then in another and seldom repeat any specific cycle. The voltages of the waves in the electrocardiogram in ventricular fibrillation are usually about 0.5 millivolt when ventricular fibrillation first begins, but they decay rapidly so that after 20 to 30 seconds, they are usually only 0.2 to 0.3 millivolt. Minute voltages of 0.1 millivolt or less may be recorded for 10 minutes or longer after ventricular fibrillation begins. As already pointed out, because no pumping of blood occurs during ventricular fibrillation, this state is lethal unless stopped by some heroic therapy, such as immediate electroshock through the heart, as explained in the next section. Electroshock Defibrillation of the Ventricles Although a moderate alternating-current voltage applied directly to the ventricles almost invariably throws the ventricles into fibrillation, a strong highvoltage alternating electrical current passed through the ventricles for a fraction of a second can stop fibrillation by throwing all the ventricular muscle into refractoriness simultaneously. This is accomplished by passing intense current through large electrodes placed on two sides of the heart. The current penetrates most of the fibers of the ventricles at the same time, thus stimulating essentially all parts of the ventricles simultaneously and causing them all to become refractory. All action potentials stop, and the heart remains quiescent for 3 to 5 seconds, after which it begins to beat again, usually with the sinus node or some other part of the heart becoming the pacemaker. However, the same re-entrant focus that had originally thrown the ventricles into fibrillation often is still present, in which case fibrillation may begin again immediately. When electrodes are applied directly to the two sides of the heart, fibrillation can usually be stopped using 110 volts of 60-cycle alternating current applied for 0.1 Chapter 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation second or 1000 volts of direct current applied for a few thousandths of a second. When applied through two electrodes on the chest wall, as shown in Figure 13–17, the usual procedure is to charge a large electrical capacitor up to several thousand volts and then to cause the capacitor to discharge for a few thousandths of a second through the electrodes and through the heart. In our laboratory, the heart of a single anesthetized dog was defibrillated 130 times through the chest wall, and the animal lived thereafter in perfectly normal condition. Hand Pumping of the Heart (Cardiopulmonary Resuscitation) as an Aid to Defibrillation Unless defibrillated within 1 minute after fibrillation begins, the heart is usually too weak to be revived by defibrillation because of the lack of nutrition from coronary blood flow. However, it is still possible to revive the heart by preliminarily pumping the heart by hand (intermittent hand squeezing) and then defibrillating the heart later. In this way, small quantities of blood are delivered into the aorta and a renewed coronary blood supply develops. Then, after a few minutes of hand pumping, electrical defibrillation often becomes possible. Indeed, fibrillating hearts have been pumped by hand for as long as 90 minutes followed by successful defibrillation. A technique for pumping the heart without opening the chest consists of intermittent thrusts of pressure on the chest wall along with artificial respiration. This, plus defibrillation, is called cardiopulmonary resuscitation, or CPR. Lack of blood flow to the brain for more than 5 to 8 minutes usually causes permanent mental impairment or even destruction of brain tissue. Even if the heart is revived, the person may die from the effects of brain damage or may live with permanent mental impairment. Several thousand volts for a few milliseconds 155 Atrial Fibrillation Remember that except for the conducting pathway through the A-V bundle, the atrial muscle mass is separated from the ventricular muscle mass by fibrous tissue. Therefore, ventricular fibrillation often occurs without atrial fibrillation. Likewise, fibrillation often occurs in the atria without ventricular fibrillation (shown to the right in Figure 13–19). The mechanism of atrial fibrillation is identical to that of ventricular fibrillation, except that the process occurs only in the atrial muscle mass instead of the ventricular mass. A frequent cause of atrial fibrillation is atrial enlargement resulting from heart valve lesions that prevent the atria from emptying adequately into the ventricles, or from ventricular failure with excess damming of blood in the atria. The dilated atrial walls provide ideal conditions of a long conductive pathway as well as slow conduction, both of which predispose to atrial fibrillation. Pumping Characteristics of the Atria During Atrial Fibrillation. For the same reasons that the ventricles will not pump blood during ventricular fibrillation, neither do the atria pump blood in atrial fibrillation. Therefore, the atria become useless as primer pumps for the ventricles. Even so, blood flows passively through the atria into the ventricles, and the efficiency of ventricular pumping is decreased only 20 to 30 per cent. Therefore, in contrast to the lethality of ventricular fibrillation, a person can live for months or even years with atrial fibrillation, although at reduced efficiency of overall heart pumping. Electrocardiogram in Atrial Fibrillation. Figure 13–18 shows the electrocardiogram during atrial fibrillation. Numerous small depolarization waves spread in all directions through the atria during atrial fibrillation. Because the waves are weak and many of them are of opposite polarity at any given time, they usually almost completely electrically neutralize one another. Therefore, in the electrocardiogram, one can see either no P waves from the atria or only a fine, high-frequency, very low voltage wavy record. Conversely, the QRS-T complexes are normal unless there is some pathology of the ventricles, but their timing is irregular, as explained next. Irregularity of Ventricular Rhythm During Atrial Fibrillation. When the atria are fibrillating, impulses arrive from the atrial muscle at the A-V node rapidly but also irregularly. Because the A-V node will not pass a second impulse for about 0.35 second after a previous one, at least 0.35 second must elapse between one ventricular contraction and the next. Then an additional but Handle for application of pressure Electrode Figure 13–17 Application of electrical current to the chest to stop ventricular fibrillation. Figure 13–18 Atrial fibrillation (lead I). The waves that can be seen are ventricular QRS and T waves. 156 Unit III The Heart Figure 13–20 Atrial flutter—2:1 and 3:1 atrial to ventricle rhythm (lead I). Atrial flutter Atrial fibrillation Figure 13–19 Pathways of impulses in atrial flutter and atrial fibrillation. variable interval of 0 to 0.6 second occurs before one of the irregular atrial fibrillatory impulses happens to arrive at the A-V node. Thus, the interval between successive ventricular contractions varies from a minimum of about 0.35 second to a maximum of about 0.95 second, causing a very irregular heartbeat. In fact, this irregularity, demonstrated by the variable spacing of the heartbeats in the electrocardiogram of Figure 13–18, is one of the clinical findings used to diagnose the condition. Also, because of the rapid rate of the fibrillatory impulses in the atria, the ventricle is driven at a fast heart rate, usually between 125 and 150 beats per minute. Electroshock Treatment of Atrial Fibrillation. In the same manner that ventricular fibrillation can be converted back to a normal rhythm by electroshock, so too can atrial fibrillation be converted by electroshock. The procedure is essentially the same as for ventricular fibrillation conversion—passage of a single strong electric shock through the heart, which throws the entire heart into refractoriness for a few seconds; a normal rhythm often follows if the heart is capable of this. Atrial Flutter Atrial flutter is another condition caused by a circus movement in the atria. It is different from atrial fibrillation, in that the electrical signal travels as a single large wave always in one direction around and around the atrial muscle mass, as shown to the left in Figure 13–19. Atrial flutter causes a rapid rate of contraction of the atria, usually between 200 and 350 beats per minute. However, because one side of the atria is contracting while the other side is relaxing, the amount of blood pumped by the atria is slight. Furthermore, the signals reach the A-V node too rapidly for all of them to be passed into the ventricles, because the refractory periods of the A-V node and A-V bundle are too long to pass more than a fraction of the atrial signals. Therefore, there are usually two to three beats of the atria for every single beat of the ventricles. Figure 13–20 shows a typical electrocardiogram in atrial flutter. The P waves are strong because of contraction of semicoordinate masses of muscle. However, note in the record that a QRS-T complex follows an atrial P wave only once for every two to three beats of the atria, giving a 2:1 or 3:1 rhythm. Cardiac Arrest A final serious abnormality of the cardiac rhythmicityconduction system is cardiac arrest. This results from cessation of all electrical control signals in the heart. That is, no spontaneous rhythm remains. Cardiac arrest is especially likely to occur during deep anesthesia, when many patients develop severe hypoxia because of inadequate respiration. The hypoxia prevents the muscle fibers and conductive fibers from maintaining normal electrolyte concentration differentials across their membranes, and their excitability may be so affected that the automatic rhythmicity disappears. In most instances of cardiac arrest from anesthesia, prolonged cardiopulmonary resuscitation (many minutes or even hours) is quite successful in reestablishing a normal heart rhythm. In some patients, severe myocardial disease can cause permanent or semipermanent cardiac arrest, which can cause death. To treat the condition, rhythmical electrical impulses from an implanted electronic cardiac pacemaker have been used successfully to keep patients alive for months to years. References Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM: What clinicians should know about the QT interval. JAMA 289:2120, 2003. 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Maron BJ: Sudden death in young athletes. N Engl J Med 349:1064, 2003. Nattel S: New ideas about atrial fibrillation 50 years on. Nature 415:219, 2002. 157 Roden DM: Drug-induced prolongation of the QT interval. N Engl J Med 350:1013, 2004. Swynghedauw B, Baillard C, Milliez P: The long QT interval is not only inherited but is also linked to cardiac hypertrophy. J Mol Med 81:336, 2003. Topol EJ: A guide to therapeutic decision-making in patients with non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol 41(4 Suppl S):S123, 2003. Wang K, Asinger RW, Marriott HJ: ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med 349:2128, 2003. Yan GX, Lankipalli RS, Burke JF, et al: Ventricular repolarization components on the electrocardiogram: cellular basis and clinical significance. J Am Coll Cardiol 42:401, 2003. Zimetbaum PJ, Josephson ME: Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 348:933, 2003. Zipes DP, Jalife J: Cardiac Electrophysiology, 3rd ed. Philadelphia: WB Saunders, 1999. U N I The Circulation 14. Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance 15. Vascular Distensibility and Functions of the Arterial and Venous Systems 16. The Microcirculation and the Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow 17. Local and Humoral Control of Blood Flow by the Tissues 18. Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure 19. Dominant Role of the Kidney in Long-Term Regulation of Arterial Pressure and in Hypertension: The Integrated System for Pressure Control 20. Cardiac Output, Venous Return, and Their Regulation 21. Muscle Blood Flow and Cardiac Output During Exercise; the Coronary Circulation and Ischemic Heart Disease 22. Cardiac Failure 23. Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects 24. Circulatory Shock and Physiology of Its Treatment T IV C H A P T E R 1 4 Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance The function of the circulation is to service the needs of the body tissues—to transport nutrients to the body tissues, to transport waste products away, to conduct hormones from one part of the body to another, and, in general, to maintain an appropriate environment in all the tissue fluids of the body for optimal survival and function of the cells. The rate of blood flow through most tissues is controlled in response to tissue need for nutrients. The heart and circulation in turn are controlled to provide the necessary cardiac output and arterial pressure to cause the needed tissue blood flow. What are the mechanisms for controlling blood volume and blood flow, and how does this relate to all the other functions of the circulation? These are some of the topics and questions that we discuss in this section on the circulation. Physical Characteristics of the Circulation The circulation, shown in Figure 14–1, is divided into the systemic circulation and the pulmonary circulation. Because the systemic circulation supplies blood flow to all the tissues of the body except the lungs, it is also called the greater circulation or peripheral circulation. Functional Parts of the Circulation. Before discussing the details of circulatory func- tion, it is important to understand the role of each part of the circulation. The function of the arteries is to transport blood under high pressure to the tissues. For this reason, the arteries have strong vascular walls, and blood flows at a high velocity in the arteries. The arterioles are the last small branches of the arterial system; they act as control conduits through which blood is released into the capillaries. The arteriole has a strong muscular wall that can close the arteriole completely or can, by relaxing, dilate it severalfold, thus having the capability of vastly altering blood flow in each tissue bed in response to the need of the tissue. The function of the capillaries is to exchange fluid, nutrients, electrolytes, hormones, and other substances between the blood and the interstitial fluid. To serve this role, the capillary walls are very thin and have numerous minute capillary pores permeable to water and other small molecular substances. The venules collect blood from the capillaries, and they gradually coalesce into progressively larger veins. The veins function as conduits for transport of blood from the venules back to the heart; equally important, they serve as a major reservoir of extra blood. Because the pressure in the venous system is very low, the venous walls are thin. Even so, they are muscular enough to contract or expand and thereby act as a controllable reservoir for the extra blood, either a small or a large amount, depending on the needs of the circulation. Volumes of Blood in the Different Parts of the Circulation. Figure 14–1 gives an overview of the circulation and lists the percentage of the total blood volume 161 162 Unit IV The Circulation Pulmonary circulation–9% Vessel Aorta Aorta Small arteries Arterioles Capillaries Venules Small veins Venae cavae Cross-Sectional Area (cm2) 2.5 20 40 2500 250 80 8 Superior vena cava Heart–7% Inferior vena cava Systemic vessels Arteries–13% Arterioles and capillaries–7% Veins, venules, and venous sinuses–64% Figure 14–1 Distribution of blood (in percentage of total blood) in the different parts of the circulatory system. in major segments of the circulation. For instance, about 84 per cent of the entire blood volume of the body is in the systemic circulation, and 16 per cent in heart and lungs. Of the 84 per cent in the systemic circulation, 64 per cent is in the veins, 13 per cent in the arteries, and 7 per cent in the systemic arterioles and capillaries. The heart contains 7 per cent of the blood, and the pulmonary vessels, 9 per cent. Most surprising is the low blood volume in the capillaries. It is here, however, that the most important function of the circulation occurs, diffusion of substances back and forth between the blood and the tissues. This function is discussed in detail in Chapter 16. Cross-Sectional Areas and Velocities of Blood Flow. If all the systemic vessels of each type were put side by side, their approximate total cross-sectional areas for the average human being would be as follows: Note particularly the much larger cross-sectional areas of the veins than of the arteries, averaging about four times those of the corresponding arteries. This explains the large storage of blood in the venous system in comparison with the arterial system. Because the same volume of blood must flow through each segment of the circulation each minute, the velocity of blood flow is inversely proportional to vascular cross-sectional area. Thus, under resting conditions, the velocity averages about 33 cm/sec in the aorta but only 1/1000 as rapidly in the capillaries, about 0.3 mm/sec. However, because the capillaries have a typical length of only 0.3 to 1 millimeter, the blood remains in the capillaries for only 1 to 3 seconds. This short time is surprising because all diffusion of nutrient food substances and electrolytes that occurs through the capillary walls must do so in this exceedingly short time. Pressures in the Various Portions of the Circulation. Because the heart pumps blood continually into the aorta, the mean pressure in the aorta is high, averaging about 100 mm Hg. Also, because heart pumping is pulsatile, the arterial pressure alternates between a systolic pressure level of 120 mm Hg and a diastolic pressure level of 80 mm Hg, as shown on the left side of Figure 14–2. As the blood flows through the systemic circulation, its mean pressure falls progressively to about 0 mm Hg by the time it reaches the termination of the venae cavae where they empty into the right atrium of the heart. The pressure in the systemic capillaries varies from as high as 35 mm Hg near the arteriolar ends to as low as 10 mm Hg near the venous ends, but their average “functional” pressure in most vascular beds is about 17 mm Hg, a pressure low enough that little of the plasma leaks through the minute pores of the capillary walls, even though nutrients can diffuse easily through these same pores to the outlying tissue cells. Note at the far right side of Figure 14–2 the respective pressures in the different parts of the pulmonary circulation. In the pulmonary arteries, the pressure is pulsatile, just as in the aorta, but the pressure level is far less: pulmonary artery systolic pressure averages about 25 mm Hg and diastolic pressure 8 mm Hg, with a mean pulmonary arterial pressure of only 16 mm Hg. The mean pulmonary capillary pressure averages only 7 mm Hg. Yet the total blood flow through the lungs each minute is the same as through the systemic circulation. The low pressures of the pulmonary system are in accord with the needs of the lungs, because all that is required is to expose the blood in the Chapter 14 163 Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance Pulmonary veins Venules Capillaries Arterioles Venae cavae Large veins Small veins Arterioles 20 Small arteries 40 Large arteries 60 Venules Capillaries 80 Aorta Pressure (mm Hg) 100 Pulmonary arteries 120 0 0 Systemic Pulmonary Figure 14–2 Normal blood pressures in the different portions of the circulatory system when a person is lying in the horizontal position. pulmonary capillaries to oxygen and other gases in the pulmonary alveoli. Basic Theory of Circulatory Function Although the details of circulatory function are complex, there are three basic principles that underlie all functions of the system. 1. The rate of blood flow to each tissue of the body is almost always precisely controlled in relation to the tissue need. When tissues are active, they need greatly increased supply of nutrients and therefore much more blood flow than when at rest—occasionally as much as 20 to 30 times the resting level. Yet the heart normally cannot increase its cardiac output more than four to seven times greater than resting levels. Therefore, it is not possible simply to increase blood flow everywhere in the body when a particular tissue demands increased flow. Instead, the microvessels of each tissue continuously monitor tissue needs, such as the availability of oxygen and other nutrients and the accumulation of carbon dioxide and other tissue waste products, and these in turn act directly on the local blood vessels, dilating or constricting them, to control local blood flow precisely to that level required for the tissue activity. Also, nervous control of the circulation from the central nervous system provides additional help in controlling tissue blood flow. 2. The cardiac output is controlled mainly by the sum of all the local tissue flows. When blood flows through a tissue, it immediately returns by way of the veins to the heart. The heart responds automatically to this increased inflow of blood by pumping it immediately into the arteries from whence it had originally come. Thus, the heart acts as an automaton, responding to the demands of the tissues. The heart, however, often needs help in the form of special nerve signals to make it pump the required amounts of blood flow. 3. In general the arterial pressure is controlled independently of either local blood flow control or cardiac output control. The circulatory system is provided with an extensive system for controlling the arterial blood pressure. For instance, if at any time the pressure falls significantly below the normal level of about 100 mm Hg, within seconds a barrage of nervous reflexes elicits a series of circulatory changes to raise the pressure back toward normal. The nervous signals especially (a) increase the force of heart pumping, (b) cause contraction of the large venous reservoirs to provide more blood to the heart, and (c) cause generalized constriction of most of the arterioles throughout the body so that more blood accumulates in the large arteries to increase the arterial pressure. Then, over more prolonged periods, hours and days, the kidneys play an additional major role in pressure control both by secreting pressure-controlling hormones and by regulating the blood volume. Thus, in summary, the needs of the individual tissues are served specifically by the circulation. In the remainder of this chapter, we begin to discuss the basic details of the management of tissue blood flow and control of cardiac output and arterial pressure. 164 Unit IV The Circulation Interrelationships Among Pressure, Flow, and Resistance Blood flow through a blood vessel is determined by two factors: (1) pressure difference of the blood between the two ends of the vessel, also sometimes called “pressure gradient” along the vessel, which is the force that pushes the blood through the vessel, and (2) the impediment to blood flow through the vessel, which is called vascular resistance. Figure 14–3 demonstrates these relationships, showing a blood vessel segment located anywhere in the circulatory system. P1 represents the pressure at the origin of the vessel; at the other end, the pressure is P2. Resistance occurs as a result of friction between the flowing blood and the intravascular endothelium all along the inside of the vessel. The flow through the vessel can be calculated by the following formula, which is called Ohm’s law: F= DP R in which F is blood flow, DP is the pressure difference (P1 - P2) between the two ends of the vessel, and R is the resistance. This formula states, in effect, that the blood flow is directly proportional to the pressure difference but inversely proportional to the resistance. Note that it is the difference in pressure between the two ends of the vessel, not the absolute pressure in the vessel, that determines rate of flow. For example, if the pressure at both ends of a vessel is 100 mm Hg and yet no difference exists between the two ends, there will be no flow despite the presence of 100 mm Hg pressure. Ohm’s law, illustrated in Equation 1, expresses the most important of all the relations that the reader needs to understand to comprehend the hemodynamics of the circulation. Because of the extreme importance of this formula, the reader should also become familiar with its other algebraic forms: DP = F ¥ R R= DP F Blood Flow Blood flow means simply the quantity of blood that passes a given point in the circulation in a given period P1 Pressure gradient P2 Blood flow Resistance Figure 14–3 Interrelationships among pressure, resistance, and blood flow. of time. Ordinarily, blood flow is expressed in milliliters per minute or liters per minute, but it can be expressed in milliliters per second or in any other unit of flow. The overall blood flow in the total circulation of an adult person at rest is about 5000 ml/min. This is called the cardiac output because it is the amount of blood pumped into the aorta by the heart each minute. Methods for Measuring Blood Flow. Many mechanical and mechanoelectrical devices can be inserted in series with a blood vessel or, in some instances, applied to the outside of the vessel to measure flow. They are called flowmeters. Electromagnetic Flowmeter. One of the most important devices for measuring blood flow without opening the vessel is the electromagnetic flowmeter, the principles of which are illustrated in Figure 14–4. Figure 14–4A shows the generation of electromotive force (electrical voltage) in a wire that is moved rapidly in a cross-wise direction through a magnetic field. This is the wellknown principle for production of electricity by the electric generator. Figure 14–4B shows that the same principle applies for generation of electromotive force in blood that is moving through a magnetic field. In this case, a blood vessel is placed between the poles of a strong magnet, and electrodes are placed on the two sides of the vessel perpendicular to the magnetic lines of force. When blood flows through the vessel, an electrical voltage proportional to the rate of blood flow is generated between the two electrodes, and this is recorded using an appropriate voltmeter or electronic recording apparatus. Figure 14–4C shows an actual “probe” that is placed on a large blood vessel to record its blood flow. The probe contains both the strong magnet and the electrodes. A special advantage of the electromagnetic flowmeter is that it can record changes in flow in less than 1/100 of a second, allowing accurate recording of pulsatile changes in flow as well as steady flow. Ultrasonic Doppler Flowmeter. Another type of flowmeter that can be applied to the outside of the vessel and that has many of the same advantages as the electromagnetic flowmeter is the ultrasonic Doppler flowmeter, shown in Figure 14–5. A minute piezoelectric crystal is mounted at one end in the wall of the device. This crystal, when energized with an appropriate electronic apparatus, transmits ultrasound at a frequency of several hundred thousand cycles per second downstream along the flowing blood. A portion of the sound is reflected by the red blood cells in the flowing blood. The reflected ultrasound waves then travel backward from the blood cells toward the crystal. These reflected waves have a lower frequency than the transmitted wave because the red cells are moving away from the transmitter crystal. This is called the Doppler effect. (It is the same effect that one experiences when a train approaches and passes by while blowing its whistle. Once the whistle has passed by the person, the pitch of the sound from the whistle suddenly becomes much lower than when the train is approaching.) For the flowmeter shown in Figure 14–5, the highfrequency ultrasound wave is intermittently cut off, and the reflected wave is received back onto the crystal and amplified greatly by the electronic apparatus. Another portion of the electronic apparatus determines the 165 Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance Chapter 14 + + 0 – S N + A 0 S N – – B + – Figure 14–4 Flowmeter of the electromagnetic type, showing generation of an electrical voltage in a wire as it passes through an electromagnetic field (A); generation of an electrical voltage in electrodes on a blood vessel when the vessel is placed in a strong magnetic field and blood flows through the vessel (B); and a modern electromagnetic flowmeter probe for chronic implantation around blood vessels (C). C Crystal A B Transmitted wave Reflected wave Figure 14–5 Ultrasonic Doppler flowmeter. frequency difference between the transmitted wave and the reflected wave, thus determining the velocity of blood flow. Like the electromagnetic flowmeter, the ultrasonic Doppler flowmeter is capable of recording rapid, pulsatile changes in flow as well as steady flow. Laminar Flow of Blood in Vessels. When blood flows at a steady rate through a long, smooth blood vessel, it flows in streamlines, with each layer of blood remaining the same distance from the vessel wall. Also, the central most portion of the blood stays in the center of the vessel. This type of flow is called laminar flow or streamline flow, and it is the opposite of turbulent flow, which is blood flowing in all directions in the vessel and continually mixing within the vessel, as discussed subsequently. C Figure 14–6 A, Two fluids (one dyed red, and the other clear) before flow begins; B, the same fluids 1 second after flow begins; C, turbulent flow, with elements of the fluid moving in a disorderly pattern. Parabolic Velocity Profile During Laminar Flow. When laminar flow occurs, the velocity of flow in the center of the vessel is far greater than that toward the outer edges. This is demonstrated in Figure 14–6. In Figure 14–6A, a vessel contains two fluids, the one at the left colored by a dye and the one at the right a clear fluid, but there is no flow in the vessel. When the fluids are made to flow, a parabolic interface develops between them, as shown 1 second later in Figure 14–6B; the portion of fluid adjacent to the vessel wall has hardly moved, the portion slightly away from the wall has moved a small distance, and the portion in the center of the vessel has moved a long distance. This effect is called the “parabolic profile for velocity of blood flow.” The cause of the parabolic profile is the following:The fluid molecules touching the wall barely move because 166 Unit IV The Circulation of adherence to the vessel wall. The next layer of molecules slips over these, the third layer over the second, the fourth layer over the third, and so forth. Therefore, the fluid in the middle of the vessel can move rapidly because many layers of slipping molecules exist between the middle of the vessel and the vessel wall; thus, each layer toward the center flows progressively more rapidly than the outer layers. Turbulent Flow of Blood Under Some Conditions. When the rate of blood flow becomes too great, when it passes by an obstruction in a vessel, when it makes a sharp turn, or when it passes over a rough surface, the flow may then become turbulent, or disorderly, rather than streamline (see Figure 14–6C).Turbulent flow means that the blood flows crosswise in the vessel as well as along the vessel, usually forming whorls in the blood called eddy currents. These are similar to the whirlpools that one frequently sees in a rapidly flowing river at a point of obstruction. When eddy currents are present, the blood flows with much greater resistance than when the flow is streamline because eddies add tremendously to the overall friction of flow in the vessel. The tendency for turbulent flow increases in direct proportion to the velocity of blood flow, the diameter of the blood vessel, and the density of the blood, and is inversely proportional to the viscosity of the blood, in accordance with the following equation: Re = n◊d ◊r h where Re is Reynolds’ number and is the measure of the tendency for turbulence to occur, n is the mean velocity of blood flow (in centimeters/second), d is the vessel diameter (in centimeters), r is density, and h is the viscosity (in poise). The viscosity of blood is normally about 1/30 poise, and the density is only slightly greater than 1. When Reynolds’ number rises above 200 to 400, turbulent flow will occur at some branches of vessels but will die out along the smooth portions of the vessels. However, when Reynolds’ number rises above approximately 2000, turbulence will usually occur even in a straight, smooth vessel. Reynolds’ number for flow in the vascular system even normally rises to 200 to 400 in large arteries; as a result there is almost always some turbulence of flow at the branches of these vessels. In the proximal portions of the aorta and pulmonary artery, Reynolds’ number can rise to several thousand during the rapid phase of ejection by the ventricles; this causes considerable turbulence in the proximal aorta and pulmonary artery where many conditions are appropriate for turbulence: (1) high velocity of blood flow, (2) pulsatile nature of the flow, (3) sudden change in vessel diameter, and (4) large vessel diameter. However, in small vessels, Reynolds’ number is almost never high enough to cause turbulence. Blood Pressure Standard Units of Pressure. Blood pressure almost always is measured in millimeters of mercury (mm Hg) because the mercury manometer (shown in Figure 14–7) has been used since antiquity as the standard 100 mm Hg pressure 0 pressure Moving sooted paper Float Anticoagulant solution Mercury Mercury manometer Figure 14–7 Recording arterial pressure with a mercury manometer, a method that has been used in the manner shown for recording pressure throughout the history of physiology. reference for measuring pressure.Actually, blood pressure means the force exerted by the blood against any unit area of the vessel wall. When one says that the pressure in a vessel is 50 mm Hg, one means that the force exerted is sufficient to push a column of mercury against gravity up to a level 50 mm high. If the pressure is 100 mm Hg, it will push the column of mercury up to 100 millimeters. Occasionally, pressure is measured in centimeters of water (cm H2O). A pressure of 10 cm H2O means a pressure sufficient to raise a column of water against gravity to a height of 10 centimeters. One millimeter of mercury pressure equals 1.36 cm water pressure because the specific gravity of mercury is 13.6 times that of water, and 1 centimeter is 10 times as great as 1 millimeter. High-Fidelity Methods for Measuring Blood Pressure. The mercury in the mercury manometer has so much inertia that it cannot rise and fall rapidly. For this reason, the mercury manometer, although excellent for recording steady pressures, cannot respond to pressure changes that occur more rapidly than about one cycle every 2 to 3 seconds. Whenever it is desired to record rapidly changing pressures, some other type of pressure recorder is needed. Figure 14–8 demonstrates the basic principles of three electronic pressure transducers commonly used for converting blood pressure and/or rapid changes in pressure into electrical signals and then recording the electrical signals on a high-speed electrical recorder. Each of these transducers uses a very thin, highly stretched metal membrane that forms one wall of the fluid chamber. The fluid chamber in turn is connected through a needle or catheter to the blood vessel in which the pressure is to be measured. When the pressure is high, the membrane bulges slightly, and when it is low, it returns toward its resting position. Chapter 14 Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance 167 any direct means. Instead, resistance must be calculated from measurements of blood flow and pressure difference between two points in the vessel. If the pressure difference between two points is 1 mm Hg and the flow is 1 ml/sec, the resistance is said to be 1 peripheral resistance unit, usually abbreviated PRU. A B Expression of Resistance in CGS Units. Occasionally, a basic physical unit called the CGS (centimeters, grams, seconds) unit is used to express resistance. This unit is dyne seconds/centimeters5. Resistance in these units can be calculated by the following formula: R Ê in Ë dyne sec ˆ 1333 ¥ mm Hg = cm5 ¯ ml sec Total Peripheral Vascular Resistance and Total Pulmonary Vascular Resistance. The rate of blood flow through the C Figure 14–8 Principles of three types of electronic transducers for recording rapidly changing blood pressures (explained in the text). In Figure 14–8A, a simple metal plate is placed a few hundredths of a centimeter above the membrane. When the membrane bulges, the membrane comes closer to the plate, which increases the electrical capacitance between these two, and this change in capacitance can be recorded using an appropriate electronic system. In Figure 14–8B, a small iron slug rests on the membrane, and this can be displaced upward into a center space inside an electrical wire coil. Movement of the iron into the coil increases the inductance of the coil, and this, too, can be recorded electronically. Finally, in Figure 14–8C, a very thin, stretched resistance wire is connected to the membrane. When this wire is stretched greatly, its resistance increases; when it is stretched less, its resistance decreases. These changes, too, can be recorded by an electronic system. With some of these high-fidelity types of recording systems, pressure cycles up to 500 cycles per second have been recorded accurately. In common use are recorders capable of registering pressure changes that occur as rapidly as 20 to 100 cycles per second, in the manner shown on the recording paper in Figure 14–8C. Resistance to Blood Flow Units of Resistance. Resistance is the impediment to blood flow in a vessel, but it cannot be measured by entire circulatory system is equal to the rate of blood pumping by the heart—that is, it is equal to the cardiac output. In the adult human being, this is approximately 100 ml/sec. The pressure difference from the systemic arteries to the systemic veins is about 100 mm Hg. Therefore, the resistance of the entire systemic circulation, called the total peripheral resistance, is about 100/100, or 1 PRU. In conditions in which all the blood vessels throughout the body become strongly constricted, the total peripheral resistance occasionally rises to as high as 4 PRU. Conversely, when the vessels become greatly dilated, the resistance can fall to as little as 0.2 PRU. In the pulmonary system, the mean pulmonary arterial pressure averages 16 mm Hg and the mean left atrial pressure averages 2 mm Hg, giving a net pressure difference of 14 mm. Therefore, when the cardiac output is normal at about 100 ml/sec, the total pulmonary vascular resistance calculates to be about 0.14 PRU (about one seventh that in the systemic circulation). “Conductance” of Blood in a Vessel and Its Relation to Resistance. Conductance is a measure of the blood flow through a vessel for a given pressure difference. This is generally expressed in terms of milliliters per second per millimeter of mercury pressure, but it can also be expressed in terms of liters per second per millimeter of mercury or in any other units of blood flow and pressure. It is evident that conductance is the exact reciprocal of resistance in accord with the following equation: Conductance = 1 Resistance Very Slight Changes in Diameter of a Vessel Can Change Its Conductance Tremendously! Slight changes in the diame- ter of a vessel cause tremendous changes in the vessel’s ability to conduct blood when the blood flow is streamlined. This is demonstrated by the experiment illustrated in Figure 14–9A, which shows three vessels with relative diameters of 1, 2, and 4 but with the same pressure difference of 100 mm Hg between the two ends of the vessels. Although the diameters of these vessels 168 Unit IV A d=1 P= 100 mm Hg d=2 The Circulation 1 ml/min 16 ml/min d=4 256 ml/min Note particularly in this equation that the rate of blood flow is directly proportional to the fourth power of the radius of the vessel, which demonstrates once again that the diameter of a blood vessel (which is equal to twice the radius) plays by far the greatest role of all factors in determining the rate of blood flow through a vessel. Importance of the Vessel Diameter “Fourth Power Law” in Determining Arteriolar Resistance. In the systemic circula- B Small vessel Large vessel Figure 14–9 A, Demonstration of the effect of vessel diameter on blood flow. B, Concentric rings of blood flowing at different velocities; the farther away from the vessel wall, the faster the flow. increase only fourfold, the respective flows are 1, 16, and 256 ml/mm, which is a 256-fold increase in flow. Thus, the conductance of the vessel increases in proportion to the fourth power of the diameter, in accordance with the following formula: Conductance µ Diameter 4 Poiseuille’s Law. The cause of this great increase in conductance when the diameter increases can be explained by referring to Figure 14–9B, which shows cross sections of a large and a small vessel. The concentric rings inside the vessels indicate that the velocity of flow in each ring is different from that in the adjacent rings because of laminar flow, which was discussed earlier in the chapter. That is, the blood in the ring touching the wall of the vessel is barely flowing because of its adherence to the vascular endothelium.The next ring of blood toward the center of the vessel slips past the first ring and, therefore, flows more rapidly. The third, fourth, fifth, and sixth rings likewise flow at progressively increasing velocities. Thus, the blood that is near the wall of the vessel flows extremely slowly, whereas that in the middle of the vessel flows extremely rapidly. In the small vessel, essentially all the blood is near the wall, so that the extremely rapidly flowing central stream of blood simply does not exist. By integrating the velocities of all the concentric rings of flowing blood and multiplying them by the areas of the rings, one can derive the following formula, known as Poiseuille’s law: F= pD Pr 4 8 hl in which F is the rate of blood flow, DP is the pressure difference between the ends of the vessel, r is the radius of the vessel, l is length of the vessel, and h is viscosity of the blood. tion, about two thirds of the total systemic resistance to blood flow is arteriolar resistance in the small arterioles. The internal diameters of the arterioles range from as little as 4 micrometers to as great as 25 micrometers. However, their strong vascular walls allow the internal diameters to change tremendously, often as much as fourfold. From the fourth power law discussed above that relates blood flow to diameter of the vessel, one can see that a fourfold increase in vessel diameter can increase the flow as much as 256-fold. Thus, this fourth power law makes it possible for the arterioles, responding with only small changes in diameter to nervous signals or local tissue chemical signals, either to turn off almost completely the blood flow to the tissue or at the other extreme to cause a vast increase in flow. Indeed, ranges of blood flow of more than 100-fold in separate tissue areas have been recorded between the limits of maximum arteriolar constriction and maximum arteriolar dilatation. Resistance to Blood Flow in Series and Parallel Vascular Circuits. Blood pumped by the heart flows from the high pressure part of the systemic circulation (i.e., aorta) to the low pressure side (i.e., vena cava) through many miles of blood vessels arranged in series and in parallel. The arteries, arterioles, capillaries, venules, and veins are collectively arranged in series. When blood vessels are arranged in series, flow through each blood vessel is the same and the total resistance to blood flow (Rtotal) is equal to the sum of the resistances of each vessel: R total = R 1 + R 2 + R 3 + R 4 . . . The total peripheral vascular resistance is therefore equal to the sum of resistances of the arteries, arterioles, capillaries, venules, and veins. In the example shown in Figure 14–10A, the total vascular resistance is equal to the sum of R1 and R2. Blood vessels branch extensively to form parallel circuits that supply blood to the many organs and tissues of the body. This parallel arrangement permits each tissue to regulate its own blood flow, to a great extent, independently of flow to other tissues. For blood vessels arranged in parallel (Figure 14–10B), the total resistance to blood flow is expressed as: 1 1 1 1 1 = + + + ... R total R 1 R 2 R 3 R 4 It is obvious that for a given pressure gradient, far greater amounts of blood will flow through this Chapter 14 Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance R1 R2 A R1 R 2 B R3 R4 169 100 100 100 90 90 90 80 80 80 70 70 70 60 60 60 50 50 50 40 40 40 30 30 30 20 20 20 10 10 10 0 0 0 Figure 14–10 Vascular resistances: A, in series and B, in parallel. parallel system than through any of the individual blood vessels. Therefore, the total resistance is far less than the resistance of any single blood vessel. Flow through each of the parallel vessels in Figure 14–10B is determined by the pressure gradient and its own resistance, not the resistance of the other parallel blood vessels. However, increasing the resistance of any of the blood vessels increases the total vascular resistance. It may seem paradoxical that adding more blood vessels to a circuit reduces the total vascular resistance. Many parallel blood vessels, however, make it easier for blood to flow through the circuit because each parallel vessel provides another pathway, or conductance, for blood flow. The total conductance (Ctotal) for blood flow is the sum of the conductance of each parallel pathway: C total = C1 + C 2 + C 3 + C 4 . . . For example, brain, kidney, muscle, gastrointestinal, skin, and coronary circulations are arranged in parallel, and each tissue contributes to the overall conductance of the systemic circulation. Blood flow through each tissue is a fraction of the total blood flow (cardiac output) and is determined by the resistance (the reciprocal of conductance) for blood flow in the tissue, as well as the pressure gradient. Therefore, amputation of a limb or surgical removal of a kidney also removes a parallel circuit and reduces the total vascular conductance and total blood flow (i.e., cardiac output) while increasing total peripheral vascular resistance. Effect of Blood Hematocrit and Blood Viscosity on Vascular Resistance and Blood Flow Note especially that another of the important factors in Poiseuille’s equation is the viscosity of the blood. The greater the viscosity, the less the flow in a vessel if all other factors are constant. Furthermore, the viscosity of normal blood is about three times as great as the viscosity of water. But what makes the blood so viscous? It is mainly the large numbers of suspended red cells in the blood, Normal Anemia Polycythemia Figure 14–11 Hematocrits in a healthy (normal) person and in patients with anemia and polycythemia. each of which exerts frictional drag against adjacent cells and against the wall of the blood vessel. Hematocrit. The percentage of the blood that is cells is called the hematocrit. Thus, if a person has a hematocrit of 40, this means that 40 per cent of the blood volume is cells and the remainder is plasma.The hematocrit of men averages about 42, while that of women averages about 38. These values vary tremendously, depending on whether the person has anemia, on the degree of bodily activity, and on the altitude at which the person resides. These changes in hematocrit are discussed in relation to the red blood cells and their oxygen transport function in Chapter 32. Hematocrit is determined by centrifuging blood in a calibrated tube, as shown in Figure 14–11. The calibration allows direct reading of the percentage of cells. Effect of Hematocrit on Blood Viscosity. The viscosity of blood increases drastically as the hematocrit increases, as shown in Figure 14–12. The viscosity of whole blood at normal hematocrit is about 3; this means that three times as much pressure is required to force whole blood as to force water through the same blood vessel. When the hematocrit rises to 60 or 70, which it often does in polycythemia, the blood viscosity can become as great as 10 times that of water, and its flow through blood vessels is greatly retarded. Other factors that affect blood viscosity are the plasma protein concentration and types of proteins in the plasma, but these effects are so much less than the effect of hematocrit that they are not significant 170 Unit IV Viscosity (water = 1) 9 Viscosity of whole blood 7 Viscosity of plasma Viscosity of water 6 Blood flow (ml/min) 10 The Circulation 8 7 6 5 4 Normal blood 3 2 Sympathetic inhibition Normal Sympathetic stimulation 5 4 Critical closing pressure 3 2 1 0 0 1 20 0 0 10 20 30 40 50 Hematocrit 60 40 60 80 100 120 140 160 180 200 Arterial pressure (mm Hg) 70 Figure 14–13 Figure 14–12 Effect of arterial pressure on blood flow through a blood vessel at different degrees of vascular tone caused by increased or decreased sympathetic stimulation of the vessel. Effect of hematocrit on blood viscosity. (Water viscosity = 1.) considerations in most hemodynamic studies. The viscosity of blood plasma is about 1.5 times that of water. Effects of Pressure on Vascular Resistance and Tissue Blood Flow From the discussion thus far, one might expect an increase in arterial pressure to cause a proportionate increase in blood flow through the various tissues of the body. However, the effect of pressure on blood flow is greater than one would expect, as shown by the upward curving lines in Figure 14–13. The reason for this is that an increase in arterial pressure not only increases the force that pushes blood through the vessels but also distends the vessels at the same time, which decreases vascular resistance. Thus, greater pressure increases the flow in both of these ways. Therefore, for most tissues, blood flow at 100 mm Hg arterial pressure is usually four to six times as great as blood flow at 50 mm Hg instead of two times as would be true if there were no effect of increasing pressure to increase vascular diameter. Note also in Figure 14–13 the large changes in blood flow that can be caused by either increased or decreased sympathetic nerve stimulation of the peripheral blood vessels. Thus, as shown in the figure, inhibition of sympathetic activity greatly dilates the vessels and can increase the blood flow twofold or more. Conversely, very strong sympathetic stimulation can constrict the vessels so much that blood flow occasionally decreases to as low as zero for a few seconds despite high arterial pressure. References See references for Chapter 15. C H A P T E R 1 5 Vascular Distensibility and Functions of the Arterial and Venous Systems Vascular Distensibility A valuable characteristic of the vascular system is that all blood vessels are distensible. We have seen one example of this in Chapter 14: When the pressure in blood vessels is increased, this dilates the blood vessels and therefore decreases their resistance. The result is increased blood flow not only because of increased pressure but also because of decreased resistance, usually giving at least twice as much flow increase for each increase in pressure as one might expect. Vascular distensibility also plays other important roles in circulatory function. For example, the distensible nature of the arteries allows them to accommodate the pulsatile output of the heart and to average out the pressure pulsations. This provides smooth, continuous flow of blood through the very small blood vessels of the tissues. The most distensible by far of all the vessels are the veins. Even slight increases in venous pressure cause the veins to store 0.5 to 1.0 liter of extra blood. Therefore, the veins provide a reservoir function for storing large quantities of extra blood that can be called into use whenever required elsewhere in the circulation. Units of Vascular Distensibility. Vascular distensibility normally is expressed as the fractional increase in volume for each millimeter of mercury rise in pressure, in accordance with the following formula: Vascular distensibility = Increase in volume Increase in pressure ¥ Original volume That is, if 1 mm Hg causes a vessel that originally contained 10 millimeters of blood to increase its volume by 1 milliliter, the distensibility would be 0.1 per mm Hg, or 10 per cent per mm Hg. Difference in Distensibility of the Arteries and the Veins. Anatomically, the walls of the arteries are far stronger than those of the veins. Consequently, the arteries, on average, are about eight times less distensible than the veins. That is, a given increase in pressure causes about eight times as much increase in blood in a vein as in an artery of comparable size. In the pulmonary circulation, the pulmonary vein distensibilities are similar to those of the systemic circulation. But, the pulmonary arteries normally operate under pressures about one sixth of those in the systemic arterial system, and their distensibilities are correspondingly greater, about six times the distensibility of systemic arteries. Vascular Compliance (or Vascular Capacitance) In hemodynamic studies, it usually is much more important to know the total quantity of blood that can be stored in a given portion of the circulation for each millimeter of mercury pressure rise than to know the distensibilities of the 171 172 Unit IV The Circulation individual vessels. This value is called the compliance or capacitance of the respective vascular bed; that is, Vascular compliance = Increase in volume Increase in pressure Compliance and distensibility are quite different. A highly distensible vessel that has a slight volume may have far less compliance than a much less distensible vessel that has a large volume because compliance is equal to distensibility times volume. The compliance of a systemic vein is about 24 times that of its corresponding artery because it is about 8 times as distensible and it has a volume about 3 times as great (8 ¥ 3 = 24). Volume-Pressure Curves of the Arterial and Venous Circulations A convenient method for expressing the relation of pressure to volume in a vessel or in any portion of the circulation is to use the so-called volume-pressure curve. The red and blue solid curves in Figure 15–1 represent, respectively, the volume-pressure curves of the normal systemic arterial system and venous system, showing that when the arterial system of the average adult person (including all the large arteries, small arteries, and arterioles) is filled with about 700 milliliters of blood, the mean arterial pressure is 100 mm Hg, but when it is filled with only 400 milliliters of blood, the pressure falls to zero. In the entire systemic venous system, the volume normally ranges from 2000 to 3500 milliliters, and a change of several hundred millimeters in this volume is required to change the venous pressure only 3 to 5 mm Hg. This mainly explains why as much as one half liter of blood can be transfused into a healthy person in only a few minutes without greatly altering function of the circulation. Effect of Sympathetic Stimulation or Sympathetic Inhibition on the Volume-Pressure Relations of the Arterial and Venous Systems. Also shown in Figure 15–1 are the effects that exciting or inhibiting the vascular sympathetic nerves has on the volume-pressure curves. It is evident that increase in vascular smooth muscle tone caused by sympathetic stimulation increases the pressure at each volume of the arteries or veins, whereas sympathetic inhibition decreases the pressure at each volume. Control of the vessels in this manner by the sympathetics is a valuable means for diminishing the dimensions of one segment of the circulation, thus transferring blood to other segments. For instance, an increase in vascular tone throughout the systemic circulation often causes large volumes of blood to shift into the heart, which is one of the principal methods that the body uses to increase heart pumping. Sympathetic control of vascular capacitance is also highly important during hemorrhage. Enhancement of sympathetic tone, especially to the veins, reduces the vessel sizes enough that the circulation continues to operate almost normally even when as much as 25 per cent of the total blood volume has been lost. Delayed Compliance (Stress-Relaxation) of Vessels 140 Pressure (mm Hg) 120 Sympathetic stimulation 100 Sympathetic inhibition 80 60 Normal volume 40 Arterial system Venous system 20 0 0 500 1000 1500 2000 2500 3000 3500 Volume (ml) Figure 15–1 “Volume-pressure curves” of the systemic arterial and venous systems, showing the effects of stimulation or inhibition of the sympathetic nerves to the circulatory system. The term “delayed compliance” means that a vessel exposed to increased volume at first exhibits a large increase in pressure, but progressive delayed stretching of smooth muscle in the vessel wall allows the pressure to return back toward normal over a period of minutes to hours. This effect is shown in Figure 15–2. In this figure, the pressure is recorded in a small segment of a vein that is occluded at both ends. An extra volume of blood is suddenly injected until the pressure rises from 5 to 12 mm Hg. Even though none of the blood is removed after it is injected, the pressure begins to decrease immediately and approaches about 9 mm Hg after several minutes. In other words, the volume of blood injected causes immediate elastic distention of the vein, but then the smooth muscle fibers of the vein begin to “creep” to longer lengths, and their tensions correspondingly decrease. This effect is a characteristic of all smooth muscle tissue and is called stress-relaxation, which was explained in Chapter 8. Delayed compliance is a valuable mechanism by which the circulation can accommodate much extra blood when necessary, such as after too large a transfusion. Delayed compliance in the reverse direction is one of the ways in which the circulation automatically adjusts itself over a period of minutes or hours to diminished blood volume after serious hemorrhage. Chapter 15 14 D co elay mp ed lia nc e 8 6 4 +20 d aye Del liance p com 2 0 0 20 40 60 Minutes 80 Pressure (mm Hg) Increased volume 10 Exponential diastolic decline (may be distorted by reflected wave) Sharp incisura Slow rise to peak Decreased volume Pressure (mm Hg) 12 173 Vascular Distensibility and Functions of the Arterial and Venous Systems – 80 Sharp upstroke – 80 – 80 0 Figure 15–2 Effect on the intravascular pressure of injecting a volume of blood into a venous segment and later removing the excess blood, demonstrating the principle of delayed compliance. 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Seconds Figure 15–3 Pressure pulse contour recorded from the ascending aorta. (Redrawn from Opdyke DF: Fed Proc 11:734, 1952.) Arterial Pressure Pulsations With each beat of the heart a new surge of blood fills the arteries. Were it not for distensibility of the arterial system, all of this new blood would have to flow through the peripheral blood vessels almost instantaneously, only during cardiac systole, and no flow would occur during diastole. However, normally the compliance of the arterial tree reduces the pressure pulsations to almost no pulsations by the time the blood reaches the capillaries; therefore, tissue blood flow is mainly continuous with very little pulsation. A typical record of the pressure pulsations at the root of the aorta is shown in Figure 15–3. In the healthy young adult, the pressure at the top of each pulse, called the systolic pressure, is about 120 mm Hg. At the lowest point of each pulse, called the diastolic pressure, it is about 80 mm Hg. The difference between these two pressures, about 40 mm Hg, is called the pulse pressure. Two major factors affect the pulse pressure: (1) the stroke volume output of the heart and (2) the compliance (total distensibility) of the arterial tree. A third, less important factor is the character of ejection from the heart during systole. In general, the greater the stroke volume output, the greater the amount of blood that must be accommodated in the arterial tree with each heartbeat, and, therefore, the greater the pressure rise and fall during systole and diastole, thus causing a greater pulse pressure. Conversely, the less the compliance of the arterial system, the greater the rise in pressure for a given stroke volume of blood pumped into the arteries. For instance, as demonstrated by the middle top curves in Figure 15–4, the pulse pressure in old age sometimes rises to as much as twice normal, because the arteries 160 120 80 Normal Arteriosclerosis Aortic stenosis 160 120 80 Normal 40 0 Patent ductus arteriosus Aortic regurgitation Figure 15–4 Aortic pressure pulse contours in arteriosclerosis, aortic stenosis, patent ductus arteriosus, and aortic regurgitation. have become hardened with arteriosclerosis and therefore are relatively noncompliant. In effect, then, pulse pressure is determined approximately by the ratio of stroke volume output to compliance of the arterial tree.Any condition of the circulation that affects either of these two factors also affects the pulse pressure. 174 Unit IV The Circulation Abnormal Pressure Pulse Contours Some conditions of the circulation also cause abnormal contours of the pressure pulse wave in addition to altering the pulse pressure. Especially distinctive among these are aortic stenosis, patent ductus arteriosus, and aortic regurgitation, each of which is shown in Figure 15–4. In aortic stenosis, the diameter of the aortic valve opening is reduced significantly, and the aortic pressure pulse is decreased significantly because of diminished blood flow outward through the stenotic valve. In patent ductus arteriosus, one half or more of the blood pumped into the aorta by the left ventricle flows immediately backward through the wide-open ductus into the pulmonary artery and lung blood vessels, thus allowing the diastolic pressure to fall very low before the next heartbeat. In aortic regurgitation, the aortic valve is absent or will not close completely. Therefore, after each heartbeat, the blood that has just been pumped into the aorta flows immediately backward into the left ventricle. As a result, the aortic pressure can fall all the way to zero between heartbeats. Also, there is no incisura in the aortic pulse contour because there is no aortic valve to close. Wave fronts Figure 15–5 Progressive stages in transmission of the pressure pulse along the aorta. Transmission of Pressure Pulses to the Peripheral Arteries When the heart ejects blood into the aorta during systole, at first only the proximal portion of the aorta becomes distended because the inertia of the blood prevents sudden blood movement all the way to the periphery. However, the rising pressure in the proximal aorta rapidly overcomes this inertia, and the wave front of distention spreads farther and farther along the aorta, as shown in Figure 15–5. This is called transmission of the pressure pulse in the arteries. The velocity of pressure pulse transmission in the normal aorta is 3 to 5 m/sec; in the large arterial branches, 7 to 10 m/sec; and in the small arteries, 15 to 35 m/sec. In general, the greater the compliance of each vascular segment, the slower the velocity, which explains the slow transmission in the aorta and the much faster transmission in the much less compliant small distal arteries. In the aorta, the velocity of transmission of the pressure pulse is 15 or more times the velocity of blood flow because the pressure pulse is simply a moving wave of pressure that involves little forward total movement of blood volume. Proximal aorta Femoral artery Radial artery Arteriole Capillary Damping of the Pressure Pulses in the Smaller Arteries, Arterioles, and Capillaries. Figure 15–6 shows typical changes in the contours of the pressure pulse as the pulse travels into the peripheral vessels. Note especially in the three lower curves that the intensity of pulsation becomes progressively less in the smaller arteries, the arterioles, and, especially, the capillaries. In fact, only when the aortic pulsations are extremely large or the arterioles are greatly dilated can pulsations be observed in the capillaries. Incisura Systole Diastole 0 1 2 Time (seconds) Figure 15–6 Changes in the pulse pressure contour as the pulse wave travels toward the smaller vessels. Chapter 15 Vascular Distensibility and Functions of the Arterial and Venous Systems This progressive diminution of the pulsations in the periphery is called damping of the pressure pulses. The cause of this is twofold: (1) resistance to blood movement in the vessels and (2) compliance of the vessels. The resistance damps the pulsations because a small amount of blood must flow forward at the pulse wave front to distend the next segment of the vessel; the greater the resistance, the more difficult it is for this to occur. The compliance damps the pulsations because the more compliant a vessel, the greater the quantity of blood required at the pulse wave front to cause an increase in pressure. Therefore, in effect, the degree of damping is almost directly proportional to the product of resistance times compliance. Clinical Methods for Measuring Systolic and Diastolic Pressures It is not reasonable to use pressure recorders that require needle insertion into an artery for making routine pressure measurements in human patients, although these are used on occasion when special studies are necessary. Instead, the clinician determines systolic and diastolic pressures by indirect means, usually by the auscultatory method. Auscultatory Method. Figure 15–7 shows the auscultatory method for determining systolic and diastolic arterial pressures. A stethoscope is placed over the antecubital artery and a blood pressure cuff is inflated around the upper arm. As long as the cuff continues to compress the arm with too little pressure to close the brachial artery, no sounds are heard from the antecubital artery with the stethoscope. However, when the cuff pressure is great enough to close the artery during part of the Sounds 120 100 175 arterial pressure cycle, a sound then is heard with each pulsation. These sounds are called Korotkoff sounds. The exact cause of Korotkoff sounds is still debated, but they are believed to be caused mainly by blood jetting through the partly occluded vessel. The jet causes turbulence in the vessel beyond the cuff, and this sets up the vibrations heard through the stethoscope. In determining blood pressure by the auscultatory method, the pressure in the cuff is first elevated well above arterial systolic pressure. As long as this cuff pressure is higher than systolic pressure, the brachial artery remains collapsed so that no blood jets into the lower artery during any part of the pressure cycle. Therefore, no Korotkoff sounds are heard in the lower artery. But then the cuff pressure gradually is reduced. Just as soon as the pressure in the cuff falls below systolic pressure, blood begins to slip through the artery beneath the cuff during the peak of systolic pressure, and one begins to hear tapping sounds from the antecubital artery in synchrony with the heartbeat. As soon as these sounds begin to be heard, the pressure level indicated by the manometer connected to the cuff is about equal to the systolic pressure. As the pressure in the cuff is lowered still more, the Korotkoff sounds change in quality, having less of the tapping quality and more of a rhythmical and harsher quality. Then, finally, when the pressure in the cuff falls to equal diastolic pressure, the artery no longer closes during diastole, which means that the basic factor causing the sounds (the jetting of blood through a squeezed artery) is no longer present. Therefore, the sounds suddenly change to a muffled quality, then disappear entirely after another 5- to 10-millimeter drop in cuff pressure. One notes the manometer pressure when the Korotkoff sounds change to the muffled quality; this pressure is about equal to the diastolic pressure. The auscultatory method for determining systolic and diastolic pressures is not entirely accurate, but it usually gives values within 10 per cent of those determined by direct catheter measurement from inside the arteries. Normal Arterial Pressures as Measured by the Auscultatory Method. Figure 15–8 shows the approximate normal 80 100 mm Hg 150 50 0 Figure 15–7 Auscultatory method for measuring systolic and diastolic arterial pressures. systolic and diastolic arterial pressures at different ages. The progressive increase in pressure with age results from the effects of aging on the blood pressure control mechanisms. We shall see in Chapter 19 that the kidneys are primarily responsible for this longterm regulation of arterial pressure; and it is well known that the kidneys exhibit definitive changes with age, especially after the age of 50 years. A slight extra increase in systolic pressure usually occurs beyond the age of 60 years. This results from hardening of the arteries, which itself is an end-stage result of atherosclerosis. The final effect is a bounding systolic pressure with considerable increase in pulse pressure, as previously explained. Mean Arterial Pressure. The mean arterial pressure is the average of the arterial pressures measured millisecond 176 Unit IV The Circulation Pressure (mm Hg) 200 Systolic 150 Mean 100 Diastolic 50 0 0 20 40 Age (years) 60 80 Figure 15–8 Changes in systolic, diastolic, and mean arterial pressures with age. The shaded areas show the approximate normal ranges. by millisecond over a period of time. It is not equal to the average of systolic and diastolic pressure because the arterial pressure remains nearer to diastolic pressure than to systolic pressure during the greater part of the cardiac cycle. Therefore, the mean arterial pressure is determined about 60 per cent by the diastolic pressure and 40 per cent by the systolic pressure. Note in Figure 15–8 that the mean pressure (solid green line) at all ages is nearer to the diastolic pressure than to the systolic pressure. Veins and Their Functions For years, the veins were considered to be nothing more than passageways for flow of blood to the heart, but it has become apparent that they perform other special functions that are necessary for operation of the circulation. Especially important, they are capable of constricting and enlarging and thereby storing either small or large quantities of blood and making this blood available when it is required by the remainder of the circulation. The peripheral veins can also propel blood forward by means of a so-called venous pump, and they even help to regulate cardiac output, an exceedingly important function that is described in detail in Chapter 20. Venous Pressures—Right Atrial Pressure (Central Venous Pressure) and Peripheral Venous Pressures To understand the various functions of the veins, it is first necessary to know something about pressure in the veins and what determines the pressure. Blood from all the systemic veins flows into the right atrium of the heart; therefore, the pressure in the right atrium is called the central venous pressure. Right atrial pressure is regulated by a balance between (1) the ability of the heart to pump blood out of the right atrium and ventricle into the lungs and (2) the tendency for blood to flow from the peripheral veins into the right atrium. If the right heart is pumping strongly, the right atrial pressure decreases. Conversely, weakness of the heart elevates the right atrial pressure. Also, any effect that causes rapid inflow of blood into the right atrium from the peripheral veins elevates the right atrial pressure. Some of the factors that can increase this venous return (and thereby increase the right atrial pressure) are (1) increased blood volume, (2) increased large vessel tone throughout the body with resultant increased peripheral venous pressures, and (3) dilatation of the arterioles, which decreases the peripheral resistance and allows rapid flow of blood from the arteries into the veins. The same factors that regulate right atrial pressure also enter into the regulation of cardiac output because the amount of blood pumped by the heart depends on both the ability of the heart to pump and the tendency for blood to flow into the heart from the peripheral vessels. Therefore, we will discuss regulation of right atrial pressure in much more depth in Chapter 20 in connection with regulation of cardiac output. The normal right atrial pressure is about 0 mm Hg, which is equal to the atmospheric pressure around the body. It can increase to 20 to 30 mm Hg under very abnormal conditions, such as (1) serious heart failure or (2) after massive transfusion of blood, which greatly increases the total blood volume and causes excessive quantities of blood to attempt to flow into the heart from the peripheral vessels. The lower limit to the right atrial pressure is usually about -3 to -5 mm Hg below atmospheric pressure. This is also the pressure in the chest cavity that surrounds the heart. The right atrial pressure approaches these low values when the heart pumps with exceptional vigor or when blood flow into the heart from the peripheral vessels is greatly depressed, such as after severe hemorrhage. Venous Resistance and Peripheral Venous Pressure Large veins have so little resistance to blood flow when they are distended that the resistance then is almost zero and is of almost no importance. However, as shown in Figure 15–9, most of the large veins that enter the thorax are compressed at many points by the surrounding tissues, so that blood flow is impeded at these points. For instance, the veins from the arms are compressed by their sharp angulations over the first rib. Also, the pressure in the neck veins often falls so low that the atmospheric pressure on the outside of the neck causes these veins to collapse. Finally, veins coursing through the abdomen are often compressed by different organs and by the intra-abdominal pressure, so that they usually are at least partially collapsed to an ovoid or slitlike state. For these reasons, the large veins do usually offer some resistance to blood flow, and because of this, the pressure in the more Chapter 15 177 Vascular Distensibility and Functions of the Arterial and Venous Systems Sagittal sinus -1 0 mm 0 mm 0 mm Atmospheric pressure collapse in neck + 6 mm + 8 mm Rib collapse Axillary collapse Intrathoracic pressure = - 4 mm Hg + 2 2 mm + 3 5 mm Abdominal pressure collapse + 4 0 mm Figure 15–9 Compression points that tend to collapse the veins entering the thorax. peripheral small veins in a person lying down is usually +4 to +6 mm Hg greater than the right atrial pressure. Effect of High Right Atrial Pressure on Peripheral Venous Pressure. When the right atrial pressure rises above its normal value of 0 mm Hg, blood begins to back up in the large veins. This enlarges the veins, and even the collapse points in the veins open up when the right atrial pressure rises above +4 to +6 mm Hg. Then, as the right atrial pressure rises still further, the additional increase causes a corresponding rise in peripheral venous pressure in the limbs and elsewhere. Because the heart must be weakened greatly to cause a rise in right atrial pressure as high as +4 to +6 mm Hg, one often finds that the peripheral venous pressure is not noticeably elevated even in the early stages of heart failure. Effect of Intra-abdominal Pressure on Venous Pressures of the Leg. The pressure in the abdominal cavity of a recum- bent person normally averages about +6 mm Hg, but it can rise to +15 to +30 mm Hg as a result of pregnancy, large tumors, or excessive fluid (called “ascites”) in the abdominal cavity. When the intraabdominal pressure does rise, the pressure in the veins of the legs must rise above the abdominal pressure before the abdominal veins will open and allow the blood to flow from the legs to the heart. Thus, if the intra-abdominal pressure is +20 mm Hg, the lowest possible pressure in the femoral veins is also +20 mm Hg. Effect of Gravitational Pressure on Venous Pressure In any body of water that is exposed to air, the pressure at the surface of the water is equal to atmospheric + 9 0 mm Figure 15–10 Effect of gravitational pressure on the venous pressures throughout the body in the standing person. pressure, but the pressure rises 1 mm Hg for each 13.6 millimeters of distance below the surface. This pressure results from the weight of the water and therefore is called gravitational pressure or hydrostatic pressure. Gravitational pressure also occurs in the vascular system of the human being because of weight of the blood in the vessels, as shown in Figure 15–10. When a person is standing, the pressure in the right atrium remains about 0 mm Hg because the heart pumps into the arteries any excess blood that attempts to accumulate at this point. However, in an adult who is standing absolutely still, the pressure in the veins of the feet is about +90 mm Hg simply because of the gravitational weight of the blood in the veins between the heart and the feet. The venous pressures at other levels of the body are proportionately between 0 and 90 mm Hg. In the arm veins, the pressure at the level of the top rib is usually about +6 mm Hg because of compression of the subclavian vein as it passes over this rib. The gravitational pressure down the length of the arm then is determined by the distance below the level of this rib. Thus, if the gravitational difference between the 178 Unit IV The Circulation level of the rib and the hand is +29 mm Hg, this gravitational pressure is added to the +6 mm Hg pressure caused by compression of the vein as it crosses the rib, making a total of +35 mm Hg pressure in the veins of the hand. The neck veins of a person standing upright collapse almost completely all the way to the skull because of atmospheric pressure on the outside of the neck. This collapse causes the pressure in these veins to remain at zero along their entire extent. The reason for this is that any tendency for the pressure to rise above this level opens the veins and allows the pressure to fall back to zero because of flow of the blood. Conversely, any tendency for the neck vein pressure to fall below zero collapses the veins still more, which further increases their resistance and again returns the pressure back to zero. The veins inside the skull, on the other hand, are in a noncollapsible chamber (the skull cavity) so that they cannot collapse. Consequently, negative pressure can exist in the dural sinuses of the head; in the standing position, the venous pressure in the sagittal sinus at the top of the brain is about -10 mm Hg because of the hydrostatic “suction” between the top of the skull and the base of the skull. Therefore, if the sagittal sinus is opened during surgery, air can be sucked immediately into the venous system; the air may even pass downward to cause air embolism in the heart, and death can ensue. Effect of the Gravitational Factor on Arterial and Other Pressures. The gravitational factor also affects pressures in the peripheral arteries and capillaries, in addition to its effects in the veins. For instance, a standing person who has a mean arterial pressure of 100 mm Hg at the level of the heart has an arterial pressure in the feet of about 190 mm Hg. Therefore, when one states that the arterial pressure is 100 mm Hg, this generally means that this is the pressure at the gravitational level of the heart but not necessarily elsewhere in the arterial vessels. Venous Valves and the “Venous Pump”: Their Effects on Venous Pressure Were it not for valves in the veins, the gravitational pressure effect would cause the venous pressure in the feet always to be about +90 mm Hg in a standing adult. However, every time one moves the legs, one tightens the muscles and compresses the veins in or adjacent to the muscles, and this squeezes the blood out of the veins. But the valves in the veins, shown in Figure 15–11, are arranged so that the direction of venous blood flow can be only toward the heart. Consequently, every time a person moves the legs or even tenses the leg muscles, a certain amount of venous blood is propelled toward the heart. This pumping system is known as the “venous pump” or “muscle pump,” and it is efficient enough that under ordinary circumstances, the venous pressure in the feet of a walking adult remains less than +20 mm Hg. If a person stands perfectly still, the venous pump does not work, and the venous pressures in the lower Deep vein Perforating vein Superficial vein Valve Figure 15–11 Venous valves of the leg. legs increase to the full gravitational value of 90 mm Hg in about 30 seconds. The pressures in the capillaries also increase greatly, causing fluid to leak from the circulatory system into the tissue spaces. As a result, the legs swell, and the blood volume diminishes. Indeed, 10 to 20 per cent of the blood volume can be lost from the circulatory system within the 15 to 30 minutes of standing absolutely still, as often occurs when a soldier is made to stand at rigid attention. Venous Valve Incompetence Causes “Varicose” Veins. The valves of the venous system frequently become “incompetent” or sometimes even are destroyed. This is especially true when the veins have been overstretched by excess venous pressure lasting weeks or months, as occurs in pregnancy or when one stands most of the time. Stretching the veins increases their cross-sectional areas, but the leaflets of the valves do not increase in size. Therefore, the leaflets of the valves no longer close completely. When this develops, the pressure in the veins of the legs increases greatly because of failure of the venous pump; this further increases the sizes of the veins and finally destroys the function of the valves entirely. Thus, the person develops “varicose veins,” which are characterized by large, bulbous protrusions of the veins beneath the skin of the entire leg, particularly the lower leg. Whenever people with varicose veins stand for more than a few minutes, the venous and capillary pressures become very high, and leakage of fluid from the capillaries causes constant edema in the legs. The edema in turn prevents adequate diffusion of nutritional materials from the capillaries to the muscle and skin cells, so that the muscles become painful and weak, and the skin frequently becomes gangrenous and ulcerates. The best treatment for such a condition is Chapter 15 Vascular Distensibility and Functions of the Arterial and Venous Systems continual elevation of the legs to a level at least as high as the heart. Tight binders on the legs also can be of considerable assistance in preventing the edema and its sequelae. Clinical Estimation of Venous Pressure. The venous pressure often can be estimated by simply observing the degree of distention of the peripheral veins—especially of the neck veins. For instance, in the sitting position, the neck veins are never distended in the normal quietly resting person. However, when the right atrial pressure becomes increased to as much as +10 mm Hg, the lower veins of the neck begin to protrude; and at +15 mm Hg atrial pressure essentially all the veins in the neck become distended. Direct Measurement of Venous Pressure and Right Atrial Pressure Venous pressure can also be measured with ease by inserting a needle directly into a vein and connecting it to a pressure recorder. The only means by which right atrial pressure can be measured accurately is by inserting a catheter through the peripheral veins and into the right atrium. Pressures measured through such central venous catheters are used almost routinely in some types of hospitalized cardiac patients to provide constant assessment of heart pumping ability. Pressure Reference Level for Measuring Venous and Other Circulatory Pressures In discussions up to this point, we often have spoken of right atrial pressure as being 0 mm Hg and arterial pressure as being 100 mm Hg, but we have not stated the gravitational level in the circulatory system to which this pressure is referred. There is one point in the circulatory system at which gravitational pressure factors caused by changes in body position of a healthy person usually do not affect the pressure measurement by more than 1 to 2 mm Hg. This is at or near the level of the tricuspid valve, as shown by the crossed axes in Figure 15–12. Therefore, all circulatory pressure measurements discussed in this text are referred to this level, which is called the reference level for pressure measurement. The reason for lack of gravitational effects at the tricuspid valve is that the heart automatically prevents Right ventricle Right atrium Natural reference point Figure 15–12 Reference point for circulatory pressure measurement (located near the tricuspid valve). 179 significant gravitational changes in pressure at this point in the following way: If the pressure at the tricuspid valve rises slightly above normal, the right ventricle fills to a greater extent than usual, causing the heart to pump blood more rapidly and therefore to decrease the pressure at the tricuspid valve back toward the normal mean value. Conversely, if the pressure falls, the right ventricle fails to fill adequately, its pumping decreases, and blood dams up in the venous system until the pressure at the tricuspid level again rises to the normal value. In other words, the heart acts as a feedback regulator of pressure at the tricuspid valve. When a person is lying on his or her back, the tricuspid valve is located at almost exactly 60 per cent of the chest thickness in front of the back. This is the zero pressure reference level for a person lying down. Blood Reservoir Function of the Veins As pointed out in Chapter 14, more than 60 per cent of all the blood in the circulatory system is usually in the veins. For this reason and also because the veins are so compliant, it is said that the venous system serves as a blood reservoir for the circulation. When blood is lost from the body and the arterial pressure begins to fall, nervous signals are elicited from the carotid sinuses and other pressure-sensitive areas of the circulation, as discussed in Chapter 18. These in turn elicit nerve signals from the brain and spinal cord mainly through sympathetic nerves to the veins, causing them to constrict. This takes up much of the slack in the circulatory system caused by the lost blood. Indeed, even after as much as 20 per cent of the total blood volume has been lost, the circulatory system often functions almost normally because of this variable reservoir function of the veins. Specific Blood Reservoirs. Certain portions of the circulatory system are so extensive and/or so compliant that they are called “specific blood reservoirs.” These include (1) the spleen, which sometimes can decrease in size sufficiently to release as much as 100 milliliters of blood into other areas of the circulation; (2) the liver, the sinuses of which can release several hundred milliliters of blood into the remainder of the circulation; (3) the large abdominal veins, which can contribute as much as 300 milliliters; and (4) the venous plexus beneath the skin, which also can contribute several hundred milliliters. The heart and the lungs, although not parts of the systemic venous reservoir system, must also be considered blood reservoirs. The heart, for instance, shrinks during sympathetic stimulation and in this way can contribute some 50 to 100 milliliters of blood; the lungs can contribute another 100 to 200 milliliters when the pulmonary pressures decrease to low values. The Spleen as a Reservoir for Storing Red Blood Cells. Figure 15–13 shows that the spleen has two separate areas for storing blood: the venous sinuses and the pulp. The sinuses can swell the same as any other part of the venous system and store whole blood. 180 Unit IV The Circulation Pulp Capillaries lined with similar cells. These cells function as part of a cleansing system for the blood, acting in concert with a similar system of reticuloendothelial cells in the venous sinuses of the liver. When the blood is invaded by infectious agents, the reticuloendothelial cells of the spleen rapidly remove debris, bacteria, parasites, and so forth. Also, in many chronic infectious processes, the spleen enlarges in the same manner that lymph nodes enlarge and then performs its cleansing function even more avidly. Venous sinuses Vein Artery Figure 15–13 Functional structures of the spleen. (Courtesy of Dr. Don W. Fawcett, Montana.) In the splenic pulp, the capillaries are so permeable that whole blood, including the red blood cells, oozes through the capillary walls into a trabecular mesh, forming the red pulp. The red cells are trapped by the trabeculae, while the plasma flows on into the venous sinuses and then into the general circulation. As a consequence, the red pulp of the spleen is a special reservoir that contains large quantities of concentrated red blood cells. These can then be expelled into the general circulation whenever the sympathetic nervous system becomes excited and causes the spleen and its vessels to contract. As much as 50 milliliters of concentrated red blood cells can be released into the circulation, raising the hematocrit 1 to 2 per cent. In other areas of the splenic pulp are islands of white blood cells, which collectively are called the white pulp. Here lymphoid cells are manufactured similar to those manufactured in the lymph nodes. They are part of the body’s immune system, described in Chapter 34. Blood-Cleansing Function of the Spleen—Removal of Old Cells Blood cells passing through the splenic pulp before entering the sinuses undergo thorough squeezing. Therefore, it is to be expected that fragile red blood cells would not withstand the trauma. For this reason, many of the red blood cells destroyed in the body have their final demise in the spleen. After the cells rupture, the released hemoglobin and the cell stroma are digested by the reticuloendothelial cells of the spleen, and the products of digestion are mainly reused by the body as nutrients, often for making new blood cells. Reticuloendothelial Cells of the Spleen The pulp of the spleen contains many large phagocytic reticuloendothelial cells, and the venous sinuses are References Badeer HS: Hemodynamics for medical students. Am J Physiol (Adv Physiol Educ) 25:44, 2001. Benetos A, Waeber B, Izzo J, Mitchell G, et al: Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications. Am J Hypertens 15:1101, 2002. Gimbrone MA Jr, Topper JN, Nagel T, et al: Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci 902:230, 2000. Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Saunders Co, 1980. Guyton AC, Jones CE: Central venous pressure: physiological significance and clinical implications. Am Heart J 86: 431, 1973. Guyton AC, Jones CE, Coleman TG: Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: WB Saunders Co, 1973. Hall J: Integration and regulation of cardiovascular function. Am J Physiol (Adv Physiol Educ) 22:s174, 1999. Hicks JW, Badeer HS: Gravity and the circulation: “open” vs. “closed” systems. Am J Physiol 262:R725-R732, 1992. Jones DW, Appel LJ, Sheps SG, et al: Measuring blood pressure accurately: New and persistent challenges. JAMA 289:1027, 2003. Lakatta EG, Levy D: Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. Part I: Aging arteries: a “set up” for vascular disease. Circulation 107:139, 2003. McAlister FA, Straus SE: Evidence based treatment of hypertension. Measurement of blood pressure: an evidence based review. BMJ 322:908, 2001. O’Brien E, Asmar R, Beilin L, et al: European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens 21:821, 2003. Perloff D, Grim C, Flack J, et al: Human blood pressure determination by sphygmomanometry. Circulation 88:2460, 1993. Rothe CF, Gersting JM: Cardiovascular interactions: an interactive tutorial and mathematical model. Am J Physiol (Adv Physiol Educ) 26:98, 2002. Safar ME, Levy BI, Struijker-Boudier H: Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 107:2864, 2003. Verdecchia P, Angeli F, Gattobigio R: Clinical usefulness of ambulatory blood pressure monitoring. J Am Soc Nephrol 15(Suppl 1):S30, 2004. C H A P T E R 1 6 The Microcirculation and the Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow The most purposeful function of the circulation occurs in the microcirculation: this is transport of nutrients to the tissues and removal of cell excreta. The small arterioles control blood flow to each tissue area, and local conditions in the tissues in turn control the diameters of the arterioles. Thus, each tissue, in most instances, controls its own blood flow in relation to its individual needs, a subject that is discussed in detail in Chapter 17. The walls of the capillaries are extremely thin, constructed of single-layer, highly permeable endothelial cells. Therefore, water, cell nutrients, and cell excreta can all interchange quickly and easily between the tissues and the circulating blood. The peripheral circulation of the whole body has about 10 billion capillaries with a total surface area estimated to be 500 to 700 square meters (about oneeighth the surface area of a football field). Indeed, it is rare that any single functional cell of the body is more than 20 to 30 micrometers away from a capillary. Structure of the Microcirculation and Capillary System The microcirculation of each organ is organized specifically to serve that organ’s needs. In general, each nutrient artery entering an organ branches six to eight times before the arteries become small enough to be called arterioles, which generally have internal diameters of only 10 to 15 micrometers. Then the arterioles themselves branch two to five times, reaching diameters of 5 to 9 micrometers at their ends where they supply blood to the capillaries. The arterioles are highly muscular, and their diameters can change manyfold. The metarterioles (the terminal arterioles) do not have a continuous muscular coat, but smooth muscle fibers encircle the vessel at intermittent points, as shown in Figure 16–1 by the black dots on the sides of the metarteriole. At the point where each true capillary originates from a metarteriole, a smooth muscle fiber usually encircles the capillary. This is called the precapillary sphincter. This sphincter can open and close the entrance to the capillary. The venules are larger than the arterioles and have a much weaker muscular coat. Yet it must be remembered that the pressure in the venules is much less than that in the arterioles, so that the venules still can contract considerably despite the weak muscle. This typical arrangement of the capillary bed is not found in all parts of the body; however, some similar arrangement serves the same purposes. Most important, the metarterioles and the precapillary sphincters are in close contact with the tissues they serve. Therefore, the local conditions of the tissues—the concentrations of nutrients, end products of metabolism, hydrogen ions, and so forth—can cause direct effects on the vessels in controlling local blood flow in each small tissue area. Structure of the Capillary Wall. Figure 16–2 shows the ultramicroscopic structure of typical endothelial cells in the capillary wall as found in most organs of the body, especially in muscles and connective tissue. Note that the wall is composed of 181 182 Unit IV Metarteriole Arteriole The Circulation Preferential channel Precapillary sphincter True capillaries Venule Figure 16–1 Structure of the mesenteric capillary bed. (Redrawn from Zweifach BW: Factors Regulating Blood Pressure. New York: Josiah Macy, Jr., Foundation, 1950.) Endothelial cell Vesicular channel?? Plasmalemmal vesicles Intercellular cleft Basement membrane Figure 16–2 Structure of the capillary wall. Note especially the intercellular cleft at the junction between adjacent endothelial cells; it is believed that most water-soluble substances diffuse through the capillary membrane along the clefts. a unicellular layer of endothelial cells and is surrounded by a very thin basement membrane on the outside of the capillary. The total thickness of the capillary wall is only about 0.5 micrometer. The internal diameter of the capillary is 4 to 9 micrometers, barely large enough for red blood cells and other blood cells to squeeze through. “Pores” in the Capillary Membrane. Studying Figure 16–2, one sees two very small passageways connecting the interior of the capillary with the exterior. One of these is an intercellular cleft, which is the thin-slit, curving channel that lies at the bottom of the figure between adjacent endothelial cells. Each cleft is interrupted periodically by short ridges of protein attachments that hold the endothelial cells together, but between these ridges fluid can percolate freely through the cleft. The cleft normally has a uniform spacing with a width of about 6 to 7 nanometers (60 to 70 angstroms), slightly smaller than the diameter of an albumin protein molecule. Because the intercellular clefts are located only at the edges of the endothelial cells, they usually represent no more than 1/1000 of the total surface area of the capillary wall. Nevertheless, the rate of thermal motion of water molecules as well as most watersoluble ions and small solutes is so rapid that all of these diffuse with ease between the interior and exterior of the capillaries through these “slit-pores,” the intercellular clefts. Also present in the endothelial cells are many minute plasmalemmal vesicles. These form at one surface of the cell by imbibing small packets of plasma or extracellular fluid. They can then move slowly through the endothelial cell. It also has been postulated that some of these vesicles coalesce to form vesicular channels all the way through the endothelial cell, which is demonstrated to the right in Figure 16–2. However, careful measurements in laboratory animals probably have proved that these vesicular forms of transport are quantitatively of little importance. Special Types of “Pores” Occur in the Capillaries of Certain Organs. The “pores” in the capillaries of some organs have special characteristics to meet the peculiar needs of the organs. Some of these characteristics are as follows: 1. In the brain, the junctions between the capillary endothelial cells are mainly “tight” junctions that allow only extremely small molecules such as water, oxygen, and carbon dioxide to pass into or out of the brain tissues. 2. In the liver, the opposite is true. The clefts between the capillary endothelial cells are wide open, so that almost all dissolved substances of the plasma, including the plasma proteins, can pass from the blood into the liver tissues. 3. The pores of the gastrointestinal capillary membranes are midway between those of the muscles and those of the liver. 4. In the glomerular tufts of the kidney, numerous small oval windows called fenestrae penetrate all the way through the middle of the endothelial cells, so that tremendous amounts of very small molecular and ionic substances (but not the large molecules of the plasma proteins) can filter through the glomeruli without having to pass through the clefts between the endothelial cells. Flow of Blood in the Capillaries—Vasomotion Blood usually does not flow continuously through the capillaries. Instead, it flows intermittently, turning on and off every few seconds or minutes. The cause of this intermittency is the phenomenon called vasomotion, which means intermittent contraction of the metarterioles and precapillary sphincters (and sometimes even the very small arterioles as well). Regulation of Vasomotion. The most important factor found thus far to affect the degree of opening and closing of the metarterioles and precapillary sphincters is the concentration of oxygen in the tissues. When Chapter 16 183 The Microcirculation and the Lymphatic System the rate of oxygen usage by the tissue is great so that tissue oxygen concentration decreases below normal, the intermittent periods of capillary blood flow occur more often, and the duration of each period of flow lasts longer, thereby allowing the capillary blood to carry increased quantities of oxygen (as well as other nutrients) to the tissues. This effect, along with multiple other factors that control local tissue blood flow, is discussed in Chapter 17. Arterial end Blood capillary Venous end Average Function of the Capillary System Despite the fact that blood flow through each capillary is intermittent, so many capillaries are present in the tissues that their overall function becomes averaged. That is, there is an average rate of blood flow through each tissue capillary bed, an average capillary pressure within the capillaries, and an average rate of transfer of substances between the blood of the capillaries and the surrounding interstitial fluid. In the remainder of this chapter, we will be concerned with these averages, although one must remember that the average functions are, in reality, the functions of literally billions of individual capillaries, each operating intermittently in response to local conditions in the tissues. Exchange of Water, Nutrients, and Other Substances Between the Blood and Interstitial Fluid Diffusion Through the Capillary Membrane By far the most important means by which substances are transferred between the plasma and the interstitial fluid is diffusion. Figure 16–3 demonstrates this process, showing that as the blood flows along the lumen of the capillary, tremendous numbers of water molecules and dissolved particles diffuse back and forth through the capillary wall, providing continual mixing between the interstitial fluid and the plasma. Diffusion results from thermal motion of the water molecules and dissolved substances in the fluid, the different molecules and ions moving first in one direction and then another, bouncing randomly in every direction. Lipid-Soluble Substances Can Diffuse Directly Through the Cell Membranes of the Capillary Endothelium. If a substance is lipid soluble, it can diffuse directly through the cell membranes of the capillary without having to go through the pores. Such substances include oxygen and carbon dioxide. Because these substances can permeate all areas of the capillary membrane, their rates of transport through the capillary membrane are many times faster than the rates for lipid-insoluble Lymphatic capillary Figure 16–3 Diffusion of fluid molecules and dissolved substances between the capillary and interstitial fluid spaces. substances, such as sodium ions and glucose that can go only through the pores. Water-Soluble, Non-Lipid-Soluble Substances Diffuse Only Through Intercellular “Pores” in the Capillary Membrane. Many substances needed by the tissues are soluble in water but cannot pass through the lipid membranes of the endothelial cells; such substances include water molecules themselves, sodium ions, chloride ions, and glucose. Despite the fact that not more than 1/1000 of the surface area of the capillaries is represented by the intercellular clefts between the endothelial cells, the velocity of thermal molecular motion in the clefts is so great that even this small area is sufficient to allow tremendous diffusion of water and water-soluble substances through these cleft-pores. To give one an idea of the rapidity with which these substances diffuse, the rate at which water molecules diffuse through the capillary membrane is about 80 times as great as the rate at which plasma itself flows linearly along the capillary. That is, the water of the plasma is exchanged with the water of the interstitial fluid 80 times before the plasma can flow the entire distance through the capillary. Effect of Molecular Size on Passage Through the Pores. The width of the capillary intercellular cleft- pores, 6 to 7 nanometers, is about 20 times the diameter of the water molecule, which is the smallest molecule that normally passes through the capillary pores. Conversely, the diameters of plasma protein molecules are slightly greater than the width of the pores. Other substances, such as sodium ions, chloride ions, glucose, and urea, have intermediate diameters. Therefore, the permeability of the capillary pores for 184 Unit IV The Circulation Table 16–1 Relative Permeability of Skeletal Muscle Capillary Pores to Different-Sized Molecules Substance Water NaCl Urea Glucose Sucrose Inulin Myoglobin Hemoglobin Albumin Molecular Weight Permeability 18 58.5 60 180 342 5,000 17,600 68,000 69,000 1.00 0.96 0.8 0.6 0.4 0.2 0.03 0.01 0.001 Free fluid vesicles Rivulets of free fluid Data from Pappenheimer JR: Passage of molecules through capillary walls. Physiol Rev 33:387, 1953. Capillary different substances varies according to their molecular diameters. Table 16–1 gives the relative permeabilities of the capillary pores in skeletal muscle for substances commonly encountered, demonstrating, for instance, that the permeability for glucose molecules is 0.6 times that for water molecules, whereas the permeability for albumin molecules is very, very slight, only 1/1000 that for water molecules. A word of caution must be issued at this point. The capillaries in different tissues have extreme differences in their permeabilities. For instance, the membrane of the liver capillary sinusoids is so permeable that even plasma proteins pass freely through these walls, almost as easily as water and other substances. Also, the permeability of the renal glomerular membrane for water and electrolytes is about 500 times the permeability of the muscle capillaries, but this is not true for the plasma proteins; for these, the capillary permeabilities are very slight, as in other tissues and organs. When we study these different organs later in this text, it should become clear why some tissues—the liver, for instance—require greater degrees of capillary permeability than others to transfer tremendous amounts of nutrients between the blood and liver parenchymal cells, and the kidneys to allow filtration of large quantities of fluid for formation of urine. Effect of Concentration Difference on Net Rate of Diffusion Through the Capillary Membrane. The “net” rate of diffu- sion of a substance through any membrane is proportional to the concentration difference of the substance between the two sides of the membrane. That is, the greater the difference between the concentrations of any given substance on the two sides of the capillary membrane, the greater the net movement of the substance in one direction through the membrane. For instance, the concentration of oxygen in capillary blood is normally greater than in the interstitial fluid. Therefore, large quantities of oxygen normally move from the blood toward the tissues. Conversely, the concentration of carbon dioxide is greater in the tissues than in the blood, which causes excess carbon dioxide Collagen fiber bundles Proteoglycan filaments Figure 16–4 Structure of the interstitium. Proteoglycan filaments are everywhere in the spaces between the collagen fiber bundles. Free fluid vesicles and small amounts of free fluid in the form of rivulets occasionally also occur. to move into the blood and to be carried away from the tissues. The rates of diffusion through the capillary membranes of most nutritionally important substances are so great that only slight concentration differences suffice to cause more than adequate transport between the plasma and interstitial fluid. For instance, the concentration of oxygen in the interstitial fluid immediately outside the capillary is no more than a few per cent less than its concentration in the plasma of the blood, yet this slight difference causes enough oxygen to move from the blood into the interstitial spaces to provide all the oxygen required for tissue metabolism, often as much as several liters of oxygen per minute during very active states of the body. The Interstitium and Interstitial Fluid About one sixth of the total volume of the body consists of spaces between cells, which collectively are called the interstitium. The fluid in these spaces is the interstitial fluid. The structure of the interstitium is shown in Figure 16–4. It contains two major types of solid structures: (1) collagen fiber bundles and (2) proteoglycan filaments. The collagen fiber bundles extend long distances in the interstitium. They are extremely strong and therefore provide most of the tensional strength of the tissues. The proteoglycan filaments, however, are extremely thin coiled or twisted molecules composed of about 98 per cent hyaluronic acid and 2 per cent protein. These molecules are so thin that they can never be seen with a light microscope and are difficult Chapter 16 185 The Microcirculation and the Lymphatic System to demonstrate even with the electron microscope. Nevertheless, they form a mat of very fine reticular filaments aptly described as a “brush pile.” Capillary pressure Plasma colloid osmotic pressure (Pc) (Pp) Interstitial fluid pressure Interstitial fluid colloid osmotic pressure (Pif) (Pif) “Gel” in the Interstitium. The fluid in the interstitium is derived by filtration and diffusion from the capillaries. It contains almost the same constituents as plasma except for much lower concentrations of proteins because proteins do not pass outward through the pores of the capillaries with ease. The interstitial fluid is entrapped mainly in the minute spaces among the proteoglycan filaments. This combination of proteoglycan filaments and fluid entrapped within them has the characteristics of a gel and therefore is called tissue gel. Because of the large number of proteoglycan filaments, it is difficult for fluid to flow easily through the tissue gel. Instead, it mainly diffuses through the gel; that is, it moves molecule by molecule from one place to another by kinetic, thermal motion rather than by large numbers of molecules moving together. Diffusion through the gel occurs about 95 to 99 per cent as rapidly as it does through free fluid. For the short distances between the capillaries and the tissue cells, this diffusion allows rapid transport through the interstitium not only of water molecules but also of electrolytes, small molecular weight nutrients, cellular excreta, oxygen, carbon dioxide, and so forth. “Free” Fluid in the Interstitium. Although almost all the fluid in the interstitium normally is entrapped within the tissue gel, occasionally small rivulets of “free” fluid and small free fluid vesicles are also present, which means fluid that is free of the proteoglycan molecules and therefore can flow freely. When a dye is injected into the circulating blood, it often can be seen to flow through the interstitium in the small rivulets, usually coursing along the surfaces of collagen fibers or surfaces of cells. The amount of “free” fluid present in normal tissues is slight, usually much less than 1 per cent. Conversely, when the tissues develop edema, these small pockets and rivulets of free fluid expand tremendously until one half or more of the edema fluid becomes freely flowing fluid independent of the proteoglycan filaments. Fluid Filtration Across Capillaries Is Determined by Hydrostatic and Colloid Osmotic Pressures, and Capillary Filtration Coefficient The hydrostatic pressure in the capillaries tends to force fluid and its dissolved substances through the capillary pores into the interstitial spaces. Conversely, osmotic pressure caused by the plasma proteins (called colloid osmotic pressure) tends to cause fluid movement by osmosis from the interstitial spaces into the blood. This osmotic pressure exerted by the plasma proteins normally prevents significant loss Figure 16–5 Fluid pressure and colloid osmotic pressure forces operate at the capillary membrane, tending to move fluid either outward or inward through the membrane pores. of fluid volume from the blood into the interstitial spaces. Also important is the lymphatic system, which returns to the circulation the small amounts of excess protein and fluid that leak from the blood into the interstitial spaces. In the remainder of this chapter, we discuss the mechanisms that control capillary filtration and lymph flow function together to regulate the respective volumes of the plasma and the interstitial fluid. Four Primary Hydrostatic and Colloid Osmotic Forces Determine Fluid Movement Through the Capillary Membrane. Figure 16–5 shows the four primary forces that determine whether fluid will move out of the blood into the interstitial fluid or in the opposite direction. These forces, called “Starling forces” in honor of the physiologist who first demonstrated their importance, are: 1. The capillary pressure (Pc), which tends to force fluid outward through the capillary membrane. 2. The interstitial fluid pressure (Pif), which tends to force fluid inward through the capillary membrane when Pif is positive but outward when Pif is negative. 3. The capillary plasma colloid osmotic pressure (Pp), which tends to cause osmosis of fluid inward through the capillary membrane. 4. The interstitial fluid colloid osmotic pressure (Pif), which tends to cause osmosis of fluid outward through the capillary membrane. If the sum of these forces, the net filtration pressure, is positive, there will be a net fluid filtration across the capillaries. If the sum of the Starling forces is negative, there will be a net fluid absorption from the interstitial spaces into the capillaries. The net filtration pressure (NFP) is calculated as: NFP = Pc - Pif - Pp + Pif As discussed later, the NFP is slightly positive under normal conditions, resulting in a net filtration of fluid across the capillaries into the interstitial space in most organs. The rate of fluid filtration in a tissue is also determined by the number and size of the pores in each capillary as well as the number of capillaries in 186 Unit IV The Circulation which blood is flowing. These factors are usually expressed together as the capillary filtration coefficient (Kf). The Kf is therefore a measure of the capacity of the capillary membranes to filter water for a given NFP and is usually expressed as ml/min per mm Hg net filtration pressure. The rate of capillary fluid filtration is therefore determined as: Filtration = K f ¥ NFP In the following sections we discuss in detail each of the forces that determine the rate of capillary fluid filtration. Gut Arterial pressure Capillary Hydrostatic Pressure Micropipette Method for Measuring Capillary Pressure. To measure pressure in a capillary by cannulation, a microscopic glass pipette is thrust directly into the capillary, and the pressure is measured by an appropriate micromanometer system. Using this method, capillary pressures have been measured in capillaries of exposed tissues of animals and in large capillary loops of the eponychium at the base of the fingernail in humans. These measurements have given pressures of 30 to 40 mm Hg in the arterial ends of the capillaries, 10 to 15 mm Hg in the venous ends, and about 25 mm Hg in the middle. Isogravimetric Method for Indirectly Measuring “Functional” Capillary Pressure. Figure 16–6 demonstrates an iso- gravimetric method for indirectly estimating capillary pressure. This figure shows a section of gut held up by one arm of a gravimetric balance. Blood is perfused through the blood vessels of the gut wall. When the arterial pressure is decreased, the resulting decrease in capillary pressure allows the osmotic pressure of the plasma proteins to cause absorption of fluid out of the gut wall and makes the weight of the gut decrease. This immediately causes displacement of the balance arm. To prevent this weight decrease, the venous pressure is increased an amount sufficient to overcome the effect of decreasing the arterial pressure. In other words, the capillary pressure is kept constant while simultaneously (1) decreasing the arterial pressure and (2) increasing the venous pressure. In the graph in the lower part of the figure, the changes in arterial and venous pressures that exactly nullify all weight changes are shown. The arterial and venous lines meet each other at a value of 17 mm Hg. Therefore, the capillary pressure must have remained at this same level of 17 mm Hg throughout these maneuvers; otherwise, either filtration or absorption of 100 80 Pressure Two experimental methods have been used to estimate the capillary hydrostatic pressure: (1) direct micropipette cannulation of the capillaries, which has given an average mean capillary pressure of about 25 mm Hg, and (2) indirect functional measurement of the capillary pressure, which has given a capillary pressure averaging about 17 mm Hg. Venous pressure Ar 60 ter ial 40 Capillary pressure = 17 mm Hg 20 s Venou 0 100 Arterial pressure 50 – venous pressure 0 Figure 16–6 Isogravimetric method for measuring capillary pressure. fluid through the capillary walls would have occurred. Thus, in a roundabout way, the “functional” capillary pressure is measured to be about 17 mm Hg. Why Is the Functional Capillary Pressure Lower than Capillary Pressure Measured by the Micropipette Method? It is clear that the aforementioned two methods do not give the same capillary pressure. However, the isogravimetric method determines the capillary pressure that exactly balances all the forces tending to move fluid into or out of the capillaries. Because such a balance of forces is the normal state, the average functional capillary pressure must be close to the pressure measured by the isogravimetric method. Therefore, one is justified in believing that the true functional capillary pressure averages about 17 mm Hg. It is easy to explain why the cannulation methods give higher pressure values. The most important reason is that these measurements usually are made in capillaries whose arterial ends are open and when Chapter 16 The Microcirculation and the Lymphatic System blood is actively flowing into the capillary. However, it should be recalled from the earlier discussion of capillary vasomotion that the metarterioles and precapillary sphincters normally are closed during a large part of the vasomotion cycle. When closed, the pressure in the capillaries beyond the closures should be almost equal to the pressure at the venous ends of the capillaries, about 10 mm Hg. Therefore, when averaged over a period of time, one would expect the functional mean capillary pressure to be much nearer to the pressure in the venous ends of the capillaries than to the pressure in the arterial ends. There are two other reasons why the functional capillary pressure is less than the values measured by cannulation. First, there are far more capillaries nearer to the venules than to the arterioles. Second, the venous capillaries are several times as permeable as the arterial capillaries. Both of these effects further decrease the functional capillary pressure to a lower value. Interstitial Fluid Hydrostatic Pressure As is true for the measurement of capillary pressure, there are several methods for measuring interstitial fluid pressure, and each of these gives slightly different values but usually values that are a few millimeters of mercury less than atmospheric pressure, that is, values called negative interstitial fluid pressure. The methods most widely used have been (1) direct cannulation of the tissues with a micropipette, (2) measurement of the pressure from implanted perforated capsules, and (3) measurement of the pressure from a cotton wick inserted into the tissue. Measurement of Interstitial Fluid Pressure Using the Micropipette. The same type of micropipette used for measuring capillary pressure can also be used in some tissues for measuring interstitial fluid pressure. The tip of the micropipette is about 1 micrometer in diameter, but even this is 20 or more times larger than the sizes of the spaces between the proteoglycan filaments of the interstitium. Therefore, the pressure that is measured is probably the pressure in a free fluid pocket. The first pressures measured using the micropipette method ranged from -1 to +2 mm Hg but were usually slightly positive. With experience and improved equipment for making such measurements, more recent pressures have averaged about -2 mm Hg, giving average pressure values in loose tissues, such as skin, that are slightly less than atmospheric pressure. Measurement of Interstitial Free Fluid Pressure in Implanted Perforated Hollow Capsules. Interstitial free fluid pressure measured by this method when using 2-centimeter diameter capsules in normal loose subcutaneous tissue averages about -6 mm Hg, but with smaller capsules, the values are not greatly different from the -2 mm Hg measured by the micropipette in Figure 16-7. Measurement of Interstitial Free Fluid Pressure by Means of a Cotton Wick. Still another method is to insert into a tissue a small Teflon tube with about eight cotton fibers 187 protruding from its end. The cotton fibers form a “wick” that makes excellent contact with the tissue fluids and transmits interstitial fluid pressure into the Teflon tube: the pressure can then be measured from the tube by usual manometric means. Pressures measured by this technique in loose subcutaneous tissue also have been negative, usually measuring -1 to -3 mm Hg. Interstitial Fluid Pressures in Tightly Encased Tissues Some tissues of the body are surrounded by tight encasements, such as the cranial vault around the brain, the strong fibrous capsule around the kidney, the fibrous sheaths around the muscles, and the sclera around the eye. In most of these, regardless of the method used for measurement, the interstitial fluid pressures are usually positive. However, these interstitial fluid pressures almost invariably are still less than the pressures exerted on the outsides of the tissues by their encasements. For instance, the cerebrospinal fluid pressure surrounding the brain of an animal lying on its side averages about +10 mm Hg, whereas the brain interstitial fluid pressure averages about +4 to +6 mm Hg. In the kidneys, the capsular pressure surrounding the kidney averages about +13 mm Hg, whereas the reported renal interstitial fluid pressures have averaged about +6 mm Hg. Thus, if one remembers that the pressure exerted on the skin is atmospheric pressure, which is considered to be zero pressure, one might formulate a general rule that the normal interstitial fluid pressure is usually several millimeters of mercury negative with respect to the pressure that surrounds each tissue. Is the True Interstitial Fluid Pressure in Loose Subcutaneous Tissue Subatmospheric? The concept that the interstitial fluid pressure is subatmospheric in many if not most tissues of the body began with clinical observations that could not be explained by the previously held concept that interstitial fluid pressure was always positive. Some of the pertinent observations are the following: 1. When a skin graft is placed on a concave surface of the body, such as in an eye socket after removal of the eye, before the skin becomes attached to the sublying socket, fluid tends to collect underneath the graft. Also, the skin attempts to shorten, with the result that it tends to pull it away from the concavity. Nevertheless, some negative force underneath the skin causes absorption of the fluid and usually literally pulls the skin back into the concavity. 2. Less than 1 mm Hg of positive pressure is required to inject tremendous volumes of fluid into loose subcutaneous tissues, such as beneath the lower eyelid, in the axillary space, and in the scrotum. Amounts of fluid calculated to be more than 100 times the amount of fluid normally in the interstitial space, when injected into these areas, cause no more than about 2 mm Hg of positive pressure. The importance of these observations is that they show that such tissues do not have 188 Unit IV The Circulation strong fibers that can prevent the accumulation of fluid. Therefore, some other mechanism, such as a negative fluid pressure system, must be available to prevent such fluid accumulation. 3. In most natural cavities of the body where there is free fluid in dynamic equilibrium with the surrounding interstitial fluids, the pressures that have been measured have been negative. Some of these are the following: Intrapleural space: -8 mm Hg Joint synovial spaces: -4 to -6 mm Hg Epidural space: -4 to -6 mm Hg 4. The implanted capsule for measuring the interstitial fluid pressure can be used to record dynamic changes in this pressure. The changes are approximately those that one would calculate to occur (1) when the arterial pressure is increased or decreased, (2) when fluid is injected into the surrounding tissue space, or (3) when a highly concentrated colloid osmotic agent is injected into the blood to absorb fluid from the tissue spaces. It is not likely that these dynamic changes could be recorded this accurately unless the capsule pressure closely approximated the true interstitial pressure. Summary—An Average Value for Negative Interstitial Fluid Pressure in Loose Subcutaneous Tissue. Although the aforementioned different methods give slightly different values for interstitial fluid pressure, there currently is a general belief among most physiologists that the true interstitial fluid pressure in loose subcutaneous tissue is slightly less subatmospheric, averaging about -3 mm Hg. Pumping by the Lymphatic System Is the Basic Cause of the Negative Interstitial Fluid Pressure The lymphatic system is discussed later in the chapter, but we need to understand here the basic role that this system plays in determining interstitial fluid pressure. The lymphatic system is a “scavenger” system that removes excess fluid, excess protein molecules, debris, and other matter from the tissue spaces. Normally, when fluid enters the terminal lymphatic capillaries, the lymph vessel walls automatically contract for a few seconds and pump the fluid into the blood circulation. This overall process creates the slight negative pressure that has been measured for fluid in the interstitial spaces. through the capillary pores, it is the proteins of the plasma and interstitial fluids that are responsible for the osmotic pressures on the two sides of the capillary membrane. To distinguish this osmotic pressure from that which occurs at the cell membrane, it is called either colloid osmotic pressure or oncotic pressure. The term “colloid” osmotic pressure is derived from the fact that a protein solution resembles a colloidal solution despite the fact that it is actually a true molecular solution. Normal Values for Plasma Colloid Osmotic Pressure. The colloid osmotic pressure of normal human plasma averages about 28 mm Hg; 19 mm of this is caused by molecular effects of the dissolved protein and 9 mm by the Donnan effect—that is, extra osmotic pressure caused by sodium, potassium, and the other cations held in the plasma by the proteins. Effect of the Different Plasma Proteins on Colloid Osmotic Pressure. The plasma proteins are a mixture that con- tains albumin, with an average molecular weight of 69,000; globulins, 140,000; and fibrinogen, 400,000. Thus, 1 gram of globulin contains only half as many molecules as 1 gram of albumin, and 1 gram of fibrinogen contains only one sixth as many molecules as 1 gram of albumin. It should be recalled from the discussion of osmotic pressure in Chapter 4 that osmotic pressure is determined by the number of molecules dissolved in a fluid rather than by the mass of these molecules. Therefore, when corrected for number of molecules rather than mass, the following chart gives both the relative mass concentrations (g/dl) of the different types of proteins in normal plasma and their respective contributions to the total plasma colloid osmotic pressure (Pp). Albumin Globulins Fibrinogen Total g/dl Pp (mm Hg) 4.5 2.5 0.3 7.3 21.8 6.0 0.2 28.0 Thus, about 80 per cent of the total colloid osmotic pressure of the plasma results from the albumin fraction, 20 per cent from the globulins, and almost none from the fibrinogen. Therefore, from the point of view of capillary and tissue fluid dynamics, it is mainly albumin that is important. Interstitial Fluid Colloid Osmotic Pressure Plasma Colloid Osmotic Pressure Proteins in the Plasma Cause Colloid Osmotic Pressure. In the basic discussion of osmotic pressure in Chapter 4, it was pointed out that only those molecules or ions that fail to pass through the pores of a semipermeable membrane exert osmotic pressure. Because the proteins are the only dissolved constituents in the plasma and interstitial fluids that do not readily pass Although the size of the usual capillary pore is smaller than the molecular sizes of the plasma proteins, this is not true of all the pores. Therefore, small amounts of plasma proteins do leak through the pores into the interstitial spaces. The total quantity of protein in the entire 12 liters of interstitial fluid of the body is slightly greater than the total quantity of protein in the plasma itself, but Chapter 16 The Microcirculation and the Lymphatic System because this volume is four times the volume of plasma, the average protein concentration of the interstitial fluid is usually only 40 per cent of that in plasma, or about 3 g/dl. Quantitatively, one finds that the average interstitial fluid colloid osmotic pressure for this concentration of proteins is about 8 mm Hg. Exchange of Fluid Volume Through the Capillary Membrane Now that the different factors affecting fluid movement through the capillary membrane have been discussed, it is possible to put all these together to see how the capillary system maintains normal fluid volume distribution between the plasma and the interstitial fluid. The average capillary pressure at the arterial ends of the capillaries is 15 to 25 mm Hg greater than at the venous ends. Because of this difference, fluid “filters” out of the capillaries at their arterial ends, but at their venous ends fluid is reabsorbed back into the capillaries. Thus, a small amount of fluid actually “flows” through the tissues from the arterial ends of the capillaries to the venous ends. The dynamics of this flow are as follows. Analysis of the Forces Causing Filtration at the Arterial End of the Capillary. The approximate average forces operative at the arterial end of the capillary that cause movement through the capillary membrane are shown as follows: 189 mm Hg Forces tending to move fluid inward: Plasma colloid osmotic pressure total inward force 28 28 Forces tending to move fluid outward: Capillary pressure (venous end of capillary) Negative interstitial free fluid pressure Interstitial fluid colloid osmotic pressure total outward force 10 3 8 21 Summation of forces: Inward Outward net inward force 28 21 7 Thus, the force that causes fluid to move into the capillary, 28 mm Hg, is greater than that opposing reabsorption, 21 mm Hg. The difference, 7 mm Hg, is the net reabsorption pressure at the venous ends of the capillaries. This reabsorption pressure is considerably less than the filtration pressure at the capillary arterial ends, but remember that the venous capillaries are more numerous and more permeable than the arterial capillaries, so that less reabsorption pressure is required to cause inward movement of fluid. The reabsorption pressure causes about nine tenths of the fluid that has filtered out of the arterial ends of the capillaries to be reabsorbed at the venous ends. The remaining one tenth flows into the lymph vessels and returns to the circulating blood. Starling Equilibrium for Capillary Exchange mm Hg Forces tending to move fluid outward: Capillary pressure (arterial end of capillary) Negative interstitial free fluid pressure Interstitial fluid colloid osmotic pressure total outward force 30 3 8 41 Forces tending to move fluid inward: Plasma colloid osmotic pressure total inward force 28 28 Summation of forces: Outward Inward net outward force (at arterial end) 41 28 13 Thus, the summation of forces at the arterial end of the capillary shows a net filtration pressure of 13 mm Hg, tending to move fluid outward through the capillary pores. This 13 mm Hg filtration pressure causes, on the average, about 1/200 of the plasma in the flowing blood to filter out of the arterial ends of the capillaries into the interstitial spaces each time the blood passes through the capillaries. Analysis of Reabsorption at the Venous End of the Capillary. The low blood pressure at the venous end of the capillary changes the balance of forces in favor of absorption as follows: E. H. Starling pointed out over a century ago that under normal conditions, a state of near-equilibrium exists at the capillary membrane. That is, the amount of fluid filtering outward from the arterial ends of capillaries equals almost exactly the fluid returned to the circulation by absorption. The slight disequilibrium that does occur accounts for the small amount of fluid that is eventually returned by way of the lymphatics. The following chart shows the principles of the Starling equilibrium. For this chart, the pressures in the arterial and venous capillaries are averaged to calculate mean functional capillary pressure for the entire length of the capillary. This calculates to be 17.3 mm Hg. mm Hg Mean forces tending to move fluid outward: Mean capillary pressure Negative interstitial free fluid pressure Interstitial fluid colloid osmotic pressure total outward force 17.3 3.0 8.0 28.3 Mean force tending to move fluid inward: Plasma colloid osmotic pressure total inward force 28.0 28.0 Summation of mean forces: Outward Inward net outward force 28.3 28.0 0.3 190 Unit IV The Circulation Thus, for the total capillary circulation, we find a near-equilibrium between the total outward forces, 28.3 mm Hg, and the total inward force, 28.0 mm Hg. This slight imbalance of forces, 0.3 mm Hg, causes slightly more filtration of fluid into the interstitial spaces than reabsorption.This slight excess of filtration is called net filtration, and it is the fluid that must be returned to the circulation through the lymphatics.The normal rate of net filtration in the entire body is only about 2 milliliters per minute. Filtration Coefficient. In the above example, an average net imbalance of forces at the capillary membranes of 0.3 mm Hg causes net fluid filtration in the entire body of 2 ml/min. Expressing this for each millimeter of mercury imbalance, one finds a net filtration rate of 6.67 milliliters of fluid per minute per millimeter of mercury for the entire body. This is called the whole body capillary filtration coefficient. The filtration coefficient can also be expressed for separate parts of the body in terms of rate of filtration per minute per millimeter of mercury per 100 grams of tissue. On this basis, the filtration coefficient of the average tissue is about 0.01 ml/min/mm Hg/100 g of tissue. But, because of extreme differences in permeabilities of the capillary systems in different tissues, this coefficient varies more than 100-fold among the different tissues. It is very small in both brain and muscle, moderately large in subcutaneous tissue, large in the intestine, and extreme in the liver and glomerulus of the kidney where the pores are either numerous or wide open. By the same token, the permeation of proteins through the capillary membranes varies greatly as well. The concentration of protein in the interstitial fluid of muscles is about 1.5 g/dl; in subcutaneous tissue, 2 g/dl; in intestine, 4 g/dl; and in liver, 6 g/dl. Skin To measure pressure Implanted capsule Blood vessels Fluid filled cavity FIGURE 16–7 Perforated capsule method for measuring interstitial fluid pressure. Effect of Abnormal Imbalance of Forces at the Capillary Membrane If the mean capillary pressure rises above 17 mm Hg, the net force tending to cause filtration of fluid into the tissue spaces rises. Thus, a 20 mm Hg rise in mean capillary pressure causes an increase in net filtration pressure from 0.3 mm Hg to 20.3 mm Hg, which results in 68 times as much net filtration of fluid into the interstitial spaces as normally occurs. To prevent accumulation of excess fluid in these spaces would require 68 times the normal flow of fluid into the lymphatic system, an amount that is 2 to 5 times too much for the lymphatics to carry away. As a result, fluid will begin to accumulate in the interstitial spaces, and edema will result. Conversely, if the capillary pressure falls very low, net reabsorption of fluid into the capillaries will occur instead of net filtration, and the blood volume will increase at the expense of the interstitial fluid volume. These effects of imbalance at the capillary membrane in relation to the development of different kinds of edema are discussed in Chapter 25. Lymphatic System The lymphatic system represents an accessory route through which fluid can flow from the interstitial spaces into the blood. Most important, the lymphatics can carry proteins and large particulate matter away from the tissue spaces, neither of which can be removed by absorption directly into the blood capillaries. This return of proteins to the blood from the interstitial spaces is an essential function without which we would die within about 24 hours. Lymph Channels of the Body Almost all tissues of the body have special lymph channels that drain excess fluid directly from the interstitial spaces. The exceptions include the superficial portions of the skin, the central nervous system, the endomysium of muscles, and the bones. But, even these tissues have minute interstitial channels called prelymphatics through which interstitial fluid can flow; this fluid eventually empties either into lymphatic vessels or, in the case of the brain, into the cerebrospinal fluid and then directly back into the blood. Essentially all the lymph vessels from the lower part of the body eventually empty into the thoracic duct, which in turn empties into the blood venous system at the juncture of the left internal jugular vein and left subclavian vein, as shown in Figure 16–8. Lymph from the left side of the head, the left arm, and parts of the chest region also enters the thoracic duct before it empties into the veins. Lymph from the right side of the neck and head, the right arm, and parts of the right thorax enters the right lymph duct (much smaller than the thoracic duct), which empties into the blood venous system at the juncture of the right subclavian vein and internal jugular vein. Terminal Lymphatic Capillaries and Their Permeability. Most of the fluid filtering from the arterial ends of blood Chapter 16 The Microcirculation and the Lymphatic System 191 Cervical nodes Sentinel node Subclavian vein R. lymphatic duct Thoracic duct Axillary nodes Cisterna chyli Abdominal nodes Inguinal nodes Peripheral lymphatics FIGURE 16–8 Lymphatic system. capillaries flows among the cells and finally is reabsorbed back into the venous ends of the blood capillaries; but on the average, about 1/10 of the fluid instead enters the lymphatic capillaries and returns to the blood through the lymphatic system rather than through the venous capillaries. The total quantity of all this lymph is normally only 2 to 3 liters each day. The fluid that returns to the circulation by way of the lymphatics is extremely important because substances of high molecular weight, such as proteins, cannot be absorbed from the tissues in any other way, although they can enter the lymphatic capillaries almost unimpeded. The reason for this is a special structure of the lymphatic capillaries, demonstrated in Figure 16–9. This figure shows the endothelial cells of the lymphatic capillary attached by anchoring filaments to the surrounding connective tissue. At the junctions of adjacent endothelial cells, the edge of one endothelial cell overlaps the edge of the adjacent cell in such a way that the overlapping edge is free to flap inward, thus forming a minute valve that opens to the interior of the lymphatic capillary. Interstitial fluid, along with its suspended particles, can push the valve open and flow directly into the lymphatic capillary. But this fluid has difficulty leaving the capillary once it has entered because any backflow closes the flap valve. Thus, the lymphatics have valves at the very tips of the terminal lymphatic capillaries as well as valves along their larger vessels up to the point where they empty into the blood circulation. Formation of Lymph Lymph is derived from interstitial fluid that flows into the lymphatics. Therefore, lymph as it first enters the terminal lymphatics has almost the same composition as the interstitial fluid. 192 Unit IV The Circulation Endothelial cells Valves Relative lymph flow 4 2 2 times/ mm Hg Anchoring filaments FIGURE 16–9 0 –6 Special structure of the lymphatic capillaries that permits passage of substances of high molecular weight into the lymph. The protein concentration in the interstitial fluid of most tissues averages about 2 g/dl, and the protein concentration of lymph flowing from these tissues is near this value. Conversely, lymph formed in the liver has a protein concentration as high as 6 g/dl, and lymph formed in the intestines has a protein concentration as high as 3 to 4 g/dl. Because about two thirds of all lymph normally is derived from the liver and intestines, the thoracic duct lymph, which is a mixture of lymph from all areas of the body, usually has a protein concentration of 3 to 5 g/dl. The lymphatic system is also one of the major routes for absorption of nutrients from the gastrointestinal tract, especially for absorption of virtually all fats in food, as discussed in Chapter 65. Indeed, after a fatty meal, thoracic duct lymph sometimes contains as much as 1 to 2 per cent fat. Finally, even large particles, such as bacteria, can push their way between the endothelial cells of the lymphatic capillaries and in this way enter the lymph. As the lymph passes through the lymph nodes, these particles are almost entirely removed and destroyed, as discussed in Chapter 33. Rate of Lymph Flow About 100 milliliters per hour of lymph flows through the thoracic duct of a resting human, and approximately another 20 milliliters flows into the circulation each hour through other channels, making a total estimated lymph flow of about 120 ml/hr or 2 to 3 liters per day. Effect of Interstitial Fluid Pressure on Lymph Flow. Figure 16–10 shows the effect of different levels of interstitial fluid pressure on lymph flow as measured in dog legs. Note that normal lymph flow is very little at interstitial fluid pressures more negative than the normal 7 times/ mm Hg –4 –2 0 2 PT (mm Hg) 4 FIGURE 16–10 Relation between interstitial fluid pressure and lymph flow in the leg of a dog. Note that lymph flow reaches a maximum when the interstitial pressure, PT, rises slightly above atmospheric pressure (0 mm Hg). (Courtesy Drs. Harry Gibson and Aubrey Taylor.) value of -6 mm Hg.Then, as the pressure rises to 0 mm Hg (atmospheric pressure), flow increases more than 20-fold. Therefore, any factor that increases interstitial fluid pressure also increases lymph flow if the lymph vessels are functioning normally. Such factors include the following: ∑ Elevated capillary pressure ∑ Decreased plasma colloid osmotic pressure ∑ Increased interstitial fluid colloid osmotic pressure ∑ Increased permeability of the capillaries All of these cause a balance of fluid exchange at the blood capillary membrane to favor fluid movement into the interstitium, thus increasing interstitial fluid volume, interstitial fluid pressure, and lymph flow all at the same time. However, note in Figure 16–10 that when the interstitial fluid pressure becomes 1 or 2 millimeters greater than atmospheric pressure (greater than 0 mm Hg), lymph flow fails to rise any further at still higher pressures. This results from the fact that the increasing tissue pressure not only increases entry of fluid into the lymphatic capillaries but also compresses the outside surfaces of the larger lymphatics, thus impeding lymph flow. At the higher pressures, these two factors balance each other almost exactly, so that lymph flow reaches what is called the “maximum lymph flow rate.” This is illustrated by the upper level plateau in Figure 16–10. Lymphatic Pump Increases Lymph Flow. Valves exist in all lymph channels; typical valves are shown in Figure Chapter 16 193 The Microcirculation and the Lymphatic System Pores Valves Lymphatic capillaries FIGURE 16–11 Collecting lymphatic Structure of lymphatic capillaries and a collecting lymphatic, showing also the lymphatic valves. 16–11 in collecting lymphatics into which the lymphatic capillaries empty. Motion pictures of exposed lymph vessels, both in animals and in human beings, show that when a collecting lymphatic or larger lymph vessel becomes stretched with fluid, the smooth muscle in the wall of the vessel automatically contracts. Furthermore, each segment of the lymph vessel between successive valves functions as a separate automatic pump. That is, even slight filling of a segment causes it to contract, and the fluid is pumped through the next valve into the next lymphatic segment. This fills the subsequent segment, and a few seconds later it, too, contracts, the process continuing all along the lymph vessel until the fluid is finally emptied into the blood circulation. In a very large lymph vessel such as the thoracic duct, this lymphatic pump can generate pressures as great as 50 to 100 mm Hg. through the junctions between the endothelial cells. Then, when the tissue is compressed, the pressure inside the capillary increases and causes the overlapping edges of the endothelial cells to close like valves. Therefore, the pressure pushes the lymph forward into the collecting lymphatic instead of backward through the cell junctions. The lymphatic capillary endothelial cells also contain a few contractile actomyosin filaments. In some animal tissues (e.g., the bat’s wing) these filaments have been observed to cause rhythmical contraction of the lymphatic capillaries in the same way that many of the small blood and larger lymphatic vessels also contract rhythmically. Therefore, it is probable that at least part of lymph pumping results from lymph capillary endothelial cell contraction in addition to contraction of the larger muscular lymphatics. Pumping Caused by External Intermittent Compression of the Lymphatics. In addition to the pumping caused Summary of Factors That Determine Lymph Flow. From the by intrinsic intermittent contraction of the lymph vessel walls, any external factor that intermittently compresses the lymph vessel also can cause pumping. In order of their importance, such factors are: ∑ Contraction of surrounding skeletal muscles ∑ Movement of the parts of the body ∑ Pulsations of arteries adjacent to the lymphatics ∑ Compression of the tissues by objects outside the body The lymphatic pump becomes very active during exercise, often increasing lymph flow 10- to 30-fold. Conversely, during periods of rest, lymph flow is sluggish, almost zero. Lymphatic Capillary Pump. The terminal lymphatic capil- lary is also capable of pumping lymph, in addition to the lymph pumping by the larger lymph vessels. As explained earlier in the chapter, the walls of the lymphatic capillaries are tightly adherent to the surrounding tissue cells by means of their anchoring filaments. Therefore, each time excess fluid enters the tissue and causes the tissue to swell, the anchoring filaments pull on the wall of the lymphatic capillary, and fluid flows into the terminal lymphatic capillary above discussion, one can see that the two primary factors that determine lymph flow are (1) the interstitial fluid pressure and (2) the activity of the lymphatic pump. Therefore, one can state that, roughly, the rate of lymph flow is determined by the product of interstitial fluid pressure times the activity of the lymphatic pump. Role of the Lymphatic System in Controlling Interstitial Fluid Protein Concentration, Interstitial Fluid Volume, and Interstitial Fluid Pressure It is already clear that the lymphatic system functions as an “overflow mechanism” to return to the circulation excess proteins and excess fluid volume from the tissue spaces. Therefore, the lymphatic system also plays a central role in controlling (1) the concentration of proteins in the interstitial fluids, (2) the volume of interstitial fluid, and (3) the interstitial fluid pressure. Let us explain how these factors interact. First, remember that small amounts of proteins leak continuously out of the blood capillaries into the 194 Unit IV The Circulation interstitium. Only minute amounts, if any, of the leaked proteins return to the circulation by way of the venous ends of the blood capillaries. Therefore, these proteins tend to accumulate in the interstitial fluid, and this in turn increases the colloid osmotic pressure of the interstitial fluids. Second, the increasing colloid osmotic pressure in the interstitial fluid shifts the balance of forces at the blood capillary membranes in favor of fluid filtration into the interstitium. Therefore, in effect, fluid is translocated osmotically outward through the capillary wall by the proteins and into the interstitium, thus increasing both interstitial fluid volume and interstitial fluid pressure. Third, the increasing interstitial fluid pressure greatly increases the rate of lymph flow, as explained previously. This in turn carries away the excess interstitial fluid volume and excess protein that has accumulated in the spaces. Thus, once the interstitial fluid protein concentration reaches a certain level and causes a comparable increase in interstitial fluid volume and interstitial fluid pressure, the return of protein and fluid by way of the lymphatic system becomes great enough to balance exactly the rate of leakage of these into the interstitium from the blood capillaries. Therefore, the quantitative values of all these factors reach a steady state; they will remain balanced at these steady state levels until something changes the rate of leakage of proteins and fluid from the blood capillaries. Significance of Negative Interstitial Fluid Pressure as a Means for Holding the Body Tissues Together Traditionally, it has been assumed that the different tissues of the body are held together entirely by connective tissue fibers. However, at many places in the body, connective tissue fibers are very weak or even absent. This occurs particularly at points where tissues slide over one another, such as the skin sliding over the back of the hand or over the face. Yet even at these places, the tissues are held together by the negative interstitial fluid pressure, which is actually a partial vacuum. When the tissues lose their negative pressure, fluid accumulates in the spaces and the condition known as edema occurs, which is discussed in Chapter 25. References Aukland K, Reed RK: Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev 73:1, 1993. D’Amico G, Bazzi C: Pathophysiology of proteinuria. Kidney Int 63:809, 2003. Dejana E: Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 5:261, 2004. Frank PG, Woodman SE, Park DS, Lisanti MP: Caveolin, caveolae, and endothelial cell function. Arterioscler Thromb Vasc Biol 23:1161, 2003. Gashev AA: Physiologic aspects of lymphatic contractile function: current perspectives. Ann N Y Acad Sci 979:178, 2002. Guyton AC: Concept of negative interstitial pressure based on pressures in implanted perforated capsules. Circ Res 12:399, 1963. Guyton AC: Interstitial fluid pressure: II. Pressure-volume curves of interstitial space. Circ Res 16:452, 1965. Guyton AC, Granger HJ, Taylor AE: Interstitial fluid pressure. Physiol Rev 51:527, 1971. Guyton AC, Prather J, Scheel K, McGehee J: Interstitial fluid pressure: IV. Its effect on fluid movement through the capillary wall. Circ Res 19:1022, 1966. Guyton AC, Scheel K, Murphree D: Interstitial fluid pressure: III. Its effect on resistance to tissue fluid mobility. Circ Res 19:412, 1966. Guyton AC, Taylor AE, Granger HJ: Circulatory Physiology II. Dynamics and Control of the Body Fluids. Philadelphia: WB Saunders Co, 1975. Michel CC, Curry FE: Microvascular permeability. Physiol Rev 79:703, 1999. Miyasaka M, Tanaka T: Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol 4:360, 2004. Oliver G: Lymphatic vasculature development. Nat Rev Immunol 4:35, 2004. Rippe B, Rosengren BI, Carlsson O, Venturoli D: Transendothelial transport: the vesicle controversy. J Vasc Res 39:375, 2002. Taylor AE, Granger DN: Exchange of macromolecules across the microcirculation. In: Renkin EM, Michel CC (eds): Handbook of Physiology. Sec. 2, Vol. IV. Bethesda: American Physiological Society, 1984, p 467. C H A P T E R 1 7 Local and Humoral Control of Blood Flow by the Tissues Local Control of Blood Flow in Response to Tissue Needs One of the most fundamental principles of circulatory function is the ability of each tissue to control its own local blood flow in proportion to its metabolic needs. What are some of the specific needs of the tissues for blood flow? The answer to this is manyfold, including the following: 1. 2. 3. 4. 5. 6. Delivery of oxygen to the tissues Delivery of other nutrients, such as glucose, amino acids, and fatty acids Removal of carbon dioxide from the tissues Removal of hydrogen ions from the tissues Maintenance of proper concentrations of other ions in the tissues Transport of various hormones and other substances to the different tissues Certain organs have special requirements. For instance, blood flow to the skin determines heat loss from the body and in this way helps to control body temperature. Also, delivery of adequate quantities of blood plasma to the kidneys allows the kidneys to excrete the waste products of the body. We shall see that most of these factors exert extreme degrees of local blood flow control. Variations in Blood Flow in Different Tissues and Organs. Note in Table 17–1 the very large blood flows in some organs—for example, several hundred milliliters per minute per 100 grams of thyroid or adrenal gland tissue and a total blood flow of 1350 ml/min in the liver, which is 95 ml/min/100 g of liver tissue. Also note the extremely large blood flow through the kidneys—1100 ml/min. This extreme amount of flow is required for the kidneys to perform their function of cleansing the blood of waste products. Conversely, most surprising is the low blood flow to all the inactive muscles of the body, only a total of 750 ml/min, even though the muscles constitute between 30 and 40 per cent of the total body mass. In the resting state, the metabolic activity of the muscles is very low, and so also is the blood flow, only 4 ml/min/100 g. Yet, during heavy exercise, muscle metabolic activity can increase more than 60-fold and the blood flow as much as 20-fold, increasing to as high as 16,000 ml/min in the body’s total muscle vascular bed (or 80 ml/ min/100 g of muscle). Importance of Blood Flow Control by the Local Tissues. One might ask the simple question: Why not simply allow a very large blood flow all the time through every tissue of the body, always enough to supply the tissue’s needs whether the activity of the tissue is little or great? The answer is equally simple: To do this would require many times more blood flow than the heart can pump. Experiments have shown that the blood flow to each tissue usually is regulated at the minimal level that will supply the tissue’s requirements— no more, no less. For instance, in tissues for which the most important requirement is delivery of oxygen, the blood flow is always controlled at a level only slightly more than required to maintain full tissue oxygenation but no more than this. 195 196 Unit IV The Circulation Table 17–1 4 Brain Heart Bronchi Kidneys Liver Portal Arterial Muscle (inactive state) Bone Skin (cool weather) Thyroid gland Adrenal glands Other tissues Total Per cent ml/min 14 4 2 22 27 (21) (6) 15 5 6 1 0.5 3.5 100.0 700 200 100 1100 1350 1050 300 750 250 300 50 25 175 5000 ml/min/100 g 50 70 25 360 95 4 3 3 160 300 1.3 Based mainly on data compiled by Dr. L. A. Sapirstein. By controlling local blood flow in such an exact way, the tissues almost never suffer from oxygen nutritional deficiency, and yet the workload on the heart is kept at a minimum. Mechanisms of Blood Flow Control Local blood flow control can be divided into two phases: (1) acute control and (2) long-term control. Acute control is achieved by rapid changes in local vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters, occurring within seconds to minutes to provide very rapid maintenance of appropriate local tissue blood flow. Long-term control, however, means slow, controlled changes in flow over a period of days, weeks, or even months. In general, these long-term changes provide even better control of the flow in proportion to the needs of the tissues. These changes come about as a result of an increase or decrease in the physical sizes and numbers of actual blood vessels supplying the tissues. Blood flow (x normal) Blood Flow to Different Organs and Tissues Under Basal Conditions 3 2 1 Normal level 0 0 1 2 3 4 5 6 7 Rate of metabolism (x normal) 8 Figure 17–1 Effect of increasing rate of metabolism on tissue blood flow. (3) in carbon monoxide poisoning (which poisons the ability of hemoglobin to transport oxygen), or (4) in cyanide poisoning (which poisons the ability of the tissues to use oxygen), the blood flow through the tissues increases markedly. Figure 17–2 shows that as the arterial oxygen saturation decreases to about 25 per cent of normal, the blood flow through an isolated leg increases about threefold; that is, the blood flow increases almost enough, but not quite enough, to make up for the decreased amount of oxygen in the blood, thus almost maintaining an exact constant supply of oxygen to the tissues. Total cyanide poisoning of oxygen usage by a local tissue area can cause local blood flow to increase as much as sevenfold, thus demonstrating the extreme effect of oxygen deficiency to increase blood flow. There are two basic theories for the regulation of local blood flow when either the rate of tissue metabolism changes or the availability of oxygen changes. They are (1) the vasodilator theory and (2) the oxygen lack theory. Vasodilator Theory for Acute Local Blood Flow Regulation—Possible Special Role of Adenosine. Accord- Acute Control of Local Blood Flow Effect of Tissue Metabolism on Local Blood Flow. Figure 17–1 shows the approximate quantitative acute effect on blood flow of increasing the rate of metabolism in a local tissue, such as in a skeletal muscle. Note that an increase in metabolism up to eight times normal increases the blood flow acutely about fourfold. Acute Local Blood Flow Regulation When Oxygen Availability Changes. One of the most necessary of the metabolic nutrients is oxygen. Whenever the availability of oxygen to the tissues decreases, such as (1) at high altitude at the top of a high mountain, (2) in pneumonia, ing to this theory, the greater the rate of metabolism or the less the availability of oxygen or some other nutrients to a tissue, the greater the rate of formation of vasodilator substances in the tissue cells. The vasodilator substances then are believed to diffuse through the tissues to the precapillary sphincters, metarterioles, and arterioles to cause dilation. Some of the different vasodilator substances that have been suggested are adenosine, carbon dioxide, adenosine phosphate compounds, histamine, potassium ions, and hydrogen tons. Most of the vasodilator theories assume that the vasodilator substance is released from the tissue mainly in response to oxygen deficiency. For instance, Chapter 17 Local and Humoral Control of Blood Flow by the Tissues 197 Precapillary sphincter Metarteriole Blood flow (x normal) 3 2 1 Sidearm capillary 0 100 75 50 25 Arterial oxygen saturation (per cent) Figure 17–2 Effect of decreasing arterial oxygen saturation on blood flow through an isolated dog leg. experiments have shown that decreased availability of oxygen can cause both adenosine and lactic acid (containing hydrogen ions) to be released into the spaces between the tissue cells; these substances then cause intense acute vasodilation and therefore are responsible, or partially responsible, for the local blood flow regulation. Many physiologists have suggested that the substance adenosine is the most important of the local vasodilators for controlling local blood flow. For example, minute quantities of adenosine are released from heart muscle cells when coronary blood flow becomes too little, and this causes enough local vasodilation in the heart to return coronary blood flow back to normal. Also, whenever the heart becomes more active than normal and the heart’s metabolism increases an extra amount, this, too, causes increased utilization of oxygen, followed by (1) decreased oxygen concentration in the heart muscle cells with (2) consequent degradation of adenosine triphosphate (ATP), which (3) increases the release of adenosine. It is believed that much of this adenosine leaks out of the heart muscle cells to cause coronary vasodilation, providing increased coronary blood flow to supply the increased nutrient demands of the active heart. Although research evidence is less clear, many physiologists also have suggested that the same adenosine mechanism is the most important controller of blood flow in skeletal muscle and many other tissues as well as in the heart. The problem with the different vasodilator theories of local blood flow regulation has been the following: It has been difficult to prove that sufficient quantities of any single vasodilator substance (including adenosine) are indeed formed in the tissues to cause all the measured increase in blood flow. But a combination of several different vasodilators could increase the blood flow sufficiently. Oxygen Lack Theory for Local Blood Flow Control. Although the vasodilator theory is widely accepted, Figure 17–3 Diagram of a tissue unit area for explanation of acute local feedback control of blood flow, showing a metarteriole passing through the tissue and a sidearm capillary with its precapillary sphincter for controlling capillary blood flow. several critical facts have made other physiologists favor still another theory, which can be called either the oxygen lack theory or, more accurately, the nutrient lack theory (because other nutrients besides oxygen are involved). Oxygen (and other nutrients as well) is required as one of the metabolic nutrients to cause vascular muscle contraction. Therefore, in the absence of adequate oxygen, it is reasonable to believe that the blood vessels simply would relax and therefore naturally dilate. Also, increased utilization of oxygen in the tissues as a result of increased metabolism theoretically could decrease the availability of oxygen to the smooth muscle fibers in the local blood vessels, and this, too, would cause local vasodilation. A mechanism by which the oxygen lack theory could operate is shown in Figure 17–3. This figure shows a tissue unit, consisting of a metarteriole with a single sidearm capillary and its surrounding tissue. At the origin of the capillary is a precapillary sphincter, and around the metarteriole are several other smooth muscle fibers. Observing such a tissue under a microscope—for example, in a bat’s wing—one sees that the precapillary sphincters are normally either completely open or completely closed. The number of precapillary sphincters that are open at any given time is roughly proportional to the requirements of the tissue for nutrition. The precapillary sphincters and metarterioles open and close cyclically several times per minute, with the duration of the open phases being proportional to the metabolic needs of the tissues for oxygen. The cyclical opening and closing is called vasomotion. Let us explain how oxygen concentration in the local tissue could regulate blood flow through the area. Because smooth muscle requires oxygen to remain 198 Unit IV The Circulation contracted, one might assume that the strength of contraction of the sphincters would increase with an increase in oxygen concentration. Consequently, when the oxygen concentration in the tissue rises above a certain level, the precapillary and metarteriole sphincters presumably would close until the tissue cells consume the excess oxygen. But when the excess oxygen is gone and the oxygen concentration falls low enough, the sphincters would open once more to begin the cycle again. Thus, on the basis of available data, either a vasodilator substance theory or an oxygen lack theory could explain acute local blood flow regulation in response to the metabolic needs of the tissues. Probably the truth lies in a combination of the two mechanisms. Possible Role of Other Nutrients Besides Oxygen in Control of Local Blood Flow. Under special conditions, it has been shown that lack of glucose in the perfusing blood can cause local tissue vasodilation. Also, it is possible that this same effect occurs when other nutrients, such as amino acids or fatty acids, are deficient, although this has not been studied adequately. In addition, vasodilation occurs in the vitamin deficiency disease beriberi, in which the patient has deficiencies of the vitamin B substances thiamine, niacin, and riboflavin. In this disease, the peripheral vascular blood flow everywhere in the body often increases twofold to threefold. Because these vitamins all are needed for oxygeninduced phosphorylation that is required to produce ATP in the tissue cells, one can well understand how deficiency of these vitamins might lead to diminished smooth muscle contractile ability and therefore also local vasodilation. emphasizes the close connection between local blood flow regulation and delivery of oxygen and other nutrients to the tissues. Active Hyperemia. When any tissue becomes highly active, such as an exercising muscle, a gastrointestinal gland during a hypersecretory period, or even the brain during rapid mental activity, the rate of blood flow through the tissue increases. Here again, by simply applying the basic principles of local blood flow control, one can easily understand this active hyperemia. The increase in local metabolism causes the cells to devour tissue fluid nutrients extremely rapidly and also to release large quantities of vasodilator substances. The result is to dilate the local blood vessels and, therefore, to increase local blood flow. In this way, the active tissue receives the additional nutrients required to sustain its new level of function. As pointed out earlier, active hyperemia in skeletal muscle can increase local muscle blood flow as much as 20-fold during intense exercise. “Autoregulation” of Blood Flow When the Arterial Pressure Changes from Normal— “Metabolic” and “Myogenic” Mechanisms In any tissue of the body, an acute increase in arterial pressure causes immediate rise in blood flow. But, within less than a minute, the blood flow in most tissues returns almost to the normal level, even though the arterial pressure is kept elevated. This return of flow toward normal is called “autoregulation of blood flow.” After autoregulation has occurred, the local blood flow in most body tissues will be related to arterial pressure approximately in accord with the solid “acute” curve in Figure 17–4. Note that between an Special Examples of Acute “Metabolic” Control of Local Blood Flow Reactive Hyperemia. When the blood supply to a tissue is blocked for a few seconds to as long an hour or more and then is unblocked, blood flow through the tissue usually increases immediately to four to seven times normal; this increased flow will continue for a few seconds if the block has lasted only a few seconds but sometimes continues for as long as many hours if the blood flow has been stopped for an hour or more. This phenomenon is called reactive hyperemia. Reactive hyperemia is another manifestation of the local “metabolic” blood flow regulation mechanism; that is, lack of flow sets into motion all of those factors that cause vasodilation. After short periods of vascular occlusion, the extra blood flow during the reactive hyperemia phase lasts long enough to repay almost exactly the tissue oxygen deficit that has accrued during the period of occlusion. This mechanism 2.5 Blood flow (x normal) The mechanisms that we have described thus far for local blood flow control are called “metabolic mechanisms” because all of them function in response to the metabolic needs of the tissues. Two additional special examples of metabolic control of local blood flow are reactive hyperemia and active hyperemia. Acute 2.0 1.5 1.0 Long-term 0.5 0 0 150 50 100 200 Arterial pressure (mm Hg) 250 Figure 17–4 Effect of different levels of arterial pressure on blood flow through a muscle. The solid red curve shows the effect if the arterial pressure is raised over a period of a few minutes. The dashed green curve shows the effect if the arterial pressure is raised extremely slowly over a period of many weeks. Chapter 17 Local and Humoral Control of Blood Flow by the Tissues arterial pressure of about 70 mm Hg and 175 mm Hg, the blood flow increases only 30 per cent even though the arterial pressure increases 150 per cent. For almost a century, two views have been proposed to explain this acute autoregulation mechanism. They have been called (1) the metabolic theory and (2) the myogenic theory. The metabolic theory can be understood easily by applying the basic principles of local blood flow regulation discussed in previous sections. Thus, when the arterial pressure becomes too great, the excess flow provides too much oxygen and too many other nutrients to the tissues. These nutrients (especially oxygen) then cause the blood vessels to constrict and the flow to return nearly to normal despite the increased pressure. The myogenic theory, however, suggests that still another mechanism not related to tissue metabolism explains the phenomenon of autoregulation. This theory is based on the observation that sudden stretch of small blood vessels causes the smooth muscle of the vessel wall to contract for a few seconds. Therefore, it has been proposed that when high arterial pressure stretches the vessel, this in turn causes reactive vascular constriction that reduces blood flow nearly back to normal. Conversely, at low pressures, the degree of stretch of the vessel is less, so that the smooth muscle relaxes and allows increased flow. The myogenic response is inherent to vascular smooth muscle and can occur in the absence of neural or hormonal influences. It is most pronounced in arterioles but can also be observed in arteries, venules, veins, and even lymphatic vessels. Myogenic contraction is initiated by stretch-induced vascular depolarization, which then rapidly increases calcium ion entry from the extracellular fluid into the cells, causing them to contract. Changes in vascular pressure may also open or close other ion channels that influence vascular contraction. The precise mechanisms by which changes in pressure cause opening or closing of vascular ion channels are still uncertain, but likely involve mechanical effects of pressure on extracellular proteins that are tethered to cytoskeleton elements of the vascular wall or to the ion channels themselves. The myogenic mechanism may be important in preventing excessive stretch of blood vessel when blood pressure is increased. However, the importance of the myogenic mechanism in blood flow regulation is unclear because this pressure sensing mechanism cannot directly detect changes in blood flow in the tissue. Indeed metabolic factors appear to override the myogenic mechanism in circumstances where the metabolic demands of the tissues are significantly increased, such as during vigorous muscle exercise, which can cause dramatic increases in skeletal muscle blood flow. Special Mechanisms for Acute Blood Flow Control in Specific Tissues Although the general mechanisms for local blood flow control discussed thus far are present in almost all tissues of the body, distinctly different mechanisms 199 operate in a few special areas. They all are discussed throughout this text in relation to specific organs, but two notable ones are as follows: 1. In the kidneys, blood flow control is vested mainly in a mechanism called tubuloglomerular feedback, in which the composition of the fluid in the early distal tubule is detected by an epithelial structure of the distal tubule itself called the macula densa. This is located where the distal tubule lies adjacent to the afferent and efferent arterioles at the nephron juxtaglomerular apparatus. When too much fluid filters from the blood through the glomerulus into the tubular system, appropriate feedback signals from the macula densa cause constriction of the afferent arterioles, in this way reducing both renal blood flow and glomerular filtration rate back to or near to normal. The details of this mechanism are discussed in Chapter 26. 2. In the brain, in addition to control of blood flow by tissue oxygen concentration, the concentrations of carbon dioxide and hydrogen ions play very prominent roles. An increase of either or both of these dilates the cerebral vessels and allows rapid washout of the excess carbon dioxide or hydrogen ions from the brain tissues. This is important because the level of excitability of the brain itself is highly dependent on exact control of both carbon dioxide concentration and hydrogen ion concentration. This special mechanism for cerebral blood flow control is presented in Chapter 61. Mechanism for Dilating Upstream Arteries When Microvascular Blood Flow Increases— The Endothelium-Derived Relaxing Factor (Nitric Oxide) The local mechanisms for controlling tissue blood flow can dilate only the very small arteries and arterioles in each tissue because tissue cell vasodilator substances or tissue cell oxygen deficiency can reach only these vessels, not the intermediate and larger arteries back upstream. Yet, when blood flow through a microvascular portion of the circulation increases, this secondarily entrains another mechanism that does dilate the larger arteries as well. This mechanism is the following: The endothelial cells lining the arterioles and small arteries synthesize several substances that, when released, can affect the degree of relaxation or contraction of the arterial wall. The most important of these is a vasodilator substance called endotheliumderived relaxing factor (EDRF), which is composed principally of nitric oxide, which has a half-life in the blood of only 6 seconds. Rapid flow of blood through the arteries and arterioles causes shear stress on the endothelial cells because of viscous drag of the blood against the vascular walls. This stress contorts the endothelial cells in the direction of flow and causes significant increase in the release of nitric oxide. The nitric oxide then relaxes the blood vessels. This is fortunate because it increases the diameters of the upstream arterial blood vessels whenever microvascular blood flow increases downstream. Without such a response, the effectiveness of local blood flow control 200 Unit IV The Circulation would be significantly decreased because a significant part of the resistance to blood flow is in the upstream small arteries. Long-Term Blood Flow Regulation Thus far, most of the mechanisms for local blood flow regulation that we have discussed act within a few seconds to a few minutes after the local tissue conditions have changed. Yet, even after full activation of these acute mechanisms, the blood flow usually is adjusted only about three quarters of the way to the exact additional requirements of the tissues. For instance, when the arterial pressure suddenly is increased from 100 to 150 mm Hg, the blood flow increases almost instantaneously about 100 per cent. Then, within 30 seconds to 2 minutes, the flow decreases back to about 15 per cent above the original control value. This illustrates the rapidity of the acute mechanisms for local blood flow regulation, but at the same time, it demonstrates that the regulation is still incomplete because there remains an excess 15 per cent increase in blood flow. However, over a period of hours, days, and weeks, a long-term type of local blood flow regulation develops in addition to the acute regulation. This long-term regulation gives far more complete regulation. For instance, in the aforementioned example, if the arterial pressure remains at 150 mm Hg indefinitely, within a few weeks the blood flow through the tissues gradually reapproaches almost exactly the normal flow level. Figure 17–4 shows by the dashed green curve the extreme effectiveness of this long-term local blood flow regulation. Note that once the long-term regulation has had time to occur, long-term changes in arterial pressure between 50 and 250 mm Hg have little effect on the rate of local blood flow. Long-term regulation of blood flow is especially important when the long-term metabolic demands of a tissue change. Thus, if a tissue becomes chronically overactive and therefore requires chronically increased quantities of oxygen and other nutrients, the arterioles and capillary vessels usually increase both in number and size within a few weeks to match the needs of the tissue—unless the circulatory system has become pathological or too old to respond. Mechanism of Long-Term Regulation— Change in “Tissue Vascularity” The mechanism of long-term local blood flow regulation is principally to change the amount of vascularity of the tissues. For instance, if the metabolism in a given tissue is increased for a prolonged period, vascularity increases; if the metabolism is decreased, vascularity decreases. Thus, there is actual physical reconstruction of the tissue vasculature to meet the needs of the tissues. This reconstruction occurs rapidly (within days) in extremely young animals. It also occurs rapidly in new growth tissue, such as in scar tissue and cancerous tissue; however, it occurs much more slowly in old, well-established tissues. Therefore, the time required for long-term regulation to take place may be only a few days in the neonate or as long as months in the elderly person. Furthermore, the final degree of response is much better in younger tissues than in older, so that in the neonate, the vascularity will adjust to match almost exactly the needs of the tissue for blood flow, whereas in older tissues, vascularity frequently lags far behind the needs of the tissues. Role of Oxygen in Long-Term Regulation. Oxygen is impor- tant not only for acute control of local blood flow but also for long-term control. One example of this is increased vascularity in tissues of animals that live at high altitudes, where the atmospheric oxygen is low. A second example is that fetal chicks hatched in low oxygen have up to twice as much tissue blood vessel conductivity as is normally true.This same effect is also dramatically demonstrated in premature human babies put into oxygen tents for therapeutic purposes. The excess oxygen causes almost immediate cessation of new vascular growth in the retina of the premature baby’s eyes and even causes degeneration of some of the small vessels that already have formed. Then when the infant is taken out of the oxygen tent, there is explosive overgrowth of new vessels to make up for the sudden decrease in available oxygen; indeed, there is often so much overgrowth that the retinal vessels grow out from the retina into the eye’s vitreous humor; and this eventually causes blindness. (This condition is called retrolental fibroplasia.) Importance of Vascular Endothelial Growth Factor in Formation of New Blood Vessels A dozen or more factors that increase growth of new blood vessels have been found, almost all of which are small peptides. Three of those that have been best characterized are vascular endothelial growth factor (VEGF), fibroblast growth factor, and angiogenin, each of which has been isolated from tissues that have inadequate blood supply. Presumably, it is deficiency of tissue oxygen or other nutrients, or both, that leads to formation of the vascular growth factors (also called “angiogenic factors”). Essentially all the angiogenic factors promote new vessel growth in the same way. They cause new vessels to sprout from other small vessels. The first step is dissolution of the basement membrane of the endothelial cells at the point of sprouting. This is followed by rapid reproduction of new endothelial cells that stream outward through the vessel wall in extended cords directed toward the source of the angiogenic factor. The cells in each cord continue to divide and rapidly fold over into a tube. Next, the tube connects with another tube budding from another donor vessel (another arteriole or venule) and forms a capillary loop through which blood begins to flow. If the flow is great enough, smooth muscle cells eventually invade the wall, so that some of the new vessels eventually grow to be new arterioles or venules or perhaps even larger vessels. Thus, angiogenesis explains the manner in which metabolic factors in local tissues can cause growth of new vessels. Chapter 17 Local and Humoral Control of Blood Flow by the Tissues Certain other substances, such as some steroid hormones, have exactly the opposite effect on small blood vessels, occasionally even causing dissolution of vascular cells and disappearance of vessels. Therefore, blood vessels can also be made to disappear when not needed. Vascularity Is Determined by Maximum Blood Flow Need, Not by Average Need. An especially valuable characteristic of long-term vascular control is that vascularity is determined mainly by the maximum level of blood flow need rather than by average need. For instance, during heavy exercise the need for whole body blood flow often increases to six to eight times the resting blood flow. This great excess of flow may not be required for more than a few minutes each day. Nevertheless, even this short need can cause enough VEGF to be formed by the muscles to increase their vascularity as required. Were it not for this capability, every time that a person attempted heavy exercise, the muscles would fail to receive the required nutrients, especially the required oxygen, so that the muscles simply would fail to contract. However, after extra vascularity does develop, the extra blood vessels normally remain mainly vasoconstricted, opening to allow extra flow only when appropriate local stimuli such as oxygen lack, nerve vasodilatory stimuli, or other stimuli call forth the required extra flow. Development of Collateral Circulation—A Phenomenon of LongTerm Local Blood Flow Regulation When an artery or a vein is blocked in virtually any tissue of the body, a new vascular channel usually develops around the blockage and allows at least partial resupply of blood to the affected tissue. The first stage in this process is dilation of small vascular loops that already connect the vessel above the blockage to the vessel below. This dilation occurs within the first minute or two, indicating that the dilation is simply a neurogenic or metabolic relaxation of the muscle fibers of the small vessels involved. After this initial opening of collateral vessels, the blood flow often is still less than one quarter that needed to supply all the tissue needs. However, further opening occurs within the ensuing hours, so that within 1 day as much as half the tissue needs may be met, and within a few days often all the tissue needs. The collateral vessels continue to grow for many months thereafter, almost always forming multiple small collateral channels rather than one single large vessel. Under resting conditions, the blood flow usually returns very near to normal, but the new channels seldom become large enough to supply the blood flow needed during strenuous tissue activity. Thus, the development of collateral vessels follows the usual principles of both acute and long-term local blood flow control, the acute control being rapid neurogenic and 201 metabolic dilation, followed chronically by manifold growth and enlargement of new vessels over a period of weeks and months. The most important example of the development of collateral blood vessels occurs after thrombosis of one of the coronary arteries. Almost all people by the age of 60 years have had at least one of the smaller branch coronary vessels close. Yet most people do not know that this has happened because collaterals have developed rapidly enough to prevent myocardial damage. It is in those other instances in which coronary insufficiency occurs too rapidly or too severely for collaterals to develop that serious heart attacks occur. Humoral Control of the Circulation Humoral control of the circulation means control by substances secreted or absorbed into the body fluids— such as hormones and ions. Some of these substances are formed by special glands and transported in the blood throughout the entire body. Others are formed in local tissue areas and cause only local circulatory effects. Among the most important of the humoral factors that affect circulatory function are the following. Vasoconstrictor Agents Norepinephrine and Epinephrine. Norepinephrine is an especially powerful vasoconstrictor hormone; epinephrine is less so and in some tissues even causes mild vasodilation. (A special example of vasodilation caused by epinephrine occurs to dilate the coronary arteries during increased heart activity.) When the sympathetic nervous system is stimulated in most or all parts of the body during stress or exercise, the sympathetic nerve endings in the individual tissues release norepinephrine, which excites the heart and contracts the veins and arterioles. In addition, the sympathetic nerves to the adrenal medullae cause these glands to secrete both norepinephrine and epinephrine into the blood. These hormones then circulate to all areas of the body and cause almost the same effects on the circulation as direct sympathetic stimulation, thus providing a dual system of control: (1) direct nerve stimulation and (2) indirect effects of norepinephrine and/or epinephrine in the circulating blood. Angiotensin II. Angiotensin II is another powerful vasoconstrictor substance. As little as one millionth of a gram can increase the arterial pressure of a human being 50 mm Hg or more. The effect of angiotensin II is to constrict powerfully the small arterioles. If this occurs in an isolated tissue area, the blood flow to that area can be severely depressed. However, the real importance of angiotensin II is that it normally acts on many of the arterioles of the body at the same time to increase the 202 Unit IV The Circulation total peripheral resistance, thereby increasing the arterial pressure. Thus, this hormone plays an integral role in the regulation of arterial pressure, as is discussed in detail in Chapter 19. Vasopressin. Vasopressin, also called antidiuretic hormone, is even more powerful than angiotensin II as a vasoconstrictor, thus making it one of the body’s most potent vascular constrictor substances. It is formed in nerve cells in the hypothalamus of the brain (see Chapter 75) but is then transported downward by nerve axons to the posterior pituitary gland, where it is finally secreted into the blood. It is clear that vasopressin could have enormous effects on circulatory function. Yet, normally, only minute amounts of vasopressin are secreted, so that most physiologists have thought that vasopressin plays little role in vascular control. However, experiments have shown that the concentration of circulating blood vasopressin after severe hemorrhage can rise high enough to increase the arterial pressure as much as 60 mm Hg. In many instances, this can, by itself, bring the arterial pressure almost back up to normal. Vasopressin has a major function to increase greatly water reabsorption from the renal tubules back into the blood (discussed in Chapter 28), and therefore to help control body fluid volume. That is why this hormone is also called antidiuretic hormone. Endothelin—A Powerful Vasoconstrictor in Damaged Blood Vessels. Still another vasoconstrictor substance that ranks along with angiotensin and vasopressin in its vasoconstrictor capability is a large 21 amino acid peptide called endothelin, which requires only nanogram quantities to cause powerful vasoconstriction. This substance is present in the endothelial cells of all or most blood vessels. The usual stimulus for release is damage to the endothelium, such as that caused by crushing the tissues or injecting a traumatizing chemical into the blood vessel. After severe blood vessel damage, release of local endothelin and subsequent vasoconstriction helps to prevent extensive bleeding from arteries as large as 5 millimeters in diameter that might have been torn open by crushing injury. Vasodilator Agents Bradykinin. Several substances called kinins cause pow- erful vasodilation when formed in the blood and tissue fluids of some organs. The kinins are small polypeptides that are split away by proteolytic enzymes from alpha2-globulins in the plasma or tissue fluids. A proteolytic enzyme of particular importance for this purpose is kallikrein, which is present in the blood and tissue fluids in an inactive form. This inactive kallikrein is activated by maceration of the blood, by tissue inflammation, or by other similar chemical or physical effects on the blood or tissues. As kallikrein becomes activated, it acts immediately on alpha2-globulin to release a kinin called kallidin that then is converted by tissue enzymes into bradykinin. Once formed, bradykinin persists for only a few minutes because it is inactivated by the enzyme carboxypeptidase or by converting enzyme, the same enzyme that also plays an essential role in activating angiotensin, as discussed in Chapter 19. The activated kallikrein enzyme is destroyed by a kallikrein inhibitor also present in the body fluids. Bradykinin causes both powerful arteriolar dilation and increased capillary permeability. For instance, injection of 1 microgram of bradykinin into the brachial artery of a person increases blood flow through the arm as much as sixfold, and even smaller amounts injected locally into tissues can cause marked local edema resulting from increase in capillary pore size. There is reason to believe that kinins play special roles in regulating blood flow and capillary leakage of fluids in inflamed tissues. It also is believed that bradykinin plays a normal role to help regulate blood flow in the skin as well as in the salivary and gastrointestinal glands. Histamine. Histamine is released in essentially every tissue of the body if the tissue becomes damaged or inflamed or is the subject of an allergic reaction. Most of the histamine is derived from mast cells in the damaged tissues and from basophils in the blood. Histamine has a powerful vasodilator effect on the arterioles and, like bradykinin, has the ability to increase greatly capillary porosity, allowing leakage of both fluid and plasma protein into the tissues. In many pathological conditions, the intense arteriolar dilation and increased capillary porosity produced by histamine cause tremendous quantities of fluid to leak out of the circulation into the tissues, inducing edema. The local vasodilatory and edema-producing effects of histamine are especially prominent during allergic reactions and are discussed in Chapter 34. Vascular Control by Ions and Other Chemical Factors Many different ions and other chemical factors can either dilate or constrict local blood vessels. Most of them have little function in overall regulation of the circulation, but some specific effects are: 1. An increase in calcium ion concentration causes vasoconstriction. This results from the general effect of calcium to stimulate smooth muscle contraction, as discussed in Chapter 8. 2. An increase in potassium ion concentration causes vasodilation. This results from the ability of potassium ions to inhibit smooth muscle contraction. 3. An increase in magnesium ion concentration causes powerful vasodilation because magnesium ions inhibit smooth muscle contraction. 4. An increase in hydrogen ion concentration (decrease in pH) causes dilation of the arterioles. Chapter 17 Local and Humoral Control of Blood Flow by the Tissues Conversely, slight decrease in hydrogen ion concentration causes arteriolar constriction. 5. Anions that have significant effects on blood vessels are acetate and citrate, both of which cause mild degrees of vasodilation. 6. An increase in carbon dioxide concentration causes moderate vasodilation in most tissues, but marked vasodilation in the brain. Also, carbon dioxide in the blood, acting on the brain vasomotor center, has an extremely powerful indirect effect, transmitted through the sympathetic nervous vasoconstrictor system, to cause widespread vasoconstriction throughout the body. References Adair TH, Gay WJ, Montani JP: Growth regulation of the vascular system: evidence for a metabolic hypothesis. Am J Physiol 259:R393, 1990. Campbell WB, Gauthier KM: What is new in endotheliumderived hyperpolarizing factors? Curr Opin Nephrol Hypertens 11:177, 2002. Chang L, Kaipainen A, Folkman J: Lymphangiogenesis new mechanisms. Ann N Y Acad Sci 979:111, 2002. Cowley AW Jr, Mori T, Mattson D, Zou AP: Role of renal NO production in the regulation of medullary blood flow. Am J Physiol Regul Integr Comp Physiol 284:R1355, 2003. Davis MJ, Hill MA: Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 79:387, 1999. Erdös EG, Marcic BM: Kinins, receptors, kininases and inhibitors—where did they lead us? Biol Chem 382:43, 2001. 203 Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 9:669, 2003. Granger HJ, Guyton AC: Autoregulation of the total systemic circulation following destruction of the central nervous system in the dog. Circ Res 25:379, 1969. Guyton AC, Coleman TG, Granger HJ: Circulation: overall regulation. Annu Rev Physiol 34:13, 1972. Hall JE, Brands MW, Henegar JR: Angiotensin II and longterm arterial pressure regulation: the overriding dominance of the kidney. J Am Soc Nephrol 10(Suppl 12):S258, 1999. Harder DR, Zhang C, Gebremedhin D: Astrocytes function in matching blood flow to metabolic activity. News Physiol Sci 17:27, 2002. Hester RL, Hammer LW: Venular-arteriolar communication in the regulation of blood flow. Am J Physiol Regul Integr Comp Physiol 282:R1280, 2002. Iglarz M, Schiffrin EL: Role of endothelin-1 in hypertension. Curr Hypertens Rep 5:144, 2003. Kerbel R, Folkman J: Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727, 2002. Losordo DW, Dimmeler S: Therapeutic angiogenesis and vasculogenesis for ischemic disease: Part I: angiogenic cytokines. Circulation 109:2487, 2004. Renkin EM: Control of microcirculation and blood-tissue exchange. In: Renkin EM, Michel CC (eds): Handbook of Physiology, Sec. 2, Vol. IV. Bethesda: American Physiological Society, 1984, p 627. Rich S, McLaughlin VV: Endothelin receptor blockers in cardiovascular disease. Circulation 108:2184, 2003. Roman RJ: P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82:131, 2002. Schnermann J, Levine DZ: Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide. Annu Rev Physiol 65:501, 2003. C H A P T E R 1 8 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure Nervous Regulation of the Circulation As discussed in Chapter 17, adjustment of blood flow tissue by tissue is mainly the function of local tissue blood flow control mechanisms. We shall see in this chapter that nervous control of the circulation has more global functions, such as redistributing blood flow to different areas of the body, increasing or decreasing pumping activity by the heart, and, especially, providing very rapid control of systemic arterial pressure. The nervous system controls the circulation almost entirely through the autonomic nervous system. The total function of this system is presented in Chapter 60, and this subject was also introduced in Chapter 17. For our present discussion, we need to present still other specific anatomical and functional characteristics, as follows. Autonomic Nervous System By far the most important part of the autonomic nervous system for regulating the circulation is the sympathetic nervous system. The parasympathetic nervous system also contributes specifically to regulation of heart function, as we shall see later in the chapter. Sympathetic Nervous System. Figure 18–1 shows the anatomy of sympathetic nervous control of the circulation. Sympathetic vasomotor nerve fibers leave the spinal cord through all the thoracic spinal nerves and through the first one or two lumbar spinal nerves. They then pass immediately into a sympathetic chain, one of which lies on each side of the vertebral column. Next, they pass by two routes to the circulation: (1) through specific sympathetic nerves that innervate mainly the vasculature of the internal viscera and the heart, as shown on the right side of Figure 18–1, and (2) almost immediately into peripheral portions of the spinal nerves distributed to the vasculature of the peripheral areas. The precise pathways of these fibers in the spinal cord and in the sympathetic chains are discussed more fully in Chapter 60. Sympathetic Innervation of the Blood Vessels. Figure 18–2 shows distribution of sympathetic nerve fibers to the blood vessels, demonstrating that in most tissues all the vessels except the capillaries, precapillary sphincters, and metarterioles are innervated. The innervation of the small arteries and arterioles allows sympathetic stimulation to increase resistance to blood flow and thereby to decrease rate of blood flow through the tissues. The innervation of the large vessels, particularly of the veins, makes it possible for sympathetic stimulation to decrease the volume of these vessels. This can push blood into the heart and thereby play a major role in regulation of heart pumping, as we shall see later in this and subsequent chapters. 204 Chapter 18 205 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure Vasomotor center Blood vessels Sympathetic chain Vagus Heart Vasoconstrictor Cardioinhibitor Vasodilator Blood vessels Figure 18–1 Anatomy of sympathetic nervous control of the circulation. Also shown by the red dashed line is a vagus nerve that carries parasympathetic signals to the heart. Sympathetic Nerve Fibers to the Heart. In addition to sympathetic nerve fibers supplying the blood vessels, sympathetic fibers also go directly to the heart, as shown in Figure 18–1 and also discussed in Chapter 9. It should be recalled that sympathetic stimulation markedly increases the activity of the heart, both increasing the heart rate and enhancing its strength and volume of pumping. Arteries Arterioles Sympathetic vasoconstriction Capillaries Parasympathetic Control of Heart Function, Especially Heart Rate. Although the parasympathetic nervous system is exceedingly important for many other autonomic functions of the body, such as control of multiple gastrointestinal actions, it plays only a minor role in regulation of the circulation. Its most important circulatory effect is to control heart rate by way of parasympathetic nerve fibers to the heart in the vagus nerves, shown in Figure 18–1 by the dashed red line from the brain medulla directly to the heart. The effects of parasympathetic stimulation on heart function were discussed in detail in Chapter 9. Veins Venules Figure 18–2 Sympathetic innervation of the systemic circulation. 206 Unit IV The Circulation Principally, parasympathetic stimulation causes a marked decrease in heart rate and a slight decrease in heart muscle contractility. Sympathetic Vasoconstrictor System and Its Control by the Central Nervous System The sympathetic nerves carry tremendous numbers of vasoconstrictor nerve fibers and only a few vasodilator fibers. The vasoconstrictor fibers are distributed to essentially all segments of the circulation, but more to some tissues than others. This sympathetic vasoconstrictor effect is especially powerful in the kidneys, intestines, spleen, and skin but much less potent in skeletal muscle and the brain. Vasomotor Center in the Brain and Its Control of the Vasoconstrictor System. Located bilaterally mainly in the retic- ular substance of the medulla and of the lower third of the pons, shown in Figures 18–1 and 18–3, is an area called the vasomotor center. This center transmits parasympathetic impulses through the vagus nerves to the heart and transmits sympathetic impulses through the spinal cord and peripheral sympathetic nerves to virtually all arteries, arterioles, and veins of the body. Although the total organization of the vasomotor center is still unclear, experiments have made it Motor Cingulate Reticular substance Mesencephalon Orbital Temporal Pons Medulla VASOMOTOR CENTER VASODILATOR VASOCONSTRICTOR Figure 18–3 Areas of the brain that play important roles in the nervous regulation of the circulation. The dashed lines represent inhibitory pathways. possible to identify certain important areas in this center, as follows: 1. A vasoconstrictor area located bilaterally in the anterolateral portions of the upper medulla. The neurons originating in this area distribute their fibers to all levels of the spinal cord, where they excite preganglionic vasoconstrictor neurons of the sympathetic nervous system. 2. A vasodilator area located bilaterally in the anterolateral portions of the lower half of the medulla. The fibers from these neurons project upward to the vasoconstrictor area just described; they inhibit the vasoconstrictor activity of this area, thus causing vasodilation. 3. A sensory area located bilaterally in the tractus solitarius in the posterolateral portions of the medulla and lower pons. The neurons of this area receive sensory nerve signals from the circulatory system mainly through the vagus and glossopharyngeal nerves, and output signals from this sensory area then help to control activities of both the vasoconstrictor and vasodilator areas of the vasomotor center, thus providing “reflex” control of many circulatory functions. An example is the baroreceptor reflex for controlling arterial pressure, which we describe later in this chapter. Continuous Partial Constriction of the Blood Vessels Is Normally Caused by Sympathetic Vasoconstrictor Tone. Under normal conditions, the vasoconstrictor area of the vasomotor center transmits signals continuously to the sympathetic vasoconstrictor nerve fibers over the entire body, causing continuous slow firing of these fibers at a rate of about one half to two impulses per second. This continual firing is called sympathetic vasoconstrictor tone. These impulses normally maintain a partial state of contraction in the blood vessels, called vasomotor tone. Figure 18–4 demonstrates the significance of vasoconstrictor tone. In the experiment of this figure, total spinal anesthesia was administered to an animal. This blocked all transmission of sympathetic nerve impulses from the spinal cord to the periphery. As a result, the arterial pressure fell from 100 to 50 mm Hg, demonstrating the effect of losing vasoconstrictor tone throughout the body. A few minutes later, a small amount of the hormone norepinephrine was injected into the blood (norepinephrine is the principal vasoconstrictor hormonal substance secreted at the endings of the sympathetic vasoconstrictor nerve fibers throughout the body). As this injected hormone was transported in the blood to all blood vessels, the vessels once again became constricted, and the arterial pressure rose to a level even greater than normal for 1 to 3 minutes, until the norepinephrine was destroyed. Control of Heart Activity by the Vasomotor Center. At the same time that the vasomotor center is controlling the amount of vascular constriction, it also controls heart activity. The lateral portions of the vasomotor center transmit excitatory impulses through the sympathetic nerve fibers to the heart when there is need to increase heart rate and contractility. Conversely, when there is need to decrease heart pumping, the medial portion of Chapter 18 207 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure Arterial pressure (mm Hg) 150 125 Total spinal anesthesia 100 75 50 Injection of norepinephrine 25 Figure 18–4 0 Effect of total spinal anesthesia on the arterial pressure, showing marked decrease in pressure resulting from loss of “vasomotor tone.” the vasomotor center sends signals to the adjacent dorsal motor nuclei of the vagus nerves, which then transmit parasympathetic impulses through the vagus nerves to the heart to decrease heart rate and heart contractility. Therefore, the vasomotor center can either increase or decrease heart activity. Heart rate and strength of heart contraction ordinarily increase when vasoconstriction occurs and ordinarily decrease when vasoconstriction is inhibited. Control of the Vasomotor Center by Higher Nervous Centers. Large numbers of small neurons located throughout the reticular substance of the pons, mesencephalon, and diencephalon can either excite or inhibit the vasomotor center. This reticular substance is shown in Figure 18–3 by the rose-colored area. In general, the neurons in the more lateral and superior portions of the reticular substance cause excitation, whereas the more medial and inferior portions cause inhibition. The hypothalamus plays a special role in controlling the vasoconstrictor system because it can exert either powerful excitatory or inhibitory effects on the vasomotor center. The posterolateral portions of the hypothalamus cause mainly excitation, whereas the anterior portion can cause either mild excitation or inhibition, depending on the precise part of the anterior hypothalamus stimulated. Many parts of the cerebral cortex can also excite or inhibit the vasomotor center. Stimulation of the motor cortex, for instance, excites the vasomotor center because of impulses transmitted downward into the hypothalamus and thence to the vasomotor center. Also, stimulation of the anterior temporal lobe, the orbital areas of the frontal cortex, the anterior part of 0 5 10 Seconds 15 20 25 the cingulate gyrus, the amygdala, the septum, and the hippocampus can all either excite or inhibit the vasomotor center, depending on the precise portions of these areas that are stimulated and on the intensity of stimulus. Thus, widespread basal areas of the brain can have profound effects on cardiovascular function. Norepinephrine—The Sympathetic Vasoconstrictor Transmitter Substance. The substance secreted at the endings of the vasoconstrictor nerves is almost entirely norepinephrine. Norepinephrine acts directly on the alpha adrenergic receptors of the vascular smooth muscle to cause vasoconstriction, as discussed in Chapter 60. Adrenal Medullae and Their Relation to the Sympathetic Vasoconstrictor System. Sympathetic impulses are transmit- ted to the adrenal medullae at the same time that they are transmitted to the blood vessels. They cause the medullae to secrete both epinephrine and norepinephrine into the circulating blood. These two hormones are carried in the blood stream to all parts of the body, where they act directly on all blood vessels, usually to cause vasoconstriction, but in an occasional tissue epinephrine causes vasodilation because it also has a “beta” adrenergic receptor stimulatory effect, which dilates rather than constricts certain vessels, as discussed in Chapter 60. Sympathetic Vasodilator System and its Control by the Central Nervous System. The sympathetic nerves to skeletal muscles carry sympathetic vasodilator fibers as well as constrictor fibers. In lower animals such as the cat, these dilator fibers release acetylcholine, not norepinephrine, at their endings, although in primates, the vasodilator 208 Unit IV The Circulation effect is believed to be caused by epinephrine exciting specific beta adrenergic receptors in the muscle vasculature. The pathway for central nervous system control of the vasodilator system is shown by the dashed lines in Figure 18–3. The principal area of the brain controlling this system is the anterior hypothalamus. Possible Unimportance of the Sympathetic Vasodilator System. It is doubtful that the sympathetic vasodilator system plays an important role in the control of the circulation in the human being because complete block of the sympathetic nerves to the muscles hardly affects the ability of these muscles to control their own blood flow in response to their needs. Yet some experiments suggest that at the onset of exercise, the sympathetic vasodilator system might cause initial vasodilation in skeletal muscles to allow anticipatory increase in blood flow even before the muscles require increased nutrients. Emotional Fainting—Vasovagal Syncope. A particularly interesting vasodilatory reaction occurs in people who experience intense emotional disturbances that cause fainting. In this case, the muscle vasodilator system becomes activated, and at the same time, the vagal cardioinhibitory center transmits strong signals to the heart to slow the heart rate markedly. The arterial pressure falls rapidly, which reduces blood flow to the brain and causes the person to lose consciousness. This overall effect is called vasovagal syncope. Emotional fainting begins with disturbing thoughts in the cerebral cortex. The pathway probably then goes to the vasodilatory center of the anterior hypothalamus next to the vagal centers of the medulla, to the heart through the vagus nerves, and also through the spinal cord to the sympathetic vasodilator nerves of the muscles. Role of the Nervous System in Rapid Control of Arterial Pressure One of the most important functions of nervous control of the circulation is its capability to cause rapid increases in arterial pressure. For this purpose, the entire vasoconstrictor and cardioaccelerator functions of the sympathetic nervous system are stimulated together. At the same time, there is reciprocal inhibition of parasympathetic vagal inhibitory signals to the heart. Thus, three major changes occur simultaneously, each of which helps to increase arterial pressure. They are as follows: 1. Almost all arterioles of the systemic circulation are constricted. This greatly increases the total peripheral resistance, thereby increasing the arterial pressure. 2. The veins especially (but the other large vessels of the circulation as well) are strongly constricted. This displaces blood out of the large peripheral blood vessels toward the heart, thus increasing the volume of blood in the heart chambers. The stretch of the heart then causes the heart to beat with far greater force and therefore to pump increased quantities of blood. This, too, increases the arterial pressure. 3. Finally, the heart itself is directly stimulated by the autonomic nervous system, further enhancing cardiac pumping. Much of this is caused by an increase in the heart rate, the rate sometimes increasing to as great as three times normal. In addition, sympathetic nervous signals have a significant direct effect to increase contractile force of the heart muscle, this, too, increasing the capability of the heart to pump larger volumes of blood. During strong sympathetic stimulation, the heart can pump about two times as much blood as under normal conditions. This contributes still more to the acute rise in arterial pressure. Rapidity of Nervous Control of Arterial Pressure. An especially important characteristic of nervous control of arterial pressure is its rapidity of response, beginning within seconds and often increasing the pressure to two times normal within 5 to 10 seconds. Conversely, sudden inhibition of nervous cardiovascular stimulation can decrease the arterial pressure to as little as one half normal within 10 to 40 seconds. Therefore, nervous control of arterial pressure is by far the most rapid of all our mechanisms for pressure control. Increase in Arterial Pressure During Muscle Exercise and Other Types of Stress An important example of the ability of the nervous system to increase the arterial pressure is the increase in pressure that occurs during muscle exercise. During heavy exercise, the muscles require greatly increased blood flow. Part of this increase results from local vasodilation of the muscle vasculature caused by increased metabolism of the muscle cells, as explained in Chapter 17. Additional increase results from simultaneous elevation of arterial pressure caused by sympathetic stimulation of the overall circulation during exercise. In most heavy exercise, the arterial pressure rises about 30 to 40 per cent, which increases blood flow almost an additional twofold. The increase in arterial pressure during exercise results mainly from the following effect: At the same time that the motor areas of the brain become activated to cause exercise, most of the reticular activating system of the brain stem is also activated, which includes greatly increased stimulation of the vasoconstrictor and cardioacceleratory areas of the vasomotor center. These increase the arterial pressure instantaneously to keep pace with the increase in muscle activity. In many other types of stress besides muscle exercise, a similar rise in pressure can also occur. For instance, during extreme fright, the arterial pressure sometimes rises to as high as double normal within a few seconds. This is called the alarm reaction, and it provides an excess of arterial pressure that can immediately supply blood to any or all muscles of the body that might need to respond instantly to cause flight from danger. Chapter 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure 209 Reflex Mechanisms for Maintaining Normal Arterial Pressure Aside from the exercise and stress functions of the autonomic nervous system to increase arterial pressure, there are multiple subconscious special nervous control mechanisms that operate all the time to maintain the arterial pressure at or near normal. Almost all of these are negative feedback reflex mechanisms, which we explain in the following sections. Glossopharyngeal nerve Hering’s nerve The Baroreceptor Arterial Pressure Control System—Baroreceptor Reflexes Carotid body Carotid sinus By far the best known of the nervous mechanisms for arterial pressure control is the baroreceptor reflex. Basically, this reflex is initiated by stretch receptors, called either baroreceptors or pressoreceptors, located at specific points in the walls of several large systemic arteries. A rise in arterial pressure stretches the baroreceptors and causes them to transmit signals into the central nervous system. “Feedback” signals are then sent back through the autonomic nervous system to the circulation to reduce arterial pressure downward toward the normal level. Vagus nerve Aortic baroreceptors Physiologic Anatomy of the Baroreceptors and Their Innervation. Baroreceptors are spray-type nerve endings that Response of the Baroreceptors to Pressure. Figure 18–6 shows the effect of different arterial pressure levels on the rate of impulse transmission in a Hering’s carotid sinus nerve. Note that the carotid sinus baroreceptors are not stimulated at all by pressures between 0 and 50 to 60 mm Hg, but above these levels, they respond progressively more rapidly and reach a maximum at about 180 mm Hg. The responses of the aortic baroreceptors are similar to those of the carotid receptors except that they operate, in general, at pressure levels about 30 mm Hg higher. Note especially that in the normal operating range of arterial pressure, around 100 mm Hg, even a slight change in pressure causes a strong change in the baroreflex signal to readjust arterial pressure back toward normal. Thus, the baroreceptor feedback mechanism functions most effectively in the pressure range where it is most needed. Figure 18–5 The baroreceptor system for controlling arterial pressure. Number of impulses from carotid sinus nerves per second lie in the walls of the arteries; they are stimulated when stretched. A few baroreceptors are located in the wall of almost every large artery of the thoracic and neck regions; but, as shown in Figure 18–5, baroreceptors are extremely abundant in (1) the wall of each internal carotid artery slightly above the carotid bifurcation, an area known as the carotid sinus, and (2) the wall of the aortic arch. Figure 18–5 shows that signals from the “carotid baroreceptors” are transmitted through very small Hering’s nerves to the glossopharyngeal nerves in the high neck, and then to the tractus solitarius in the medullary area of the brain stem. Signals from the “aortic baroreceptors” in the arch of the aorta are transmitted through the vagus nerves also to the same tractus solitarius of the medulla. DI = maximum DP 0 80 160 244 Arterial blood pressure (mm Hg) Figure 18–6 Activation of the baroreceptors at different levels of arterial pressure. DI, change in carotid sinus nerve impulses per second; DP, change in arterial blood pressure in mm Hg. 210 Unit IV The Circulation The baroreceptors respond extremely rapidly to changes in arterial pressure; in fact, the rate of impulse firing increases in the fraction of a second during each systole and decreases again during diastole. Furthermore, the baroreceptors respond much more to a rapidly changing pressure than to a stationary pressure. That is, if the mean arterial pressure is 150 mm Hg but at that moment is rising rapidly, the rate of impulse transmission may be as much as twice that when the pressure is stationary at 150 mm Hg. Arterial pressure (mm Hg) Circulatory Reflex Initiated by the Baroreceptors. After the baroreceptor signals have entered the tractus solitarius of the medulla, secondary signals inhibit the vasoconstrictor center of the medulla and excite the vagal parasympathetic center. The net effects are (1) vasodilation of the veins and arterioles throughout the peripheral circulatory system and (2) decreased heart rate and strength of heart contraction. Therefore, excitation of the baroreceptors by high pressure in the arteries reflexly causes the arterial pressure to decrease because of both a decrease in peripheral resistance and a decrease in cardiac output. Conversely, low pressure has opposite effects, reflexly causing the pressure to rise back toward normal. Figure 18–7 shows a typical reflex change in arterial pressure caused by occluding the two common carotid arteries. This reduces the carotid sinus pressure; as a result, the baroreceptors become inactive and lose their inhibitory effect on the vasomotor center. The vasomotor center then becomes much more active than usual, causing the aortic arterial pressure to rise and remain elevated during the 10 minutes that the 150 100 Both common carotids clamped Carotids released 50 0 0 2 4 6 8 10 Minutes 12 14 Figure 18–7 Typical carotid sinus reflex effect on aortic arterial pressure caused by clamping both common carotids (after the two vagus nerves have been cut). carotids are occluded. Removal of the occlusion allows the pressure in the carotid sinuses to rise, and the carotid sinus reflex now causes the aortic pressure to fall immediately to slightly below normal as a momentary overcompensation and then return to normal in another minute. Function of the Baroreceptors During Changes in Body Posture. The ability of the baroreceptors to maintain relatively constant arterial pressure in the upper body is important when a person stands up after having been lying down. Immediately on standing, the arterial pressure in the head and upper part of the body tends to fall, and marked reduction of this pressure could cause loss of consciousness. However, the falling pressure at the baroreceptors elicits an immediate reflex, resulting in strong sympathetic discharge throughout the body. This minimizes the decrease in pressure in the head and upper body. Pressure “Buffer” Function of the Baroreceptor Control System. Because the baroreceptor system opposes either increases or decreases in arterial pressure, it is called a pressure buffer system, and the nerves from the baroreceptors are called buffer nerves. Figure 18–8 shows the importance of this buffer function of the baroreceptors. The upper record in this figure shows an arterial pressure recording for 2 hours from a normal dog, and the lower record shows an arterial pressure recording from a dog whose baroreceptor nerves from both the carotid sinuses and the aorta had been removed. Note the extreme variability of pressure in the denervated dog caused by simple events of the day, such as lying down, standing, excitement, eating, defecation, and noises. Figure 18–9 shows the frequency distributions of the mean arterial pressures recorded for a 24-hour day in both the normal dog and the denervated dog. Note that when the baroreceptors were functioning normally the mean arterial pressure remained throughout the day within a narrow range between 85 and 115 mm Hg—indeed, during most of the day at almost exactly 100 mm Hg. Conversely, after denervation of the baroreceptors, the frequency distribution curve became the broad, low curve of the figure, showing that the pressure range increased 2.5-fold, frequently falling to as low as 50 mm Hg or rising to over 160 mm Hg. Thus, one can see the extreme variability of pressure in the absence of the arterial baroreceptor system. In summary, a primary purpose of the arterial baroreceptor system is to reduce the minute by minute variation in arterial pressure to about one third that which would occur were the baroreceptor system not present. Are the Baroreceptors Important in Long-Term Regulation of Arterial Pressure? Although the arterial baroreceptors provide powerful moment-to-moment control of arterial pressure, their importance in long-term blood pressure regulation has been controversial. One reason that the baroreceptors have been considered Chapter 18 211 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure NORMAL 200 Percentage of occurrence 6 Arterial pressure (mm Hg) 100 0 24 DENERVATED 200 5 Normal 4 3 2 Denervated 1 0 0 50 100 150 200 250 Mean arterial pressure (mm Hg) 100 Figure 18–9 0 Time (min) 24 Frequency distribution curves of the arterial pressure for a 24-hour period in a normal dog and in the same dog several weeks after the baroreceptors had been denervated. (Redrawn from Cowley AW Jr, Liard JP, Guyton AC: Role of baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ Res 32:564, 1973. By permission of the American Heart Association, Inc.) Figure 18–8 Two-hour records of arterial pressure in a normal dog (above) and in the same dog (below) several weeks after the baroreceptors had been denervated. (Redrawn from Cowley AW Jr, Liard JF, Guyton AC: Role of baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ Res 32:564, 1973. By permission of the American Heart Association, Inc.) by some physiologists to be relatively unimportant in chronic regulation of arterial pressure chronically is that they tend to reset in 1 to 2 days to the pressure level to which they are exposed. That is, if the arterial pressure rises from the normal value of 100 mm Hg to 160 mm Hg, a very high rate of baroreceptor impulses are at first transmitted. During the next few minutes, the rate of firing diminishes considerably; then it diminishes much more slowly during the next 1 to 2 days, at the end of which time the rate of firing will have returned to nearly normal despite the fact that the mean arterial pressure still remains at 160 mm Hg. Conversely, when the arterial pressure falls to a very low level, the baroreceptors at first transmit no impulses, but gradually, over 1 to 2 days, the rate of baroreceptor firing returns toward the control level. This “resetting” of the baroreceptors may attenuate their potency as a control system for correcting disturbances that tend to change arterial pressure for longer than a few days at a time. Experimental studies, however, have suggested that the baroreceptors do not completely reset and may therefore contribute to long-term blood pressure regulation, especially by influencing sympathetic nerve activity of the kidneys. For example, with prolonged increases in arterial pressure, the baroreceptor reflexes may mediate decreases in renal sympathetic nerve activity that promote increased excretion of sodium and water by the kidneys. This, in turn, causes a gradual decrease in blood volume, which helps to restore arterial pressure toward normal. Thus, long-term regulation of mean arterial pressure by the baroreceptors requires interaction with additional systems, principally the renal–body fluid–pressure control system (along with its associated nervous and hormonal mechanisms), discussed in Chapters 19 and 29. Control of Arterial Pressure by the Carotid and Aortic Chemoreceptors—Effect of Oxygen Lack on Arterial Pressure. Closely associated with the baroreceptor pressure control system is a chemoreceptor reflex that operates in much the same way as the baroreceptor reflex except that chemoreceptors, instead of stretch receptors, initiate the response. The chemoreceptors are chemosensitive cells sensitive to oxygen lack, carbon dioxide excess, and hydrogen ion excess. They are located in several small chemoreceptor organs about 2 millimeters in size (two carotid bodies, one of which lies in the bifurcation of each common carotid artery, and usually one to three aortic bodies adjacent to the aorta). The chemoreceptors excite nerve fibers that, along with the 212 Unit IV baroreceptor fibers, pass through Hering’s nerves and the vagus nerves into the vasomotor center of the brain stem. Each carotid or aortic body is supplied with an abundant blood flow through a small nutrient artery, so that the chemoreceptors are always in close contact with arterial blood. Whenever the arterial pressure falls below a critical level, the chemoreceptors become stimulated because diminished blood flow causes decreased oxygen as well as excess buildup of carbon dioxide and hydrogen ions that are not removed by the slowly flowing blood. The signals transmitted from the chemoreceptors excite the vasomotor center, and this elevates the arterial pressure back toward normal. However, this chemoreceptor reflex is not a powerful arterial pressure controller until the arterial pressure falls below 80 mm Hg. Therefore, it is at the lower pressures that this reflex becomes important to help prevent still further fall in pressure. The chemoreceptors are discussed in much more detail in Chapter 41 in relation to respiratory control, in which they play a far more important role than in pressure control. Atrial and Pulmonary Artery Reflexes That Help Regulate Arterial Pressure and Other Circulatory Factors. Both the atria and the pulmonary arteries have in their walls stretch receptors called low-pressure receptors. They are similar to the baroreceptor stretch receptors of the large systemic arteries.These low-pressure receptors play an important role, especially in minimizing arterial pressure changes in response to changes in blood volume. To give an example, if 300 milliliters of blood suddenly are infused into a dog with allreceptors intact, the arterial pressure rises only about 15 mm Hg. With the arterial baroreceptors denervated, the pressure rises about 40 mm Hg. If the low-pressure receptors also are denervated, the pressure rises about 100 mm Hg. Thus, one can see that even though the low-pressure receptors in the pulmonary artery and in the atria cannot detect the systemic arterial pressure, they do detect simultaneous increases in pressure in the lowpressure areas of the circulation caused by increase in volume, and they elicit reflexes parallel to the baroreceptor reflexes to make the total reflex system more potent for control of arterial pressure. Atrial Reflexes That Activate the Kidneys—The “Volume Reflex.” Stretch of the atria also causes significant reflex dilation of the afferent arterioles in the kidneys. And still other signals are transmitted simultaneously from the atria to the hypothalamus to decrease secretion of antidiuretic hormone. The decreased afferent arteriolar resistance in the kidneys causes the glomerular capillary pressure to rise, with resultant increase in filtration of fluid into the kidney tubules. The diminution of antidiuretic hormone diminishes the reabsorption of water from the tubules. Combination of these two effects— increase in glomerular filtration and decrease in reabsorption of the fluid—increases fluid loss by the kidneys and reduces an increased blood volume back toward normal. (We will also see in Chapter 19 that atrial stretch caused by increased blood volume also elicits a hormonal effect on the kidneys—release of atrial natriuretic peptide that adds still further to the excretion of fluid in the urine and return of blood volume toward normal.) The Circulation All these mechanisms that tend to return the blood volume back toward normal after a volume overload act indirectly as pressure controllers as well as blood volume controllers because excess volume drives the heart to greater cardiac output and leads, therefore, to greater arterial pressure. This volume reflex mechanism is discussed again in Chapter 29, along with other mechanisms of blood volume control. Atrial Reflex Control of Heart Rate (the Bainbridge Reflex). An increase in atrial pressure also causes an increase in heart rate, sometimes increasing the heart rate as much as 75 per cent. A small part of this increase is caused by a direct effect of the increased atrial volume to stretch the sinus node: it was pointed out in Chapter 10 that such direct stretch can increase the heart rate as much as 15 per cent. An additional 40 to 60 per cent increase in rate is caused by a nervous reflex called the Bainbridge reflex. The stretch receptors of the atria that elicit the Bainbridge reflex transmit their afferent signals through the vagus nerves to the medulla of the brain. Then efferent signals are transmitted back through vagal and sympathetic nerves to increase heart rate and strength of heart contraction. Thus, this reflex helps prevent damming of blood in the veins, atria, and pulmonary circulation. Central Nervous System Ischemic Response—Control of Arterial Pressure by the Brain’s Vasomotor Center in Response to Diminished Brain Blood Flow Most nervous control of blood pressure is achieved by reflexes that originate in the baroreceptors, the chemoreceptors, and the low-pressure receptors, all of which are located in the peripheral circulation outside the brain. However, when blood flow to the vasomotor center in the lower brain stem becomes decreased severely enough to cause nutritional deficiency—that is, to cause cerebral ischemia—the vasoconstrictor and cardioaccelerator neurons in the vasomotor center respond directly to the ischemia and become strongly excited. When this occurs, the systemic arterial pressure often rises to a level as high as the heart can possibly pump. This effect is believed to be caused by failure of the slowly flowing blood to carry carbon dioxide away from the brain stem vasomotor center: at low levels of blood flow to the vasomotor center, the local concentration of carbon dioxide increases greatly and has an extremely potent effect in stimulating the sympathetic vasomotor nervous control areas in the brain’s medulla. It is possible that other factors, such as buildup of lactic acid and other acidic substances in the vasomotor center, also contribute to the marked stimulation and elevation in arterial pressure. This arterial pressure elevation in response to cerebral ischemia is known as the central nervous system ischemic response, or simply CNS ischemic response. The magnitude of the ischemic effect on vasomotor activity is tremendous: it can elevate the mean arterial pressure for as long as 10 minutes sometimes to as high as 250 mm Hg. The degree of sympathetic vasoconstriction caused by intense cerebral ischemia is often so great that some of the peripheral vessels become totally or almost totally occluded. The kidneys, for instance, often Chapter 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure Pen recorder Arterial pressure Zero pressure 213 CSF pressure raised CSF pressure reduced Moving paper Figure 18–10 “Cushing reaction,” showing a rapid rise in arterial pressure resulting from increased cerebrospinal fluid (CSF) pressure. Pressure bottle Connector to subarachnoid space entirely cease their production of urine because of renal arteriolar constriction in response to the sympathetic discharge. Therefore, the CNS ischemic response is one of the most powerful of all the activators of the sympathetic vasoconstrictor system. Importance of the CNS Ischemic Response as a Regulator of Arterial Pressure. Despite the powerful nature of the CNS ischemic response, it does not become significant until the arterial pressure falls far below normal, down to 60 mm Hg and below, reaching its greatest degree of stimulation at a pressure of 15 to 20 mm Hg. Therefore, it is not one of the normal mechanisms for regulating arterial pressure. Instead, it operates principally as an emergency pressure control system that acts rapidly and very powerfully to prevent further decrease in arterial pressure whenever blood flow to the brain decreases dangerously close to the lethal level. It is sometimes called the “last ditch stand” pressure control mechanism. Cushing Reaction. The so-called Cushing reaction is a special type of CNS ischemic response that results from increased pressure of the cerebrospinal fluid around the brain in the cranial vault. For instance, when the cerebrospinal fluid pressure rises to equal the arterial pressure, it compresses the whole brain as well as the arteries in the brain and cuts off the blood supply to the brain.This initiates a CNS ischemic response that causes the arterial pressure to rise. When the arterial pressure has risen to a level higher than the cerebrospinal fluid pressure, blood will flow once again into the vessels of the brain to relieve the brain ischemia. Ordinarily, the blood pressure comes to a new equilibrium level slightly higher than the cerebrospinal fluid pressure, thus allowing blood to begin again to flow through the brain. A typical Cushing reaction is shown in Figure 18–10, caused in this instance by pumping fluid under pressure into the cranial vault around the brain. The Cushing reaction helps protect the vital centers of the brain from loss of nutrition if ever the cerebrospinal fluid pressure rises high enough to compress the cerebral arteries. Arterial pressure transducer Special Features of Nervous Control of Arterial Pressure Role of the Skeletal Nerves and Skeletal Muscles in Increasing Cardiac Output and Arterial Pressure Although most rapidly acting nervous control of the circulation is effected through the autonomic nervous system, at least two conditions in which the skeletal nerves and muscles also play major roles in circulatory responses are the following. Abdominal Compression Reflex. When a baroreceptor or chemoreceptor reflex is elicited, nerve signals are transmitted simultaneously through skeletal nerves to skeletal muscles of the body, particularly to the abdominal muscles. This compresses all the venous reservoirs of the abdomen, helping to translocate blood out of the abdominal vascular reservoirs toward the heart. As a result, increased quantities of blood are made available for the heart to pump. This overall response is called the abdominal compression reflex. The resulting effect on the circulation is the same as that caused by sympathetic vasoconstrictor impulses when they constrict the veins: an increase in both cardiac output and arterial pressure. The abdominal compression reflex is probably much more important than has been realized in the past because it is well known that people whose skeletal muscles have been paralyzed are considerably more prone to hypotensive episodes than are people with normal skeletal muscles. Increased Cardiac Output and Arterial Pressure Caused by Skeletal Muscle Contraction During Exercise. When the skeletal muscles contract during exercise, they compress blood vessels throughout the body. Even anticipation of exercise tightens the muscles, thereby compressing the vessels in the muscles and in the abdomen. The Unit IV resulting effect is to translocate blood from the peripheral vessels into the heart and lungs and, therefore, to increase the cardiac output. This is an essential effect in helping to cause the fivefold to sevenfold increase in cardiac output that sometimes occurs in heavy exercise. The increase in cardiac output in turn is an essential ingredient in increasing the arterial pressure during exercise, an increase usually from a normal mean of 100 mm Hg up to 130 to 160 mm Hg. Respiratory Waves in the Arterial Pressure With each cycle of respiration, the arterial pressure usually rises and falls 4 to 6 mm Hg in a wavelike manner, causing respiratory waves in the arterial pressure. The waves result from several different effects, some of which are reflex in nature, as follows: 1. Many of the “breathing signals” that arise in the respiratory center of the medulla “spill over” into the vasomotor center with each respiratory cycle. 2. Every time a person inspires, the pressure in the thoracic cavity becomes more negative than usual, causing the blood vessels in the chest to expand. This reduces the quantity of blood returning to the left side of the heart and thereby momentarily decreases the cardiac output and arterial pressure. 3. The pressure changes caused in the thoracic vessels by respiration can excite vascular and atrial stretch receptors. Although it is difficult to analyze the exact relations of all these factors in causing the respiratory pressure waves, the net result during normal respiration is usually an increase in arterial pressure during the early part of expiration and a decrease in pressure during the remainder of the respiratory cycle. During deep respiration, the blood pressure can rise and fall as much as 20 mm Hg with each respiratory cycle. The Circulation Pressure (mm Hg) 214 200 160 120 80 40 0 A 100 60 B Figure 18–11 A, Vasomotor waves caused by oscillation of the CNS ischemic response. B, Vasomotor waves caused by baroreceptor reflex oscillation. pressure in turn reduces the baroreceptor stimulation and allows the vasomotor center to become active once again, elevating the pressure to a high value. The response is not instantaneous, and it is delayed until a few seconds later. This high pressure then initiates another cycle, and the oscillation continues on and on. The chemoreceptor reflex can also oscillate to give the same type of waves. This reflex usually oscillates simultaneously with the baroreceptor reflex. It probably plays the major role in causing vasomotor waves when the arterial pressure is in the range of 40 to 80 mm Hg because in this low range, chemoreceptor control of the circulation becomes powerful, whereas baroreceptor control becomes weaker. Oscillation of the CNS Ischemic Response. The record in Arterial Pressure “Vasomotor” Waves—Oscillation of Pressure Reflex Control Systems Often while recording arterial pressure from an animal, in addition to the small pressure waves caused by respiration, some much larger waves are also noted—as great as 10 to 40 mm Hg at times—that rise and fall more slowly than the respiratory waves. The duration of each cycle varies from 26 seconds in the anesthetized dog to 7 to 10 seconds in the unanesthetized human. These waves are called vasomotor waves or “Mayer waves.” Such records are demonstrated in Figure 18–11, showing the cyclical rise and fall in arterial pressure. The cause of vasomotor waves is “reflex oscillation” of one or more nervous pressure control mechanisms, some of which are the following. Oscillation of the Baroreceptor and Chemoreceptor Reflexes. The vasomotor waves of Figure 18–11B are often seen in experimental pressure recordings, although usually much less intense than shown in the figure. They are caused mainly by oscillation of the baroreceptor reflex. That is, a high pressure excites the baroreceptors; this then inhibits the sympathetic nervous system and lowers the pressure a few seconds later. The decreased Figure 18–11A resulted from oscillation of the CNS ischemic pressure control mechanism. In this experiment, the cerebrospinal fluid pressure was raised to 160 mm Hg, which compressed the cerebral vessels and initiated a CNS ischemic pressure response up to 200 mm Hg. When the arterial pressure rose to such a high value, the brain ischemia was relieved and the sympathetic nervous system became inactive. As a result, the arterial pressure fell rapidly back to a much lower value, causing brain ischemia once again. The ischemia then initiated another rise in pressure. Again the ischemia was relieved and again the pressure fell. This repeated itself cyclically as long as the cerebrospinal fluid pressure remained elevated. Thus, any reflex pressure control mechanism can oscillate if the intensity of “feedback” is strong enough and if there is a delay between excitation of the pressure receptor and the subsequent pressure response. The vasomotor waves are of considerable theoretical importance because they show that the nervous reflexes that control arterial pressure obey the same principles as those applicable to mechanical and electrical control systems. For instance, if the feedback “gain” is too great in the guiding mechanism of an automatic pilot for an airplane and there is also delay in response time of the guiding mechanism, the plane will oscillate from side to side instead of following a straight course. Chapter 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure References Antunes-Rodrigues J, De Castro M, Elias LLK, et al: Neuroendocrine control of body fluid metabolism. Physiol Rev 84: 169, 2004. Cao WH, Fan W, Morrison SF: Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus. Neuroscience 126:229, 2004. Cowley AW Jr, Guyton AC: Baroreceptor reflex contribution in angiotensin II–induced hypertension. Circulation 50:61, 1974. DiBona GF: Peripheral and central interactions between the renin-angiotensin system and the renal sympathetic nerves in control of renal function. Ann N Y Acad Sci 940:395, 2001. DiCarlo SE, Bishop VS: Central baroreflex resetting as a means of increasing and decreasing sympathetic outflow and arterial pressure. Ann N Y Acad Sci 940:324, 2001. Esler M, Lambert G, Brunner-La Rocca HP, et al: Sympathetic nerve activity and neurotransmitter release in humans: translation from pathophysiology into clinical practice. Acta Physiol Scand 177:275, 2003. Floras JS: Arterial baroreceptor and cardiopulmonary reflex control of sympathetic outflow in human heart failure. Ann N Y Acad Sci 940:500, 2001. Felder RB, Francis J, Zhang ZH, et al: Heart failure and the brain: new perspectives. Am J Physiol Regul Integr Comp Physiol 284:R259, 2003. Goldstein DS, Robertson D, Esler M, et al: Dysautonomias: clinical disorders of the autonomic nervous system. Ann Intern Med 137:753, 2002. Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Saunders Co, 1980. 215 Hall JE, Hildebrandt DA, Kuo J: Obesity hypertension: role of leptin and sympathetic nervous system. Am J Hypertens 14:103S, 2001. Ketch T, Biaggioni I, Robertson R, Robertson D: Four faces of baroreflex failure: hypertensive crisis, volatile hypertension, orthostatic tachycardia, and malignant vagotonia. Circulation 105:2518, 2002. Krieger EM, Da Silva GJ, Negrao CE: Effects of exercise training on baroreflex control of the cardiovascular system. Ann N Y Acad Sci 940:338, 2001. Lohmeier TE, Lohmeier JR, Warren S, et al: Sustained activation of the central baroreceptor pathway in angiotensin hypertension. Hypertension 39:550, 2002. Lohmeier TE: The sympathetic nervous system and longterm blood pressure regulation. Am J Hypertens 14:147S, 2001. Malpas SC: What sets the long-term level of sympathetic nerve activity: is there a role for arterial baroreceptors? Am J Physiol Regul Integr Comp Physiol 286:R1, 2004. Mifflin SW:What does the brain know about blood pressure? News Physiol Sci 16:266, 2001. Morrison SF: Differential control of sympathetic outflow. Am J Physiol Regul Integr Comp Physiol 281:R683, 2001. Sved AF, Ito S, Sved JC: Brainstem mechanisms of hypertension: role of the rostral ventrolateral medulla. Curr Hypertens Rep 5:262, 2003 . Thrasher TN: Unloading arterial baroreceptors causes neurogenic hypertension. Am J Physiol Regul Integr Comp Physiol 282:R1044, 2002. Zucker IH, Wang W, Pliquett RU, et al: The regulation of sympathetic outflow in heart failure. The roles of angiotensin II, nitric oxide, and exercise training. Ann N Y Acad Sci 940:431, 2001. C H A P T E R 1 Dominant Role of the Kidney in Long-Term Regulation of Arterial Pressure and in Hypertension: The Integrated System for Pressure Control Short-term control of arterial pressure by the sympathetic nervous system, as discussed in Chapter 18, occurs primarily through the effects of the nervous system on total peripheral vascular resistance and capacitance, and on cardiac pumping ability. The body, however, also has powerful mechanisms for regulating arterial pressure week after week and month after month. This long-term control of arterial pressure is closely intertwined with homeostasis of body fluid volume, which is determined by the balance between the fluid intake and output. For long-term survival, fluid intake and output must be precisely balanced, a task that is performed by multiple nervous and hormonal controls, and by local control systems within the kidneys that regulate their excretion of salt and water. In this chapter we discuss these renal–body fluid systems that play a dominant role in long-term blood pressure regulation. Renal–Body Fluid System for Arterial Pressure Control The renal–body fluid system for arterial pressure control is a simple one: When the body contains too much extracellular fluid, the blood volume and arterial pressure rise. The rising pressure in turn has a direct effect to cause the kidneys to excrete the excess extracellular fluid, thus returning the pressure back toward normal. In the phylogenetic history of animal development, this renal–body fluid system for pressure control is a primitive one. It is fully operative in one of the lowest of vertebrates, the hagfish. This animal has a low arterial pressure, only 8 to 14 mm Hg, and this pressure increases almost directly in proportion to its blood volume. The hagfish continually drinks sea water, which is absorbed into its blood, increasing the blood volume as well as the pressure. However, when the pressure rises too high, the kidney simply excretes the excess volume into the urine and relieves the pressure. At low pressure, the kidney excretes far less fluid than is ingested. Therefore, because the hagfish continues to drink, extracellular fluid volume, blood volume, and pressure all build up again to the higher levels. Throughout the ages, this primitive mechanism of pressure control has survived almost exactly as it functions in the hagfish; in the human being, kidney output of water and salt is just as sensitive to pressure changes as in the hagfish, if not more so. Indeed, an increase in arterial pressure in the human of only a few millimeters of mercury can double renal output of water, which is called pressure diuresis, as well as double the output of salt, which is called pressure natriuresis. 216 9 217 The Integrated System for Pressure Control 4000 Cardiac output (ml/min) 8 7 6 5 3000 2000 1000 3 2 1 0 0 Urinary output (ml/min) 4 4 3 2 1 0 Arterial pressure (mm Hg) Urinary volume output (x normal) Chapter 19 225 200 175 150 125 100 75 50 20 40 60 80 100 120 140 160 180 200 Arterial pressure (mm Hg) Figure 19–1 Typical renal urinary output curve measured in a perfused isolated kidney, showing pressure diuresis when the arterial pressure rises above normal. Infusion period 0 10 20 30 40 50 60 Time (minutes) In the human being, the renal–body fluid system for arterial pressure control, just as in the hagfish, is the fundamental basis for long-term arterial pressure control. However, through the stages of evolution, multiple refinements have been added to make this system much more exact in its control in the human being. An especially important refinement, as we shall see, has been addition of the renin-angiotensin mechanism. Quantitation of Pressure Diuresis as a Basis for Arterial Pressure Control Figure 19–1 shows the approximate average effect of different arterial pressure levels on urinary volume output by an isolated kidney, demonstrating markedly increased output of volume as the pressure rises. This increased urinary output is the phenomenon of pressure diuresis. The curve in this figure is called a renal urinary output curve or a renal function curve. In the human being, at an arterial pressure of 50 mm Hg, the urine output is essentially zero. At 100 mm Hg it is normal, and at 200 mm Hg it is about six to eight times normal. Furthermore, not only does increasing the arterial pressure increase urine volume output, but it causes approximately equal increase in sodium output, which is the phenomenon of pressure natriuresis. An Experiment Demonstrating the Renal–Body Fluid System for Arterial Pressure Control. Figure 19–2 shows the results of a research experiment in dogs in which all the nervous reflex mechanisms for blood pressure control were first blocked. Then the arterial pressure was suddenly elevated by infusing about 400 milliliters of blood intravenously. Note the instantaneous increase 120 Figure 19–2 Increases in cardiac output, urinary output, and arterial pressure caused by increased blood volume in dogs whose nervous pressure control mechanisms had been blocked. This figure shows return of arterial pressure to normal after about an hour of fluid loss into the urine. (Courtesy Dr. William Dobbs.) in cardiac output to about double normal and increase in mean arterial pressure to 205 mm Hg, 115 mm Hg above its resting level. Shown by the middle curve is the effect of this increased arterial pressure on urine output, which increased 12-fold. Along with this tremendous loss of fluid in the urine, both the cardiac output and the arterial pressure returned to normal during the subsequent hour. Thus, one sees an extreme capability of the kidneys to eliminate fluid volume from the body in response to high arterial pressure and in so doing to return the arterial pressure back to normal. Graphical Analysis of Pressure Control by the Renal–Body Fluid Mechanism, Demonstrating an “Infinite Feedback Gain” Feature. Figure 19–3 shows a graphical method that can be used for analyzing arterial pressure control by the renal–body fluid system. This analysis is based on two separate curves that intersect each other: (1) the renal output curve for water and salt in response to rising arterial pressure, which is the same renal output curve as that shown in Figure 19–1, and (2) the curve (or line) that represents the net water and salt intake. Over a long period, the water and salt output must equal the intake. Furthermore, the only place on the graph in Figure 19–3 at which output equals intake is 218 Unit IV The Circulation 8 Renal output of water and salt A 6 8 4 6 4 Equilibrium point 2 0 0 50 100 150 250 Arterial pressure (mm Hg) Intake or output (x normal) Intake or output (x normal) Water and salt intake Elevated pressure Normal 2 0 0 8 50 100 150 200 250 200 250 B Elevated pressure 6 4 Figure 19–3 Analysis of arterial pressure regulation by equating the “renal output curve” with the “salt and water intake curve.” The equilibrium point describes the level to which the arterial pressure will be regulated. (That small portion of the salt and water intake that is lost from the body through nonrenal routes is ignored in this and similar figures in this chapter.) Normal 2 0 0 50 100 150 Arterial pressure (mm Hg) Figure 19–4 where the two curves intersect, which is called the equilibrium point. Now, let us see what happens if the arterial pressure becomes some value that is different from that at the equilibrium point. First, assume that the arterial pressure rises to 150 mm Hg. At this level, the graph shows that renal output of water and salt is about three times as great as the intake. Therefore, the body loses fluid, the blood volume decreases, and the arterial pressure decreases. Furthermore, this “negative balance” of fluid will not cease until the pressure falls all the way back exactly to the equilibrium level. Indeed, even when the arterial pressure is only 1 mm Hg greater than the equilibrium level, there still is slightly more loss of water and salt than intake, so that the pressure continues to fall that last 1 mm Hg until the pressure eventually returns exactly to the equilibrium point. If the arterial pressure falls below the equilibrium point, the intake of water and salt is greater than the output. Therefore, body fluid volume increases, blood volume increases, and the arterial pressure rises until once again it returns exactly to the equilibrium point. This return of the arterial pressure always exactly back to the equilibrium point is the infinite feedback gain principle for control of arterial pressure by the renal–body fluid mechanism. Two Determinants of the Long-Term Arterial Pressure Level. In Figure 19–3, one can also see that two basic long-term factors determine the long-term arterial pressure level. This can be explained as follows. Two ways in which the arterial pressure can be increased: A, by shifting the renal output curve in the right-hand direction toward a higher pressure level or B, by increasing the intake level of salt and water. As long as the two curves representing (1) renal output of salt and water and (2) intake of salt and water remain exactly as they are shown in Figure 19–3, the long-term mean arterial pressure level will always readjust exactly to 100 mm Hg, which is the pressure level depicted by the equilibrium point of this figure. Furthermore, there are only two ways in which the pressure of this equilibrium point can be changed from the 100 mm Hg level. One of these is by shifting the pressure level of the renal output curve for salt and water; and the other is by changing the level of the water and salt intake line. Therefore, expressed simply, the two primary determinants of the long-term arterial pressure level are as follows: 1. The degree of pressure shift of the renal output curve for water and salt 2. The level of the water and salt intake line Operation of these two determinants in the control of arterial pressure is demonstrated in Figure 19–4. In Figure 19–4A, some abnormality of the kidneys has caused the renal output curve to shift 50 mm Hg in the high-pressure direction (to the right). Note that the equilibrium point has also shifted to 50 mm Hg higher than normal. Therefore, one can state that if the renal output curve shifts to a new pressure level, so will the 219 Arterial pressure Hypothyroidism c Removal of four limbs ia 100 outp ut 50 0 40 Failure of Increased Total Peripheral Resistance to Elevate the Long-Term Level of Arterial Pressure if Fluid Intake and Renal Function Do Not Change Now is the chance for the reader to see whether he or she really understands the renal–body fluid mechanism for arterial pressure control. Recalling the basic equation for arterial pressure—arterial pressure equals cardiac output times total peripheral resistance—it is clear that an increase in total peripheral resistance should elevate the arterial pressure. Indeed, when the total peripheral resistance is acutely increased, the arterial pressure does rise immediately. Yet if the kidneys continue to function normally, the acute rise in arterial pressure usually is not maintained. Instead, the arterial pressure returns all the way to normal within a day or so. Why? The answer to this is the following: Increasing resistance in the blood vessels everywhere else in the body besides in the kidneys does not change the equilibrium point for blood pressure control as dictated by the kidneys (see again Figures 19–3 and 19–4). Instead, the kidneys immediately begin to respond to the high arterial pressure, causing pressure diuresis and pressure natriuresis. Within hours, large amounts of salt and water are lost from the body, and this continues until the arterial pressure returns exactly to the pressure level of the equilibrium point. As proof of this principle that changes in total peripheral resistance do not affect the long-term level of arterial pressure if function of the kidneys is still normal, carefully study Figure 19–5. This figure shows the approximate cardiac outputs and the arterial pressures in different clinical conditions in which the longterm total peripheral resistance is either much less than or much greater than normal, but kidney excretion of salt and water is normal. Note in all these different clinical conditions that the arterial pressure is also exactly normal. (A word of caution! Many times when the total peripheral resistance increases, this increases the intrarenal vascular resistance at the same time, which alters the function of the kidney and can cause rd Normal Ca 150 Pulmonary disease Paget's disease 200 Anemia arterial pressure follow to this new pressure level within a few days. Figure 19–4B shows how a change in the level of salt and water intake also can change the arterial pressure. In this case, the intake level has increased fourfold and the equilibrium point has shifted to a pressure level of 160 mm Hg, 60 mm Hg above the normal level. Conversely, a decrease in the intake level would reduce the arterial pressure. Thus, it is impossible to change the long-term mean arterial pressure level to a new value without changing one or both of the two basic determinants of long-term arterial pressure—either (1) the level of salt and water intake or (2) the degree of shift of the renal function curve along the pressure axis. However, if either of these is changed, one finds the arterial pressure thereafter to be regulated at a new pressure level, at the pressure level at which the two new curves intersect. Beriberi AV shunts Hyperthyroidism The Integrated System for Pressure Control Arterial pressure and cardiac output (per cent of normal) Chapter 19 60 80 100 120 140 Total peripheral resistance (per cent of normal) 160 Figure 19–5 Relations of total peripheral resistance to the long-term levels of arterial pressure and cardiac output in different clinical abnormalities. In these conditions, the kidneys were functioning normally. Note that changing the whole-body total peripheral resistance caused equal and opposite changes in cardiac output but in all cases had no effect on arterial pressure. (Redrawn from Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Saunders Co, 1980.) hypertension by shifting the renal function curve to a higher pressure level, in the manner shown in Figure 19–4A. We see an example of this later in this chapter when we discuss hypertension caused by vasoconstrictor mechanisms. But it is the increase in renal resistance that is the culprit, not the increased total peripheral resistance—an important distinction!) Increased Fluid Volume Can Elevate Arterial Pressure by Increasing Cardiac Output or Total Peripheral Resistance The overall mechanism by which increased extracellular fluid volume elevates arterial pressure is given in the schema of Figure 19–6. The sequential events are (1) increased extracellular fluid volume (2) increases the blood volume, which (3) increases the mean circulatory filling pressure, which (4) increases venous return of blood to the heart, which (5) increases cardiac output, which (6) increases arterial pressure. Note especially in this schema the two ways in which an increase in cardiac output can increase the arterial pressure. One of these is the direct effect of increased cardiac output to increase the pressure, and the other is an indirect effect to raise total peripheral vascular resistance through autoregulation of blood flow. The second effect can be explained as follows. Referring back to Chapter 17, let us recall that whenever an excess amount of blood flows through a 220 Unit IV The Circulation Increased extracellular fluid volume Increased blood volume Increased mean circulatory filling pressure Increased venous return of blood to the heart Increased cardiac output Autoregulation Increased total peripheral resistance Increased arterial pressure Figure 19–6 Sequential steps by which increased extracellular fluid volume increases the arterial pressure. Note especially that increased cardiac output has both a direct effect to increase arterial pressure and an indirect effect by first increasing the total peripheral resistance. tissue, the local tissue vasculature constricts and decreases the blood flow back toward normal. This phenomenon is called “autoregulation,” which means simply regulation of blood flow by the tissue itself. When increased blood volume increases the cardiac output, the blood flow increases in all tissues of the body, so that this autoregulation mechanism constricts blood vessels all over the body. This in turn increases the total peripheral resistance. Finally, because arterial pressure is equal to cardiac output times total peripheral resistance, the secondary increase in total peripheral resistance that results from the autoregulation mechanism helps greatly in increasing the arterial pressure. For instance, only a 5 to 10 per cent increase in cardiac output can increase the arterial pressure from the normal mean arterial pressure of 100 mm Hg up to 150 mm Hg. In fact, the slight increase in cardiac output is often unmeasurable. Importance of Salt (NaCl) in the Renal–Body Fluid Schema for Arterial Pressure Regulation Although the discussions thus far have emphasized the importance of volume in regulation of arterial pressure, experimental studies have shown that an increase in salt intake is far more likely to elevate the arterial pressure than is an increase in water intake.The reason for this is that pure water is normally excreted by the kidneys almost as rapidly as it is ingested, but salt is not excreted so easily. As salt accumulates in the body, it also indirectly increases the extracellular fluid volume for two basic reasons: 1. When there is excess salt in the extracellular fluid, the osmolality of the fluid increases, and this in turn stimulates the thirst center in the brain, making the person drink extra amounts of water to return the extracellular salt concentration to normal. This increases the extracellular fluid volume. 2. The increase in osmolality caused by the excess salt in the extracellular fluid also stimulates the hypothalamic-posterior pituitary gland secretory mechanism to secrete increased quantities of antidiuretic hormone. (This is discussed in Chapter 28.) The antidiuretic hormone then causes the kidneys to reabsorb greatly increased quantities of water from the renal tubular fluid, thereby diminishing the excreted volume of urine but increasing the extracellular fluid volume. Thus, for these important reasons, the amount of salt that accumulates in the body is the main determinant of the extracellular fluid volume. Because only small increases in extracellular fluid and blood volume can often increase the arterial pressure greatly, accumulation of even a small amount of extra salt in the body can lead to considerable elevation of arterial pressure. Chronic Hypertension (High Blood Pressure) Is Caused by Impaired Renal Fluid Excretion When a person is said to have chronic hypertension (or “high blood pressure”), it is meant that his or her mean arterial pressure is greater than the upper range of the accepted normal measure. A mean arterial pressure greater than 110 mm Hg (normal is about 90 mm Hg) is considered to be hypertensive. (This level of mean pressure occurs when the diastolic blood pressure is greater than about 90 mm Hg and the systolic pressure is greater than about 135 mm Hg.) In severe hypertension, the mean arterial pressure can rise to 150 to 170 mm Hg, with diastolic pressure as high as 130 mm Hg and systolic pressure occasionally as high as 250 mm Hg. Even moderate elevation of arterial pressure leads to shortened life expectancy. At severely high pressures—mean arterial pressures 50 per cent or more above normal—a person can expect to live no more than a few more years unless appropriately treated. The lethal effects of hypertension are caused mainly in three ways: 1. Excess workload on the heart leads to early heart failure and coronary heart disease, often causing death as a result of a heart attack. 2. The high pressure frequently damages a major blood vessel in the brain, followed by death of Chapter 19 221 The Integrated System for Pressure Control 0.9% NaCl Tap water 0.9% NaCl 150 Mean arterial pressure (per cent of control) 140 130 120 35–45% of left kidney removed 110 Entire right kidney removed 100 0 0 20 40 60 80 100 Days Figure 19–7 Average effect on arterial pressure of drinking 0.9 per cent saline solution instead of water in four dogs with 70 per cent of their renal tissue removed. (Redrawn from Langston JB, Guyton AC, Douglas BH, Dorsett PE: Circ Res 12:508, 1963. By permission of the American Heart Association, Inc.) major portions of the brain; this is a cerebral infarct. Clinically it is called a “stroke.” Depending on which part of the brain is involved, a stroke can cause paralysis, dementia, blindness, or multiple other serious brain disorders. 3. High pressure almost always causes injury in the kidneys, producing many areas of renal destruction and, eventually, kidney failure, uremia, and death. Lessons learned from the type of hypertension called “volume-loading hypertension” have been crucial in understanding the role of the renal–body fluid volume mechanism for arterial pressure regulation. Volume-loading hypertension means hypertension caused by excess accumulation of extracellular fluid in the body, some examples of which follow. Experimental Volume-Loading Hypertension Caused by Reduced Renal Mass Along with Simultaneous Increase in Salt Intake. Figure 19–7 shows a typical experiment demonstrating volume-loading hypertension in a group of dogs with 70 per cent of their kidney mass removed. At the first circled point on the curve, the two poles of one of the kidneys were removed, and at the second circled point, the entire opposite kidney was removed, leaving the animals with only 30 per cent of normal renal mass. Note that removal of this amount of kidney mass increased the arterial pressure an average of only 6 mm Hg. Then, the dogs were given salt solution to drink instead of water. Because salt solution fails to quench the thirst, the dogs drank two to four times the normal amounts of volume, and within a few days, their average arterial pressure rose to about 40 mm Hg above normal. After 2 weeks, the dogs were given tap water again instead of salt solution; the pressure returned to normal within 2 days. Finally, at the end of the experiment, the dogs were given salt solution again, and this time the pressure rose much more rapidly to an even higher level because the dogs had already learned to tolerate the salt solution and therefore drank much more. Thus, this experiment demonstrates volume-loading hypertension. If the reader considers again the basic determinants of long-term arterial pressure regulation, he or she can immediately understand why hypertension occurred in the volume-loading experiment of Figure 19–7. First, reduction of the kidney mass to 30 per cent of normal greatly reduced the ability of the kidneys to excrete salt and water. Therefore, salt and water accumulated in the body and in a few days raised the arterial pressure high enough to excrete the excess salt and water intake. Sequential Changes in Circulatory Function During the Development of Volume-Loading Hypertension. It is especially instructive to study the sequential changes in circulatory function during progressive development of volume-loading hypertension. Figure 19–8 shows these sequential changes. A week or so before the point labeled “0” days, the kidney mass had already been decreased to only 30 per cent of normal. Then, at this 222 Extracellular fluid volume (liters) Blood volume (liters) 6.0 5.5 5.0 7.0 6.5 6.0 5.5 5.0 Arterial pressure (mm Hg) 20 19 18 17 16 15 Total peripheral resistance Cardiac output (L/min) (mm Hg/L/min) Unit IV 33% 4% 20% 5% 40% 5% 28 26 24 22 20 18 150 140 130 120 110 0 The Circulation 33% –13% Figure 19–8 40% 30% 0 2 4 6 8 10 12 Days point, the intake of salt and water was increased to about six times normal and kept at this high intake thereafter. The acute effect was to increase extracellular fluid volume, blood volume, and cardiac output to 20 to 40 per cent above normal. Simultaneously, the arterial pressure began to rise but not nearly so much at first as did the fluid volumes and cardiac output. The reason for this slower rise in pressure can be discerned by studying the total peripheral resistance curve, which shows an initial decrease in total peripheral resistance. This decrease was caused by the baroreceptor mechanism discussed in Chapter 18, which tried to prevent the rise in pressure. However, after 2 to 4 days, the baroreceptors adapted (reset) and were no longer able to prevent the rise in pressure. At this time, the arterial pressure had risen almost to its full height because of the increase in cardiac output, even though the total peripheral resistance was still almost at the normal level. After these early acute changes in the circulatory variables had occurred, more prolonged secondary changes occurred during the next few weeks. Especially important was a progressive increase in total peripheral resistance, while at the same time the cardiac output decreased almost all the way back to normal, mainly as a result of the long-term blood flow autoregulation mechanism that is discussed in detail in 14 Progressive changes in important circulatory system variables during the first few weeks of volume-loading hypertension. Note especially the initial increase in cardiac output as the basic cause of the hypertension. Subsequently, the autoregulation mechanism returns the cardiac output almost to normal while simultaneously causing a secondary increase in total peripheral resistance. (Modified from Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Saunders Co, 1980.) Chapter 17 and earlier in this chapter. That is, after the cardiac output had risen to a high level and had initiated the hypertension, the excess blood flow through the tissues then caused progressive constriction of the local arterioles, thus returning the local blood flows in all the body tissues and also the cardiac output almost all the way back to normal, while simultaneously causing a secondary increase in total peripheral resistance. Note, too, that the extracellular fluid volume and blood volume returned almost all the way back to normal along with the decrease in cardiac output. This resulted from two factors: First, the increase in arteriolar resistance decreased the capillary pressure, which allowed the fluid in the tissue spaces to be absorbed back into the blood. Second, the elevated arterial pressure now caused the kidneys to excrete the excess volume of fluid that had initially accumulated in the body. Last, let us take stock of the final state of the circulation several weeks after the initial onset of volume loading. We find the following effects: 1. Hypertension 2. Marked increase in total peripheral resistance 3. Almost complete return of the extracellular fluid volume, blood volume, and cardiac output back to normal Chapter 19 223 The Integrated System for Pressure Control Therefore, we can divide volume-loading hypertension into two separate sequential stages: The first stage results from increased fluid volume causing increased cardiac output. This increase in cardiac output causes the hypertension. The second stage in volume-loading hypertension is characterized by high blood pressure and high total peripheral resistance but return of the cardiac output so near to normal that the usual measuring techniques frequently cannot detect an abnormally elevated cardiac output. Thus, the increased total peripheral resistance in volume-loading hypertension occurs after the hypertension has developed and, therefore, is secondary to the hypertension rather than being the cause of the hypertension. Volume-Loading Hypertension in Patients Who Have No Kidneys but Are Being Maintained on an Artificial Kidney When a patient is maintained on an artificial kidney, it is especially important to keep the patient’s body fluid volume at a normal level—that is, it is important to remove an appropriate amount of water and salt each time the patient is dialyzed. If this is not done and extracellular fluid volume is allowed to increase, hypertension almost invariably develops in exactly the same way as shown in Figure 19–8. That is, the cardiac output increases at first and causes hypertension. Then the autoregulation mechanism returns the cardiac output back toward normal while causing a secondary increase in total peripheral resistance. Therefore, in the end, the hypertension is a high peripheral resistance type of hypertension. Hypertension Caused by Primary Aldosteronism Another type of volume-loading hypertension is caused by excess aldosterone in the body or, occasionally, by excesses of other types of steroids. A small tumor in one of the adrenal glands occasionally secretes large quantities of aldosterone, which is the condition called “primary aldosteronism.” As discussed in Chapter 29, aldosterone increases the rate of reabsorption of salt and water by the tubules of the kidneys, thereby reducing the loss of these in the urine while at the same time causing an increase in blood volume and extracellular fluid volume. Consequently, hypertension occurs. And, if salt intake is increased at the same time, the hypertension becomes even greater. Furthermore, if the condition persists for months or years, the excess arterial pressure often causes pathological changes in the kidneys that make the kidneys retain even more salt and water in addition to that caused directly by the aldosterone. Therefore, the hypertension often finally becomes lethally severe. Here again, in the early stages of this type of hypertension, the cardiac output is increased, but in later stages, the cardiac output generally returns almost to normal while the total peripheral resistance becomes secondarily elevated, as explained earlier in the chapter for primary volume-loading hypertension. The Renin-Angiotensin System: Its Role in Pressure Control and in Hypertension Aside from the capability of the kidneys to control arterial pressure through changes in extracellular fluid volume, the kidneys also have another powerful mechanism for controlling pressure. It is the reninangiotensin system. Renin is a protein enzyme released by the kidneys when the arterial pressure falls too low. In turn, it raises the arterial pressure in several ways, thus helping to correct the initial fall in pressure. Components of the Renin-Angiotensin System Figure 19–9 shows the functional steps by which the renin-angiotensin system helps to regulate arterial pressure. Renin is synthesized and stored in an inactive form called prorenin in the juxtaglomerular cells (JG cells) of the kidneys. The JG cells are modified smooth muscle cells located in the walls of the afferent Decreased arterial pressure Renin (kidney) Renin substrate (angiotensinogen) Angiotensin I Converting enzyme (lung) Angiotensin II Angiotensinase (Inactivated) Renal retention Vasoconstriction of salt and water Increased arterial pressure Figure 19–9 Renin-angiotensin vasoconstrictor mechanism for arterial pressure control. Unit IV The Circulation arterioles immediately proximal to the glomeruli. When the arterial pressure falls, intrinsic reactions in the kidneys themselves cause many of the prorenin molecules in the JG cells to split and release renin. Most of the renin enters the renal blood and then passes out of the kidneys to circulate throughout the entire body. However, small amounts of the renin do remain in the local fluids of the kidney and initiate several intrarenal functions. Renin itself is an enzyme, not a vasoactive substance. As shown in the schema of Figure 19–9, renin acts enzymatically on another plasma protein, a globulin called renin substrate (or angiotensinogen), to release a 10-amino acid peptide, angiotensin I. Angiotensin I has mild vasoconstrictor properties but not enough to cause significant changes in circulatory function. The renin persists in the blood for 30 minutes to 1 hour and continues to cause formation of still more angiotensin I during this entire time. Within a few seconds to minutes after formation of angiotensin I, two additional amino acids are split from the angiotensin I to form the 8-amino acid peptide angiotensin II. This conversion occurs almost entirely in the lungs while the blood flows through the small vessels of the lungs, catalyzed by an enzyme called converting enzyme that is present in the endothelium of the lung vessels. Angiotensin II is an extremely powerful vasoconstrictor, and it also affects circulatory function in other ways as well. However, it persists in the blood only for 1 or 2 minutes because it is rapidly inactivated by multiple blood and tissue enzymes collectively called angiotensinases. During its persistence in the blood, angiotensin II has two principal effects that can elevate arterial pressure. The first of these, vasoconstriction in many areas of the body, occurs rapidly. Vasoconstriction occurs intensely in the arterioles and much less so in the veins. Constriction of the arterioles increases the total peripheral resistance, thereby raising the arterial pressure, as demonstrated at the bottom of the schema in Figure 19–9. Also, the mild constriction of the veins promotes increased venous return of blood to the heart, thereby helping the heart pump against the increasing pressure. The second principal means by which angiotensin increases the arterial pressure is to decrease excretion of both salt and water by the kidneys. This slowly increases the extracellular fluid volume, which then increases the arterial pressure during subsequent hours and days. This long-term effect, acting through the extracellular fluid volume mechanism, is even more powerful than the acute vasoconstrictor mechanism in eventually raising the arterial pressure. Rapidity and Intensity of the Vasoconstrictor Pressure Response to the Renin-Angiotensin System Figure 19–10 shows a typical experiment demonstrating the effect of hemorrhage on the arterial pressure under two separate conditions: (1) with the renin-angiotensin system functioning and (2) without Arterial pressure (mm Hg) 224 100 With renin-angiotensin system 75 Without renin-angiotensin system 50 25 Hemorrhage 0 0 10 20 30 40 Minutes Figure 19–10 Pressure-compensating effect of the renin-angiotensin vasoconstrictor system after severe hemorrhage. (Drawn from experiments by Dr. Royce Brough.) the system functioning (the system was interrupted by a renin-blocking antibody). Note that after hemorrhage—enough to cause acute decrease of the arterial pressure to 50 mm Hg—the arterial pressure rose back to 83 mm Hg when the renin-angiotensin system was functional. Conversely, it rose to only 60 mm Hg when the renin-angiotensin system was blocked. This shows that the renin-angiotensin system is powerful enough to return the arterial pressure at least halfway back to normal within a few minutes after severe hemorrhage. Therefore, sometimes it can be of lifesaving service to the body, especially in circulatory shock. Note also that the renin-angiotensin vasoconstrictor system requires about 20 minutes to become fully active. Therefore, it is somewhat slower to act for pressure control than are the nervous reflexes and the sympathetic norepinephrine-epinephrine system. Effect of Angiotensin in the Kidneys to Cause Renal Retention of Salt and Water— An Especially Important Means for Long-Term Control of Arterial Pressure Angiotensin causes the kidneys to retain both salt and water in two major ways: 1. Angiotensin acts directly on the kidneys to cause salt and water retention. 2. Angiotensin causes the adrenal glands to secrete aldosterone, and the aldosterone in turn increases salt and water reabsorption by the kidney tubules. Thus, whenever excess amounts of angiotensin circulate in the blood, the entire long-term renal–body fluid mechanism for arterial pressure control automatically becomes set to a higher arterial pressure level than normal. Chapter 19 225 The Integrated System for Pressure Control Mechanisms of the Direct Renal Effects of Angiotensin to Cause Renal Retention of Salt and Water. Angiotensin has several Stimulation of Aldosterone Secretion by Angiotensin, and the Effect of Aldosterone in Increasing Salt and Water Retention by the Kidneys. Angiotensin is also one of the most powerful stimulators of aldosterone secretion by the adrenal glands, as we shall discuss in relation to body fluid regulation in Chapter 29 and in relation to adrenal gland function in Chapter 77. Therefore, when the renin-angiotensin system becomes activated, the rate of aldosterone secretion usually also increases; and an important subsequent function of aldosterone is to cause marked increase in sodium reabsorption by the kidney tubules, thus increasing the total body extracellular fluid sodium. This increased sodium then causes water retention, as already explained, increasing the extracellular fluid volume and leading secondarily to still more long-term elevation of the arterial pressure. Thus both the direct effect of angiotensin on the kidney and its effect acting through aldosterone are important in long-term arterial pressure control. However, research in our own laboratory has suggested that the direct effect of angiotensin on the kidneys is perhaps three or more times as potent as the indirect effect acting through aldosterone—even though the indirect effect is the one most widely known. Quantitative Analysis of Arterial Pressure Changes Caused by Angiotensin. Figure 19–11 shows a quantitative analysis of the effect of angiotensin in arterial pressure control. This figure shows two renal output curves as well as a line depicting normal level of sodium intake. The lefthand renal output curve is that measured in dogs whose renin-angiotensin system had been blocked by the drug captopril (which blocks the conversion of angiotensin I to angiotensin II, the active form of angiotensin). The right-hand curve was measured in dogs infused continuously with angiotensin II at a level about 2.5 times the normal rate of angiotensin formation in the blood. Note the shift of the renal output curve toward higher pressure levels under the influence of angiotensin II. This shift is caused by both the direct effects of angiotensin on the kidney and the indirect effect acting through aldosterone secretion, as explained above. Finally, note the two equilibrium points, one for zero angiotensin showing an arterial pressure level of 75 mm Hg, and one for elevated angiotensin showing a pressure level of 115 mm Hg. Therefore, the effect of Angiotensin levels in the blood (times normal) 0 Sodium intake and output (times normal) direct renal effects that make the kidneys retain salt and water. One major effect is to constrict the renal arterioles, thereby diminishing blood flow through the kidneys. As a result, less fluid filters through the glomeruli into the tubules. Also, the slow flow of blood reduces the pressure in the peritubular capillaries, which causes rapid reabsorption of fluid from the tubules. And still a third effect is that angiotensin has important direct actions on the tubular cells themselves to increase tubular reabsorption of sodium and water. The total result of all these effects is significant, sometimes decreasing urine output less than one fifth of normal. 2.5 10 8 6 4 Equilibrium points 2 Normal Intake 0 0 60 80 100 120 140 160 Arterial pressure (mm Hg) Figure 19–11 Effect of two angiotensin II levels in the blood on the renal output curve, showing regulation of the arterial pressure at an equilibrium point of 75 mm Hg when the angiotensin II level is low and at 115 mm Hg when the angiotensin II level is high. angiotensin to cause renal retention of salt and water can have a powerful effect in promoting chronic elevation of the arterial pressure. Role of the Renin-Angiotensin System in Maintaining a Normal Arterial Pressure Despite Wide Variations in Salt Intake One of the most important functions of the reninangiotensin system is to allow a person to eat either very small or very large amounts of salt without causing great changes in either extracellular fluid volume or arterial pressure. This function is explained by the schema in Figure 19–12, which shows that the initial effect of increased salt intake is to elevate the extracellular fluid volume and this in turn to elevate the arterial pressure. Then, the increased arterial pressure causes increased blood flow through the kidneys, which reduces the rate of secretion of renin to a much lower level and leads sequentially to decreased renal retention of salt and water, return of the extracellular fluid volume almost to normal, and, finally, return of the arterial pressure also almost to normal. Thus, the renin-angiotensin system is an automatic feedback mechanism that helps maintain the arterial pressure at or near the normal level even when salt intake is increased. Or, when salt intake is decreased below normal, exactly opposite effects take place. To emphasize the efficacy of the renin-angiotensin system in controlling arterial pressure, when the system functions normally, the pressure rises no more 226 Unit IV The Circulation Increased salt intake Increased extracellular volume Increased arterial pressure Decreased renin and angiotensin Renal artery constricted Constriction released Decreased renal retention of salt and water Systemic arterial pressure 200 Return of arterial pressure almost to normal Pressure (mm Hg) Return of extracellular volume almost to normal Figure 19–12 than 4 to 6 mm Hg in response to as much as a 50-fold increase in salt intake. Conversely, when the reninangiotensin system is blocked, the same increase in salt intake sometimes causes the pressure to rise 10 times the normal increase, often as much as 50 to 60 mm Hg. Types of Hypertension in Which Angiotensin Is Involved: Hypertension Caused by a Renin-Secreting Tumor or by Infusion of Angiotensin II Occasionally a tumor of the renin-secreting juxtaglomerular cells (the JG cells) occurs and secretes tremendous quantities of renin; in turn, equally large quantities of angiotensin II are formed. In all patients in whom this has occurred, severe hypertension has developed. Also, when large amounts of angiotensin are infused continuously for days or weeks into animals, similar severe long-term hypertension develops. We have already noted that angiotensin can increase the arterial pressure in two ways: 1. By constricting the arterioles throughout the entire body, thereby increasing the total peripheral resistance and arterial pressure; this effect occurs within seconds after one begins to infuse angiotensin. Distal renal arterial pressure 100 50 Times normal Sequential events by which increased salt intake increases the arterial pressure, but feedback decrease in activity of the renin angiotensin system returns the arterial pressure almost to the normal level. 150 7 Renin secretion 1 0 0 4 8 12 Days Figure 19–13 Effect of placing a constricting clamp on the renal artery of one kidney after the other kidney has been removed. Note the changes in systemic arterial pressure, renal artery pressure distal to the clamp, and rate of renin secretion. The resulting hypertension is called “one-kidney” Goldblatt hypertension. 2. By causing the kidneys to retain salt and water; over a period of days, this, too, causes hypertension and is the principal cause of the long-term continuation of the elevated pressure. “One-Kidney” Goldblatt Hypertension. When one kidney is removed and a constrictor is placed on the renal artery of the remaining kidney, as shown in Figure 19–13, the immediate effect is greatly reduced pressure in the renal artery beyond the constrictor, as demonstrated by the dashed curve in the figure. Then, within seconds or minutes, the systemic arterial pressure begins to rise and continues to rise for several days. The pressure usually rises rapidly for the first hour or so, and this is Chapter 19 The Integrated System for Pressure Control followed by a slower additional rise during the next several days. When the systemic arterial pressure reaches its new stable pressure level, the renal arterial pressure (the dashed curve in the figure) will have returned almost all the way back to normal.The hypertension produced in this way is called “one-kidney” Goldblatt hypertension in honor of Dr. Goldblatt, who first studied the important quantitative features of hypertension caused by renal artery constriction. The early rise in arterial pressure in Goldblatt hypertension is caused by the renin-angiotensin vasoconstrictor mechanism. That is, because of poor blood flow through the kidney after acute constriction of the renal artery, large quantities of renin are secreted by the kidney, as demonstrated by the lowermost curve in Figure 19–13, and this causes increased angiotensin II and aldosterone in the blood. The angiotensin in turn raises the arterial pressure acutely. The secretion of renin rises to a peak in an hour or so but returns nearly to normal in 5 to 7 days because the renal arterial pressure by that time has also risen back to normal, so that the kidney is no longer ischemic. The second rise in arterial pressure is caused by retention of salt and water by the constricted kidney (that is also stimulated by angiotensin II and aldosterone). In 5 to 7 days, the body fluid volume will have increased enough to raise the arterial pressure to its new sustained level. The quantitative value of this sustained pressure level is determined by the degree of constriction of the renal artery. That is, the aortic pressure must rise high enough so that renal arterial pressure distal to the constrictor is enough to cause normal urine output. “Two-Kidney” Goldblatt Hypertension. Hypertension also can result when the artery to only one kidney is constricted while the artery to the other kidney is normal. This hypertension results from the following mechanism: The constricted kidney secretes renin and also retains salt and water because of decreased renal arterial pressure in this kidney. Then the “normal” opposite kidney retains salt and water because of the renin produced by the ischemic kidney. This renin causes formation of angiotension II and aldosterone both of which circulate to the opposite kidney and cause it also to retain salt and water. Thus, both kidneys, but for different reasons, become salt and water retainers. Consequently, hypertension develops. Hypertension Caused by Diseased Kidneys That Secrete Renin Chronically. Often, patchy areas of one or both kidneys are diseased and become ischemic because of local vascular constrictions, whereas other areas of the kidneys are normal. When this occurs, almost identical effects occur as in the two-kidney type of Goldblatt hypertension. That is, the patchy ischemic kidney tissue secretes renin, and this in turn, acting through the formation of angiotensin II, causes the remaining kidney mass also to retain salt and water. Indeed, one of the most common causes of renal hypertension, especially in older persons, is such patchy ischemic kidney disease. 227 Other Types of Hypertension Caused by Combinations of Volume Loading and Vasoconstriction Hypertension in the Upper Part of the Body Caused by Coarctation of the Aorta. One out of every few thousand babies is born with pathological constriction or blockage of the aorta at a point beyond the aortic arterial branches to the head and arms but proximal to the renal arteries, a condition called coarctation of the aorta. When this occurs, blood flow to the lower body is carried by multiple, small collateral arteries in the body wall, with much vascular resistance between the upper aorta and the lower aorta. As a consequence, the arterial pressure in the upper part of the may be 40-50 per cent higher than that in the lower body. The mechanism of this upper-body hypertension is almost identical to that of one-kidney Goldblatt hypertension.That is, when a constrictor is placed on the aorta above the renal arteries, the blood pressure in both kidneys at first falls, renin is secreted, angiotensin and aldosterone are formed, and hypertension occurs in the upper body. The arterial pressure in the lower body at the level of the kidneys rises approximately to normal, but high pressure persists in the upper body. The kidneys are no longer ischemic, so that secretion of renin and formation of angiotensin and aldosterone return to normal. Likewise, in coarctation of the aorta, the arterial pressure in the lower body is usually almost normal, whereas the pressure in the upper body is far higher than normal. Role of Autoregulation in the Hypertension Caused by Aortic Coarctation. A significant feature of hypertension caused by aortic coarctation is that blood flow in the arms, where the pressure may be 40 to 60 per cent above normal, is almost exactly normal. Also, blood flow in the legs, where the pressure is not elevated, is almost exactly normal. How could this be, with the pressure in the upper body 40 to 60 per cent greater than in the lower body? The answer is not that there are differences in vasoconstrictor substances in the blood of the upper and lower body, because the same blood flows to both areas. Likewise, the nervous system innervates both areas of the circulation similarly, so that there is no reason to believe that there is a difference in nervous control of the blood vessels. The only reasonable answer is that long-term autoregulation develops so nearly completely that the local blood flow control mechanisms have compensated almost 100 per cent for the differences in pressure. The result is that, in both the high-pressure area and the low-pressure area, the local blood flow is controlled almost exactly in accord with the needs of the tissue and not in accord with the level of the pressure. One of the reasons these observations are so important is that they demonstrate how nearly complete the longterm autoregulation process can be. Hypertension in Preeclampsia (Toxemia of Pregnancy). Approx- imately 5 to 10 per cent of expectant mothers develop a syndrome called preeclampsia (also called toxemia of pregnancy). One of the manifestations of preeclampsia is hypertension that usually subsides after delivery of the baby. Although the precise causes of preeclampsia are not completely understood, ischemia of the placenta and subsequent release by the placenta of toxic factors are believed to play a role in causing many of the man- 228 Unit IV ifestations of this disorder, including hypertension in the mother. Substances released by the ischemic placenta, in turn, cause dysfunction of vascular endothelial cells throughout the body, including the blood vessels of the kidneys.This endothelial dysfunction decreases release of nitric oxide and other vasodilator substances, causing vasoconstriction, decreased rate of fluid filtration from the glomeruli into the renal tubules, impaired renalpressure natriuresis, and development of hypertension. Another pathological abnormality that may contribute to hypertension in preeclampsia is thickening of the kidney glomerular membranes (perhaps caused by an autoimmune process), which also reduces the rate of glomerular fluid filtration. For obvious reasons, the arterial pressure level required to cause normal formation of urine becomes elevated, and the long-term level of arterial pressure becomes correspondingly elevated. These patients are especially prone to extra degrees of hypertension when they have excess salt intake. Neurogenic Hypertension. Acute neurogenic hypertension can be caused by strong stimulation of the sympathetic nervous system. For instance, when a person becomes excited for any reason or at times during states of anxiety, the sympathetic system becomes excessively stimulated, peripheral vasoconstriction occurs everywhere in the body, and acute hypertension ensues. Acute Neurogenic Hypertension Caused by Sectioning the Baroreceptor Nerves. Another type of acute neurogenic hyper- tension occurs when the nerves leading from the baroreceptors are cut or when the tractus solitarius is destroyed in each side of the medulla oblongata (these are the areas where the nerves from the carotid and aortic baroreceptors connect in the brain stem). The sudden cessation of normal nerve signals from the baroreceptors has the same effect on the nervous pressure control mechanisms as a sudden reduction of the arterial pressure in the aorta and carotid arteries. That is, loss of the normal inhibitory effect on the vasomotor center caused by normal baroreceptor nervous signals allows the vasomotor center suddenly to become extremely active and the mean arterial pressure to increase from 100 mm Hg to as high as 160 mm Hg. The pressure returns to nearly normal within about 2 days because the response of the vasomotor center to the absent baroreceptor signal fades away, which is called central “resetting” of the baroreceptor pressure control mechanism. Therefore, the neurogenic hypertension caused by sectioning the baroreceptor nerves is mainly an acute type of hypertension, not a chronic type. Spontaneous Hereditary Hypertension in Lower Animals. Spon- taneous hereditary hypertension has been observed in a number of strains of lower animals, including several different strains of rats, at least one strain of rabbits, and at least one strain of dogs. In the strain of rats that has been studied to the greatest extent, the Okamoto strain, there is evidence that in early development of the hypertension, the sympathetic nervous system is considerably more active than in normal rats. However, in the late stages of this type of hypertension, two structural changes have been observed in the nephrons of the kidneys: (1) increased preglomerular renal arterial resistance and (2) decreased permeability of the glomerular membranes. These structural changes could easily be the basis for the long-term continuance of the The Circulation hypertension. In other strains of hypertensive rats, impaired renal function also has been observed. “Primary (Essential) Hypertension” About 90 to 95 per cent of all people who have hypertension are said to have “primary hypertension,” also widely known as “essential hypertension” by many clinicians. These terms mean simply that the hypertension is of unknown origin, in contrast to those forms of hypertension that are secondary to known causes, such as renal artery stenosis. In some patients with primary hypertension, there is a strong hereditary tendency, the same as occurs in animal strains of genetic hypertension discussed above. In most patients, excess weight gain and sedentary lifestyle appear to play a major role in causing hypertension. The majority of patients with hypertension are overweight, and studies of different populations suggest that excess weight gain and obesity may account for as much as 65 to 70 percent of the risk for developing primary hypertension. Clinical studies have clearly shown the value of weight loss for reducing blood pressure in most patients with hypertension. In fact, new clinical guidelines for treating hypertension recommend increased physical activity and weight loss as a first step in treating most patients with hypertension. Some of the characteristics of primary hypertension caused by excess weight gain and obesity include: 1. Cardiac output is increased due, in part, to the additional blood flow required for the extra adipose tissue. However, blood flow in the heart, kidneys, gastrointestinal tract, and skeletal muscle also increases with weight gain due to increased metabolic rate and growth of the organs and tissues in response to their increased metabolic demands. As the hypertension is sustained for many months and years, total peripheral vascular resistance may be increased. 2. Sympathetic nerve activity, especially in the kidneys, is increased in overweight patients. The causes of increased sympathetic activity in obesity are not fully understood, but recent studies suggest that hormones, such as leptin, released from fat cells may directly stimulate multiple regions of the hypothalamus, which, in turn, have an excitatory influence on the vasomotor centers of the brain medulla. 3. Angiotensin II and aldosterone levels are increased two- to threefold in many obese patients. This may be caused partly by increased sympathetic nerve stimulation, which increases renin release by the kidneys and therefore formation of angiotensin II, which, in turn, stimulates the adrenal gland to secrete aldosterone. 4. The renal-pressure natriuresis mechanism is impaired, and the kidneys will not excrete adequate amounts of salt and water unless the arterial pressure is high or unless kidney function is somehow improved. In other words, if the mean arterial pressure in the essential hypertensive person is 150 mm Hg, acute reduction of the mean arterial pressure artificially to the normal value of The Integrated System for Pressure Control Chapter 19 100 mm Hg (but without otherwise altering renal function except for the decreased pressure) will cause almost total anuria, and the person will retain salt and water until the pressure rises back to the elevated value of 150 mm Hg. Chronic reductions in arterial pressure with effective antihypertensive therapies, however, usually do not cause marked salt and water retention by the kidneys because these therapies also improve renal-pressure natriuresis, as discussed below. Experimental studies in obese animals and obese patients suggest that impaired renal-pressure natriuresis in obesity hypertension is caused mainly by increased renal tubular reabsorption of salt and water due to increased sympathetic nerve activity and increased levels of angiotensin II and aldosterone. However, if hypertension is not effectively treated, there may also be vascular damage in the kidneys that can reduce the glomerular filtration rate and increase the severity of the hypertension. Eventually uncontrolled hypertension associated with obesity can lead to severe vascular injury and complete loss of kidney function. Graphical Analysis of Arterial Pressure Control in Essential Hypertension. Figure 19–14 is a graphical analysis of essential hypertension. The curves of this figure are called sodium-loading renal function curves because the arterial pressure in each instance is increased very slowly, over many days or weeks, by gradually Normal Nonsalt-sensitive Salt-sensitive Salt intake and output (times normal) 6 5 4 High intake E B B1 3 Normal 2 Normal intake 1 D Essential hypertension A C 0 0 50 100 150 Arterial pressure (mm Hg) Figure 19–14 Analysis of arterial pressure regulation in (1) nonsalt-sensitive essential hypertension and (2) salt-sensitive essential hypertension. (Redrawn from Guyton AC, Coleman TG, Young DB, et al: Salt balance and long-term blood pressure control. Annu Rev Med 31:15, 1980. With permission, from the Annual Review of Medicine, ” 1980, by Annual Reviews http://www.AnnualReviews.org.) 229 increasing the level of sodium intake. The sodiumloading type of curve can be determined by increasing the level of sodium intake to a new level every few days, then waiting for the renal output of sodium to come into balance with the intake, and at the same time recording the changes in arterial pressure. When this procedure is used in essential hypertensive patients, two types of curves, shown to the right in Figure 19–14, can be recorded in essential hypertensive patients, one called (1) nonsalt-sensitive hypertension and the other (2) salt-sensitive hypertension. Note in both instances that the curves are shifted to the right, to a much higher pressure level than for normal people. Now, let us plot on this same graph (1) a normal level of salt intake and (2) a high level of salt intake representing 3.5 times the normal intake. In the case of the person with nonsalt-sensitive essential hypertension, the arterial pressure does not increase significantly when changing from normal salt intake to high salt intake. Conversely, in those patients who have salt-sensitive essential hypertension, the high salt intake significantly exacerbates the hypertension. Two additional points should be emphasized: (1) Salt-sensitivity of blood pressure is not an all-or-none characteristic—it is a quantitative characteristic, with some individuals being more salt-sensitive than others. (2) Salt-sensitivity of blood pressure is not a fixed characteristic; instead, blood pressure usually becomes more salt-sensitive as a person ages, especially after 50 or 60 years of age. The reason for the difference between nonsaltsensitive essential hypertension and salt-sensitive hypertension is presumably related to structural or functional differences in the kidneys of these two types of hypertensive patients. For example, salt-sensitive hypertension may occur with different types of chronic renal disease due to gradual loss of the functional units of the kidneys (the nephrons) or to normal aging as discussed in Chapter 31. Abnormal function of the renin-angiotensin system can also cause blood pressure to become salt-sensitive, as discussed previously in this chapter. Treatment of Essential Hypertension. Current guidelines for treating hypertension recommend, as a first step, lifestyle modifications that are aimed at increasing physical activity and weight loss in most patients. Unfortunately, many patients are unable to lose weight, and pharmacological treatment with antihypertensive drugs must be initiated. Two general classes of drugs are used to treat hypertension: (1) vasodilator drugs that increase renal blood flow and (2) natriuretic or diuretic drugs that decrease tubular reabsorption of salt and water. Vasodilator drugs usually cause vasodilation in many other tissues of the body as well as in the kidneys. Different ones act in one of the following ways: (1) by inhibiting sympathetic nervous signals to the kidneys or by blocking the action of the sympathetic transmitter substance on the renal vasculature, (2) by directly relaxing the smooth muscle of the renal vasculature, or (3) by blocking the action of the The Circulation Summary of the Integrated, Multifaceted System for Arterial Pressure Regulation By now, it is clear that arterial pressure is regulated not by a single pressure controlling system but instead by several interrelated systems, each of which performs a specific function. For instance, when a person bleeds severely so that the pressure falls suddenly, two problems confront the pressure control system. The first is survival, that is, to return the arterial pressure immediately to a high enough level that the person can live through the acute episode. The second is to return the blood volume eventually to its normal level so that the circulatory system can re-establish full normality, including return of the arterial pressure all the way back to its normal value, not merely back to a pressure level required for survival. In Chapter 18, we saw that the first line of defense against acute changes in arterial pressure is the nervous control system. In this chapter, we have emphasized a second line of defense achieved mainly by kidney mechanisms for long-term control of arterial pressure. However, there are other pieces to the puzzle. Figure 19–15 helps to put these together. Figure 19–15 shows the approximate immediate (seconds and minutes) and long-term (hours and days) control responses, expressed as feedback gain, of eight arterial pressure control mechanism. These mechanisms can be divided into three groups: (1) those that react rapidly, within seconds or minutes; (2) those that respond over an intermediate time period, minutes or hours; and (3) those that provide long-term arterial pressure regulation, days, months, and years. Let us see how they fit together as a total, integrated system for pressure control. Rapidly Acting Pressure Control Mechanisms, Acting Within Seconds or Minutes. The rapidly acting pressure control mechanisms are almost entirely acute nervous reflexes or other nervous responses. Note in Figure 19–15 the three mechanisms that show responses within seconds. They are (1) the baroreceptor feedback mechanism, (2) the central nervous system ischemic mechanism, and (3) the chemoreceptor mechanism. Not only do these mechanisms begin to react within seconds, but they are also powerful. After any acute fall in pressure, as might be caused by severe hemorrhage, the nervous mechanisms combine (1) to cause constriction of the veins and provide transfer of blood into the heart, Renin-angiotensin-vasoconstriction • CNS isc he Baroreceptors m ic re sp Chemorec eptor s re ess Str la on x a ti on se Renal – b 11 10 9 8 7 6 5 4 3 2 1 0 • !! volume pr lood es control sure renin-angiotensin system on the renal vasculature or renal tubules. Those drugs that reduce reabsorption of salt and water by the renal tubules include especially drugs that block active transport of sodium through the tubular wall; this blockage in turn also prevents the reabsorption of water, as explained earlier in the chapter. These natriuretic or diuretic drugs are discussed in greater detail in Chapter 31. Acute change in pressure at this time Unit IV Maximum feedback gain at optimal pressure 230 sterone A ldo ry id ift Flu sh illa p Ca 0 15 30 1 2 4 8 1632 1 2 4 816 1 2 4 8 16 • Seconds Minutes Hours Days Time after sudden change in pressure Figure 19–15 Approximate potency of various arterial pressure control mechanisms at different time intervals after onset of a disturbance to the arterial pressure. Note especially the infinite gain (∞) of the renal body fluid pressure control mechanism that occurs after a few weeks’ time. (Redrawn from Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Saunders Co, 1980.) (2) to cause increased heart rate and contractility of the heart to provide greater pumping capacity by the heart, and (3) to cause constriction of most peripheral arterioles to impede flow of blood out of the arteries; all these effects occur almost instantly to raise the arterial pressure back into a survival range. When the pressure suddenly rises too high, as might occur in response to rapid overadministration of a blood transfusion, the same control mechanisms operate in the reverse direction, again returning the pressure back toward normal. Pressure Control Mechanisms That Act After Many Minutes. Several pressure control mechanisms exhibit significant responses only after a few minutes following acute arterial pressure change. Three of these, shown in Figure 19–15, are (1) the renin-angiotensin vasoconstrictor mechanism, (2) stress-relaxation of the vasculature, and (3) shift of fluid through the tissue capillary walls in and out of the circulation to readjust the blood volume as needed. We have already described at length the role of the renin-angiotensin vasoconstrictor system to provide a semi-acute means for increasing the arterial pressure when this is needed. The stress-relaxation mechanism is demonstrated by the following example: When the pressure in the blood vessels becomes too high, they become stretched and keep on stretching more and more for minutes or hours; as a result, the pressure in Chapter 19 The Integrated System for Pressure Control the vessels falls toward normal. This continuing stretch of the vessels, called stress-relaxation, can serve as an intermediate-term pressure “buffer.” The capillary fluid shift mechanism means simply that any time capillary pressure falls too low, fluid is absorbed through the capillary membranes from the tissues into the circulation, thus building up the blood volume and increasing the pressure in the circulation. Conversely, when the capillary pressure rises too high, fluid is lost out of the circulation into the tissues, thus reducing the blood volume as well as virtually all the pressures throughout the circulation. These three intermediate mechanisms become mostly activated within 30 minutes to several hours. During this time, the nervous mechanisms usually become less and less effective, which explains the importance of these non-nervous, intermediate time pressure control measures. Long-Term Mechanisms for Arterial Pressure Regulation. The goal of this chapter has been to explain the role of the kidneys in long-term control of arterial pressure. To the far right in Figure 19–15 is shown the renal-blood volume pressure control mechanism (which is the same as the renal–body fluid pressure control mechanism), demonstrating that it takes a few hours to begin showing significant response. Yet it eventually develops a feedback gain for control of arterial pressure equal to infinity. This means that this mechanism can eventually return the arterial pressure all the way back, not merely partway back, to that pressure level that provides normal output of salt and water by the kidneys. By now, the reader should be familiar with this concept, which has been the major point of this chapter. It must also be remembered that many factors can affect the pressure-regulating level of the renal–body fluid mechanism. One of these, shown in Figure 19–15, is aldosterone. A decrease in arterial pressure leads within minutes to an increase in aldosterone secretion, and over the next hour or days, this plays an important role in modifying the pressure control characteristics of the renal–body fluid mechanism. Especially important is interaction of the renin-angiotensin system with the aldosterone and renal fluid mechanisms. For instance, a person’s salt intake varies tremendously from one day to another. We have seen in this chapter that the salt intake can decrease to as little as 1/10 normal or can increase to 10 to 15 times normal and yet the regulated level of the mean arterial pressure will change only a few millimeters of mercury if the renin-angiotensin-aldosterone system is fully operative. But, without a functional renin-angiotensin-aldosterone system, blood pressure becomes very sensitive to changes in salt intake. Thus, arterial pressure control begins with the lifesaving measures of the nervous 231 pressure controls, then continues with the sustaining characteristics of the intermediate pressure controls, and, finally, is stabilized at the long-term pressure level by the renal–body fluid mechanism. This long-term mechanism in turn has multiple interactions with the renin-angiotensin-aldosterone system, the nervous system, and several other factors that provide special blood pressure control capabilities for special purposes. References Chobanian AV, Bakris GL, Black HR, et al: Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 42:1206, 2003. Cowley AW J: Long-term control of arterial blood pressure. Physiol Rev 72:231, 1992. Granger JP, Alexander BT, Bennett WA, Khalil RA: Pathophysiology of pregnancy-induced hypertension. Am J Hypertens 14:178S, 2001. Granger JP, Alexander BT: Abnormal pressure-natriuresis in hypertension: role of nitric oxide. Acta Physiol Scand 168:161, 2000. Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Saunders Co, 1980. Guyton AC: Blood pressure control—special role of the kidneys and body fluids. Science 252:1813, 1991. Guyton AC, Coleman TG, Cowley AW Jr, et al: Arterial pressure regulation: overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med 52:584, 1972. Hall JE:The kidney, hypertension, and obesity. Hypertension 41:625, 2003. Hall JE, Brands MW, Henegar JR: Angiotensin II and longterm arterial pressure regulation: the overriding dominance of the kidney. J Am Soc Nephrol 10(Suppl 12):S258, 1999. Hall JE, Guyton AC, Brands MW: Pressure-volume regulation in hypertension. Kidney Int Suppl 55:S35, 1996. Hall JE, Jones DW, Kuo JJ, et al: Impact of the obesity epidemic on hypertension and renal disease. Curr Hypertens Rep 5:386, 2003. Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human hypertension. Cell 104:545, 2001. Manning RD Jr, Hu L, Tan DY, Meng S: Role of abnormal nitric oxide systems in salt-sensitive hypertension. Am J Hypertens 14:68S, 2001. Oparil S, Zaman MA, Calhoun DA: Pathogenesis of hypertension. Ann Intern Med 139:761, 2003. O’Shaughnessy KM, Karet FE: Salt handling and hypertension. J Clin Invest 113:1075, 2004. Reckelhoff JF: Gender differences in the regulation of blood pressure. Hypertension 37:1199, 2001. Rossier BC: Negative regulators of sodium transport in the kidney: key factors in understanding salt-sensitive hypertension? J Clin Invest 111:947, 2003. C H A P T E R 2 0 Cardiac Output, Venous Return, and Their Regulation Cardiac output is the quantity of blood pumped into the aorta each minute by the heart. This is also the quantity of blood that flows through the circulation. Cardiac output is perhaps the most important factor that we have to consider in relation to the circulation. Venous return is the quantity of blood flowing from the veins into the right atrium each minute. The venous return and the cardiac output must equal each other except for a few heartbeats at a time when blood is temporarily stored in or removed from the heart and lungs. Normal Values for Cardiac Output at Rest and During Activity Cardiac output varies widely with the level of activity of the body. The following factors, among others, directly affect cardiac output: (1) the basic level of body metabolism, (2) whether the person is exercising, (3) the person’s age, and (4) size of the body. For young, healthy men, resting cardiac output averages about 5.6 L/min. For women, this value is about 4.9 L/min. When one considers the factor of age as well—because with increasing age, body activity diminishes—the average cardiac output for the resting adult, in round numbers, is often stated to be almost exactly 5 L/min. Cardiac Index Experiments have shown that the cardiac output increases approximately in proportion to the surface area of the body.Therefore, cardiac output is frequently stated in terms of the cardiac index, which is the cardiac output per square meter of body surface area. The normal human being weighing 70 kilograms has a body surface area of about 1.7 square meters, which means that the normal average cardiac index for adults is about 3 L/min/m2 of body surface area. Effect of Age on Cardiac Output. Figure 20–1 shows the cardiac output, expressed as cardiac index, at different ages. Rising rapidly to a level greater than 4 L/min/m2 at age 10 years, the cardiac index declines to about 2.4 L/min/m2 at age 80 years. We will see later in the chapter that the cardiac output is regulated throughout life almost directly in proportion to the overall bodily metabolic activity. Therefore, the declining cardiac index is indicative of declining activity with age. Control of Cardiac Output by Venous Return—Role of the Frank-Starling Mechanism of the Heart When one states that cardiac output is controlled by venous return, this means that it is not the heart itself that is the primary controller of cardiac output. 232 2 2 15 10 5 0 0 0 10 20 30 40 50 60 70 Cardiac output and cardiac index 30 Oxygen consumption 4 25 3 20 15 Dexter Douglas Christensen Donald 10 5 0 0 1951 1922 1931 1055 2 1 0 200 400 600 800 1000 1200 14001600 Work output during exercise (kg-m/min) 1 1 35 Oxygen consumption (L/min) Cardiac index (L/min/m2 ) 3 3 Cardiac index (L/min/m2) 4 4 0 233 Cardiac Output, Venous Return, and Their Regulation Cardiac output (L/min/m2) Chapter 20 Figure 20–2 80 Age in years Figure 20–1 Cardiac index for the human being (cardiac output per square meter of surface area) at different ages. (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) Instead, it is the various factors of the peripheral circulation that affect flow of blood into the heart from the veins, called venous return, that are the primary controllers. The main reason peripheral factors are usually more important than the heart itself in controlling cardiac output is that the heart has a built-in mechanism that normally allows it to pump automatically whatever amount of blood that flows into the right atrium from the veins. This mechanism, called the Frank-Starling law of the heart, was discussed in Chapter 9. Basically, this law states that when increased quantities of blood flow into the heart, the increased blood stretches the walls of the heart chambers. As a result of the stretch, the cardiac muscle contracts with increased force, and this empties the extra blood that has entered from the systemic circulation. Therefore, the blood that flows into the heart is automatically pumped without delay into the aorta and flows again through the circulation. Another important factor, discussed in Chapter 10, is that stretching the heart causes the heart to pump faster—at an increased heart rate.That is, stretch of the sinus node in the wall of the right atrium has a direct effect on the rhythmicity of the node itself to increase heart rate as much as 10 to 15 per cent. In addition, the stretched right atrium initiates a nervous reflex called the Bainbridge reflex, passing first to the vasomotor center of the brain and then back to the heart by way of the sympathetic nerves and vagi, also to increase the heart rate. Effect of increasing levels of exercise to increase cardiac output (red solid line) and oxygen consumption (blue dashed line). (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) Under most normal unstressful conditions, the cardiac output is controlled almost entirely by peripheral factors that determine venous return. However, we shall see later in the chapter that if the returning blood does become more than the heart can pump, then the heart becomes the limiting factor that determines cardiac output. Cardiac Output Regulation Is the Sum of Blood Flow Regulation in All the Local Tissues of the Body—Tissue Metabolism Regulates Most Local Blood Flow The venous return to the heart is the sum of all the local blood flows through all the individual tissue segments of the peripheral circulation. Therefore, it follows that cardiac output regulation is the sum of all the local blood flow regulations. The mechanisms of local blood flow regulation were discussed in Chapter 17. In most tissues, blood flow increases mainly in proportion to each tissue’s metabolism. For instance, local blood flow almost always increases when tissue oxygen consumption increases; this effect is demonstrated in Figure 20–2 for different levels of exercise. Note that at each increasing level of work output during exercise, the oxygen consumption and the cardiac output increase in parallel to each other. To summarize, cardiac output is determined by the sum of all the various factors throughout the body that control local blood flow. All the local blood flows summate to form the venous return, and the heart automatically pumps this returning blood back into the arteries to flow around the system again. 25 20 out put 50 Cardiac output (L/min) Anemia 100 ac The Circulation Hypothyroidism di r 150 Removal of both arms and legs 200 Pulmonary disease Paget’s disease Normal Beriberi AV shunts Hyperthyroidism Unit IV Ca Arterial pressure or cardiac output (percentage of normal) 234 Hypereffective 15 Normal 10 Hypoeffective 5 0 40 60 80 100 120 140 160 0 –4 Total peripheral resistance (percentage of normal) 0 +4 +8 Right atrial pressure (mm Hg) Figure 20–3 Figure 20–4 Chronic effect of different levels of total peripheral resistance on cardiac output, showing a reciprocal relationship between total peripheral resistance and cardiac output. (Redrawn from Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Saunders Co, 1980.) Effect of Total Peripheral Resistance on the Long-Term Cardiac Output Level. Figure 20–3 is the same as Figure 19–5. It is repeated here to illustrate an extremely important principle in cardiac output control: Under most normal conditions, the long-term cardiac output level varies reciprocally with changes in total peripheral resistance. Note in Figure 20–3 that when the total peripheral resistance is exactly normal (at the 100 per cent mark in the figure), the cardiac output is also normal. Then, when the total peripheral resistance increases above normal, the cardiac output falls; conversely, when the total peripheral resistance decreases, the cardiac output increases. One can easily understand this by reconsidering one of the forms of Ohm’s law, as expressed in Chapter 14: Cardiac Output = Arterial Pressure Total Peripheral Resistance The meaning of this formula, and of Figure 20–3, is simply the following: Any time the long-term level of total peripheral resistance changes (but no other functions of the circulation change), the cardiac output changes quantitatively in exactly the opposite direction. The Heart Has Limits for the Cardiac Output That It Can Achieve There are definite limits to the amount of blood that the heart can pump, which can be expressed quantitatively in the form of cardiac output curves. Cardiac output curves for the normal heart and for hypoeffective and hypereffective hearts. (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) Figure 20–4 demonstrates the normal cardiac output curve, showing the cardiac output per minute at each level of right atrial pressure. This is one type of cardiac function curve, which was discussed in Chapter 9. Note that the plateau level of this normal cardiac output curve is about 13 L/min, 2.5 times the normal cardiac output of about 5 L/min. This means that the normal human heart, functioning without any special stimulation, can pump an amount of venous return up to about 2.5 times the normal venous return before the heart becomes a limiting factor in the control of cardiac output. Shown in Figure 20–4 are several other cardiac output curves for hearts that are not pumping normally. The uppermost curves are for hypereffective hearts that are pumping better than normal. The lowermost curves are for hypoeffective hearts that are pumping at levels below normal. Factors That Can Cause Hypereffective Heart Only two types of factors usually can make the heart a better pump than normal. They are (1) nervous stimulation and (2) hypertrophy of the heart muscle. Effect of Nervous Excitation to Increase Heart Pumping. In Chapter 9, we saw that a combination of (1) sympathetic stimulation and (2) parasympathetic inhibition does two things to increase the pumping effectiveness of the heart: (1) it greatly increases the heart rate— sometimes, in young people, from the normal level of 235 Cardiac Output, Venous Return, and Their Regulation 72 beats/min up to 180 to 200 beats/min—and (2) it increases the strength of heart contraction (which is called increased “contractility”) to twice its normal strength. Combining these two effects, maximal nervous excitation of the heart can raise the plateau level of the cardiac output curve to almost twice the plateau of the normal curve, as shown by the 25-liter level of the uppermost curve in Figure 20–4. Cardiac output (L/min) Chapter 20 6 5 4 3 2 0 Dinitrophenol With pressure control A long-term increased workload, but not so much excess load that it damages the heart, causes the heart muscle to increase in mass and contractile strength in the same way that heavy exercise causes skeletal muscles to hypertrophy. For instance, it is common for the hearts of marathon runners to be increased in mass by 50 to 75 per cent. This increases the plateau level of the cardiac output curve, sometimes 60 to 100 per cent, and therefore allows the heart to pump much greater than usual amounts of cardiac output. When one combines nervous excitation of the heart and hypertrophy, as occurs in marathon runners, the total effect can allow the heart to pump as much 30 to 40 L/min, about 21/2 times normal; this increased level of pumping is one of the most important factors in determining the runner’s running time. Without pressure control Factors That Cause a Hypoeffective Heart Any factor that decreases the heart’s ability to pump blood causes hypoeffectivity. Some of the factors that can do this are the following: Coronary artery blockage, causing a “heart attack” Inhibition of nervous excitation of the heart Pathological factors that cause abnormal heart rhythm or rate of heartbeat Valvular heart disease Increased arterial pressure against which the heart must pump, such as in hypertension Congenital heart disease Myocarditis Cardiac hypoxia What Is the Role of the Nervous System in Controlling Cardiac Output? Importance of the Nervous System in Maintaining the Arterial Pressure When the Venous Return and Cardiac Output Increase Figure 20–5 shows an important difference in cardiac output control with and without a functioning autonomic nervous system. The solid curves demonstrate the effect in the normal dog of intense dilation of the peripheral blood vessels caused by administering the drug dinitrophenol, which increased the metabolism of virtually all tissues of the body about fourfold. Note that with nervous control to keep the arterial pressure from falling, dilating all the peripheral blood vessels caused almost no change in arterial pressure but increased the cardiac output almost fourfold. Arterial pressure (mm Hg) Increased Pumping Effectiveness Caused by Heart Hypertrophy. 100 75 50 0 0 10 20 30 Minutes Figure 20–5 Experiment in a dog to demonstrate the importance of nervous maintenance of the arterial pressure as a prerequisite for cardiac output control. Note that with pressure control, the metabolic stimulant dinitrophenol increases cardiac output greatly; without pressure control, the arterial pressure falls and the cardiac output rises very little. (Drawn from experiments by Dr. M. Banet.) However, after autonomic control of the nervous system had been blocked, none of the normal circulatory reflexes for maintaining the arterial pressure could function, and vasodilation of the vessels with dinitrophenol (dashed curves) then caused a profound fall in arterial pressure to about one half normal, and the cardiac output rose only 1.6-fold instead of 4-fold. Thus, maintenance of a normal arterial pressure by the nervous reflexes, by mechanisms explained in Chapter 18, is essential to achieve high cardiac outputs when the peripheral tissues dilate their vessels to increase the venous return. Effect of the Nervous System to Increase the Arterial Pressure During Exercise. During exercise, intense increase in metabolism in active skeletal muscles acts directly on the muscle arterioles to relax them and to allow adequate oxygen and other nutrients needed to sustain muscle contraction. Obviously, this greatly decreases the total peripheral resistance, which normally would decrease the arterial pressure also. However, the nervous system immediately compensates. The same brain activity that sends motor signals to the muscles sends simultaneous signals into the autonomic nervous centers of the brain to excite circulatory activity, causing large vein constriction, increased heart rate, and increased contractility of the heart. All these changes acting together increase the arterial pressure above normal, which in turn forces still more blood flow through the active muscles. In summary, when local tissue vessels dilate and thereby increase venous return and cardiac output 236 Unit IV The Circulation and at the same time increase the cardiac output to above normal. 1. Beriberi. This disease is caused by insufficient quantity of the vitamin thiamine (vitamin B1) in the diet. Lack of this vitamin causes diminished ability of the tissues to use some cellular nutrients, and the local tissue blood flow mechanisms in turn cause marked compensatory peripheral vasodilation. Sometimes the total peripheral resistance decreases to as little as one-half normal. Consequently, the long-term levels of venous return and cardiac output also often increase to twice normal. 2. Arteriovenous fistula (shunt). Earlier, we pointed out that whenever a fistula (also called an AV shunt) occurs between a major artery and a major vein, tremendous amounts of blood flow directly from the artery into the vein. This, too, greatly decreases the total peripheral resistance and, likewise, increases the venous return and cardiac output. 3. Hyperthyroidism. In hyperthyroidism, the metabolism of most tissues of the body becomes greatly increased. Oxygen usage increases, and vasodilator products are released from the tissues. Therefore, the total peripheral resistance decreases markedly because of the local tissue blood flow control reactions throughout the body; consequently, the venous return and cardiac output often increase to 40 to 80 per cent above normal. 4. Anemia. In anemia, two peripheral effects greatly decrease the total peripheral resistance. One of these is reduced viscosity of the blood, resulting from the decreased concentration of red blood above normal, the nervous system plays an exceedingly important role in preventing the arterial pressure from falling to disastrously low levels. In fact, during exercise, the nervous system goes even further, providing additional signals to raise the arterial pressure even above normal, which serves to increase the cardiac output an extra 30 to 100 per cent. Pathologically High and Pathologically Low Cardiac Outputs In healthy human beings, the cardiac outputs are surprisingly constant from one person to another. However, multiple clinical abnormalities can cause either high or low cardiac outputs. Some of the more important of these are shown in Figure 20–6. High Cardiac Output Caused by Reduced Total Peripheral Resistance The left side of Figure 20–6 identifies conditions that commonly cause cardiac outputs higher than normal. One of the distinguishing features of these conditions is that they all result from chronically reduced total peripheral resistance. None of them result from excessive excitation of the heart itself, which we will explain subsequently. For the present, let us look at some of the conditions that can decrease the peripheral resistance 200 7 175 6 125 4 Control (young adults) 100 2 Cardiac shock (7) Traumatic shock (4) Severe valve disease (29) Mild shock (4) Myocardial infarction (22) Mild valve disease (31) 3 Hypertension (47) Control (young adults) (308) Paget’s disease (9) Pregnancy (46) Pulmonary disease (29) 0 Anxiety (21) 25 Beriberi (5) 50 Anemia (75) 75 Hyperthyroidism (29) Average 45-year-old adult Cardiac index (L/min/m2) 5 AV shunts (33) Cardiac output (per cent of control) 150 1 0 Figure 20–6 Cardiac output in different pathological conditions. The numbers in parentheses indicate number of patients studied in each condition. (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) Chapter 20 Cardiac Output, Venous Return, and Their Regulation cells. The other is diminished delivery of oxygen to the tissues, which causes local vasodilation. As a consequence, the cardiac output increases greatly. Any other factor that decreases the total peripheral resistance chronically also increases the cardiac output. Low Cardiac Output Figure 20–6 shows at the far right several conditions that cause abnormally low cardiac output. These conditions fall into two categories: (1) those abnormalities that cause the pumping effectiveness of the heart to fall too low and (2) those that cause venous return to fall too low. Decreased Cardiac Output Caused by Cardiac Factors. When- ever the heart becomes severely damaged, regardless of the cause, its limited level of pumping may fall below that needed for adequate blood flow to the tissues. Some examples of this include (1) severe coronary blood vessel blockage and consequent myocardial infarction, (2) severe valvular heart disease, (3) myocarditis, (4) cardiac tamponade, and (5) cardiac metabolic derangements. The effects of several of these are shown on the right in Figure 20–6, demonstrating the low cardiac outputs that result. When the cardiac output falls so low that the tissues throughout the body begin to suffer nutritional deficiency, the condition is called cardiac shock. This is discussed fully in Chapter 22 in relation to cardiac failure. Decrease in Cardiac Output Caused by Non-cardiac Peripheral Factors—Decreased Venous Return. Anything that inter- feres with venous return also can lead to decreased cardiac output. Some of these factors are the following: 1. Decreased blood volume. By far, the most common non-cardiac peripheral factor that leads to decreased cardiac output is decreased blood volume, resulting most often from hemorrhage. It is clear why this condition decreases the cardiac output: Loss of blood decreases the filling of the vascular system to such a low level that there is not enough blood in the peripheral vessels to create peripheral vascular pressures high enough to push the blood back to the heart. 2. Acute venous dilation. On some occasions, the peripheral veins become acutely vasodilated. This results most often when the sympathetic nervous system suddenly becomes inactive. For instance, fainting often results from sudden loss of sympathetic nervous system activity, which causes the peripheral capacitative vessels, especially the veins, to dilate markedly. This decreases the filling pressure of the vascular system because the blood volume can no longer create adequate pressure in the now flaccid peripheral blood vessels. As a result, the blood “pools” in the vessels and does not return to the heart. 3. Obstruction of the large veins. On rare occasions, the large veins leading into the heart become obstructed, so that the blood in the peripheral vessels cannot flow back into the heart. Consequently, the cardiac output falls markedly. 4. Decreased tissue mass, especially decreased skeletal muscle mass. With normal aging or with prolonged periods of physical inactivity, there is usually a reduction in the size of the skeletal muscles. This, in turn, decreases the total oxygen consumption and 237 blood flow needs of the muscles, resulting in decreases in skeletal muscle blood flow and cardiac output. Regardless of the cause of low cardiac output, whether it be a peripheral factor or a cardiac factor, if ever the cardiac output falls below that level required for adequate nutrition of the tissues, the person is said to suffer circulatory shock. This condition can be lethal within a few minutes to a few hours. Circulatory shock is such an important clinical problem that it is discussed in detail in Chapter 24. A More Quantitative Analysis of Cardiac Output Regulation Our discussion of cardiac output regulation thus far is adequate for understanding the factors that control cardiac output in most simple conditions. However, to understand cardiac output regulation in especially stressful situations, such as the extremes of exercise, cardiac failure, and circulatory shock, a more complex quantitative analysis is presented in the following sections. To perform the more quantitative analysis, it is necessary to distinguish separately the two primary factors concerned with cardiac output regulation: (1) the pumping ability of the heart, as represented by cardiac output curves, and (2) the peripheral factors that affect flow of blood from the veins into the heart, as represented by venous return curves. Then one can put these curves together in a quantitative way to show how they interact with each other to determine cardiac output, venous return, and right atrial pressure at the same time. Cardiac Output Curves Used in the Quantitative Analysis Some of the cardiac output curves used to depict quantitative heart pumping effectiveness have already been shown in Figure 20–4. However, an additional set of curves is required to show the effect on cardiac output caused by changing external pressures on the outside of the heart, as explained in the next section. Effect of External Pressure Outside the Heart on Cardiac Output Curves. Figure 20–7 shows the effect of changes in exter- nal cardiac pressure on the cardiac output curve. The normal external pressure is equal to the normal intrapleural pressure (the pressure in the chest cavity), which is -4 mm Hg. Note in the figure that a rise in intrapleural pressure, to -2 mm Hg, shifts the entire cardiac output curve to the right by the same amount. This shift occurs because to fill the cardiac chambers with blood requires an extra 2 mm Hg right atrial pressure to overcome the increased pressure on the outside of the heart. Likewise, an increase in intrapleural pressure to +2 mm Hg requires a 6 mm Hg increase in right atrial pressure from the normal -4 mm Hg, which shifts the entire cardiac output curve 6 mm Hg to the right. Some of the factors that can alter the intrapleural pressure and thereby shift the cardiac output curve are the following: 1. Cyclical changes of intrapleural pressure during respiration, which are about ±2 mm Hg during normal breathing but can be as much as ±50 mm Hg during strenuous breathing. 238 Unit IV The Circulation Hypereffective–increased intrapleural pressure al pr essu re = + l eu r e onad r ap Int I n tr a mp iac t Card N 0 –4 0 +4 +8 +12 Right atrial pressure (mm Hg) 15 Cardiac output (L/min) Hg 2m m u r al s s ure press ure = – –5 Hg aple ressu re = u r al p ap le Intr ma l (in 5 traple ural pre 10 ) Hg 2m m mm . =– 4m m 5 or Cardiac output (L/min) 15 Normal 10 Hypoeffective–reduced intrapleural pressure 5 0 –4 0 +4 +8 +12 Right atrial pressure (mm Hg) Figure 20–7 Cardiac output curves at different levels of intrapleural pressure and at different degrees of cardiac tamponade. (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) 2. Breathing against a negative pressure, which shifts the curve to a more negative right atrial pressure (to the left). 3. Positive pressure breathing, which shifts the curve to the right. 4. Opening the thoracic cage, which increases the intrapleural pressure to 0 mm Hg and shifts the cardiac output curve to the right 4 mm Hg. 5. Cardiac tamponade, which means accumulation of a large quantity of fluid in the pericardial cavity around the heart with resultant increase in external cardiac pressure and shifting of the curve to the right. Note in Figure 20–7 that cardiac tamponade shifts the upper parts of the curves farther to the right than the lower parts because the external “tamponade” pressure rises to higher values as the chambers of the heart fill to increased volumes during high cardiac output. Combinations of Different Patterns of Cardiac Output Curves. Figure 20–8 shows that the final cardiac output curve can change as a result of simultaneous changes in (a) external cardiac pressure and (b) effectiveness of the heart as a pump. Thus, by knowing what is happening to the external pressure as well as to the capability of the heart as a pump, one can express the momentary ability of the heart to pump blood by a single cardiac output curve. Venous Return Curves There remains the entire systemic circulation that must be considered before total analysis of cardiac regulation can be achieved. To analyze the function of the systemic circulation, we first remove the heart and lungs from the circulation of an animal and replace them with a pump and artificial oxygenator system. Then, different factors, such blood volume, vascular resistances, and central venous pressure in the right atrium, are altered to determine how the systemic circulation operates in different circulatory states. In these studies, one finds Figure 20–8 Combinations of two major patterns of cardiac output curves showing the effect of alterations in both extracardiac pressure and effectiveness of the heart as a pump. (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) three principal factors that affect venous return to the heart from the systemic circulation. They are as follows: 1. Right atrial pressure, which exerts a backward force on the veins to impede flow of blood from the veins into the right atrium. 2. Degree of filling of the systemic circulation (measured by the mean systemic filling pressure), which forces the systemic blood toward the heart (this is the pressure measured everywhere in the systemic circulation when all flow of blood is stopped—we discuss this in detail later). 3. Resistance to blood flow between the peripheral vessels and the right atrium. These factors can all be expressed quantitatively by the venous return curve, as we explain in the next sections. Normal Venous Return Curve In the same way that the cardiac output curve relates pumping of blood by the heart to right atrial pressure, the venous return curve relates venous return also to right atrial pressure—that is, the venous flow of blood into the heart from the systemic circulation at different levels of right atrial pressure. The curve in Figure 20–9 is the normal venous return curve. This curve shows that when heart pumping capability becomes diminished and causes the right atrial pressure to rise, the backward force of the rising atrial pressure on the veins of the systemic circulation decreases venous return of blood to the heart. If all nervous circulatory reflexes are prevented from acting, venous return decreases to zero when the right atrial pressure rises to about +7 mm Hg. Such a slight rise in right atrial pressure causes a drastic decrease in venous return because the systemic circulation is a distensible bag, so that any increase in back pressure causes blood to dam up in this bag instead of returning to the heart. At the same time that the right atrial pressure is rising and causing venous stasis, pumping by the heart also Normal venous return curve. The plateau is caused by collapse of the large veins entering the chest when the right atrial pressure falls below atmospheric pressure. Note also that venous return becomes zero when the right atrial pressure rises to equal the mean systemic filling pressure. Plateau Transitional zone 5 Mean systemic filling pressure Do wn slo pe 0 –8 approaches zero because of decreasing venous return. Both the arterial and the venous pressures come to equilibrium when all flow in the systemic circulation ceases at a pressure of 7 mm Hg, which, by definition, is the mean systemic filling pressure (Psf). Plateau in the Venous Return Curve at Negative Atrial Pressures—Caused by Collapse of the Large Veins. When the right atrial pressure falls below zero—that is, below atmospheric pressure—further increase in venous return almost ceases. And by the time the right atrial pressure has fallen to about -2 mm Hg, the venous return will have reached a plateau. It remains at this plateau level even though the right atrial pressure falls to -20 mm Hg, -50 mm Hg, or even further.This plateau is caused by collapse of the veins entering the chest. Negative pressure in the right atrium sucks the walls of the veins together where they enter the chest, which prevents any additional flow of blood from the peripheral veins. Consequently, even very negative pressures in the right atrium cannot increase venous return significantly above that which exists at a normal atrial pressure of 0 mm Hg. Mean Circulatory Filling Pressure and Mean Systemic Filling Pressure, and Their Effect on Venous Return When heart pumping is stopped by shocking the heart with electricity to cause ventricular fibrillation or is stopped in any other way, flow of blood everywhere in the circulation ceases a few seconds later.Without blood flow, the pressures everywhere in the circulation become equal. This equilibrated pressure level is called the mean circulatory filling pressure. –4 0 +4 +8 Right atrial pressure (mm Hg) Mean circulatory filling pressure (mm Hg) Figure 20–9 239 Cardiac Output, Venous Return, and Their Regulation Venous return (L/min) Chapter 20 Strong sympathetic stimulation Normal circulatory system Complete sympathetic inhibition Normal volume 14 12 10 8 6 4 2 0 –0 1000 2000 3000 4000 5000 6000 7000 Volume (ml) Figure 20–10 Effect of changes in total blood volume on the mean circulatory filling pressure (i.e., “volume-pressure curves” for the entire circulatory system). These curves also show the effects of strong sympathetic stimulation and complete sympathetic inhibition. Effect of Blood Volume on Mean Circulatory Filling Pressure. Effect of Sympathetic Nervous Stimulation of the Circulation on Mean Circulatory Filling Pressure. The green curve and blue The greater the volume of blood in the circulation, the greater is the mean circulatory filling pressure because extra blood volume stretches the walls of the vasculature. The red curve in Figure 20–10 shows the approximate normal effect of different levels of blood volume on the mean circulatory filling pressure. Note that at a blood volume of about 4000 milliliters, the mean circulatory filling pressure is close to zero because this is the “unstressed volume” of the circulation, but at a volume of 5000 milliliters, the filling pressure is the normal value of 7 mm Hg. Similarly, at still higher volumes, the mean circulatory filling pressure increases almost linearly. curve in Figure 20–10 show the effects, respectively, of high and low levels of sympathetic nervous activity on the mean circulatory filling pressure. Strong sympathetic stimulation constricts all the systemic blood vessels as well as the larger pulmonary blood vessels and even the chambers of the heart. Therefore, the capacity of the system decreases, so that at each level of blood volume, the mean circulatory filling pressure is increased. At normal blood volume, maximal sympathetic stimulation increases the mean circulatory filling pressure from 7 mm Hg to about 2.5 times that value, or about 17 mm Hg. 240 Unit IV The Circulation Conversely, complete inhibition of the sympathetic nervous system relaxes both the blood vessels and the heart, decreasing the mean circulatory filling pressure from the normal value of 7 mm Hg down to about 4 mm Hg. Before leaving Figure 20–10, note specifically how steep the curves are.This means that even slight changes in blood volume or slight changes in the capacity of the system caused by various levels of sympathetic activity can have large effects on the mean circulatory filling pressure. Mean Systemic Filling Pressure and Its Relation to Mean Circulatory Filling Pressure. The mean systemic filling pressure, Psf, is slightly different from the mean circulatory filling pressure. It is the pressure measured everywhere in the systemic circulation after blood flow has been stopped by clamping the large blood vessels at the heart, so that the pressures in the systemic circulation can be measured independently from those in the pulmonary circulation. The mean systemic pressure, although almost impossible to measure in the living animal, is the important pressure for determining venous return. The mean systemic filling pressure, however, is almost always nearly equal to the mean circulatory filling pressure because the pulmonary circulation has less than one eighth as much capacitance as the systemic circulation and only about one tenth as much blood volume. Effect on the Venous Return Curve of Changes in Mean Systemic Filling Pressure. Figure 20–11 shows the effects on the Venous return (L/min) venous return curve caused by increasing or decreasing the mean systemic filling pressure (Psf). Note in Figure 20–11 that the normal mean systemic filling pressure is 7 mm Hg. Then, for the uppermost curve in the figure, the mean systemic filling pressure has been increased to 14 mm Hg, and for the lowermost curve, has been decreased to 3.5 mm Hg. These curves demonstrate that the greater the mean systemic filling pressure (which also means the greater the “tightness” with which the circulatory system is filled with blood) the more the venous return curve shifts upward and to the right. 10 Psf = 3.5 Psf = 7 No 5 Psf = 14 rm al 0 –4 0 +4 +8 +12 Conversely, the lower the mean systemic filling pressure, the more the curve shifts downward and to the left. To express this another way, the greater the system is filled, the easier it is for blood to flow into the heart. The less the filling, the more difficult it is for blood to flow into the heart. “Pressure Gradient for Venous Return”—When This Is Zero, There Is No Venous Return. When the right atrial pressure rises to equal the mean systemic filling pressure, there is no longer any pressure difference between the peripheral vessels and the right atrium. Consequently, there can no longer be any blood flow from any peripheral vessels back to the right atrium. However, when the right atrial pressure falls progressively lower than the mean systemic filling pressure, the flow to the heart increases proportionately, as one can see by studying any of the venous return curves in Figure 20–11. That is, the greater the difference between the mean systemic filling pressure and the right atrial pressure, the greater becomes the venous return. Therefore, the difference between these two pressures is called the pressure gradient for venous return. Resistance to Venous Return In the same way that mean systemic filling pressure represents a pressure pushing venous blood from the periphery toward the heart, there is also resistance to this venous flow of blood. It is called the resistance to venous return. Most of the resistance to venous return occurs in the veins, although some occurs in the arterioles and small arteries as well. Why is venous resistance so important in determining the resistance to venous return? The answer is that when the resistance in the veins increases, blood begins to be dammed up, mainly in the veins themselves. But the venous pressure rises very little because the veins are highly distensible. Therefore, this rise in venous pressure is not very effective in overcoming the resistance, and blood flow into the right atrium decreases drastically. Conversely, when arteriolar and small artery resistances increase, blood accumulates in the arteries, which have a capacitance only 1/30 as great as that of the veins. Therefore, even slight accumulation of blood in the arteries raises the pressure greatly—30 times as much as in the veins—and this high pressure does overcome much of the increased resistance. Mathematically, it turns out that about two thirds of the so-called “resistance to venous return” is determined by venous resistance, and about one third by the arteriolar and small artery resistance. Venous return can be calculated by the following formula: Right atrial pressure (mm Hg) VR = Figure 20–11 Venous return curves showing the normal curve when the mean systemic filling pressure (Psf) is 7 mm Hg, and showing the effect of altering the Psf to either 3.5 or 14 mm Hg. (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) Psf - PRA RVR in which VR is venous return, Psf is mean systemic filling pressure, PRA is right atrial pressure, and RVR is resistance to venous return. In the healthy human adult, the values for these are as follows: venous return equals 5 L/min, mean systemic filling pressure equals 7 mm Hg, right atrial pressure equals 0 mm Hg, and resistance to venous return equals 1.4 mm Hg per liter of blood flow. Chapter 20 241 Cardiac Output, Venous Return, and Their Regulation 20 Normal resistance 2 ¥ resistance 1/2 resistance Venous return (L/min) 15 1/ 10 2 re sis ta nc Norm al r es ista nc e 2 ¥ resist ance e Venous return (L/min) 15 5 1/3 resistance 10 5 Psf = 10.5 Psf = 10 Psf = 2.3 Psf = 7 0 –4 0 Psf = 7 +4 +8 +12 Right atrial pressure (mm Hg) 0 –4 0 +4 +8 Right atrial pressure (mm Hg) Figure 20–13 Figure 20–12 Venous return curves depicting the effect of altering the “resistance to venous return.” Psf, mean systemic filling pressure. (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) Effect of Resistance to Venous Return on the Venous Return Curve. Figure 20–12 demonstrates the effect of different levels of resistance to venous return on the venous return curve, showing that a decrease in this resistance to one-half normal allows twice as much flow of blood and, therefore, rotates the curve upward to twice as great a slope. Conversely, an increase in resistance to twice normal rotates the curve downward to one-half as great a slope. Note also that when the right atrial pressure rises to equal the mean systemic filling pressure, venous return becomes zero at all levels of resistance to venous return because when there is no pressure gradient to cause flow of blood, it makes no difference what the resistance is in the circulation; the flow is still zero. Therefore, the highest level to which the right atrial pressure can rise, regardless of how much the heart might fail, is equal to the mean systemic filling pressure. Combinations of Venous Return Curve Patterns. Figure 20–13 shows effects on the venous return curve caused by simultaneous changes in mean systemic pressure (Psf) and resistance to venous return, demonstrating that both these factors can operate simultaneously. Analysis of Cardiac Output and Right Atrial Pressure, Using Simultaneous Cardiac Output and Venous Return Curves In the complete circulation, the heart and the systemic circulation must operate together. This means that (1) the venous return from the systemic circulation must Combinations of the major patterns of venous return curves, showing the effects of simultaneous changes in mean systemic filling pressure (Psf) and in “resistance to venous return.” (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) equal the cardiac output from the heart and (2) the right atrial pressure is the same for both the heart and the systemic circulation. Therefore, one can predict the cardiac output and right atrial pressure in the following way: (1) Determine the momentary pumping ability of the heart and depict this in the form of a cardiac output curve; (2) determine the momentary state of flow from the systemic circulation into the heart and depict this in the form of a venous return curve; and (3) “equate” these curves against each other, as shown in Figure 20–14. Two curves in the figure depict the normal cardiac output curve (red line) and the normal venous return curve (blue line). There is only one point on the graph, point A, at which the venous return equals the cardiac output and at which the right atrial pressure is the same for both the heart and the systemic circulation. Therefore, in the normal circulation, the right atrial pressure, cardiac output, and venous return are all depicted by point A, called the equilibrium point, giving a normal value for cardiac output of 5 liters per minute and a right atrial pressure of 0 mm Hg . Effect of Increased Blood Volume on Cardiac Output. A sudden increase in blood volume of about 20 per cent increases the cardiac output to about 2.5 to 3 times normal. An analysis of this effect is shown in Figure 20–14. Immediately on infusing the large quantity of extra blood, the increased filling of the system causes the mean systemic filling pressure (Psf) to increase to 16 mm Hg, which shifts the venous return curve to the right. At the same time, the increased blood volume distends the blood vessels, thus reducing their resistance and thereby reducing the resistance to venous return, which rotates the curve upward. As a result of these two effects, the venous return curve of Figure 20–14 is shifted to the Unit IV The Circulation 20 15 B 10 A 5 Psf = 7 Psf = 16 0 –4 0 +4 +8 +12 Right atrial pressure (mm Hg) +16 Cardiac output and venous return (L/min) Cardiac output and venous return (L/min) 242 25 Maximal sympathetic stimulation Moderate sympathetic stimulation 20 Normal Spinal anesthesia 15 D 10 C A 5 B 0 –4 0 +4 +8 +12 Right atrial pressure (mm Hg) +16 Figure 20–14 The two solid curves demonstrate an analysis of cardiac output and right atrial pressure when the cardiac output (red line) and venous return (blue line) curves are normal. Transfusion of blood equal to 20 per cent of the blood volume causes the venous return curve to become the dashed curve; as a result, the cardiac output and right atrial pressure shift from point A to point B. Psf, mean systemic filling pressure. right. This new curve equates with the cardiac output curve at point B, showing that the cardiac output and venous return increase 2.5 to 3 times, and that the right atrial pressure rises to about +8 mm Hg. Further Compensatory Effects Initiated in Response to Increased Blood Volume. The greatly increased cardiac output caused by increased blood volume lasts for only a few minutes because several compensatory effects immediately begin to occur: (1) The increased cardiac output increases the capillary pressure so that fluid begins to transude out of the capillaries into the tissues, thereby returning the blood volume toward normal. (2) The increased pressure in the veins causes the veins to continue distending gradually by the mechanism called stress-relaxation, especially causing the venous blood reservoirs, such as the liver and spleen, to distend, thus reducing the mean systemic pressure. (3) The excess blood flow through the peripheral tissues causes autoregulatory increase in the peripheral resistance, thus increasing the resistance to venous return. These factors cause the mean systemic filling pressure to return back toward normal and the resistance vessels of the systemic circulation to constrict. Therefore, gradually, over a period of 10 to 40 minutes, the cardiac output returns almost to normal. Effect of Sympathetic Stimulation on Cardiac Output. Sympathetic stimulation affects both the heart and the systemic circulation: (1) It makes the heart a stronger pump. (2) In the systemic circulation, it increases the mean systemic filling pressure because of contraction of the peripheral vessels—especially the veins—and it increases the resistance to venous return. In Figure 20–15, the normal cardiac output and venous return curves are depicted; these equate with Figure 20–15 Analysis of the effect on cardiac output of (1) moderate sympathetic stimulation (from point A to point C), (2) maximal sympathetic stimulation (point D), and (3) sympathetic inhibition caused by total spinal anesthesia (point B). (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) each other at point A, which represents a normal venous return and cardiac output of 5 L/min and a right atrial pressure of 0 min Hg. Note in the figure that maximal sympathetic stimulation (green curves) increases the mean systemic filling pressure to 17 mm Hg (depicted by the point at which the venous return curve reaches the zero venous return level).And the sympathetic stimulation also increases pumping effectiveness of the heart by nearly 100 per cent. As a result, the cardiac output rises from the normal value at equilibrium point A to about double normal at equilibrium point D—and yet the right atrial pressure hardly changes. Thus, different degrees of sympathetic stimulation can increase the cardiac output progressively to about twice normal for short periods of time, until other compensatory effects occur within seconds or minutes. Effect of Sympathetic Inhibition on Cardiac Output. The sym- pathetic nervous system can be blocked by inducing total spinal anesthesia or by using some drug, such as hexamethonium, that blocks transmission of nerve signals through the autonomic ganglia. The lowermost curves in Figure 20–15 show the effect of sympathetic inhibition caused by total spinal anesthesia, demonstrating that (1) the mean systemic filling pressure falls to about 4 mm Hg and (2) the effectiveness of the heart as a pump decreases to about 80 per cent of normal. The cardiac output falls from point A to point B, which is a decrease to about 60 per cent of normal. Effect of Opening a Large Arteriovenous Fistula. Figure 20–16 shows various stages of circulatory changes that occur after opening a large arteriovenous fistula, that is, after making an opening directly between a large artery and a large vein. 1. The two red curves crossing at point A show the normal condition. Chapter 20 Flow (L/min) D 20 Cardiac output and venous return (L/min) 243 Cardiac Output, Venous Return, and Their Regulation C 15 B 20 15 10 5 0 0 10 A 5 1 Seconds 2 Figure 20–17 Pulsatile blood flow in the root of the aorta recorded using an electromagnetic flowmeter. 0 –4 0 +4 +8 Right atrial pressure (mm Hg) +12 Figure 20–16 Analysis of successive changes in cardiac output and right atrial pressure in a human being after a large arteriovenous (AV) fistula is suddenly opened. The stages of the analysis, as shown by the equilibrium points, are A, normal conditions; B, immediately after opening the AV fistula; C, 1 minute or so after the sympathetic reflexes have become active; and D, several weeks after the blood volume has increased and the heart has begun to hypertrophy. (Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.) 2. The curves crossing at point B show the circulatory condition immediately after opening the large fistula. The principal effects are (1) a sudden and precipitous rotation of the venous return curve upward caused by the large decrease in resistance to venous return when blood is allowed to flow with almost no impediment directly from the large arteries into the venous system, bypassing most of the resistance elements of the peripheral circulation, and (2) a slight increase in the level of the cardiac output curve because opening the fistula decreases the peripheral resistance and allows an acute fall in arterial pressure against which the heart can pump more easily. The net result, depicted by point B, is an increase in cardiac output from 5 L/min up to 13 L/min and an increase in right atrial pressure to about +3 mm Hg. 3. Point C represents the effects about 1 minute later, after the sympathetic nerve reflexes have restored the arterial pressure almost to normal and caused two other effects: (1) an increase in the mean systemic filling pressure (because of constriction of all veins and arteries) from 7 to 9 mm Hg, thus shifting the venous return curve 2 mm Hg to the right, and (2) further elevation of the cardiac output curve because of sympathetic nervous excitation of the heart. The cardiac output now rises to almost 16 L/min, and the right atrial pressure to about 4 mm Hg. 4. Point D shows the effect after several more weeks. By this time, the blood volume has increased because the slight reduction in arterial pressure and the sympathetic stimulation have both reduced kidney output of urine. The mean systemic filling pressure has now risen to +12 mm Hg, shifting the venous return curve another 3 mm Hg to the right. Also, the prolonged increased workload on the heart has caused the heart muscle to hypertrophy slightly, raising the level of the cardiac output curve still further. Therefore, point D shows a cardiac output now of almost 20 L/min and a right atrial pressure of about 6 mm Hg. Other Analyses of Cardiac Output Regulation. In Chapter 21, analysis of cardiac output regulation during exercise is presented, and in Chapter 22, analyses of cardiac output regulation at various stages of congestive heart failure are shown. Methods for Measuring Cardiac Output In animal experiments, one can cannulate the aorta, pulmonary artery, or great veins entering the heart and measure the cardiac output using any type of flowmeter. An electromagnetic or ultrasonic flowmeter can also be placed on the aorta or pulmonary artery to measure cardiac output. In the human, except in rare instances, cardiac output is measured by indirect methods that do not require surgery. Two of the methods commonly used are the oxygen Fick method and the indicator dilution method. Pulsatile Output of the Heart as Measured by an Electromagnetic or Ultrasonic Flowmeter Figure 20–17 shows a recording in a dog of blood flow in the root of the aorta made using an electromagnetic flowmeter. It demonstrates that the blood flow rises rapidly to a peak during systole, and then at the end of systole reverses for a fraction of a second. This reverse flow causes the aortic valve to close and the flow to return to zero. 244 Unit IV The Circulation Measurement of Cardiac Output Using the Oxygen Fick Principle The Fick principle is explained by Figure 20–18. This figure shows that 200 milliliters of oxygen are being absorbed from the lungs into the pulmonary blood each minute. It also shows that the blood entering the right heart has an oxygen concentration of 160 milliliters per liter of blood, whereas that leaving the left heart has an oxygen concentration of 200 milliliters per liter of blood. From these data, one can calculate that each liter of blood passing through the lungs absorbs 40 milliliters of oxygen. Because the total quantity of oxygen absorbed into the blood from the lungs each minute is 200 milliliters, dividing 200 by 40 calculates a total of five 1-liter portions of blood that must pass through the pulmonary circulation each minute to absorb this amount of oxygen. Therefore, the quantity of blood flowing through the lungs each minute is 5 liters, which is also a measure of the cardiac output. Thus, the cardiac output can be calculated by the following formula: Cardiac output (L min) O2 absorbed per minute by the lungs (ml min) = Arteriovenous O2 difference (ml L of blood) LUNGS Oxygen used = 200 ml/min O2 = 160 ml/L right heart Cardiac output = 5000 ml/min To measure cardiac output by the so-called “indicator dilution method,” a small amount of indicator, such as a dye, is injected into a large systemic vein or, preferably, into the right atrium. This passes rapidly through the right side of the heart, then through the blood vessels of the lungs, through the left side of the heart and, finally, into the systemic arterial system. The concentration of the dye is recorded as the dye passes through one of the peripheral arteries, giving a curve as shown in Figure 20–19. In each of these instances, 5 milligrams of Cardio-Green dye was injected at zero time. In the top recording, none of the dye passed into the arterial tree until about 3 seconds after the injection, but then the arterial concentration of the dye rose rapidly to a maximum in about 6 to 7 seconds. After that, the concentration fell rapidly, but before the concentration reached zero, some of the dye had already circulated all the way through some of the peripheral systemic vessels and returned through the heart for a second time. Consequently, the dye concentration in the artery began to rise again. For the purpose of calculation, it is necessary to extrapolate the early down-slope of the curve to the zero point, as shown by the dashed portion of each curve. In this way, the extrapolated time-concentration curve of the dye in the systemic artery without recirculation can be measured in its first portion and estimated reasonably accurately in its latter portion. Once the extrapolated time-concentration curve has been determined, one then calculates the mean concentration of dye in the arterial blood for the duration of the curve. For instance, in the top example of Figure 20–19, this was done by measuring the area under the 5 mg injected Dye concentration in artery (mg/dl) In applying this Fick procedure for measuring cardiac output in the human being, mixed venous blood is usually obtained through a catheter inserted up the brachial vein of the forearm, through the subclavian vein, down to the right atrium, and, finally, into the right ventricle or pulmonary artery. And systemic arterial blood can then be obtained from any systemic artery in the body. The rate of oxygen absorption by the lungs is measured by the rate of disappearance of oxygen from the respired air, using any type of oxygen meter. Indicator Dilution Method for Measuring Cardiac Output 0.5 0.4 0.3 0.2 0.1 0 0 0.5 0.4 0.3 0.2 0.1 0 0 O2 = 200 ml/L left heart 10 20 30 20 30 5 mg injected 10 Seconds Figure 20–19 Figure 20–18 Fick principle for determining cardiac output. Extrapolated dye concentration curves used to calculate two separate cardiac outputs by the dilution method. (The rectangular areas are the calculated average concentrations of dye in the arterial blood for the durations of the respective extrapolated curves.) Chapter 20 Cardiac Output, Venous Return, and Their Regulation entire initial and extrapolated curve and then averaging the concentration of dye for the duration of the curve; one can see from the shaded rectangle straddling the curve in the upper figure that the average concentration of dye was 0.25 mg/dl of blood and that the duration of this average value was 12 seconds. A total of 5 milligrams of dye had been injected at the beginning of the experiment. For blood carrying only 0.25 milligram of dye in each deciliter to carry the entire 5 milligrams of dye through the heart and lungs in 12 seconds, a total of 20 1-deciliter portions of blood would have passed through the heart during the 12 seconds, which would be the same as a cardiac output of 2 L/12 sec, or 10 L/min. We leave it to the reader to calculate the cardiac output from the bottom extrapolated curve of Figure 20–19. To summarize, the cardiac output can be determined using the following formula: Cardiac output (ml min) = Milligrams of dye injected ¥ 60 Ê Average concentration of dyeˆ Ê Duration ofˆ Á in each milliliter of blood ˜ ¥ Á the curve ˜ Ë for the duration of the curve ¯ Ë in seconds ¯ References Brengelmann GL: A critical analysis of the view that right atrial pressure determines venous return. J Appl Physiol 94:849, 2003. Gaasch WH, Zile MR: Left ventricular diastolic dysfunction and diastolic heart failure. Annu Rev Med. 55:373, 2004. 245 Guyton AC: Venous return. In: Hamilton WF (ed): Handbook of Physiology. Sec 2, Vol. 2. Baltimore, Williams & Wilkins, 1963, p 1099. Guyton AC: Determination of cardiac output by equating venous return curves with cardiac response curves. Physiol Rev 35:123, 1955. Guyton AC, Coleman TG, Granger HJ: Circulation: overall regulation. Annu Rev Physiol 34:13, 1972. Guyton AC, Jones CE, Coleman TG: Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: WB Saunders Co, 1973. Guyton AC, Lindsey AW, Kaufmann BN: Effect of mean circulatory filling pressure and other peripheral circulatory factors on cardiac output. Am J Physiol 180:463-468, 1955. Koch WJ, Lefkowitz RJ, Rockman HA: Functional consequences of altering myocardial adrenergic receptor signaling. Annu Rev Physiol 62:237, 2000. Rockman HA, Koch WJ, Lefkowitz RJ: Seven-transmembrane-spanning receptors and heart function. Nature 415:206, 2002. Rothe CF: Mean circulatory filling pressure: its meaning and measurement. J Appl Physiol 74:499, 1993. Rothe CF: Reflex control of veins and vascular capacitance. Physiol Rev 63:1281, 1983. Sarnoff SJ, Berglund E: Ventricular function. 1. Starling’s law of the heart, studied by means of simultaneous right and left ventricular function curves in the dog. Circulation 9:706-718, 1953. Uemura K, Sugimachi M, Kawada T, et al: A novel framework of circulatory equilibrium. Am J Physiol Heart Circ Physiol 286:H2376, 2004. Vatner SF, Braunwald E: Cardiovascular control mechanisms in the conscious state. N Engl J Med 293:970, 1975. C H A P T E R 2 1 Muscle Blood Flow and Cardiac Output During Exercise; the Coronary Circulation and Ischemic Heart Disease In this chapter we consider (1) blood flow to the skeletal muscles and (2) coronary blood flow to the heart. Regulation of each of these is achieved mainly by local control of vascular resistance in response to muscle tissue metabolic needs. In addition, related subjects are discussed, such as (1) cardiac output control during exercise, (2) characteristics of heart attacks, and (3) the pain of angina pectoris. Blood Flow in Skeletal Muscle and Blood Flow Regulation During Exercise Very strenuous exercise is one of the most stressful conditions that the normal circulatory system faces. This is true because there is such a large mass of skeletal muscle in the body, all of it requiring large amounts of blood flow. Also, the cardiac output often must increase in the non-athlete to four to five times normal, or in the well-trained athlete to six to seven times normal. Rate of Blood Flow Through the Muscles During rest, blood flow through skeletal muscle averages 3 to 4 ml/min/100 g of muscle. During extreme exercise in the well-conditioned athlete, this can increase 15- to 25-fold, rising to 50 to 80 ml/min/100 g of muscle. Blood Flow During Muscle Contractions. Figure 21–1 shows a record of blood flow changes in a calf muscle of a human leg during strong rhythmical muscular exercise. Note that the flow increases and decreases with each muscle contraction. At the end of the contractions, the blood flow remains very high for a few seconds but then fades toward normal during the next few minutes. The cause of the lower flow during the muscle contraction phase of exercise is compression of the blood vessels by the contracted muscle. During strong tetanic contraction, which causes sustained compression of the blood vessels, the blood flow can be almost stopped, but this also causes rapid weakening of the contraction. Increased Blood Flow in Muscle Capillaries During Exercise. During rest, some muscle capillaries have little or no flowing blood. But during strenuous exercise, all the capillaries open. This opening of dormant capillaries diminishes the distance that oxygen and other nutrients must diffuse from the capillaries to the contracting muscle fibers and sometimes contributes a twofold to threefold increased capillary surface area through which oxygen and nutrients can diffuse from the blood. 246 Chapter 21 Muscle Blood Flow and Cardiac Output During Exercise 247 Blood flow (100 ml/min) (in some species of animals) sympathetic vasodilator nerves as well. Rhythmic exercise 40 20 Calf flow 0 0 10 16 18 Minutes Figure 21–1 Effects of muscle exercise on blood flow in the calf of a leg during strong rhythmical contraction. The blood flow was much less during contractions than between contractions. (Adapted from Barcroft and Dornhorst: J Physiol 109:402, 1949.) Control of Blood Flow Through the Skeletal Muscles Local Regulation—Decreased Oxygen in Muscle Greatly Enhances Flow. The tremendous increase in muscle blood flow that occurs during skeletal muscle activity is caused primarily by chemical effects acting directly on the muscle arterioles to cause dilation. One of the most important chemical effects is reduction of oxygen in the muscle tissues. That is, during muscle activity, the muscle uses oxygen rapidly, thereby decreasing the oxygen concentration in the tissue fluids. This in turn causes local arteriolar vasodilation both because the arteriolar walls cannot maintain contraction in the absence of oxygen and because oxygen deficiency causes release of vasodilator substances. The most important vasodilator substance is probably adenosine, but experiments have shown that even large amounts of adenosine infused directly into a muscle artery cannot sustain vasodilation in skeletal muscle for more than about 2 hours. Fortunately, even after the muscle blood vessels have become insensitive to the vasodilator effects of adenosine, still other vasodilator factors continue to maintain increased capillary blood flow as long as the exercise continues. These factors include (1) potassium ions, (2) adenosine triphosphate (ATP), (3) lactic acid, and (4) carbon dioxide. We still do not know quantitatively how great a role each of these plays in increasing muscle blood flow during muscle activity; this subject was discussed in additional detail in Chapter 17. Nervous Control of Muscle Blood Flow. In addition to local tissue vasodilator mechanisms, skeletal muscles are provided with sympathetic vasoconstrictor nerves and Sympathetic Vasoconstrictor Nerves. The sympathetic vasoconstrictor nerve fibers secrete norepinephrine at their nerve endings. When maximally activated, this can decrease blood flow through resting muscles to as little as one half to one third normal. This vasoconstriction is of physiologic importance in circulatory shock and during other periods of stress when it is necessary to maintain a normal or even high arterial pressure. In addition to the norepinephrine secreted at the sympathetic vasoconstrictor nerve endings, the medullae of the two adrenal glands also secrete large amounts of norepinephrine plus even more epinephrine into the circulating blood during strenuous exercise. The circulating norepinephrine acts on the muscle vessels to cause a vasoconstrictor effect similar to that caused by direct sympathetic nerve stimulation. The epinephrine, however, often has a slight vasodilator effect because epinephrine excites more of the beta adrenergic receptors of the vessels, which are vasodilator receptors, in contrast to the alpha vasoconstrictor receptors excited especially by norepinephrine. These receptors are discussed in Chapter 60. Total Body Circulatory Readjustments During Exercise Three major effects occur during exercise that are essential for the circulatory system to supply the tremendous blood flow required by the muscles. They are (1) mass discharge of the sympathetic nervous system throughout the body with consequent stimulatory effects on the entire circulation, (2) increase in arterial pressure, and (3) increase in cardiac output. Effects of Mass Sympathetic Discharge At the onset of exercise, signals are transmitted not only from the brain to the muscles to cause muscle contraction but also into the vasomotor center to initiate mass sympathetic discharge throughout the body. Simultaneously, the parasympathetic signals to the heart are attenuated. Therefore, three major circulatory effects result. First, the heart is stimulated to greatly increased heart rate and increased pumping strength as a result of the sympathetic drive to the heart plus release of the heart from normal parasympathetic inhibition. Second, most of the arterioles of the peripheral circulation are strongly contracted, except for the arterioles in the active muscles, which are strongly vasodilated by the local vasodilator effects in the muscles as noted above. Thus, the heart is stimulated to supply the increased blood flow required by the muscles, while at the same time blood flow through most nonmuscular areas of the body is temporarily reduced, thereby temporarily “lending” their blood supply to the muscles. This accounts for as much as 2 L/min of extra blood flow to the muscles, which is Unit IV The Circulation exceedingly important when one thinks of a person running for his life—even a fractional increase in running speed may make the difference between life and death. Two of the peripheral circulatory systems, the coronary and cerebral systems, are spared this vasoconstrictor effect because both these circulatory areas have poor vasoconstrictor innervation—fortunately so because both the heart and the brain are as essential to exercise as are the skeletal muscles. Third, the muscle walls of the veins and other capacitative areas of the circulation are contracted powerfully, which greatly increases the mean systemic filling pressure. As we learned in Chapter 20, this is one of the most important factors in promoting increase in venous return of blood to the heart and, therefore, in increasing the cardiac output. Increase in Arterial Pressure During Exercise— An Important Result of Increased Sympathetic Stimulation One of the most important effects of increased sympathetic stimulation in exercise is to increase the arterial pressure. This results from multiple stimulatory effects, including (1) vasoconstriction of the arterioles and small arteries in most tissues of the body except the active muscles, (2) increased pumping activity by the heart, and (3) a great increase in mean systemic filling pressure caused mainly by venous contraction. These effects, working together, virtually always increase the arterial pressure during exercise. This increase can be as little as 20 mm Hg or as great as 80 mm Hg, depending on the conditions under which the exercise is performed. When a person performs exercise under tense conditions but uses only a few muscles, the sympathetic nervous response still occurs everywhere in the body. In the few active muscles, vasodilation occurs, but everywhere else in the body the effect is mainly vasoconstriction, often increasing the mean arterial pressure to as high as 170 mm Hg. Such a condition might occur in a person standing on a ladder and nailing with a hammer on the ceiling above. The tenseness of the situation is obvious. Conversely, when a person performs massive whole-body exercise, such as running or swimming, the increase in arterial pressure is often only 20 to 40 mm Hg. This lack of a large increase in pressure results from the extreme vasodilation that occurs simultaneously in large masses of active muscle. Why Is the Arterial Pressure Increase During Exercise Important? When muscles are stimulated maximally in a lab- oratory experiment but without allowing the arterial pressure to rise, muscle blood flow seldom rises more than about eightfold. Yet, we know from studies of marathon runners that muscle blood flow can increase from as little as 1 L/min for the whole body during rest to at least 20 L/min during maximal activity. Therefore, it is clear that muscle blood flow can increase much more than occurs in the aforementioned simple laboratory experiment. What is the difference? Mainly, the arterial pressure rises during normal exercise. Let us 25 Cardiac output and venous return (L/min) 248 B 20 15 10 A 5 0 –4 0 +4 +8 +12 +16 +20 +24 Right atrial pressure (mm Hg) Figure 21–2 Graphical analysis of change in cardiac output and right atrial pressure with onset of strenuous exercise. Black curves, normal circulation. Red curves, heavy exercise. assume, for instance, that the arterial pressure rises 30 per cent, a common increase during heavy exercise. This 30 per cent increase causes 30 per cent more force to push blood through the muscle tissue vessels. But this is not the only important effect; the extra pressure also stretches the walls of the vessels so much that muscle total flow often rises to more than 20 times normal. Importance of the Increase in Cardiac Output During Exercise Many different physiologic effects occur at the same time during exercise to increase cardiac output approximately in proportion to the degree of exercise. In fact, the ability of the circulatory system to provide increased cardiac output for delivery of oxygen and other nutrients to the muscles during exercise is equally as important as the strength of the muscles themselves in setting the limit for continued muscle work. For instance, marathon runners who can increase their cardiac outputs the most are generally the same persons who have record-breaking running times. Graphical Analysis of the Changes in Cardiac Output During Heavy Exercise. Figure 21–2 shows a graphical analysis of the large increase in cardiac output that occurs during heavy exercise. The cardiac output and venous return curves crossing at point A give the analysis for the normal circulation; and the curves crossing at point B analyze heavy exercise. Note that the great increase in cardiac output requires significant changes in both the cardiac output curve and the venous return curve, as follow. The increased level of the cardiac output curve is easy to understand. It results almost entirely from sympathetic stimulation of the heart that causes (1) Chapter 21 249 Muscle Blood Flow and Cardiac Output During Exercise increased heart rate, often up to rates as high as 170 to 190 beats/min, and (2) increased strength of contraction of the heart, often to as much as twice normal. Without this increased level of the output curve, the increase in cardiac output would be limited to the plateau level of the normal heart, which would be a maximum increase of cardiac output of only about 2.5-fold rather than the 4-fold that can commonly be achieved by the untrained runner and the 7-fold that can be achieved in some marathon runners. Now study the venous return curves. If no change occurred from the normal venous return curve, the cardiac output could hardly rise at all in exercise because the upper plateau level of the normal venous return curve is only 6 L/min. Yet two important changes do occur: 1. The mean systemic filling pressure rises tremendously at the onset of heavy exercise. This results partly from the sympathetic stimulation that contracts the veins and other capacitative parts of the circulation. In addition, tensing of the abdominal and other skeletal muscles of the body compresses many of the internal vessels, thus providing more compression of the entire capacitative vascular system, causing a still greater increase in mean systemic filling pressure. During maximal exercise, these two effects together can increase the mean systemic filling pressure from a normal level of 7 mm Hg to as high as 30 mm Hg. 2. The slope of the venous return curve rotates upward. This is caused by decreased resistance in virtually all the blood vessels in active muscle tissue, which also causes resistance to venous return to decrease, thus increasing the upward slope of the venous return curve. Therefore, the combination of increased mean systemic filling pressure and decreased resistance to venous return raises the entire level of the venous return curve. In response to the changes in both the venous return curve and the cardiac output curve, the new equilibrium point in Figure 21–2 for cardiac output and right atrial pressure is now point B, in contrast to the normal level at point A. Note especially that the right atrial pressure has hardly changed, having risen only 1.5 mm Hg. In fact, in a person with a strong heart, the right atrial pressure often falls below normal in very heavy exercise because of the greatly increased sympathetic stimulation of the heart during exercise. Aortic valve Left coronary artery Right coronary artery Figure 21–3 The coronary arteries. Physiologic Anatomy of the Coronary Blood Supply Figure 21–3 shows the heart and its coronary blood supply. Note that the main coronary arteries lie on the surface of the heart and smaller arteries then penetrate from the surface into the cardiac muscle mass. It is almost entirely through these arteries that the heart receives its nutritive blood supply. Only the inner 1/10 millimeter of the endocardial surface can obtain significant nutrition directly from the blood inside the cardiac chambers, so that this source of muscle nutrition is minuscule. The left coronary artery supplies mainly the anterior and left lateral portions of the left ventricle, whereas the right coronary artery supplies most of the right ventricle as well as the posterior part of the left ventricle in 80 to 90 per cent of people. Most of the coronary venous blood flow from the left ventricular muscle returns to the right atrium of the heart by way of the coronary sinus—which is about 75 per cent of the total coronary blood flow. And most of the coronary venous blood from the right ventricular muscle returns through small anterior cardiac veins that flow directly into the right atrium, not by way of the coronary sinus. A very small amount of coronary venous blood also flows back into the heart through very minute thebesian veins, which empty directly into all chambers of the heart. Coronary Circulation Normal Coronary Blood Flow About one third of all deaths in the affluent society of the Western world result from coronary artery disease, and almost all elderly people have at least some impairment of the coronary artery circulation. For this reason, understanding normal and pathological physiology of the coronary circulation is one of the most important subjects in medicine. The resting coronary blood flow in the human being averages about 225 ml/min, which is about 4 to 5 per cent of the total cardiac output. During strenuous exercise, the heart in the young adult increases its cardiac output fourfold to sevenfold, and it pumps this blood against a higher than normal arterial pressure. Consequently, the work 250 Unit IV The Circulation Coronary blood flow (ml/min) Epicardial coronary arteries Cardiac muscle 300 Subendocardial arterial plexus 200 Figure 21–5 Diagram of the epicardial, intramuscular, and subendocardial coronary vasculature. 100 0 Systole Diastole Figure 21–4 Phasic flow of blood through the coronary capillaries of the human left ventricle during cardiac systole and diastole (as extrapolated from measured flows in dogs). output of the heart under severe conditions may increase sixfold to ninefold. At the same time, the coronary blood flow increases threefold to fourfold to supply the extra nutrients needed by the heart. This increase is not as much as the increase in workload, which means that the ratio of energy expenditure by the heart to coronary blood flow increases. Thus, the “efficiency” of cardiac utilization of energy increases to make up for the relative deficiency of coronary blood supply. Phasic Changes in Coronary Blood Flow During Systole and Diastole—Effect of Cardiac Muscle Compression. Figure 21–4 shows the changes in blood flow through the nutrient capillaries of the left ventricular coronary system in milliliters per minute in the human heart during systole and diastole, as extrapolated from experiments in lower animals. Note from this diagram that the coronary capillary blood flow in the left ventricle muscle falls to a low value during systole, which is opposite to flow in vascular beds elsewhere in the body. The reason for this is strong compression of the left ventricular muscle around the intramuscular vessels during systolic contraction. During diastole, the cardiac muscle relaxes and no longer obstructs blood flow through the left ventricular muscle capillaries, so that blood flows rapidly during all of diastole. Blood flow through the coronary capillaries of the right ventricle also undergoes phasic changes during the cardiac cycle, but because the force of contraction of the right ventricular muscle is far less than that of the left ventricular muscle, the inverse phasic changes are only partial in contrast to those in the left ventricular muscle. Epicardial Versus Subendocardial Coronary Blood Flow—Effect of Intramyocardial Pressure. Figure 21–5 demonstrates the special arrangement of the coronary vessels at different depths in the heart muscle, showing on the outer surface epicardial coronary arteries that supply most of the muscle. Smaller, intramuscular arteries derived from the epicardial arteries penetrate the muscle, supplying the needed nutrients. Lying immediately beneath the endocardium is a plexus of subendocardial arteries. During systole, blood flow through the subendocardial plexus of the left ventricle, where the intramuscular coronary vessels are compressed greatly by ventricular muscle contraction, tends to be reduced. But the extra vessels of the subendocardial plexus normally compensate for this. Later in the chapter, we will see that this peculiar difference between blood flow in the epicardial and subendocardial arteries plays an important role in certain types of coronary ischemia. Control of Coronary Blood Flow Local Muscle Metabolism Is the Primary Controller of Coronary Flow Blood flow through the coronary system is regulated mostly by local arteriolar vasodilation in response to cardiac muscle need for nutrition. That is, whenever the vigor of cardiac contraction is increased, regardless of cause, the rate of coronary blood flow also increases. Conversely, decreased heart activity is accompanied by decreased coronary flow. This local regulation of coronary blood flow is almost identical to that occurring in many other tissues of the body, especially in the skeletal muscles all over the body. Oxygen Demand as a Major Factor in Local Coronary Blood Flow Regulation. Blood flow in the coronaries usually is reg- ulated almost exactly in proportion to the need of the cardiac musculature for oxygen. Normally, about 70 per cent of the oxygen in the coronary arterial blood is removed as the blood flows through the heart muscle. Because not much oxygen is left, very little additional oxygen can be supplied to the heart musculature unless the coronary blood flow increases. Fortunately, the coronary blood flow does increase almost in direct proportion to any additional metabolic consumption of oxygen by the heart. However, the exact means by which increased oxygen consumption causes coronary dilation has not been determined. It is speculated by many research workers that a decrease in the oxygen Chapter 21 Muscle Blood Flow and Cardiac Output During Exercise 251 concentration in the heart causes vasodilator substances to be released from the muscle cells and that these dilate the arterioles. A substance with great vasodilator propensity is adenosine. In the presence of very low concentrations of oxygen in the muscle cells, a large proportion of the cell’s ATP degrades to adenosine monophosphate; then small portions of this are further degraded and release adenosine into the tissue fluids of the heart muscle, with resultant increase in local coronary blood flow. After the adenosine causes vasodilation, much of it is reabsorbed into the cardiac cells to be reused. Adenosine is not the only vasodilator product that has been identified. Others include adenosine phosphate compounds, potassium ions, hydrogen ions, carbon dioxide, bradykinin, and, possibly, prostaglandins and nitric oxide. Yet, difficulties with the vasodilator hypothesis exist. First, pharmacologic agents that block or partially block the vasodilator effect of adenosine do not prevent coronary vasodilation caused by increased heart muscle activity. Second, studies in skeletal muscle have shown that continued infusion of adenosine maintains vascular dilation for only 1 to 3 hours, and yet muscle activity still dilates the local blood vessels even when the adenosine can no longer dilate them. Therefore, the other vasodilator mechanisms listed above must be remembered. There is much more extensive sympathetic innervation of the coronary vessels. In Chapter 60, we see that the sympathetic transmitter substances norepinephrine and epinephrine can have either vascular constrictor or vascular dilator effects, depending on the presence or absence of constrictor or dilator receptors in the blood vessel walls. The constrictor receptors are called alpha receptors and the dilator receptors are called beta receptors. Both alpha and beta receptors exist in the coronary vessels. In general, the epicardial coronary vessels have a preponderance of alpha receptors, whereas the intramuscular arteries may have a preponderance of beta receptors. Therefore, sympathetic stimulation can, at least theoretically, cause slight overall coronary constriction or dilation, but usually constriction. In some people, the alpha vasoconstrictor effects seem to be disproportionately severe, and these people can have vasospastic myocardial ischemia during periods of excess sympathetic drive, often with resultant anginal pain. Metabolic factors—especially myocardial oxygen consumption—are the major controllers of myocardial blood flow. Whenever the direct effects of nervous stimulation alter the coronary blood flow in the wrong direction, the metabolic control of coronary flow usually overrides the direct coronary nervous effects within seconds. Nervous Control of Coronary Blood Flow Special Features of Cardiac Muscle Metabolism Stimulation of the autonomic nerves to the heart can affect coronary blood flow both directly and indirectly. The direct effects result from action of the nervous transmitter substances acetylcholine from the vagus nerves and norepinephrine and epinephrine from the sympathetic nerves on the coronary vessels themselves. The indirect effects result from secondary changes in coronary blood flow caused by increased or decreased activity of the heart. The indirect effects, which are mostly opposite to the direct effects, play a far more important role in normal control of coronary blood flow. Thus, sympathetic stimulation, which releases norepinephrine and epinephrine, increases both heart rate and heart contractility as well as increases the rate of metabolism of the heart. In turn, the increased metabolism of the heart sets off local blood flow regulatory mechanisms for dilating the coronary vessels, and the blood flow increases approximately in proportion to the metabolic needs of the heart muscle. In contrast, vagal stimulation, with its release of acetylcholine, slows the heart and has a slight depressive effect on heart contractility. These effects in turn decrease cardiac oxygen consumption and, therefore, indirectly constrict the coronary arteries. Direct Effects of Nervous Stimuli on the Coronary Vasculature. The distribution of parasympathetic (vagal) nerve fibers to the ventricular coronary system is not very great. However, the acetylcholine released by parasympathetic stimulation has a direct effect to dilate the coronary arteries. The basic principles of cellular metabolism, discussed in Chapters 67 through 72, apply to cardiac muscle the same as for other tissues, but there are some quantitative differences. Most important, under resting conditions, cardiac muscle normally consumes fatty acids to supply most of its energy instead of carbohydrates (about 70 per cent of the energy is derived from fatty acids). However, as is also true of other tissues, under anaerobic or ischemic conditions, cardiac metabolism must call on anaerobic glycolysis mechanisms for energy. Unfortunately, glycolysis consumes tremendous quantities of the blood glucose and at the same time forms large amounts of lactic acid in the cardiac tissue, which is probably one of the causes of cardiac pain in cardiac ischemic conditions, as discussed later in this chapter. As is true in other tissues, more than 95 per cent of the metabolic energy liberated from foods is used to form ATP in the mitochondria. This ATP in turn acts as the conveyer of energy for cardiac muscular contraction and other cellular functions. In severe coronary ischemia, the ATP degrades first to adenosine diphosphate, then to adenosine monophosphate and adenosine. Because the cardiac muscle cell membrane is slightly permeable to adenosine, much of this can diffuse from the muscle cells into the circulating blood. The released adenosine is believed to be one of the substances that causes dilation of the coronary arterioles during coronary hypoxia, as discussed earlier. 252 Unit IV The Circulation However, loss of adenosine also has a serious cellular consequence. Within as little as 30 minutes of severe coronary ischemia, as occurs after a myocardial infarct, about one half of the adenine base can be lost from the affected cardiac muscle cells. Furthermore, this loss can be replaced by new synthesis of adenine at a rate of only 2 per cent per hour. Therefore, once a serious bout of coronary ischemia has persisted for 30 or more minutes, relief of the ischemia may be too late to save the lives of the cardiac cells. This almost certainly is one of the major causes of cardiac cellular death during myocardial ischemia. Ischemic Heart Disease The most common cause of death in Western culture is ischemic heart disease, which results from insufficient coronary blood flow. About 35 per cent of people in the United States die of this cause. Some deaths occur suddenly as a result of acute coronary occlusion or fibrillation of the heart, whereas other deaths occur slowly over a period of weeks to years as a result of progressive weakening of the heart pumping process. In this chapter, we discuss acute coronary ischemia caused by acute coronary occlusion and myocardial infarction. In Chapter 22, we discuss congestive heart failure, the most frequent cause of which is slowly increasing coronary ischemia and weakening of the cardiac muscle. Atherosclerosis as a Cause of Ischemic Heart Disease. The most frequent cause of diminished coronary blood flow is atherosclerosis. The atherosclerotic process is discussed in connection with lipid metabolism in Chapter 68. Briefly, this process is the following. In people who have genetic predisposition to atherosclerosis, or in people who eat excessive quantities of cholesterol and have a sedentary lifestyle, large quantities of cholesterol gradually become deposited beneath the endothelium at many points in arteries throughout the body. Gradually, these areas of deposit are invaded by fibrous tissue and frequently become calcified. The net result is the development of atherosclerotic plaques that actually protrude into the vessel lumens and either block or partially block blood flow. A common site for development of atherosclerotic plaques is the first few centimeters of the major coronary arteries. the flowing blood. Because the plaque presents an unsmooth surface, blood platelets adhere to it, fibrin is deposited, and red blood cells become entrapped to form a blood clot that grows until it occludes the vessel. Or, occasionally, the clot breaks away from its attachment on the atherosclerotic plaque and flows to a more peripheral branch of the coronary arterial tree, where it blocks the artery at that point. A thrombus that flows along the artery in this way and occludes the vessel more distally is called a coronary embolus. 2. Many clinicians believe that local muscular spasm of a coronary artery also can occur. The spasm might result from direct irritation of the smooth muscle of the arterial wall by the edges of an arteriosclerotic plaque, or it might result from local nervous reflexes that cause excess coronary vascular wall contraction. The spasm may then lead to secondary thrombosis of the vessel. Lifesaving Value of Collateral Circulation in the Heart. The degree of damage to the heart muscle caused either by slowly developing atherosclerotic constriction of the coronary arteries or by sudden coronary occlusion is determined to a great extent by the degree of collateral circulation that has already developed or that can open within minutes after the occlusion. In a normal heart, almost no large communications exist among the larger coronary arteries. But many anastomoses do exist among the smaller arteries sized 20 to 250 micrometers in diameter, as shown in Figure 21–6. When a sudden occlusion occurs in one of the larger coronary arteries, the small anastomoses begin to Artery Vein Acute Coronary Occlusion Acute occlusion of a coronary artery most frequently occurs in a person who already has underlying atherosclerotic coronary heart disease but almost never in a person with a normal coronary circulation. Acute occlusion can result from any one of several effects, two of which are the following: 1. The atherosclerotic plaque can cause a local blood clot called a thrombus, which in turn occludes the artery. The thrombus usually occurs where the arteriosclerotic plaque has broken through the endothelium, thus coming in direct contact with Artery Vein Figure 21–6 Minute anastomoses in the normal coronary arterial system. Chapter 21 253 Muscle Blood Flow and Cardiac Output During Exercise dilate within seconds. But the blood flow through these minute collaterals is usually less than one half that needed to keep alive most of the cardiac muscle that they now supply; the diameters of the collateral vessels do not enlarge much more for the next 8 to 24 hours. But then collateral flow does begin to increase, doubling by the second or third day and often reaching normal or almost normal coronary flow within about 1 month. Because of these developing collateral channels, many patients recover almost completely from various degrees of coronary occlusion when the area of muscle involved is not too great. When atherosclerosis constricts the coronary arteries slowly over a period of many years rather than suddenly, collateral vessels can develop at the same time while the atherosclerosis becomes more and more severe. Therefore, the person may never experience an acute episode of cardiac dysfunction. But, eventually, the sclerotic process develops beyond the limits of even the collateral blood supply to provide the needed blood flow, and sometimes the collateral blood vessels themselves develop atherosclerosis. When this occurs, the heart muscle becomes severely limited in its work output, often so much so that the heart cannot pump even normally required amounts of blood flow. This is one of the most common causes of the cardiac failure that occurs in vast numbers of older people. Myocardial Infarction Immediately after an acute coronary occlusion, blood flow ceases in the coronary vessels beyond the occlusion except for small amounts of collateral flow from surrounding vessels. The area of muscle that has either zero flow or so little flow that it cannot sustain cardiac muscle function is said to be infarcted. The overall process is called a myocardial infarction. Soon after the onset of the infarction, small amounts of collateral blood begin to seep into the infarcted area, and this, combined with progressive dilation of local blood vessels, causes the area to become overfilled with stagnant blood. Simultaneously the muscle fibers use the last vestiges of the oxygen in the blood, causing the hemoglobin to become totally de-oxygenated. Therefore, the infarcted area takes on a bluish-brown hue, and the blood vessels of the area appear to be engorged despite lack of blood flow. In later stages, the vessel walls become highly permeable and leak fluid; the local muscle tissue becomes edematous, and the cardiac muscle cells begin to swell because of diminished cellular metabolism.Within a few hours of almost no blood supply, the cardiac muscle cells die. Cardiac muscle requires about 1.3 milliliters of oxygen per 100 grams of muscle tissue per minute just to remain alive. This is in comparison with about 8 milliliters of oxygen per 100 grams delivered to the normal resting left ventricle each minute. Therefore, if there is even 15 to 30 per cent of normal resting coronary blood flow, the muscle will not die. In the central portion of a large infarct, however, where there is almost no collateral blood flow, the muscle does die. Subendocardial Infarction. The subendocardial muscle frequently becomes infarcted even when there is no evidence of infarction in the outer surface portions of the heart. The reason for this is that the subendocardial muscle has extra difficulty obtaining adequate blood flow because the blood vessels in the subendocardium are intensely compressed by systolic contraction of the heart, as explained earlier. Therefore, any condition that compromises blood flow to any area of the heart usually causes damage first in the subendocardial regions, and the damage then spreads outward toward the epicardium. Causes of Death After Acute Coronary Occlusion The most common causes of death after acute myocardial infarction are (1) decreased cardiac output; (2) damming of blood in the pulmonary blood vessels and then death resulting from pulmonary edema; (3) fibrillation of the heart; and, occasionally, (4) rupture of the heart. Decreased Cardiac Output—Systolic Stretch and Cardiac Shock. When some of the cardiac muscle fibers are not functioning and others are too weak to contract with great force, the overall pumping ability of the affected ventricle is proportionately depressed. Indeed, the overall pumping strength of the infarcted heart is often decreased more than one might expect because of a phenomenon called systolic stretch, shown in Figure 21–7. That is, when the normal portions of the ventricular muscle contract, the ischemic portion of the muscle, whether this be dead or simply nonfunctional, instead of contracting is forced outward by the pressure that develops inside the ventricle. Therefore, Normal contraction Non-functional muscle Systolic stretch Figure 21–7 Systolic stretch in an area of ischemic cardiac muscle. 254 Unit IV The Circulation much of the pumping force of the ventricle is dissipated by bulging of the area of nonfunctional cardiac muscle. When the heart becomes incapable of contracting with sufficient force to pump enough blood into the peripheral arterial tree, cardiac failure and death of peripheral tissues ensue as a result of peripheral ischemia. This condition is called coronary shock, cardiogenic shock, cardiac shock, or low cardiac output failure. It is discussed more fully in the next chapter. Cardiac shock almost always occurs when more than 40 per cent of the left ventricle is infarcted. And death occurs in about 85 per cent of patients once they develop cardiac shock. heart is not pumping blood forward, it must be damming blood in the atria and in the blood vessels of the lungs or in the systemic circulation. This leads to increased capillary pressures, particularly in the lungs. This damming of blood in the veins often causes little difficulty during the first few hours after myocardial infarction. Instead, symptoms develop a few days later for the following reason: The acutely diminished cardiac output leads to diminished blood flow to the kidneys. Then, for reasons that are discussed in Chapter 22. the kidneys fail to excrete enough urine. This adds progressively to the total blood volume and, therefore, leads to congestive symptoms. Consequently, many patients who seemingly are getting along well during the first few days after onset of heart failure will suddenly develop acute pulmonary edema and often will die within a few hours after appearance of the initial pulmonary symptoms. increases the irritability of the cardiac musculature and, therefore, its likelihood of fibrillating. 2. Ischemia of the muscle causes an “injury current,” which is described in Chapter 12 in relation to electrocardiograms in patients with acute myocardial infarction. That is, the ischemic musculature often cannot completely repolarize its membranes after a heart beat, so that the external surface of this muscle remains negative with respect to normal cardiac muscle membrane potential elsewhere in the heart. Therefore, electric current flows from this ischemic area of the heart to the normal area and can elicit abnormal impulses that can cause fibrillation. 3. Powerful sympathetic reflexes often develop after massive infarction, principally because the heart does not pump an adequate volume of blood into the arterial tree. The sympathetic stimulation also increases irritability of the cardiac muscle and thereby predisposes to fibrillation. 4. Cardiac muscle weakness caused by the myocardial infarction often causes the ventricle to dilate excessively. This increases the pathway length for impulse conduction in the heart and frequently causes abnormal conduction pathways all the way around the infarcted area of the cardiac muscle. Both of these effects predispose to development of circus movements because, as discussed in Chapter 13, excess prolongation of conduction pathways in the ventricles allows impulses to reenter muscle that is already recovering from refractoriness, thereby initiating a “circus movement” cycle of new excitation and causing the process to continue on and on. Fibrillation of the Ventricles After Myocardial Infarction. Rupture of the Infarcted Area. During the first day or so Many people who die of coronary occlusion die because of sudden ventricular fibrillation. The tendency to develop fibrillation is especially great after a large infarction, but fibrillation can sometimes occur after small occlusions as well. Indeed, some patients with chronic coronary insufficiency die suddenly from fibrillation without any acute infarction. There are two especially dangerous periods after coronary infarction during which fibrillation is most likely to occur. The first is during the first 10 minutes after the infarction occurs. Then there is a short period of relative safety, followed by a secondary period of cardiac irritability beginning 1 hour or so later and lasting for another few hours. Fibrillation can also occur many days after the infarct but less likely so. At least four factors enter into the tendency for the heart to fibrillate: 1. Acute loss of blood supply to the cardiac muscle causes rapid depletion of potassium from the ischemic musculature. This also increases the potassium concentration in the extracellular fluids surrounding the cardiac muscle fibers. Experiments in which potassium has been injected into the coronary system have demonstrated that an elevated extracellular potassium concentration after an acute infarct, there is little danger of rupture of the ischemic portion of the heart, but a few days later, the dead muscle fibers begin to degenerate, and the heart wall becomes stretched very thin. When this happens, the dead muscle bulges outward severely with each heart contraction, and this systolic stretch becomes greater and greater until finally the heart ruptures. In fact, one of the means used in assessing progress of severe myocardial infarction is to record by cardiac imaging (i.e., x-rays) whether the degree of systolic stretch is worsening. When a ventricle does rupture, loss of blood into the pericardial space causes rapid development of cardiac tamponade—that is, compression of the heart from the outside by blood collecting in the pericardial cavity. Because of this compression of the heart, blood cannot flow into the right atrium, and the patient dies of suddenly decreased cardiac output. Damming of Blood in the Body’s Venous System. When the Stages of Recovery from Acute Myocardial Infarction The upper left part of Figure 21–8 shows the effects of acute coronary occlusion in a patient with a small area Chapter 21 Mild ischemia Nonfunctional Muscle Blood Flow and Cardiac Output During Exercise Mild ischemia Nonfunctional Dead fibers Nonfunctional Dead fibers Fibrous tissue Figure 21–8 Top, Small and large areas of coronary ischemia. Bottom, Stages of recovery from myocardial infarction. of muscle ischemia; to the right is shown a heart with a large area of ischemia. When the area of ischemia is small, little or no death of the muscle cells may occur, but part of the muscle often does become temporarily nonfunctional because of inadequate nutrition to support muscle contraction. When the area of ischemia is large, some of the muscle fibers in the center of the area die rapidly, within 1 to 3 hours where there is total cessation of coronary blood supply. Immediately around the dead area is a nonfunctional area, with failure of contraction and usually failure of impulse conduction. Then, extending circumferentially around the nonfunctional area is an area that is still contracting but weakly so because of mild ischemia. Replacement of Dead Muscle by Scar Tissue. In the lower part of Figure 21–8, the various stages of recovery after a large myocardial infarction are shown. Shortly after the occlusion, the muscle fibers in the center of the ischemic area die. Then, during the ensuing days, this area of dead fibers becomes bigger because many of the marginal fibers finally succumb to the prolonged ischemia. At the same time, because of enlargement of collateral arterial channels supplying the outer rim of the infarcted area, much of the nonfunctional muscle recovers. After a few days to three weeks, most of the nonfunctional muscle becomes functional again or dies—one or the other. In the meantime, fibrous tissue begins developing among the dead fibers because ischemia can stimulate growth of fibroblasts and promote development of greater than normal quantities of fibrous tissue. Therefore, the dead muscle tissue is gradually replaced by fibrous tissue. Then, because it is a general property of fibrous tissue to undergo progressive contraction and dissolution, the fibrous scar may grow smaller over a period of several months to a year. Finally, the normal areas of the heart gradually hypertrophy to compensate at least partially for the lost dead cardiac musculature. By these means, the 255 heart recovers either partially or almost completely within a few months. Value of Rest in Treating Myocardial Infarction. The degree of cardiac cellular death is determined by the degree of ischemia and the workload on the heart muscle. When the workload is greatly increased, such as during exercise, in severe emotional strain, or as a result of fatigue, the heart needs increased oxygen and other nutrients for sustaining its life. Furthermore, anastomotic blood vessels that supply blood to ischemic areas of the heart must also still supply the areas of the heart that they normally supply. When the heart becomes excessively active, the vessels of the normal musculature become greatly dilated. This allows most of the blood flowing into the coronary vessels to flow through the normal muscle tissue, thus leaving little blood to flow through the small anastomotic channels into the ischemic area, so that the ischemic condition worsens. This condition is called the “coronary steal” syndrome. Consequently, one of the most important factors in the treatment of a patient with myocardial infarction is observance of absolute body rest during the recovery process. Function of the Heart After Recovery from Myocardial Infarction Occasionally, a heart that has recovered from a large myocardial infarction returns almost to full functional capability, but more frequently its pumping capability is permanently decreased below that of a healthy heart. This does not mean that the person is necessarily a cardiac invalid or that the resting cardiac output is depressed below normal, because the normal heart is capable of pumping 300 to 400 per cent more blood per minute than the body requires during rest—that is, a normal person has a “cardiac reserve” of 300 to 400 per cent. Even when the cardiac reserve is reduced to as little as 100 per cent, the person can still perform normal activity of a quiet, restful type but not strenuous exercise that would overload the heart. Pain in Coronary Heart Disease Normally, a person cannot “feel” his or her heart, but ischemic cardiac muscle often does cause pain sensation—sometimes severe pain. Exactly what causes this pain is not known, but it is believed that ischemia causes the muscle to release acidic substances, such as lactic acid, or other pain-promoting products, such as histamine, kinins, or cellular proteolytic enzymes, that are not removed rapidly enough by the slowly moving coronary blood flow. The high concentrations of these abnormal products then stimulate pain nerve endings in the cardiac muscle, sending pain impulses through sensory afferent nerve fibers into the central nervous system. Angina Pectoris In most people who develop progressive constriction of their coronary arteries, cardiac pain, called angina 256 Unit IV The Circulation pectoris, begins to appear whenever the load on the heart becomes too great in relation to the available coronary blood flow. This pain is usually felt beneath the upper sternum over the heart, and in addition it is often referred to distant surface areas of the body, most commonly to the left arm and left shoulder but also frequently to the neck and even to the side of the face. The reason for this distribution of pain is that the heart originates during embryonic life in the neck, as do the arms. Therefore, both the heart and these surface areas of the body receive pain nerve fibers from the same spinal cord segments. Most people who have chronic angina pectoris feel pain when they exercise or when they experience emotions that increase metabolism of the heart or temporarily constrict the coronary vessels because of sympathetic vasoconstrictor nerve signals. The pain usually lasts for only a few minutes. However, some patients have such severe and lasting ischemia that the pain is present all the time. The pain is frequently described as hot, pressing, and constricting; it is of such quality that it usually makes the patient stop all unnecessary body activity and come to a complete state of rest. Treatment with Drugs. Several vasodilator drugs, when administered during an acute anginal attack, can often give immediate relief from the pain. Commonly used vasodilators are nitroglycerin and other nitrate drugs. A second class of drugs that are used for prolonged treatment of angina pectoris is the beta blockers, such as propranolol. These drugs block sympathetic beta adrenergic receptors, which prevents sympathetic enhancement of heart rate and cardiac metabolism during exercise or emotional episodes. Therefore, therapy with a beta blocker decreases the need of the heart for extra metabolic oxygen during stressful conditions. For obvious reasons, this can also reduce the number of anginal attacks as well as their severity. Surgical Treatment of Coronary Disease Aortic-Coronary Bypass Surgery. In many patients with coronary ischemia, the constricted areas of the coronary arteries are located at only a few discrete points blocked by atherosclerotic disease, and the coronary vessels elsewhere are normal or almost normal. A surgical procedure was developed in the 1960s, called aortic-coronary bypass, for removing a section of a subcutaneous vein from an arm or leg and then grafting this vein from the root of the aorta to the side of a peripheral coronary artery beyond the atherosclerotic blockage point. One to five such grafts are usually performed, each of which supplies a peripheral coronary artery beyond a block. Anginal pain is relieved in most patients. Also, in patients whose hearts have not become too severely damaged before the operation, the coronary bypass procedure may provide the patient with normal survival expectation. Conversely, if the heart has already been severely damaged, the bypass procedure is likely to be of little value. Coronary Angioplasty. Since the 1980s, a procedure has been used to open partially blocked coronary vessels before they become totally occluded. This procedure, called coronary artery angioplasty, is the following: A small balloon-tipped catheter, about 1 millimeter in diameter, is passed under radiographic guidance into the coronary system and pushed through the partially occluded artery until the balloon portion of the catheter straddles the partially occluded point. Then the balloon is inflated with high pressure, which markedly stretches the diseased artery. After this procedure is performed, the blood flow through the vessel often increases threefold to fourfold, and more than three quarters of the patients who undergo the procedure are relieved of the coronary ischemic symptoms for at least several years, although many of the patients still eventually require coronary bypass surgery. Still newer procedures for opening atherosclerotic coronary arteries are constantly in experimental development. One of these employs a laser beam from the tip of a coronary artery catheter aimed at the atherosclerotic lesion. The laser literally dissolves the lesion without substantially damaging the rest of the arterial wall. Another development has been a minute metal “sleeve” placed inside a coronary artery dilated by angioplasty to hold the artery open, thus preventing its restenosis. References Casscells W, Nahai M, Willerson JT: Vulnerable atherosclerotic plaque: a multifocal disease. Circulation 107:2072, 2003. Cohn PF, Fox KM, Daly C: Silent myocardial ischemia. Circulation 108:1263, 2003. Dalal H, Evans PH, Campbell JL: Recent developments in secondary prevention and cardiac rehabilitation after acute myocardial infarction. BMJ 328:693, 2004. Freedman SB, Isner JM: Therapeutic angiogenesis for coronary artery disease. Ann Intern Med 136:54, 2002. Gehlbach BK, Geppert E: The pulmonary manifestations of left heart failure. Chest 125:669, 2004. Guyton AC, Jones CE, Coleman TG: Circulatory Pathology: Cardiac Output and Its Regulation. Philadelphia: WB Saunders Co, 1973. Hao H, Gabbiani J, Bochaton-Piallat M: Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis development. Arterioscler Thromb Vasc Biol 23:1510, 2003. Hester RL, Hammer LW: Venular-arteriolar communication in the regulation of blood flow. Am J Physiol 282:R1280, 2002. Hochman JS: Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. Circulation 107: 2998, 2003. Joyner MJ, Dietz NM: Sympathetic vasodilation in human muscle. Acta Physiol Scand 177:329, 2003. Chapter 21 Muscle Blood Flow and Cardiac Output During Exercise Koerselman J, van der Graaf Y, de Jaegere PP, Grobbee DE: Coronary collaterals: an important and underexposed aspect of coronary artery disease. Circulation 107:2507, 2003. Libby P: Inflammation in atherosclerosis. Nature 420:868, 2002. Richardson RS: Oxygen transport and utilization: an integration of the muscle systems. Adv Physiol Educ 27:183, 2003. 257 Ridker PM: Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107:363, 2003. Tsai AG, Johnson PC, Intaglietta M: Oxygen gradients in the microcirculation. Physiol Rev 83:933, 2003. Yellon DM, Downey JM: Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113, 2003. C H A P T E R 2 Cardiac Failure One of the most important ailments that must be treated by the physician is cardiac failure (“heart failure”). This can result from any heart condition that reduces the ability of the heart to pump blood. The cause usually is decreased contractility of the myocardium resulting from diminished coronary blood flow. However, failure can also be caused by damaged heart valves, external pressure around the heart, vitamin B deficiency, primary cardiac muscle disease, or any other abnormality that makes the heart a hypoeffective pump. In this chapter, we discuss mainly cardiac failure caused by ischemic heart disease resulting from partial blockage of the coronary blood vessels. In Chapter 23, we discuss valvular and congenital heart disease. Definition of Cardiac Failure. The term “cardiac failure” means simply failure of the heart to pump enough blood to satisfy the needs of the body. Dynamics of the Circulation in Cardiac Failure Acute Effects of Moderate Cardiac Failure If a heart suddenly becomes severely damaged, such as by myocardial infarction, the pumping ability of the heart is immediately depressed. As a result, two main effects occur: (1) reduced cardiac output and (2) damming of blood in the veins, resulting in increased venous pressure. The progressive changes in heart pumping effectiveness at different times after an acute myocardial infarction are shown graphically in Figure 22–1. The top curve of this figure shows a normal cardiac output curve. Point A on this curve is the normal operating point, showing a normal cardiac output under resting conditions of 5 L/min and a right atrial pressure of 0 mm Hg. Immediately after the heart becomes damaged, the cardiac output curve becomes greatly lowered, falling to the lowest curve at the bottom of the graph. Within a few seconds, a new circulatory state is established at point B rather than point A, illustrating that the cardiac output has fallen to 2 L/min, about two-fifths normal, whereas the right atrial pressure has risen to +4 mm Hg because venous blood returning to the heart from the body is dammed up in the right atrium. This low cardiac output is still sufficient to sustain life for perhaps a few hours, but it is likely to be associated with fainting. Fortunately, this acute stage usually lasts for only a few seconds because sympathetic nerve reflexes occur immediately and compensate, to a great extent, for the damaged heart, as follows. Compensation for Acute Cardiac Failure by Sympathetic Nervous Reflexes. When the cardiac output falls precariously low, many of the circulatory reflexes discussed in Chapter 18 are immediately activated. The best known of these is the baroreceptor reflex, which is activated by diminished arterial pressure. It is probable that the chemoreceptor reflex, the central nervous system ischemic response, and even reflexes that originate in the damaged heart also contribute to activating the sympathetic nervous system. But whatever the reflexes might be, the sympathetics become strongly stimulated within a few seconds, and the 258 2 Chapter 22 Normal heart Partially recovered heart Damaged heart + sympathetic stimulation Cardiac output (L/min) 15 Acutely damaged heart 10 A 5 D B 0 –2 0 +2 +4 +6 259 The sympathetic reflexes become maximally developed in about 30 seconds. Therefore, a person who has a sudden, moderate heart attack might experience nothing more than cardiac pain and a few seconds of fainting. Shortly thereafter, with the aid of the sympathetic reflex compensations, the cardiac output may return to a level adequate to sustain the person if he or she remains quiet, although the pain might persist. Chronic Stage of Failure—Fluid Retention Helps to Compensate Cardiac Output C –4 Cardiac Failure +8 +10 +12 +14 Right atrial pressure (mm Hg) Figure 22–1 Progressive changes in the cardiac output curve after acute myocardial infarction. Both the cardiac output and right atrial pressure change progressively from point A to point D (illustrated by the black line) over a period of seconds, minutes, days, and weeks. parasympathetic nervous signals to the heart become reciprocally inhibited at the same time. Strong sympathetic stimulation has two major effects on the circulation: first on the heart itself, and second on the peripheral vasculature. If all the ventricular musculature is diffusely damaged but is still functional, sympathetic stimulation strengthens this damaged musculature. If part of the muscle is nonfunctional and part of it is still normal, the normal muscle is strongly stimulated by sympathetic stimulation, in this way partially compensating for the nonfunctional muscle. Thus, the heart, one way or another, becomes a stronger pump. This effect is also demonstrated in Figure 22–1, showing after sympathetic compensation about twofold elevation of the very low cardiac output curve. Sympathetic stimulation also increases venous return because it increases the tone of most of the blood vessels of the circulation, especially the veins, raising the mean systemic filling pressure to 12 to 14 mm Hg, almost 100 per cent above normal. As discussed in Chapter 20, this increased filling pressure greatly increases the tendency for blood to flow from the veins back into the heart. Therefore, the damaged heart becomes primed with more inflowing blood than usual, and the right atrial pressure rises still further, which helps the heart to pump still larger quantities of blood. Thus, in Figure 22–1, the new circulatory state is depicted by point C, showing a cardiac output of 4.2 L/min and a right atrial pressure of 5 mm Hg. After the first few minutes of an acute heart attack, a prolonged semi-chronic state begins, characterized mainly by two events: (1) retention of fluid by the kidneys and (2) varying degrees of recovery of the heart itself over a period of weeks to months, as illustrated by the light green curve in Figure 22–1; this was also discussed in Chapter 21. Renal Retention of Fluid and Increase in Blood Volume Occur for Hours to Days A low cardiac output has a profound effect on renal function, sometimes causing anuria when the cardiac output falls to one-half to two-thirds normal. In general, the urine output remains reduced below normal as long as the cardiac output and arterial pressure remain significantly less than normal, and urine output usually does not return all the way to normal after an acute heart attack until the cardiac output and arterial pressure rise either all the way back to normal or almost to normal. Moderate Fluid Retention in Cardiac Failure Can Be Beneficial. Many cardiologists formerly considered fluid retention always to have a detrimental effect in cardiac failure. But it is now known that a moderate increase in body fluid and blood volume is an important factor in helping to compensate for the diminished pumping ability of the heart by increasing the venous return. The increased blood volume increases venous return in two ways: First, it increases the mean systemic filling pressure, which increases the pressure gradient for causing venous flow of blood toward the heart. Second, it distends the veins, which reduces the venous resistance and allows even more ease of flow of blood to the heart. If the heart is not too greatly damaged, this increased venous return can often fully compensate for the heart’s diminished pumping ability—enough in fact that even when the heart’s pumping ability is reduced to as low as 40 to 50 per cent of normal, the increased venous return can often cause an entirely normal cardiac output as long as the person remains in a quiet resting state. When the heart’s pumping capability is reduced still more, blood flow to the kidneys finally becomes too low for the kidneys to excrete enough salt and water to equal salt and water intake. Therefore, fluid 260 Unit IV The Circulation retention begins and continues indefinitely, unless major therapeutic procedures are used to prevent this. Furthermore, because the heart is already pumping at its maximum pumping capacity, this excess fluid no longer has a beneficial effect on the circulation. Instead, severe edema develops throughout the body, which can be very detrimental in itself and can lead to death. thetic stimulation gradually abates toward normal for the following reasons: The partial recovery of the heart can elevate the cardiac output curve the same as sympathetic stimulation can. Therefore, as the heart recovers even slightly, the fast pulse rate, cold skin, and pallor resulting from sympathetic stimulation in the acute stage of cardiac failure gradually disappear. Detrimental Effects of Excess Fluid Retention in Severe Cardiac Failure. In contrast to the beneficial effects of moder- Summary of the Changes That Occur After Acute Cardiac Failure— “Compensated Heart Failure” ate fluid retention in cardiac failure, in severe failure extreme excesses of fluid can have serious physiological consequences. They include (1) overstretching of the heart, thus weakening the heart still more; (2) filtration of fluid into the lungs, causing pulmonary edema and consequent deoxygenation of the blood; and (3) development of extensive edema in most parts of the body.These detrimental effects of excessive fluid are discussed in later sections of this chapter. Recovery of the Myocardium After Myocardial Infarction After a heart becomes suddenly damaged as a result of myocardial infarction, the natural reparative processes of the body begin immediately to help restore normal cardiac function. For instance, a new collateral blood supply begins to penetrate the peripheral portions of the infarcted area of the heart, often causing much of the heart muscle in the fringe areas to become functional again. Also, the undamaged portion of the heart musculature hypertrophies, in this way offsetting much of the cardiac damage. The degree of recovery depends on the type of cardiac damage, and it varies from no recovery to almost complete recovery. After acute myocardial infarction, the heart ordinarily recovers rapidly during the first few days and weeks and achieves most of its final state of recovery within 5 to 7 weeks, although mild degrees of additional recovery can continue for months. The Cardiac Output Curve After Partial Recovery. Figure 22–1 shows function of the partially recovered heart a week or so after acute myocardial infarction. By this time, considerable fluid has been retained in the body and the tendency for venous return has increased markedly as well; therefore, the right atrial pressure has risen even more. As a result, the state of the circulation is now changed from point C to point D, which shows a normal cardiac output of 5 L/min but right atrial pressure increased to 6 mm Hg. Because the cardiac output has returned to normal, renal output of fluid also returns to normal, and no further fluid retention occurs, except that the retention of fluid that has already occurred continues to maintain moderate excesses of fluid. Therefore, except for the high right atrial pressure represented by point D in this figure, the person now has essentially normal cardiovascular dynamics as long as he or she remains at rest. If the heart recovers to a significant extent and if adequate fluid volume has been retained, the sympa- To summarize the events discussed in the past few sections describing the dynamics of circulatory changes after an acute, moderate heart attack, we can divide the stages into (1) the instantaneous effect of the cardiac damage; (2) compensation by the sympathetic nervous system, which occurs mainly within the first 30 seconds to 1 minute; and (3) chronic compensations resulting from partial heart recovery and renal retention of fluid. All these changes are shown graphically by the black curve in Figure 22–1. The progression of this curve shows the normal state of the circulation (point A), the state a few seconds after the heart attack but before sympathetic reflexes have occurred (point B), the rise in cardiac output toward normal caused by sympathetic stimulation (point C), and final return of the cardiac output almost exactly to normal after several days to several weeks of partial cardiac recovery and fluid retention (point D). This final state is called compensated heart failure. Compensated Heart Failure. Note especially in Figure 22–1 that the maximum pumping ability of the partly recovered heart, as depicted by the plateau level of the light green curve, is still depressed to less than one-half normal. This demonstrates that an increase in right atrial pressure can maintain the cardiac output at a normal level despite continued weakness of the heart. Thus many people, especially older people, have normal resting cardiac outputs but mildly to moderately elevated right atrial pressures because of various degrees of “compensated heart failure.” These persons may not know that they have cardiac damage because the damage often has occurred a little at a time, and the compensation has occurred concurrently with the progressive stages of damage. When a person is in compensated heart failure, any attempt to perform heavy exercise usually causes immediate return of the symptoms of acute failure because the heart is not able to increase its pumping capacity to the levels required for the exercise. Therefore, it is said that the cardiac reserve is reduced in compensated heart failure. This concept of cardiac reserve is discussed more fully later in the chapter. Dynamics of Severe Cardiac Failure— Decompensated Heart Failure If the heart becomes severely damaged, no amount of compensation, either by sympathetic nervous reflexes Chapter 22 or by fluid retention, can make the excessively weakened heart pump a normal cardiac output. As a consequence, the cardiac output cannot rise high enough to make the kidneys excrete normal quantities of fluid. Therefore, fluid continues to be retained, the person develops more and more edema, and this state of events eventually leads to death. This is called decompensated heart failure. Thus, the main cause of decompensated heart failure is failure of the heart to pump sufficient blood to make the kidneys excrete daily the necessary amounts of fluid. Graphical Analysis of Decompensated Heart Failure. Figure 22–2 shows greatly depressed cardiac output at different times (points A to F) after the heart has become severely weakened. Point A on this curve represents the approximate state of the circulation before any compensation has occurred, and point B, the state a few minutes later after sympathetic stimulation has compensated as much as it can but before fluid retention has begun. At this time, the cardiac output has risen to 4 L/min and the right atrial pressure has risen to 5 mm Hg. The person appears to be in reasonably good condition, but this state will not remain stable because the cardiac output has not risen high enough to cause adequate kidney excretion of fluid; therefore, fluid retention continues and can eventually be the cause of death. These events can be explained quantitatively in the following way. Note the straight line in Figure 22–2, at a cardiac output level of 5 L/min. This is approximately the critical cardiac output level that is required in the normal adult person to make the kidneys re-establish normal fluid balance—that is, for the output of salt and water to be as great as the intake of these. At any cardiac output below this level, all the fluid-retaining mechanisms discussed in the earlier section remain in play and the body fluid volume increases progressively. And because of this progressive increase in fluid volume, the mean systemic filling pressure of the Cardiac output (L/min) Critical cardiac output level for normal fluid balance 5.0 B 2.5 C D E A F 0 –4 0 +4 +8 +12 +16 Right atrial pressure (mm Hg) Figure 22–2 Greatly depressed cardiac output that indicates decompensated heart disease. Progressive fluid retention raises the right atrial pressure over a period of days, and the cardiac output progresses from point A to point F, until death occurs. Cardiac Failure 261 circulation continues to rise; this forces progressively increasing quantities of blood from the person’s peripheral veins into the right atrium, thus increasing the right atrial pressure. After 1 day or so, the state of the circulation changes in Figure 22–2 from point B to point C—the right atrial pressure rising to 7 mm Hg and the cardiac output to 4.2 L/min. Note again that the cardiac output is still not high enough to cause normal renal output of fluid; therefore, fluid continues to be retained. After another day or so, the right atrial pressure rises to 9 mm Hg, and the circulatory state becomes that depicted by point D. Still, the cardiac output is not enough to establish normal fluid balance. After another few days of fluid retention, the right atrial pressure has risen still further, but by now, cardiac function is beginning to decline toward a lower level.This decline is caused by overstretch of the heart, edema of the heart muscle, and other factors that diminish the heart’s pumping performance. It is now clear that further retention of fluid will be more detrimental than beneficial to the circulation. Yet the cardiac output still is not high enough to bring about normal renal function, so that fluid retention not only continues but accelerates because of the falling cardiac output (and falling arterial pressure that also occurs). Consequently, within a few days, the state of the circulation has reached point F on the curve, with the cardiac output now less than 2.5 L/min and the right atrial pressure 16 mm Hg. This state has approached or reached incompatibility with life, and the patient dies. This state of heart failure in which the failure continues to worsen is called decompensated heart failure. Thus, one can see from this analysis that failure of the cardiac output (and arterial pressure) to rise to the critical level required for normal renal function results in (1) progressive retention of more and more fluid, which causes (2) progressive elevation of the mean systemic filling pressure, and (3) progressive elevation of the right atrial pressure until finally the heart is so overstretched or so edematous that it cannot pump even moderate quantities of blood and, therefore, fails completely. Clinically, one detects this serious condition of decompensation principally by the progressing edema, especially edema of the lungs, which leads to bubbling rales in the lungs and to dyspnea (air hunger). All clinicians know that lack of appropriate therapy when this state of events occurs leads to rapid death. of Decompensation. The decompensation process can often be stopped by (1) strengthening the heart in any one of several ways, especially by administration of a cardiotonic drug, such as digitalis, so that the heart becomes strong enough to pump adequate quantities of blood required to make the kidneys function normally again, or (2) administering diuretic drugs to increase kidney excretion while at the same time reducing water and salt intake, which brings about a balance between fluid intake and output despite low cardiac output. Treatment 262 Unit IV The Circulation Both methods stop the decompensation process by re-establishing normal fluid balance, so that at least as much fluid leaves the body as enters it. it can cause death by suffocation in 20 to 30 minutes, which we discuss more fully later in the chapter. Mechanism of Action of the Cardiotonic Drugs Such as Digitalis. Cardiotonic drugs, such as digitalis, when Low-Output Cardiac Failure— Cardiogenic Shock administered to a person with a healthy heart, have little effect on increasing the contractile strength of the cardiac muscle. However, when administered to a person with a chronically failing heart, the same drugs can sometimes increase the strength of the failing myocardium as much as 50 to 100 per cent. Therefore, they are one of the mainstays of therapy in chronic heart failure. Digitalis and other cardiotonic glycosides are believed to strengthen heart contraction by increasing the quantity of calcium ions in muscle fibers. In the failing heart muscle, the sarcoplasmic reticulum fails to accumulate normal quantities of calcium and, therefore, cannot release enough calcium ions into the free-fluid compartment of the muscle fibers to cause full contraction of the muscle. One effect of digitalis is to depress the calcium pump of the cell membrane of the cardiac muscle fibers. This pump normally pumps calcium ions out of the muscle. However, in the case of a failing heart, extra calcium is needed to increase the muscle contractile force. Therefore, it is usually beneficial to depress the calcium pumping mechanism a moderate amount using digitalis, allowing the muscle fiber intracellular calcium level to rise slightly. Unilateral Left Heart Failure In the discussions thus far in this chapter, we have considered failure of the heart as a whole. Yet, in a large number of patients, especially those with early acute failure, left-sided failure predominates over rightsided failure, and in rare instances, the right side fails without significant failure of the left side. Therefore, we need especially to discuss the special features of unilateral heart failure. When the left side of the heart fails without concomitant failure of the right side, blood continues to be pumped into the lungs with usual right heart vigor, whereas it is not pumped adequately out of the lungs by the left heart into the systemic circulation. As a result, the mean pulmonary filling pressure rises because of shift of large volumes of blood from the systemic circulation into the pulmonary circulation. As the volume of blood in the lungs increases, the pulmonary capillary pressure increases, and if this rises above a value approximately equal to the colloid osmotic pressure of the plasma, about 28 mm Hg, fluid begins to filter out of the capillaries into the lung interstitial spaces and alveoli, resulting in pulmonary edema. Thus, among the most important problems of left heart failure are pulmonary vascular congestion and pulmonary edema. In severe, acute left heart failure, pulmonary edema occasionally occurs so rapidly that In many instances after acute heart attacks and often after prolonged periods of slow progressive cardiac deterioration, the heart becomes incapable of pumping even the minimal amount of blood flow required to keep the body alive. Consequently, all the body tissues begin to suffer and even to deteriorate, often leading to death within a few hours to a few days. The picture then is one of circulatory shock, as explained in Chapter 24. Even the cardiovascular system suffers from lack of nutrition, and it, too (along with the remainder of the body), deteriorates, thus hastening death. This circulatory shock syndrome caused by inadequate cardiac pumping is called cardiogenic shock or simply cardiac shock. Once a person develops cardiogenic shock, the survival rate is often less than 15 per cent. Vicious Circle of Cardiac Deterioration in Cardiogenic Shock. The discussion of circulatory shock in Chapter 24 emphasizes the tendency for the heart to become progressively more damaged when its coronary blood supply is reduced during the course of the shock. That is, the low arterial pressure that occurs during shock reduces the coronary blood supply even more. This makes the heart still weaker, which makes the arterial pressure fall still more, which makes the shock still worse, the process eventually becoming a vicious circle of cardiac deterioration. In cardiogenic shock caused by myocardial infarction, this problem is greatly compounded by already existing coronary vessel blockage. For instance, in a healthy heart, the arterial pressure usually must be reduced below about 45 mm Hg before cardiac deterioration sets in. However, in a heart that already has a blocked major coronary vessel, deterioration sets in when the coronary arterial pressure falls below 80 to 90 mm Hg. In other words, even a small decrease in arterial pressure can now set off a vicious circle of cardiac deterioration. For this reason, in treating myocardial infarction, it is extremely important to prevent even short periods of hypotension. Physiology of Treatment. Often a patient dies of cardiogenic shock before the various compensatory processes can return the cardiac output (and arterial pressure) to a life-sustaining level. Therefore, treatment of this condition is one of the most important problems in the management of acute heart attacks. Immediate administration of digitalis is often used for strengthening the heart if the ventricular muscle shows signs of deterioration. Also, infusion of whole blood, plasma, or a blood pressure–raising drug is used to sustain the arterial pressure. If the arterial pressure can be elevated high enough, the coronary blood flow Chapter 22 often will increase enough to prevent the vicious circle of deterioration. And this allows enough time for appropriate compensatory mechanisms in circulatory system to correct the shock. Some success has also been achieved in saving the lives of patients in cardiogenic shock by using one of the following procedures: (1) surgically removing the clot in the coronary artery, often in combination with coronary bypass graft, or (2) catheterizing the blocked coronary artery and infusing either streptokinase or tissue-type plasminogen activator enzymes that cause dissolution of the clot. The results occasionally are astounding when one of these procedures is instituted within the first hour of cardiogenic shock but of little, if any, benefit after 3 hours. Edema in Patients with Cardiac Failure Inability of Acute Cardiac Failure to Cause Peripheral Edema. Acute left heart failure can cause terrific and rapid congestion of the lungs, with development of pulmonary edema and even death within minutes to hours. However, either left or right heart failure is very slow to cause peripheral edema. This can best be explained by referring to Figure 22–3. When a previously healthy heart acutely fails as a pump, the aortic pressure falls and the right atrial pressure rises. As the cardiac output approaches zero, these two pressures approach each other at an equilibrium value of about 13 mm Hg. Capillary pressure also falls from its normal value of 17 mm Hg to the new equilibrium pressure Mean aortic pressure Capillary pressure Pressure (mm Hg) 100 Right atrial pressure 80 60 40 13 mm Hg 20 0 Normal 1/2 Normal Zero Cardiac output Figure 22–3 Progressive changes in mean aortic pressure, peripheral tissue capillary pressure, and right atrial pressure as the cardiac output falls from normal to zero. Cardiac Failure 263 of 13 mm Hg. Thus, severe acute cardiac failure often causes a fall in peripheral capillary pressure rather than a rise. Therefore, animal experiments, as well as experience in humans, show that acute cardiac failure almost never causes immediate development of peripheral edema. Long-Term Fluid Retention by the Kidneys— The Cause of Peripheral Edema in Persisting Heart Failure After the first day or so of overall heart failure or of right-ventricular heart failure, peripheral edema does begin to occur principally because of fluid retention by the kidneys. The retention of fluid increases the mean systemic filling pressure, resulting in increased tendency for blood to return to the heart. This elevates the right atrial pressure to a still higher value and returns the arterial pressure back toward normal. Therefore, the capillary pressure now also rises markedly, thus causing loss of fluid into the tissues and development of severe edema. There are three known causes of the reduced renal output of urine during cardiac failure, all of which are equally important but in different ways. 1. Decreased glomerular filtration. A decrease in cardiac output has a tendency to reduce the glomerular pressure in the kidneys because of (1) reduced arterial pressure and (2) intense sympathetic constriction of the afferent arterioles of the kidney. As a consequence, except in the mildest degrees of heart failure, the glomerular filtration rate becomes less than normal. It is clear from the discussion of kidney function in Chapters 26 through 29 that even a slight decrease in glomerular filtration often markedly decreases urine output. When the cardiac output falls to about one-half normal, this can result in almost complete anuria. 2. Activation of the renin-angiotensin system and increased reabsorption of water and salt by the renal tubules. The reduced blood flow to the kidneys causes marked increase in renin secretion by the kidneys, and this in turn causes the formation of angiotensin, as described in Chapter 19. The angiotensin in turn has a direct effect on the arterioles of the kidneys to decrease further the blood flow through the kidneys, which especially reduces the pressure in the capillaries surrounding the renal tubules, promoting greatly increased reabsorption of both water and salt from the tubules. Therefore, loss of water and salt into the urine decreases greatly, and large quantities of salt and water accumulate in the blood and interstitial fluids everywhere in the body. 3. Increased aldosterone secretion. In the chronic stage of heart failure, large quantities of aldosterone are secreted by the adrenal cortex. This results mainly from the effect of angiotensin to stimulate aldosterone secretion by the adrenal cortex. But some of the increase in aldosterone secretion often results from increased plasma 264 Unit IV The Circulation potassium. Excess potassium is one of the most powerful stimuli known for aldosterone secretion, and the potassium concentration rises in response to reduced renal function in cardiac failure. The elevated aldosterone level further increases the reabsorption of sodium from the renal tubules. This in turn leads to a secondary increase in water reabsorption for two reasons: First, as the sodium is reabsorbed, it reduces the osmotic pressure in the tubules but increases the osmotic pressure in the renal interstitial fluids; these changes promote osmosis of water into the blood. Second, the absorbed sodium and anions that go with the sodium, mainly chloride ions, increase the osmotic concentration of the extracellular fluid everywhere in the body. This elicits antidiuretic hormone secretion by the hypothalamic–posterior pituitary gland system (discussed in Chapter 29). The antidiuretic hormone in turn promotes still greater increase in tubular reabsorption of water. Role of Atrial Natriuretic Factor to Delay Onset of Cardiac Decompensation. Atrial natriuretic factor (ANF) is a hormone released by the atrial walls of the heart when they become stretched. Because heart failure almost always causes excessive increase in both the right and left atrial pressures that stretch the atrial walls, the circulating levels of ANF in the blood increase fivefold to tenfold in severe heart failure. The ANF in turn has a direct effect on the kidneys to increase greatly their excretion of salt and water. Therefore, ANF plays a natural role to help prevent extreme congestive symptoms during cardiac failure. The renal effects of ANF are discussed in Chapter 29. Acute Pulmonary Edema in Late-Stage Heart Failure—Another Lethal Vicious Circle A frequent cause of death in heart failure is acute pulmonary edema occurring in patients who have already had chronic heart failure for a long time. When this occurs in a person without new cardiac damage, it usually is set off by some temporary overload of the heart, such as might result from a bout of heavy exercise, some emotional experience, or even a severe cold. The acute pulmonary edema is believed to result from the following vicious circle: 1. A temporarily increased load on the already weak left ventricle initiates the vicious circle. Because of limited pumping capacity of the left heart, blood begins to dam up in the lungs. 2. The increased blood in the lungs elevates the pulmonary capillary pressure, and a small amount of fluid begins to transude into the lung tissues and alveoli. 3. The increased fluid in the lungs diminishes the degree of oxygenation of the blood. 4. The decreased oxygen in the blood further weakens the heart and also weakens the arterioles everywhere in the body, thus causing peripheral vasodilation. 5. The peripheral vasodilation increases venous return of blood from the peripheral circulation still more. 6. The increased venous return further increases the damming of the blood in the lungs, leading to still more transudation of fluid, more arterial oxygen desaturation, more venous return, and so forth. Thus, a vicious circle has been established. Once this vicious circle has proceeded beyond a certain critical point, it will continue until death of the patient unless heroic therapeutic measures are used within minutes. The types of heroic therapeutic measures that can reverse the process and save the patient’s life include the following: 1. Putting tourniquets on both arms and legs to sequester much of the blood in the veins and, therefore, decrease the workload on the left side of the heart 2. Bleeding the patient 3. Giving a rapidly acting diuretic, such as furosemide, to cause rapid loss of fluid from the body 4. Giving the patient pure oxygen to breathe to reverse the blood oxygen desaturation, the heart deterioration, and the peripheral vasodilation 5. Giving the patient a rapidly acting cardiotonic drug, such as digitalis, to strengthen the heart This vicious circle of acute pulmonary edema can proceed so rapidly that death can occur in 20 minutes to 1 hour. Therefore, any procedure that is to be successful must be instituted immediately. Cardiac Reserve The maximum percentage that the cardiac output can increase above normal is called the cardiac reserve. Thus, in the healthy young adult, the cardiac reserve is 300 to 400 per cent. In athletically trained persons, it is occasionally 500 to 600 per cent. But in heart failure, there is no cardiac reserve. As an example of normal reserve, during severe exercise the cardiac output of a healthy young adult can rise to about five times normal; this is an increase above normal of 400 per cent—that is, a cardiac reserve of 400 per cent. Any factor that prevents the heart from pumping blood satisfactorily will decrease the cardiac reserve. This can result from ischemic heart disease, primary myocardial disease, vitamin deficiency that affects cardiac muscle, physical damage to the myocardium, valvular heart disease, and many other factors, some of which are shown in Figure 22–4. Diagnosis of Low Cardiac Reserve—Exercise Test. As long as persons with low cardiac reserve remain in a state of rest, they usually will not know that they have heart disease. However, a diagnosis of low cardiac reserve usually can be easily made by requiring the person to exercise either on a treadmill or by walking up and down steps, either of which requires greatly increased cardiac output. The increased load on the heart rapidly uses up the small amount of reserve that is available, Cardiac reserve (%) 600 Athlete 500 Normal 400 300 200 100 0 Normal operation Mild valvular disease Moderate coronary disease Diphtheria Severe coronary thrombosis Severe valvular disease 265 Cardiac Failure Cardiac output and venous return (L/min) Chapter 22 15 Normal 10 A 5 C D B 0 –4 –2 0 2 4 6 8 10 12 Right atrial pressure (mm Hg) 14 Figure 22–5 Progressive changes in cardiac output and right atrial pressure during different stages of cardiac failure. Figure 22–4 Cardiac reserve in different conditions, showing less than zero reserve for two of the conditions. and the cardiac output soon fails to rise high enough to sustain the body’s new level of activity. The acute effects are as follows: 1. Immediate and sometimes extreme shortness of breath (dyspnea) resulting from failure of the heart to pump sufficient blood to the tissues, thereby causing tissue ischemia and creating a sensation of air hunger 2. Extreme muscle fatigue resulting from muscle ischemia, thus limiting the person’s ability to continue with the exercise 3. Excessive increase in heart rate because the nervous reflexes to the heart overreact in an attempt to overcome the inadequate cardiac output Exercise tests are part of the armamentarium of the cardiologist. These tests take the place of cardiac output measurements that cannot be made with ease in most clinical settings. Quantitative Graphical Method for Analysis of Cardiac Failure circulation. The two curves passing through Point A are (1) the normal cardiac output curve and (2) the normal venous return curve. As pointed out in Chapter 20, there is only one point on each of these two curves at which the circulatory system can operate. This point is where the two curves cross at point A. Therefore, the normal state of the circulation is a cardiac output and venous return of 5 L/min and a right atrial pressure of 0 mm Hg. Effect of Acute Heart Attack. During the first few seconds after a moderately severe heart attack, the cardiac output curve falls to the lowermost curve. During these few seconds, the venous return curve still has not changed because the peripheral circulatory system is still operating normally. Therefore, the new state of the circulation is depicted by point B, where the new cardiac output curve crosses the normal venous return curve. Thus, the right atrial pressure rises immediately to 4 mm Hg, whereas the cardiac output falls to 2 L/min. Effect of Sympathetic Reflexes. Within the next 30 Although it is possible to understand most general principles of cardiac failure using mainly qualitative logic, as we have done thus far in this chapter, one can grasp the importance of the different factors in cardiac failure with far greater depth by using more quantitative approaches. One such approach is the graphical method for analysis of cardiac output regulation introduced in Chapter 20. In the remaining sections of this chapter, we analyze several aspects of cardiac failure, using this graphical technique. Graphical Analysis of Acute Heart Failure and Chronic Compensation Figure 22–5 shows cardiac output and venous return curves for different states of the heart and peripheral seconds, the sympathetic reflexes become very active. They affect both the cardiac output and the venous return curves, raising both of them. Sympathetic stimulation can increase the plateau level of the cardiac output curve as much as 30 to 100 per cent. It can also increase the mean systemic filling pressure (depicted by the point where the venous return curve crosses the zero venous return axis) by several millimeters of mercury—in this figure, from a normal value of 7 mm Hg up to 10 mm Hg. This increase in mean systemic filling pressure shifts the entire venous return curve to the right and upward. The new cardiac output and venous return curves now equilibrate at point C, that is, at a right atrial pressure of +5 mm Hg and a cardiac output of 4 L/min. 266 Unit IV The Circulation Compensation During the Next Few Days. During the ensuing week, the cardiac output and venous return curves rise further because of (1) some recovery of the heart and (2) renal retention of salt and water, which raises the mean systemic filling pressure still further— this time up to +12 mm Hg. The two new curves now equilibrate at point D. Thus, the cardiac output has now returned to normal. The right atrial pressure, however, has risen still further to +6 mm Hg. Because the cardiac output is now normal, renal output is also normal, so that a new state of equilibrated fluid balance has been achieved. The circulatory system will continue to function at point D and remain stable, with a normal cardiac output and an elevated right atrial pressure, until some additional extrinsic factor changes either the cardiac output curve or the venous return curve. Using this technique for analysis, one can see especially the importance of moderate fluid retention and how it eventually leads to a new stable state of the circulation in mild to moderate heart failure. And one can also see the interrelation between mean systemic filling pressure and cardiac pumping at various degrees of heart failure. Note that the events described in Figure 22–5 are the same as those presented in Figure 22–1, but in Figure 22–5, they are presented in a more quantitative manner. Graphical Analysis of “Decompensated” Cardiac Failure Cardiac output and venous return (L/min) The black cardiac output curve in Figure 22–6 is the same as the curve shown in Figure 22–2, a very low curve that has already reached a degree of recovery as great as this heart can achieve. In this figure, we have added venous return curves that occur during successive days after the acute fall of the cardiac output curve to this low level. At point A, the curve at time zero equates with the normal venous return curve to give a cardiac output of about 3 L/min. However, stimulation of the sympathetic nervous system, caused by this low cardiac output, increases the mean systemic filling pressure within 30 seconds from 7 to 10.5 mm Hg. This shifts the venous return curve upward and to the right to produce the curve labeled “autonomic compensation.” Thus, the new venous return curve equates with the cardiac output curve at point B. The cardiac output has been improved to a level of 4 L/min but at the expense of an additional rise in right atrial pressure to 5 mm Hg. The cardiac output of 4 L/min is still too low to cause the kidneys to function normally. Therefore, fluid continues to be retained, and the mean systemic filling pressure rises from 10.5 to almost 13 mm Hg. Now the venous return curve becomes that labeled “2nd day” and equilibrates with the cardiac output curve at point C. The cardiac output rises to 4.2 L/min and the right atrial pressure to 7 mm Hg. During the succeeding days, the cardiac output never rises quite high enough to re-establish normal renal function. Fluid continues to be retained, the mean systemic filling pressure continues to rise, the venous return curve continues to shift to the right, and the equilibrium point between the venous return curve and the cardiac output curve also shifts progressively to point D, to point E, and, finally, to point F. The equilibration process is now on the down slope of the cardiac output curve, so that further retention of fluid causes only more severe cardiac edema and a detrimental effect on cardiac output. The condition accelerates downhill until death occurs. Thus, “decompensation” results from the fact that the cardiac output curve never rises to the critical level of 5 L/min needed to re-establish normal kidney excretion of fluid that would be required to cause balance between fluid input and output. Treatment of Decompensated Heart Disease with Digitalis. Let 15 8th 6th day 4th day 10 5 day Critical cardiac output level for normal fluid balance 2nd day Autonomic com pen sat ion ous Normal v en retu rn A B C D E F 0 –4 –2 0 2 4 6 8 10 12 Right atrial pressure (mm Hg) 14 16 Figure 22–6 Graphical analysis of decompensated heart disease showing progressive shift of the venous return curve to the right as a result of continued fluid retention. us assume that the stage of decompensation has already reached point E in Figure 22–6, and let us proceed to the same point E in Figure 22–7. At this time, digitalis is given to strengthen the heart. This raises the cardiac output curve to the level shown in Figure 22–7, but there is not an immediate change in the venous return curve. Therefore, the new cardiac output curve equates with the venous return curve at point G. The cardiac output is now 5.7 L/min, a value greater than the critical level of 5 liters required to make the kidneys excrete normal amounts of urine. Therefore, the kidneys eliminate much more fluid than normally, causing diuresis, a well-known therapeutic effect of digitalis. The progressive loss of fluid over a period of several days reduces the mean systemic filling pressure back down to 11.5 mm Hg, and the new venous return curve becomes the curve labeled “Several days later.” This curve equates with the cardiac output curve of the digitalized heart at point H, at an output of 5 L/min and a right atrial pressure of 4.6 mm Hg. This cardiac First d ay 10 S everal d G H t e ar dh ize f a ili n g l a e ly git ver art Di Se he 5 0 –4 –2 0 2 4 6 E 8 10 12 14 16 Right atrial pressure (mm Hg) 25 20 15 Normal venous return curve 10 5 A la ays late r Critical cardiac output level for normal fluid balance Cardiac output and venous return (L/min) 15 267 Cardiac Failure u fist AV Cardiac output and venous return (L/min) Chapter 22 Normal cardiac output curve B C Beriberi heart disease 0 –4 –2 0 2 4 6 8 10 12 14 16 Right atrial pressure (mm Hg) Figure 22–7 Treatment of decompensated heart disease showing the effect of digitalis in elevating the cardiac output curve, this in turn causing increased urine output and progressive shift of the venous return curve to the left. Figure 22–8 output is precisely that required for normal fluid balance. Therefore, no additional fluid will be lost and none will be gained. Consequently, the circulatory system has now stabilized, or in other words, the decompensation of the heart failure has been “compensated.” And to state this another way, the final steady-state condition of the circulation is defined by the crossing point of three curves: the cardiac output curve, the venous return curve, and the critical level for normal fluid balance. The compensatory mechanisms automatically stabilize the circulation when all three curves cross at the same point. Graphical Analysis of High-Output Cardiac Failure Figure 22–8 gives an analysis of two types of highoutput cardiac failure. One of these is caused by an arteriovenous fistula that overloads the heart because of excessive venous return, even though the pumping capability of the heart is not depressed. The other is caused by beriberi, in which the venous return is greatly increased because of diminished systemic vascular resistance, but at the same time, the pumping capability of the heart is depressed. Arteriovenous Fistula. The “normal” curves of Figure 22–8 depict the normal cardiac output and normal venous return curves. These equate with each other at point A, which depicts a normal cardiac output of 5 L/ min and a normal right atrial pressure of 0 mm Hg. Now let us assume that the systemic resistance (the total peripheral resistance) becomes greatly decreased because of opening a large arteriovenous fistula (a direct opening between a large artery and a large vein). The venous return curve rotates upward to give the curve labeled “AV fistula.” This venous return curve equates with the normal cardiac output curve at point B, with a cardiac output of 12.5 L/min and a right atrial pressure of 3 mm Hg. Thus, the cardiac output has become greatly elevated, the right atrial pressure Graphical analysis of two types of conditions that can cause highoutput cardiac failure: (1) arteriovenous (AV) fistula and (2) beriberi heart disease. is slightly elevated, and there are mild signs of peripheral congestion. If the person attempts to exercise, he or she will have little cardiac reserve because the heart is already being used almost to maximum capacity to pump the extra blood through the arteriovenous fistula. This condition resembles a failure condition and is called “high-output failure,” but in reality, the heart is overloaded by excess venous return. Beriberi. Figure 22–8 shows the approximate changes in the cardiac output and venous return curves caused by beriberi. The decreased level of the cardiac output curve is caused by weakening of the heart because of the avitaminosis (mainly lack of thiamine) that causes the beriberi syndrome. The weakening of the heart has decreased the blood flow to the kidneys. Therefore, the kidneys have retained a large amount of extra body fluid, which in turn has increased the mean systemic filling pressure (represented by the point where the venous return curve now intersects the zero cardiac output level) from the normal value of 7 mm Hg up to 11 mm Hg. This has shifted the venous return curve to the right. Finally, the venous return curve has rotated upward from the normal curve because the avitaminosis has dilated the peripheral blood vessels, as explained in Chapter 17. The two blue curves (cardiac output curve and venous return curve) intersect with each other at point C, which describes the circulatory condition in beriberi, with a right atrial pressure in this instance of 9 mm Hg and a cardiac output about 65 per cent above normal; this high cardiac output occurs despite the weak heart, as demonstrated by the depressed plateau level of the cardiac output curve. 268 Unit IV The Circulation References Andrew P: Diastolic heart failure demystified. Chest 124:744, 2003. Braunwald E, Zipes DP, Liby P: A Textbook for Cardiovascular Medicine. 6th Ed. Philadelphia: WB Saunders Co, 2001. Dorn GW 2nd, Molkentin JD: Manipulating cardiac contractility in heart failure: data from mice and men. Circulation 109:150, 2004. Ducas J, Grech ED: ABC of interventional cardiology. Percutaneous coronary intervention: cardiogenic shock. BMJ 326:1450, 2003. Eikelboom J, White H, Yusuf S: The evolving role of direct thrombin inhibitors in acute coronary syndromes. J Am Coll Cardiol 41(4 Suppl S):70S, 2003. Floras JS: Sympathetic activation in human heart failure: diverse mechanisms, therapeutic opportunities. Acta Physiol Scand 177:391, 2003. Gavras H, Brunner HR: Role of angiotensin and its inhibition in hypertension, ischemic heart disease, and heart failure. Hypertension 37:342, 2001. Gehlbach BK, Geppert E: The pulmonary manifestations of left heart failure. Chest 125:669, 2004. Guyton AC, Jones CE, Coleman TG: Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: WB Saunders Co, 1973. Hochman JS: Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. Circulation 107: 2998, 2003. Lohmeier TE: Neurohumoral regulation of arterial pressure in hemorrhage and heart failure. Am J Physiol Regul Integr Comp Physiol 283:R810, 2002. Mehra MR, Gheorghiade M, Bonow RO: Mitral regurgitation in chronic heart failure: more questions than answers? Curr Cardiol Rep 6:96, 2004. McMurray J, Pfeffer MA: New therapeutic options in congestive heart failure: Part I. Circulation 105:2099, 2002. McMurray J, Pfeffer MA: New therapeutic options in congestive heart failure: Part II. Circulation 105:2223, 2002 Pfisterer M: Right ventricular involvement in myocardial infarction and cardiogenic shock. Lancet 362:392, 2003. Ruskoaho H: Cardiac hormones as diagnostic tools in heart failure. Endocr Rev 24:341, 2003. Shlipak MG: Pharmacotherapy for heart failure in patients with renal insufficiency. Ann Intern Med 138:917, 2003. Sjaastad I, Wasserstrom JA, Sejersted OM: Heart failure— a challenge to our current concepts of excitationcontraction coupling. J Physiol 546:33, 2003. Spodick DH: Acute cardiac tamponade. N Engl J Med 349:684, 2003. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 105:1387, 2002. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation 105:1503, 2002. C H A P T E R 2 3 Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects Function of the heart valves was discussed in Chapter 9, where it was pointed out that closing of the valves causes audible sounds. Ordinarily, no audible sounds occur when the valves open. In this chapter, we first discuss the factors that cause the sounds in the heart under normal and abnormal conditions. Then we discuss what happens in the overall circulatory system when valvular or congenital heart defects are present. Heart Sounds Normal Heart Sounds Listening with a stethoscope to a normal heart, one hears a sound usually described as “lub, dub, lub, dub.”The “lub” is associated with closure of the atrioventricular (A-V) valves at the beginning of systole, and the “dub” is associated with closure of the semilunar (aortic and pulmonary) valves at the end of systole. The “lub” sound is called the first heart sound, and the “dub” is called the second heart sound, because the normal pumping cycle of the heart is considered to start when the A-V valves close at the onset of ventricular systole. Causes of the First and Second Heart Sounds. The earliest explanation for the cause of the heart sounds was that the “slapping” together of the valve leaflets sets up vibrations. However, this has been shown to cause little, if any, of the sound, because the blood between the leaflets cushions the slapping effect and prevents significant sound. Instead, the cause is vibration of the taut valves immediately after closure, along with vibration of the adjacent walls of the heart and major vessels around the heart. That is, in generating the first heart sound, contraction of the ventricles first causes sudden backflow of blood against the A-V valves (the tricuspid and mitral valves), causing them to close and bulge toward the atria until the chordae tendineae abruptly stop the back bulging. The elastic tautness of the chordae tendineae and of the valves then causes the back surging blood to bounce forward again into each respective ventricle. This causes the blood and the ventricular walls, as well as the taut valves, to vibrate and causes vibrating turbulence in the blood. The vibrations travel through the adjacent tissues to the chest wall, where they can be heard as sound by using the stethoscope. The second heart sound results from sudden closure of the semilunar valves at the end of systole. When the semilunar valves close, they bulge backward toward the ventricles, and their elastic stretch recoils the blood back into the arteries, which causes a short period of reverberation of blood back and forth between the walls of the arteries and the semilunar valves, as well as between these valves and the ventricular walls. The vibrations occurring in the arterial walls are then transmitted mainly along the arteries. When the vibrations of the vessels or ventricles come into contact with a “sounding board,” such as the chest wall, they create sound that can be heard. 269 270 Unit IV The Circulation Duration and Pitch of the First and Second Heart Sounds. The duration of each of the heart sounds is slightly more than 0.10 second—the first sound about 0.14 second, and the second about 0.11 second. The reason for the shorter second sound is that the semilunar valves are more taut than the A-V valves, so that they vibrate for a shorter time than do the A-V valves. The audible range of frequency (pitch) in the first and second heart sounds, as shown in Figure 23–1, begins at the lowest frequency the ear can detect, about 40 cycles/sec, and goes up above 500 cycles/sec. When special electronic apparatus is used to record these sounds, by far a larger proportion of the recorded sound is at frequencies and sound levels below the audible range, going down to 3 to 4 cycles/sec and peaking at about 20 cycles/sec, as illustrated by the lower shaded area in Figure 23–1. For this reason, major portions of the heart sounds can be recorded electronically in phonocardiograms even though they cannot be heard with a stethoscope. The second heart sound normally has a higher frequency than the first heart sound for two reasons: (1) the tautness of the semilunar valves in comparison with the much less taut A-V valves, and (2) the greater elastic coefficient of the taut arterial walls that provide the principal vibrating chambers for the second sound, in comparison with the much looser, less elastic ventricular chambers that provide the vibrating system for the first heart sound. The clinician uses these differences to distinguish special characteristics of the two respective sounds. Third Heart Sound. Occasionally a weak, rumbling third heart sound is heard at the beginning of the middle Heart sounds Inaudible and murmurs 100 Dynes/cm2 ho 0.1 Heart sounds and murmurs 0.01 sound can sometimes be recorded in the phonocardiogram, but it can almost never be heard with a stethoscope because of its weakness and very low frequency—usually 20 cycles/sec or less. This sound occurs when the atria contract, and presumably, it is caused by the inrush of blood into the ventricles, which initiates vibrations similar to those of the third heart sound. Chest Surface Areas for Auscultation of Normal Heart Sounds Listening to the sounds of the body, usually with the aid of a stethoscope, is called auscultation. Figure 23–2 shows the areas of the chest wall from which the different heart valvular sounds can best be distinguished. Although the sounds from all the valves can be heard from all these areas, the cardiologist distinguishes the sounds from the different valves by a process of Pulmonic area Speech area Th res Atrial Heart Sound (Fourth Heart Sound). An atrial heart Aortic area 10 1 third of diastole. A logical but unproved explanation of this sound is oscillation of blood back and forth between the walls of the ventricles initiated by inrushing blood from the atria. This is analogous to running water from a faucet into a paper sack, the inrushing water reverberating back and forth between the walls of the sack to cause vibrations in its walls. The reason the third heart sound does not occur until the middle third of diastole is believed to be that in the early part of diastole, the ventricles are not filled sufficiently to create even the small amount of elastic tension necessary for reverberation. The frequency of this sound is usually so low that the ear cannot hear it, yet it can often be recorded in the phonocardiogram. ld of au dib ility 0.001 0.0001 0 8 32 64 128 256 512 1024 2048 4096 Frequency in cycles per second Figure 23–1 Amplitude of different-frequency vibrations in the heart sounds and heart murmurs in relation to the threshold of audibility, showing that the range of sounds that can be heard is between 40 and 520 cycles/sec. (Modified from Butterworth JS, Chassin JL, McGrath JJ: Cardiac Auscultation, 2nd ed. New York: Grune & Stratton, 1960.) Tricuspid area Mitral area Figure 23–2 Chest areas from which sound from each valve is best heard. Chapter 23 Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects 271 Valvular Lesions 1st A 2nd 3rd Rheumatic Valvular Lesions Atrial Normal B Aortic stenosis C Mitral regurgitation D Aortic regurgitation E Mitral stenosis F Patent ductus arteriosus Diastole Systole Diastole Systole Figure 23–3 Phonocardiograms from normal and abnormal hearts. elimination. That is, he or she moves the stethoscope from one area to another, noting the loudness of the sounds in different areas and gradually picking out the sound components from each valve. The areas for listening to the different heart sounds are not directly over the valves themselves. The aortic area is upward along the aorta because of sound transmission up the aorta, and the pulmonic area is upward along the pulmonary artery. The tricuspid area is over the right ventricle, and the mitral area is over the apex of the left ventricle, which is the portion of the heart nearest the surface of the chest; the heart is rotated so that the remainder of the left ventricle lies more posteriorly. Phonocardiogram If a microphone specially designed to detect low-frequency sound is placed on the chest, the heart sounds can be amplified and recorded by a high-speed recording apparatus. The recording is called a phonocardiogram, and the heart sounds appear as waves, as shown schematically in Figure 23–3. Recording A is an example of normal heart sounds, showing the vibrations of the first, second, and third heart sounds and even the very weak atrial sound. Note specifically that the third and atrial heart sounds are each a very low rumble. The third heart sound can be recorded in only one third to one half of all people, and the atrial heart sound can be recorded in perhaps one fourth of all people. By far the greatest number of valvular lesions results from rheumatic fever. Rheumatic fever is an autoimmune disease in which the heart valves are likely to be damaged or destroyed. It is usually initiated by streptococcal toxin in the following manner. The sequence of events almost always begins with a preliminary streptococcal infection caused specifically by group A hemolytic streptococci. These bacteria initially cause a sore throat, scarlet fever, or middle ear infection. But the streptococci also release several different proteins against which the person’s reticuloendothelial system produces antibodies. The antibodies react not only with the streptococcal protein but also with other protein tissues of the body, often causing severe immunologic damage. These reactions continue to take place as long as the antibodies persist in the blood—1 year or more. Rheumatic fever causes damage especially in certain susceptible areas, such as the heart valves. The degree of heart valve damage is directly correlated with the concentration and persistence of the antibodies. The principles of immunity that relate to this type of reaction are discussed in Chapter 34, and it is noted in Chapter 31 that acute glomerular nephritis of the kidneys has a similar immunologic basis. In rheumatic fever, large hemorrhagic, fibrinous, bulbous lesions grow along the inflamed edges of the heart valves. Because the mitral valve receives more trauma during valvular action than any of the other valves, it is the one most often seriously damaged, and the aortic valve is second most frequently damaged. The right heart valves, the tricuspid and pulmonary valves, are usually affected much less severely, probably because the low-pressure stresses that act on these valves are slight compared with the high-pressure stresses that act on the left heart valves. Scarring of the Valves. The lesions of acute rheumatic fever frequently occur on adjacent valve leaflets simultaneously, so that the edges of the leaflets become stuck together. Then, weeks, months, or years later, the lesions become scar tissue, permanently fusing portions of adjacent valve leaflets. Also, the free edges of the leaflets, which are normally filmy and free-flapping, often become solid, scarred masses. A valve in which the leaflets adhere to one another so extensively that blood cannot flow through it normally is said to be stenosed. Conversely, when the valve edges are so destroyed by scar tissue that they cannot close as the ventricles contract, regurgitation (backflow) of blood occurs when the valve should be closed. Stenosis usually does not occur without the coexistence of at least some degree of regurgitation, and vice versa. Other Causes of Valvular Lesions. Stenosis or lack of one or more leaflets of a valve also occurs occasionally as a congenital defect. Complete lack of leaflets is rare; 272 Unit IV The Circulation congenital stenosis is more common, as is discussed later in this chapter. Heart Murmurs Caused by Valvular Lesions As shown by the phonocardiograms in Figure 23–3, many abnormal heart sounds, known as “heart murmurs,” occur when there are abnormalities of the valves, as follows. Systolic Murmur of Aortic Stenosis. In aortic stenosis, blood is ejected from the left ventricle through only a small fibrous opening of the aortic valve. Because of the resistance to ejection, sometimes the blood pressure in the left ventricle rises as high as 300 mm Hg, while the pressure in the aorta is still normal. Thus, a nozzle effect is created during systole, with blood jetting at tremendous velocity through the small opening of the valve. This causes severe turbulence of the blood in the root of the aorta. The turbulent blood impinging against the aortic walls causes intense vibration, and a loud murmur (see recording B, Figure 23–3) occurs during systole and is transmitted throughout the superior thoracic aorta and even into the large arteries of the neck. This sound is harsh and in severe stenosis may be so loud that it can be heard several feet away from the patient. Also, the sound vibrations can often be felt with the hand on the upper chest and lower neck, a phenomenon known as a “thrill.” Diastolic Murmur of Aortic Regurgitation. In aortic regurgitation, no abnormal sound is heard during systole, but during diastole, blood flows backward from the high-pressure aorta into the left ventricle, causing a “blowing” murmur of relatively high pitch with a swishing quality heard maximally over the left ventricle (see recording D, Figure 23–3). This murmur results from turbulence of blood jetting backward into the blood already in the low-pressure diastolic left ventricle. Systolic Murmur of Mitral Regurgitation. In mitral regurgi- tation, blood flows backward through the mitral valve into the left atrium during systole. This also causes a high-frequency “blowing,” swishing sound (see recording C, Figure 23–3) similar to that of aortic regurgitation but occurring during systole rather than diastole. It is transmitted most strongly into the left atrium. However, the left atrium is so deep within the chest that it is difficult to hear this sound directly over the atrium. As a result, the sound of mitral regurgitation is transmitted to the chest wall mainly through the left ventricle to the apex of the heart. Diastolic Murmur of Mitral Stenosis. In mitral stenosis, blood passes with difficulty through the stenosed mitral valve from the left atrium into the left ventricle, and because the pressure in the left atrium seldom rises above 30 mm Hg, a large pressure differential forcing blood from the left atrium into the left ventricle does not develop. Consequently, the abnormal sounds heard in mitral stenosis (see recording E, Figure 23–3) are usually weak and of very low frequency, so that most of the sound spectrum is below the low-frequency end of human hearing. During the early part of diastole, a left ventricle with a stenotic mitral valve has so little blood in it and its walls are so flabby that blood does not reverberate back and forth between the walls of the ventricle. For this reason, even in severe mitral stenosis, no murmur may be heard during the first third of diastole. Then, after partial filling, the ventricle has stretched enough for blood to reverberate, and a low rumbling murmur begins. of Valvular Murmurs. Phonocardiograms B, C, D, and E of Figure 23–3 show, respectively, idealized records obtained from patients with aortic stenosis, mitral regurgitation, aortic regurgitation, and mitral stenosis. It is obvious from these phonocardiograms that the aortic stenotic lesion causes the loudest murmur, and the mitral stenotic lesion causes the weakest. The phonocardiograms show how the intensity of the murmurs varies during different portions of systole and diastole, and the relative timing of each murmur is also evident. Note especially that the murmurs of aortic stenosis and mitral regurgitation occur only during systole, whereas the murmurs of aortic regurgitation and mitral stenosis occur only during diastole. If the reader does not understand this timing, extra review should be undertaken until it is understood. Phonocardiograms Abnormal Circulatory Dynamics in Valvular Heart Disease Dynamics of the Circulation in Aortic Stenosis and Aortic Regurgitation In aortic stenosis, the contracting left ventricle fails to empty adequately, whereas in aortic regurgitation, blood flows backward into the ventricle from the aorta after the ventricle has just pumped the blood into the aorta. Therefore, in either case, the net stroke volume output of the heart is reduced. Several important compensations take place that can ameliorate the severity of the circulatory defects. Some of these compensations are the following. Hypertrophy of the Left Ventricle. In both aortic stenosis and aortic regurgitation, the left ventricular musculature hypertrophies because of the increased ventricular workload. In regurgitation, the left ventricular chamber also enlarges to hold all the regurgitant blood from the aorta. Sometimes the left ventricular muscle mass increases fourfold to fivefold, creating a tremendously large left side of the heart. When the aortic valve is seriously stenosed, the hypertrophied muscle allows the left ventricle to develop as much as 400 mm Hg intraventricular pressure at systolic peak. Chapter 23 Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects 273 In severe aortic regurgitation, sometimes the hypertrophied muscle allows the left ventricle to pump a stroke volume output as great as 250 milliliters, although as much as three fourths of this blood returns to the ventricle during diastole, and only one fourth flows through the aorta to the body. development of serious pulmonary edema. Ordinarily, lethal edema does not occur until the mean left atrial pressure rises above 25 mm Hg and sometimes as high as 40 mm Hg, because the lung lymphatic vasculature enlarges manyfold and can carry fluid away from the lung tissues extremely rapidly. Increase in Blood Volume. Another effect that helps compensate for the diminished net pumping by the left ventricle is increased blood volume. This results from (1) an initial slight decrease in arterial pressure, plus (2) peripheral circulatory reflexes that the decrease in pressure induces. These together diminish renal output of urine, causing the blood volume to increase and the mean arterial pressure to return to normal. Also, red cell mass eventually increases because of a slight degree of tissue hypoxia. The increase in blood volume tends to increase venous return to the heart. This, in turn, causes the left ventricle to pump with the extra power required to overcome the abnormal pumping dynamics. Enlarged Left Atrium and Atrial Fibrillation. The high left atrial pressure in mitral valvular disease also causes progressive enlargement of the left atrium, which increases the distance that the cardiac electrical excitatory impulse must travel in the atrial wall. This pathway may eventually become so long that it predisposes to development of excitatory signal circus movements, as discussed in Chapter 13. Therefore, in late stages of mitral valvular disease, especially in mitral stenosis, atrial fibrillation usually occurs. This further reduces the pumping effectiveness of the heart and causes further cardiac debility. Eventual Failure of the Left Ventricle, and Development of Pulmonary Edema In the early stages of aortic stenosis or aortic regurgitation, the intrinsic ability of the left ventricle to adapt to increasing loads prevents significant abnormalities in circulatory function in the person during rest, other than increased work output required of the left ventricle. Therefore, considerable degrees of aortic stenosis or aortic regurgitation often occur before the person knows that he or she has serious heart disease (such as a resting left ventricular systolic pressure as high as 200 mm Hg in aortic stenosis or a left ventricular stroke volume output as high as double normal in aortic regurgitation). Beyond a critical stage in these aortic valve lesions, the left ventricle finally cannot keep up with the work demand. As a consequence, the left ventricle dilates and cardiac output begins to fall; blood simultaneously dams up in the left atrium and in the lungs behind the failing left ventricle. The left atrial pressure rises progressively, and at mean left atrial pressures above 25 to 40 mm Hg, serious edema appears in the lungs, as discussed in detail in Chapter 38. Dynamics of Mitral Stenosis and Mitral Regurgitation In mitral stenosis, blood flow from the left atrium into the left ventricle is impeded, and in mitral regurgitation, much of the blood that has flowed into the left ventricle during diastole leaks back into the left atrium during systole rather than being pumped into the aorta. Therefore, either of these conditions reduces net movement of blood from the left atrium into the left ventricle. Pulmonary Edema in Mitral Valvular Disease. The buildup of blood in the left atrium causes progressive increase in left atrial pressure, and this eventually results in Compensation in Early Mitral Valvular Disease. As also occurs in aortic valvular disease and in many types of congenital heart disease, the blood volume increases in mitral valvular disease principally because of diminished excretion of water and salt by the kidneys. This increased blood volume increases venous return to the heart, thereby helping to overcome the effect of the cardiac debility.Therefore, after compensation, cardiac output may fall only minimally until the late stages of mitral valvular disease, even though the left atrial pressure is rising. As the left atrial pressure rises, blood begins to dam up in the lungs, eventually all the way back to the pulmonary artery. In addition, incipient edema of the lungs causes pulmonary arteriolar constriction. These two effects together increase systolic pulmonary arterial pressure and also right ventricular pressure, sometimes to as high as 60 mm Hg, which is more than double normal. This, in turn, causes hypertrophy of the right side of the heart, which partially compensates for its increased workload. Circulatory Dynamics During Exercise in Patients with Valvular Lesions During exercise, large quantities of venous blood are returned to the heart from the peripheral circulation. Therefore, all the dynamic abnormalities that occur in the different types of valvular heart disease become tremendously exacerbated. Even in mild valvular heart disease, in which the symptoms may be unrecognizable at rest, severe symptoms often develop during heavy exercise. For instance, in patients with aortic valvular lesions, exercise can cause acute left ventricular failure followed by acute pulmonary edema. Also, in patients with mitral disease, exercise can cause so much damming of blood in the lungs that serious or even lethal pulmonary edema may ensue in as little as 10 minutes. Even in mild to moderate cases of valvular disease, the patient’s cardiac reserve diminishes in proportion 274 Unit IV The Circulation to the severity of the valvular dysfunction. That is, the cardiac output does not increase as much as it should during exercise. Therefore, the muscles of the body fatigue rapidly because of too little increase in muscle blood flow. Head and upper extremities Right lung Ductus arteriosus Aorta Left lung Abnormal Circulatory Dynamics in Congenital Heart Defects Occasionally, the heart or its associated blood vessels are malformed during fetal life; the defect is called a congenital anomaly. There are three major types of congenital anomalies of the heart and its associated vessels: (1) stenosis of the channel of blood flow at some point in the heart or in a closely allied major blood vessel; (2) an anomaly that allows blood to flow backward from the left side of the heart or aorta to the right side of the heart or pulmonary artery, thus failing to flow through the systemic circulation—called a leftto-right shunt; and (3) an anomaly that allows blood to flow directly from the right side of the heart into the left side of the heart, thus failing to flow through the lungs—called a right-to-left shunt. The effects of the different stenotic lesions are easily understood. For instance, congenital aortic valve stenosis results in the same dynamic effects as aortic valve stenosis caused by other valvular lesions, namely, a tendency to develop serious pulmonary edema and a reduced cardiac output. Another type of congenital stenosis is coarctation of the aorta, often occurring near the level of the diaphragm. This causes the arterial pressure in the upper part of the body (above the level of the coarctation) to be much greater than the pressure in the lower body because of the great resistance to blood flow through the coarctation to the lower body; part of the blood must go around the coarctation through small collateral arteries, as discussed in Chapter 19. Patent Ductus Arteriosus— A Left-to-Right Shunt During fetal life, the lungs are collapsed, and the elastic compression of the lungs that keeps the alveoli collapsed keeps most of the lung blood vessels collapsed as well. Therefore, resistance to blood flow through the lungs is so great that the pulmonary arterial pressure is high in the fetus. Also, because of low resistance to blood flow from the aorta through the large vessels of the placenta, the pressure in the aorta of the fetus is lower than normal—in fact, lower than in the pulmonary artery. This causes almost all the pulmonary arterial blood to flow through a special artery present in the fetus that connects the pulmonary artery with the aorta (Figure 23–4), called the ductus arteriosus, thus bypassing the lungs. This allows immediate recirculation of the blood through the systemic arteries of the fetus without the blood going through the Trunk and lower extremities Pulmonary Left artery pulmonary artery Figure 23–4 Patent ductus arteriosus, showing by the intensity of the pink color that dark venous blood changes into oxygenated blood at different points in the circulation. The right-hand diagram shows backflow of blood from the aorta into the pulmonary artery and then through the lungs for a second time. lungs. This lack of blood flow through the lungs is not detrimental to the fetus because the blood is oxygenated by the placenta. Closure of the Ductus Arteriosus After Birth. As soon as a baby is born and begins to breathe, the lungs inflate; not only do the alveoli fill with air, but also the resistance to blood flow through the pulmonary vascular tree decreases tremendously, allowing the pulmonary arterial pressure to fall. Simultaneously, the aortic pressure rises because of sudden cessation of blood flow from the aorta through the placenta. Thus, the pressure in the pulmonary artery falls, while that in the aorta rises. As a result, forward blood flow through the ductus arteriosus ceases suddenly at birth, and in fact, blood begins to flow backward through the ductus from the aorta into the pulmonary artery. This new state of backward blood flow causes the ductus arteriosus to become occluded within a few hours to a few days in most babies, so that blood flow through the ductus does not persist. The ductus is believed to close because the oxygen concentration of the aortic blood now flowing through it is about twice as high as that of the blood flowing from the pulmonary artery into the ductus during fetal life. The oxygen presumably constricts the muscle in the ductus wall. This is discussed further in Chapter 83. Unfortunately, in about 1 of every 5500 babies, the ductus does not close, causing the condition known as patent ductus arteriosus, which is shown in Figure 23–4. Dynamics of the Circulation with a Persistent Patent Ductus. During the early months of an infant’s life, a patent ductus usually does not cause severely abnormal function. But as the child grows older, the differential between the high pressure in the aorta and the lower Chapter 23 Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects pressure in the pulmonary artery progressively increases, with corresponding increase in backward flow of blood from the aorta into the pulmonary artery. Also, the high aortic blood pressure usually causes the diameter of the partially open ductus to increase with time, making the condition even worse. Head and upper extremities Right lung Recirculation Through the Lungs. In an older child with a patent ductus, one half to two thirds of the aortic blood flows backward through the ductus into the pulmonary artery, then through the lungs, and finally back into the left ventricle and aorta, passing through the lungs and left side of the heart two or more times for every one time that it passes through the systemic circulation. These people do not show cyanosis until later in life, when the heart fails or the lungs become congested. Indeed, early in life, the arterial blood is often better oxygenated than normal because of the extra times it passes through the lungs. Diminished Cardiac and Respiratory Reserve. The major effects of patent ductus arteriosus on the patient are decreased cardiac and respiratory reserve. The left ventricle is pumping about two or more times the normal cardiac output, and the maximum that it can pump after hypertrophy of the heart has occurred is about four to seven times normal. Therefore, during exercise, the net blood flow through the remainder of the body can never increase to the levels required for strenuous activity. With even moderately strenuous exercise, the person is likely to become weak and may even faint from momentary heart failure. The high pressures in the pulmonary vessels caused by excess flow through the lungs often lead to pulmonary congestion and pulmonary edema. As a result of the excessive load on the heart, and especially because the pulmonary congestion becomes progressively more severe with age, most patients with uncorrected patent ductus die from heart disease between ages 20 and 40 years. Heart Sounds: Machinery Murmur. In a newborn infant with patent ductus arteriosus, occasionally no abnormal heart sounds are heard because the quantity of reverse blood flow through the ductus may be insufficient to cause a heart murmur. But as the baby grows older, reaching age 1 to 3 years, a harsh, blowing murmur begins to be heard in the pulmonary artery area of the chest, as shown in recording F, Figure 23–3. This sound is much more intense during systole when the aortic pressure is high and much less intense during diastole when the aortic pressure falls low, so that the murmur waxes and wanes with each beat of the heart, creating the so-called machinery murmur. Surgical Treatment. Surgical treatment of patent ductus arteriosus is extremely simple; one need only ligate the patent ductus or divide it and then close the two ends. In fact, this was one of the first successful heart surgeries ever performed. 275 Left lung Trunk and lower extremities Figure 23–5 Tetralogy of Fallot, showing by the intensity of the pink color that most of the dark venous blood is shunted from the right ventricle into the aorta without passing through the lungs. Tetralogy of Fallot— A Right-to-Left Shunt Tetralogy of Fallot is shown in Figure 23–5; it is the most common cause of “blue baby.” Most of the blood bypasses the lungs, so the aortic blood is mainly unoxygenated venous blood. In this condition, four abnormalities of the heart occur simultaneously: 1. The aorta originates from the right ventricle rather than the left, or it overrides a hole in the septum, as shown in Figure 23–5, receiving blood from both ventricles. 2. The pulmonary artery is stenosed, so that much lower than normal amounts of blood pass from the right ventricle into the lungs; instead, most of the blood passes directly into the aorta, thus bypassing the lungs. 3. Blood from the left ventricle flows either through a ventricular septal hole into the right ventricle and then into the aorta or directly into the aorta that overrides this hole. 4. Because the right side of the heart must pump large quantities of blood against the high pressure in the aorta, its musculature is highly developed, causing an enlarged right ventricle. Abnormal Circulatory Dynamics. It is readily apparent that the major physiological difficulty caused by tetralogy of Fallot is the shunting of blood past the lungs without its becoming oxygenated. As much as 75 per cent of the venous blood returning to the heart passes directly 276 Unit IV The Circulation from the right ventricle into the aorta without becoming oxygenated. A diagnosis of tetralogy of Fallot is usually based on (1) the fact that the baby’s skin is cyanotic (blue); (2) measurement of high systolic pressure in the right ventricle, recorded through a catheter; (3) characteristic changes in the radiological silhouette of the heart, showing an enlarged right ventricle; and (4) angiograms (x-ray pictures) showing abnormal blood flow through the interventricular septal hole and into the overriding aorta, but much less flow through the stenosed pulmonary artery. Surgical Treatment. Tetralogy of Fallot can usually be treated successfully by surgery. The usual operation is to open the pulmonary stenosis, close the septal defect, and reconstruct the flow pathway into the aorta. When surgery is successful, the average life expectancy increases from only 3 to 4 years to 50 or more years. passing the blood between thin membranes or through thin tubes that are permeable to oxygen and carbon dioxide. The different systems have all been fraught with many difficulties, including hemolysis of the blood, development of small clots in the blood, likelihood of small bubbles of oxygen or small emboli of antifoam agent passing into the arteries of the patient, necessity for large quantities of blood to prime the entire system, failure to exchange adequate quantities of oxygen, and necessity to use heparin to prevent blood coagulation in the extracorporeal system. Heparin also interferes with adequate hemostasis during the surgical procedure. Yet despite these difficulties, in the hands of experts, patients can be kept alive on artificial heart-lung machines for many hours while operations are performed on the inside of the heart. Causes of Congenital Anomalies Hypertrophy of the Heart in Valvular and Congenital Heart Disease One of the most common causes of congenital heart defects is a viral infection in the mother during the first trimester of pregnancy when the fetal heart is being formed. Defects are particularly prone to develop when the expectant mother contracts German measles; thus, obstetricians often advise termination of pregnancy if German measles occurs in the first trimester. Some congenital defects of the heart are hereditary, because the same defect has been known to occur in identical twins as well as in succeeding generations. Children of patients surgically treated for congenital heart disease have about a 10 times greater chance of having congenital heart disease than other children do. Congenital defects of the heart are also frequently associated with other congenital defects of the baby’s body. Hypertrophy of cardiac muscle is one of the most important mechanisms by which the heart adapts to increased workloads, whether these loads are caused by increased pressure against which the heart muscle must contract or by increased cardiac output that must be pumped. Some physicians believe that the increased strength of contraction of the heart muscle causes the hypertrophy; others believe that the increased metabolic rate of the muscle is the primary stimulus. Regardless of which of these is correct, one can calculate approximately how much hypertrophy will occur in each chamber of the heart by multiplying ventricular output by the pressure against which the ventricle must work, with emphasis on pressure. Thus, hypertrophy occurs in most types of valvular and congenital disease, sometimes causing heart weights as great as 800 grams instead of the normal 300 grams. Use of Extracorporeal Circulation During Cardiac Surgery References It is almost impossible to repair intracardiac defects surgically while the heart is still pumping. Therefore, many types of artificial heart-lung machines have been developed to take the place of the heart and lungs during the course of operation. Such a system is called extracorporeal circulation. The system consists principally of a pump and an oxygenating device. Almost any type of pump that does not cause hemolysis of the blood seems to be suitable. Methods used for oxygenating blood include (1) bubbling oxygen through the blood and removing the bubbles from the blood before passing it back into the patient, (2) dripping the blood downward over the surfaces of plastic sheets in the presence of oxygen, (3) passing the blood over surfaces of rotating discs, or (4) Arad M, Seidman JG, Seidman CE: Phenotypic diversity in hypertrophic cardiomyopathy. Hum Mol Genet 11:2499, 2002. Braunwald E, Seidman CE, Sigwart U: Contemporary evaluation and management of hypertrophic cardiomyopathy. Circulation 106:1312, 2002. Brickner ME, Hillis LD, Lange RA: Congenital heart disease in adults: second of two parts. N Engl J Med 342:334, 2000. Gottdiener JS: Overview of stress echocardiography: uses, advantages, and limitations. Curr Probl Cardiol 28:485, 2003. Grech ED: Non-coronary percutaneous intervention. BMJ 327:97, 2003. Guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 98:1949, 1998. Hoffman JI, Kaplan S: The incidence of congenital heart disease. J Am Coll Cardiol 39:1890, 2002. Chapter 23 Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects Levi DS, Alejos JC, Moore JW: Future of interventional cardiology in pediatrics. Curr Opin Cardiol 18:79, 2003. Maron BJ: Hypertrophic cardiomyopathy: a systematic review. JAMA 287:1308, 2002. McDonald M, Currie BJ, Carapetis JR: Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis 4:240, 2004. Nishimura RA, Holmes DR Jr: Clinical practice: hypertrophic obstructive cardiomyopathy. N Engl J Med 350: 1320, 2004. Reimold SC, Rutherford JD: Clinical practice: valvular heart disease in pregnancy. N Engl J Med 349:52, 2003. 277 Rosenhek R, Burder T, Pozenta G, et al: Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 343:611, 2000. Turgeman Y, Atar S, Rosenfeld T: The subvalvular apparatus in rheumatic mitral stenosis: methods of assessment and therapeutic implications. Chest 124:1929, 2003. Yacoub MH, Cohn LH: Novel approaches to cardiac valve repair: from structure to function. Part II. Circulation 109:942, 2004. Yoerger DM, Weyman AE: Hypertrophic obstructive cardiomyopathy: mechanism of obstruction and response to therapy. Rev Cardiovasc Med 4:199, 2003. C H A P T E R 2 Circulatory Shock and Physiology of Its Treatment Circulatory shock means generalized inadequate blood flow through the body, to the extent that the body tissues are damaged because of too little flow, especially because of too little oxygen and other nutrients delivered to the tissue cells. Even the cardiovascular system itself—the heart musculature, walls of the blood vessels, vasomotor system, and other circulatory parts—begins to deteriorate, so that the shock, once begun, is prone to become progressively worse. Physiologic Causes of Shock Circulatory Shock Caused by Decreased Cardiac Output Shock usually results from inadequate cardiac output. Therefore, any condition that reduces the cardiac output far below normal will likely lead to circulatory shock. Two types of factors can severely reduce cardiac output: 1. Cardiac abnormalities that decrease the ability of the heart to pump blood. These include especially myocardial infarction but also toxic states of the heart, severe heart valve dysfunction, heart arrhythmias, and other conditions. The circulatory shock that results from diminished cardiac pumping ability is called cardiogenic shock. This is discussed in detail in Chapter 22, where it is pointed out that as many as 85 per cent of people who develop cardiogenic shock do not survive. 2. Factors that decrease venous return also decrease cardiac output because the heart cannot pump blood that does not flow into it. The most common cause of decreased venous return is diminished blood volume, but venous return can also be reduced as a result of decreased vascular tone, especially of the venous blood reservoirs, or obstruction to blood flow at some point in the circulation, especially in the venous return pathway to the heart. Circulatory Shock That Occurs Without Diminished Cardiac Output Occasionally, the cardiac output is normal or even greater than normal, yet the person is in circulatory shock. This can result from (1) excessive metabolism of the body, so that even a normal cardiac output is inadequate, or (2) abnormal tissue perfusion patterns, so that most of the cardiac output is passing through blood vessels besides those that supply the local tissues with nutrition. The specific causes of shock are discussed later in the chapter. For the present, it is important to note that all of them lead to inadequate delivery of nutrients to critical tissues and critical organs and also cause inadequate removal of cellular waste products from the tissues. 278 4 Chapter 24 279 Circulatory Shock and Physiology of Its Treatment In the minds of many physicians, the arterial pressure level is the principal measure of adequacy of circulatory function. However, the arterial pressure can often be seriously misleading. At times, a person may be in severe shock and still have an almost normal arterial pressure because of powerful nervous reflexes that keep the pressure from falling. At other times, the arterial pressure can fall to half of normal, but the person still has normal tissue perfusion and is not in shock. In most types of shock, especially shock caused by severe blood loss, the arterial blood pressure decreases at the same time as the cardiac output decreases, although usually not as much. Cardiac output and arterial pressure (percentage of normal) What Happens to the Arterial Pressure in Circulatory Shock? Arterial pressure 100 50 Cardiac output 0 0 10 20 30 40 50 Percentage of total blood removed Figure 24–1 Effect of hemorrhage on cardiac output and arterial pressure. Tissue Deterioration Is the End Result of Circulatory Shock, Whatever the Cause Once circulatory shock reaches a critical state of severity, regardless of its initiating cause, the shock itself breeds more shock. That is, the inadequate blood flow causes the body tissues to begin deteriorating, including the heart and circulatory system itself. This causes an even greater decrease in cardiac output, and a vicious circle ensues, with progressively increasing circulatory shock, less adequate tissue perfusion, more shock, and so forth until death. It is with this late stage of circulatory shock that we are especially concerned, because appropriate physiologic treatment can often reverse the rapid slide to death. Stages of Shock Because the characteristics of circulatory shock change with different degrees of severity, shock is divided into the following three major stages: 1. A nonprogressive stage (sometimes called the compensated stage), in which the normal circulatory compensatory mechanisms eventually cause full recovery without help from outside therapy. 2. A progressive stage, in which, without therapy, the shock becomes steadily worse until death. 3. An irreversible stage, in which the shock has progressed to such an extent that all forms of known therapy are inadequate to save the person’s life, even though, for the moment, the person is still alive. Now, let us discuss the stages of circulatory shock caused by decreased blood volume, which illustrate the basic principles. Then we can consider special characteristics of shock initiated by other causes. Shock Caused by Hypovolemia—Hemorrhagic Shock Hypovolemia means diminished blood volume. Hemorrhage is the most common cause of hypovolemic shock. Hemorrhage decreases the filling pressure of the circulation and, as a consequence, decreases venous return. As a result, the cardiac output falls below normal, and shock may ensue. Relationship of Bleeding Volume to Cardiac Output and Arterial Pressure Figure 24–1 shows the approximate effects on both cardiac output and arterial pressure of removing blood from the circulatory system over a period of about 30 minutes. About 10 per cent of the total blood volume can be removed with almost no effect on either arterial pressure or cardiac output, but greater blood loss usually diminishes the cardiac output first and later the arterial pressure, both of which fall to zero when about 35 to 45 per cent of the total blood volume has been removed. Sympathetic Reflex Compensations in Shock—Their Special Value to Maintain Arterial Pressure. The decrease in arte- rial pressure after hemorrhage—as well as decreases in pressures in the pulmonary arteries and veins in the thorax—causes powerful sympathetic reflexes (initiated mainly by the arterial baroreceptors and other vascular stretch receptors, as explained in Chapter 18). These reflexes stimulate the sympathetic vasoconstrictor system throughout the body, resulting in three important effects: (1) The arterioles constrict in most parts of the systemic circulation, thereby increasing the total peripheral resistance. (2) The veins and venous reservoirs constrict, thereby helping to maintain adequate venous return despite diminished blood 280 Arterial pressure (percentage of control value) Unit IV The Circulation I 100 90 80 70 60 50 40 30 20 10 0 II III IV V VI 0 60 120 180 240 300 Time in minutes volume. (3) Heart activity increases markedly, sometimes increasing the heart rate from the normal value of 72 beats/min to as high as 160 to 180 beats/min. Value of the Sympathetic Nervous Reflexes. In the absence of the sympathetic reflexes, only 15 to 20 per cent of the blood volume can be removed over a period of 30 minutes before a person dies; this is in contrast to a 30 to 40 per cent loss of blood volume that a person can sustain when the reflexes are intact. Therefore, the reflexes extend the amount of blood loss that can occur without causing death to about twice that which is possible in their absence. 360 Figure 24–2 Time course of arterial pressure in dogs after different degrees of acute hemorrhage. Each curve represents average results from six dogs. The sympathetic stimulation does not cause significant constriction of either the cerebral or the cardiac vessels. In addition, in both these vascular beds, local blood flow autoregulation is excellent, which prevents moderate decreases in arterial pressure from significantly decreasing their blood flows. Therefore, blood flow through the heart and brain is maintained essentially at normal levels as long as the arterial pressure does not fall below about 70 mm Hg, despite the fact that blood flow in some other areas of the body might be decreased to as little as one third to one quarter normal by this time because of vasoconstriction. Greater Effect of the Sympathetic Nervous Reflexes in Maintaining Arterial Pressure than in Maintaining Cardiac Output. Referring again to Figure 24–1, note Progressive and Nonprogressive Hemorrhagic Shock that the arterial pressure is maintained at or near normal levels in the hemorrhaging person longer than is the cardiac output. The reason for this is that the sympathetic reflexes are geared more for maintaining arterial pressure than for maintaining output. They increase the arterial pressure mainly by increasing the total peripheral resistance, which has no beneficial effect on cardiac output; however, the sympathetic constriction of the veins is important to keep venous return and cardiac output from falling too much, in addition to their role in maintaining arterial pressure. Especially interesting is the second plateau occurring at about 50 mm Hg in the arterial pressure curve of Figure 24–1. This results from activation of the central nervous system ischemic response, which causes extreme stimulation of the sympathetic nervous system when the brain begins to suffer from lack of oxygen or from excess buildup of carbon dioxide, as discussed in Chapter 18. This effect of the central nervous system ischemic response can be called the “last-ditch stand” of the sympathetic reflexes in their attempt to keep the arterial pressure from falling too low. Figure 24–2 shows an experiment that we performed in dogs to demonstrate the effects of different degrees of sudden acute hemorrhage on the subsequent course of arterial pressure. The dogs were bled rapidly until their arterial pressures fell to different levels. Those dogs whose pressures fell immediately to no lower than 45 mm Hg (groups I, II, and III) all eventually recovered; the recovery occurred rapidly if the pressure fell only slightly (group I) but occurred slowly if it fell almost to the 45 mm Hg level (group III). When the arterial pressure fell below 45 mm Hg (groups IV, V, and VI), all the dogs died, although many of them hovered between life and death for hours before the circulatory system deteriorated to the stage of death. This experiment demonstrates that the circulatory system can recover as long as the degree of hemorrhage is no greater than a certain critical amount. Crossing this critical threshold by even a few milliliters of blood loss makes the eventual difference between life and death. Thus, hemorrhage beyond a certain critical level causes shock to become progressive. That is, the shock itself causes still more shock, and the condition becomes a vicious circle that eventually leads to deterioration of the circulation and to death. Protection of Coronary and Cerebral Blood Flow by the Reflexes. A special value of the maintenance Nonprogressive Shock—Compensated Shock of normal arterial pressure even in the presence of decreasing cardiac output is protection of blood flow through the coronary and cerebral circulatory systems. If shock is not severe enough to cause its own progression, the person eventually recovers. Therefore, shock of this lesser degree is called nonprogressive Chapter 24 Circulatory Shock and Physiology of Its Treatment shock. It is also called compensated shock, meaning that the sympathetic reflexes and other factors compensate enough to prevent further deterioration of the circulation. The factors that cause a person to recover from moderate degrees of shock are all the negative feedback control mechanisms of the circulation that attempt to return cardiac output and arterial pressure back to normal levels. They include the following: 1. Baroreceptor reflexes, which elicit powerful sympathetic stimulation of the circulation. 2. Central nervous system ischemic response, which elicits even more powerful sympathetic stimulation throughout the body but is not activated significantly until the arterial pressure falls below 50 mm Hg. 3. Reverse stress-relaxation of the circulatory system, which causes the blood vessels to contract around the diminished blood volume, so that the blood volume that is available more adequately fills the circulation. 4. Formation of angiotensin by the kidneys, which constricts the peripheral arteries and also causes decreased output of water and salt by the kidneys, both of which help prevent progression of shock. 5. Formation of vasopressin (antidiuretic hormone) by the posterior pituitary gland, which constricts the peripheral arteries and veins and greatly increases water retention by the kidneys. 6. Compensatory mechanisms that return the blood volume back toward normal, including absorption of large quantities of fluid from the intestinal tract, absorption of fluid into the blood capillaries from the interstitial spaces of the body, conservation of water and salt by the kidneys, and increased thirst and increased appetite for salt, which make the person drink water and eat salty foods if able. The sympathetic reflexes provide immediate help toward bringing about recovery because they become maximally activated within 30 seconds to a minute after hemorrhage. The angiotensin and vasopressin mechanisms, as well as the reverse stress-relaxation that causes contraction of the blood vessels and venous reservoirs, all require 10 minutes to 1 hour to respond completely, but they aid greatly in increasing the arterial pressure or increasing the circulatory filling pressure and thereby increasing the return of blood to the heart. Finally, readjustment of blood volume by absorption of fluid from the interstitial spaces and intestinal tract, as well as oral ingestion and absorption of additional quantities of water and salt, may require from 1 to 48 hours, but recovery eventually takes place, provided the shock does not become severe enough to enter the progressive stage. “Progressive Shock” Is Caused by a Vicious Circle of Cardiovascular Deterioration Figure 24–3 shows some of the positive feedbacks that further depress cardiac output in shock, thus causing 281 the shock to become progressive. Some of the more important feedbacks are the following. Cardiac Depression. When the arterial pressure falls low enough, coronary blood flow decreases below that required for adequate nutrition of the myocardium. This weakens the heart muscle and thereby decreases the cardiac output more. Thus, a positive feedback cycle has developed, whereby the shock becomes more and more severe. Figure 24–4 shows cardiac output curves extrapolated to the human heart from experiments in dogs, demonstrating progressive deterioration of the heart at different times after the onset of shock. A dog was bled until the arterial pressure fell to 30 mm Hg, and the pressure was held at this level by further bleeding or retransfusion of blood as required. Note from the second curve in the figure that there was little deterioration of the heart during the first 2 hours, but by 4 hours, the heart had deteriorated about 40 per cent; then, rapidly, during the last hour of the experiment (after 4 hours of low coronary blood pressure), the heart deteriorated completely. Thus, one of the important features of progressive shock, whether it is hemorrhagic in origin or caused in another way, is eventual progressive deterioration of the heart. In the early stages of shock, this plays very little role in the condition of the person, partly because deterioration of the heart is not severe during the first hour or so of shock, but mainly because the heart has tremendous reserve capability that normally allows it to pump 300 to 400 per cent more blood than is required by the body for adequate bodywide tissue nutrition. In the latest stages of shock, however, deterioration of the heart is probably the most important factor in the final lethal progression of the shock. Vasomotor Failure. In the early stages of shock, various circulatory reflexes cause intense activity of the sympathetic nervous system. This, as discussed earlier, helps delay depression of the cardiac output and especially helps prevent decreased arterial pressure. However, there comes a point when diminished blood flow to the brain’s vasomotor center depresses the center so much that it, too, becomes progressively less active and finally totally inactive. For instance, complete circulatory arrest to the brain causes, during the first 4 to 8 minutes, the most intense of all sympathetic discharges, but by the end of 10 to 15 minutes, the vasomotor center becomes so depressed that no further evidence of sympathetic discharge can be demonstrated. Fortunately, the vasomotor center usually does not fail in the early stages of shock if the arterial pressure remains above 30 mm Hg. Blockage of Very Small Vessels—“Sludged Blood.” In time, blockage occurs in many of the very small blood vessels in the circulatory system, and this also causes the shock to progress. The initiating cause of this blockage is sluggish blood flow in the microvessels. Because tissue metabolism continues despite the low flow, large amounts of acid, both carbonic acid and 282 Unit IV The Circulation Decreased cardiac output Decreased arterial pressure Decreased systemic blood flow Decreased cardiac nutrition Decreased nutrition of tissues Decreased nutrition of brain Decreased nutrition of vascular system Intravascular clotting Tissue ischemia Decreased vasomotor activity Increased capillary permeability Release of toxins Vascular dilation Venous pooling of blood Cardiac depression Decreased blood volume Decreased venous return Figure 24–3 Different types of “positive feedback” that can lead to progression of shock. lactic acid, continue to empty into the local blood vessels and greatly increase the local acidity of the blood. This acid, plus other deterioration products from the ischemic tissues, causes local blood agglutination, resulting in minute blood clots, leading to very small plugs in the small vessels. Even if the vessels do not become plugged, an increased tendency for the blood cells to stick to one another makes it more difficult for blood to flow through the microvasculature, giving rise to the term sludged blood. Increased Capillary Permeability. After many hours of capillary hypoxia and lack of other nutrients, the permeability of the capillaries gradually increases, and large quantities of fluid begin to transude into the tissues. This decreases the blood volume even more, with a resultant further decrease in cardiac output, making the shock still more severe. Capillary hypoxia does not cause increased capillary permeability until the late stages of prolonged shock. Release of Toxins by Ischemic Tissue. Throughout the history of research in the field of shock, it has been suggested that shock causes tissues to release toxic substances, such as histamine, serotonin, and tissue enzymes, that cause further deterioration of the circulatory system. Quantitative studies have proved the significance of at least one toxin, endotoxin, in some types of shock. Cardiac Depression Caused by Endotoxin. Endotoxin is released from the bodies of dead gram-negative bacteria in the intestines. Diminished blood flow to the intestines often causes enhanced formation and absorption of this toxic substance. The circulating toxin then causes increased cellular metabolism despite inadequate nutrition of the cells; this has a specific effect on the heart muscle, causing cardiac depression. Endotoxin can play a major role in some types of shock, especially “septic shock,” discussed later in the chapter. Chapter 24 Circulatory Shock and Physiology of Its Treatment 283 15 Cardiac output (L/min) 0 time 2 hours 10 4 hours 41/2 hours 43/4 hours 5 5 hours 0 –4 0 4 8 12 Right atrial pressure (mm Hg) Figure 24–4 Cardiac output curves of the heart at different times after hemorrhagic shock begins. (These curves are extrapolated to the human heart from data obtained in dog experiments by Dr. J. W. Crowell.) Figure 24–5 Generalized Cellular Deterioration. As shock becomes severe, many signs of generalized cellular deterioration occur throughout the body. One organ especially affected is the liver, as illustrated in Figure 24–5. This occurs mainly because of lack of enough nutrients to support the normally high rate of metabolism in liver cells, but also partly because of the extreme exposure of the liver cells to any vascular toxin or other abnormal metabolic factor occurring in shock. Among the damaging cellular effects that are known to occur in most body tissues are the following: 1. Active transport of sodium and potassium through the cell membrane is greatly diminished. As a result, sodium and chloride accumulate in the cells, and potassium is lost from the cells. In addition, the cells begin to swell. 2. Mitochondrial activity in the liver cells, as well as in many other tissues of the body, becomes severely depressed. 3. Lysosomes in the cells in widespread tissue areas begin to break open, with intracellular release of hydrolases that cause further intracellular deterioration. 4. Cellular metabolism of nutrients, such as glucose, eventually becomes greatly depressed in the last stages of shock. The actions of some hormones are depressed as well, including almost 100 per cent depression of the action of insulin. All these effects contribute to further deterioration of many organs of the body, including especially (1) the liver, with depression of its many metabolic and detoxification functions; (2) the lungs, with eventual development of pulmonary edema and poor ability to oxygenate the blood; and (3) the heart, thereby further depressing its contractility. Necrosis of the central portion of a liver lobule in severe circulatory shock. (Courtesy Dr. J. W. Crowell.) Tissue Necrosis in Severe Shock—Patchy Areas of Necrosis Occur Because of Patchy Blood Flows in Different Organs. Not all cells of the body are equally damaged by shock, because some tissues have better blood supplies than others. For instance, the cells adjacent to the arterial ends of capillaries receive better nutrition than cells adjacent to the venous ends of the same capillaries. Therefore, one would expect more nutritive deficiency around the venous ends of capillaries than elsewhere. This is precisely the effect that Crowell discovered in studying tissue areas in many parts of the body. For instance, Figure 24–5 shows necrosis in the center of a liver lobule, the portion of the lobule that is last to be exposed to the blood as it passes through the liver sinusoids. Similar punctate lesions occur in heart muscle, although here a definite repetitive pattern, such as occurs in the liver, cannot be demonstrated. Nevertheless, the cardiac lesions play an important role in leading to the final irreversible stage of shock. Deteriorative lesions also occur in the kidneys, especially in the epithelium of the kidney tubules, leading to kidney failure and occasionally uremic death several days later. Deterioration of the lungs also often leads to respiratory distress and death several days later—called the shock lung syndrome. Acidosis in Shock. Most metabolic derangements that occur in shocked tissue can lead to blood acidosis all through the body. This results from poor delivery of oxygen to the tissues, which greatly diminishes oxidative metabolism of the foodstuffs. When this occurs, the cells obtain most of their energy by the anaerobic The Circulation process of glycolysis, which leads to tremendous quantities of excess lactic acid in the blood. In addition, poor blood flow through tissues prevents normal removal of carbon dioxide. The carbon dioxide reacts locally in the cells with water to form high concentrations of intracellular carbonic acid; this, in turn, reacts with various tissue chemicals to form still other intracellular acidic substances. Thus, another deteriorative effect of shock is both generalized and local tissue acidosis, leading to further progression of the shock itself. Positive Feedback Deterioration of Tissues in Shock and the Vicious Circle of Progressive Shock All the factors just discussed that can lead to further progression of shock are types of positive feedback. That is, each increase in the degree of shock causes a further increase in the shock. However, positive feedback does not necessarily lead to a vicious circle. Whether a vicious circle develops depends on the intensity of the positive feedback. In mild degrees of shock, the negative feedback mechanisms of the circulation—sympathetic reflexes, reverse stress-relaxation mechanism of the blood reservoirs, absorption of fluid into the blood from the interstitial spaces, and others—can easily overcome the positive feedback influences and, therefore, cause recovery. But in severe degrees of shock, the deteriorative feedback mechanisms become more and more powerful, leading to such rapid deterioration of the circulation that all the normal negative feedback systems of circulatory control acting together cannot return the cardiac output to normal. Considering once again the principles of positive feedback and vicious circle discussed in Chapter 1, one can readily understand why there is a critical cardiac output level above which a person in shock recovers and below which a person enters a vicious circle of circulatory deterioration that proceeds until death. Irreversible Shock After shock has progressed to a certain stage, transfusion or any other type of therapy becomes incapable of saving the person’s life. The person is then said to be in the irreversible stage of shock. Ironically, even in this irreversible stage, therapy can, on rare occasions, return the arterial pressure and even the cardiac output to normal or near normal for short periods, but the circulatory system nevertheless continues to deteriorate, and death ensues in another few minutes to few hours. Figure 24–6 demonstrates this effect, showing that transfusion during the irreversible stage can sometimes cause the cardiac output (as well as the arterial pressure) to return to normal. However, the cardiac output soon begins to fall again, and subsequent transfusions have less and less effect. By this time, multiple deteriorative changes have occurred in the muscle cells of the heart that may not necessarily affect 100 Hemorrhage Unit IV Cardiac output (percentage of normal) 284 75 50 Progressive stage Transfusion 25 Irreversible shock 0 0 30 60 90 Minutes 120 150 Figure 24–6 Failure of transfusion to prevent death in irreversible shock. the heart’s immediate ability to pump blood but, over a long period, depress heart pumping enough to cause death. Beyond a certain point, so much tissue damage has occurred, so many destructive enzymes have been released into the body fluids, so much acidosis has developed, and so many other destructive factors are now in progress that even a normal cardiac output for a few minutes cannot reverse the continuing deterioration. Therefore, in severe shock, a stage is eventually reached at which the person will die even though vigorous therapy might still return the cardiac output to normal for short periods. Depletion of Cellular High-Energy Phosphate Reserves in Irreversible Shock. The high-energy phosphate reserves in the tissues of the body, especially in the liver and the heart, are greatly diminished in severe degrees of shock. Essentially all the creatine phosphate has been degraded, and almost all the adenosine triphosphate has downgraded to adenosine diphosphate, adenosine monophosphate, and, eventually, adenosine. Then much of this adenosine diffuses out of the cells into the circulating blood and is converted into uric acid, a substance that cannot re-enter the cells to reconstitute the adenosine phosphate system. New adenosine can be synthesized at a rate of only about 2 per cent of the normal cellular amount an hour, meaning that once the high-energy phosphate stores of the cells are depleted, they are difficult to replenish. Thus, one of the most devastating end results of deterioration in shock, and the one that is perhaps most significant for development of the final state of irreversibility, is this cellular depletion of these highenergy compounds. Hypovolemic Shock Caused by Plasma Loss Loss of plasma from the circulatory system, even without loss of red blood cells, can sometimes be severe enough to reduce the total blood volume Chapter 24 Circulatory Shock and Physiology of Its Treatment markedly, causing typical hypovolemic shock similar in almost all details to that caused by hemorrhage. Severe plasma loss occurs in the following conditions: 1. Intestinal obstruction is often a cause of severely reduced plasma volume. Distention of the intestine in intestinal obstruction partly blocks venous blood flow in the intestinal walls, which increases intestinal capillary pressure. This in turn causes fluid to leak from the capillaries into the intestinal walls and also into the intestinal lumen. Because the lost fluid has a high protein content, the result is reduced total blood plasma protein as well as reduced plasma volume. 2. In almost all patients who have severe burns or other denuding conditions of the skin, so much plasma is lost through the denuded skin areas that the plasma volume becomes markedly reduced. The hypovolemic shock that results from plasma loss has almost the same characteristics as the shock caused by hemorrhage, except for one additional complicating factor: the blood viscosity increases greatly as a result of increased red blood cell concentration in the remaining blood, and this exacerbates the sluggishness of blood flow. Loss of fluid from all fluid compartments of the body is called dehydration; this, too, can reduce the blood volume and cause hypovolemic shock similar to that resulting from hemorrhage. Some of the causes of this type of shock are (1) excessive sweating, (2) fluid loss in severe diarrhea or vomiting, (3) excess loss of fluid by nephrotic kidneys, (4) inadequate intake of fluid and electrolytes, or (5) destruction of the adrenal cortices, with loss of aldosterone secretion and consequent failure of the kidneys to reabsorb sodium, chloride, and water, which occurs in the absence of the adrenocortical hormone aldosterone. Hypovolemic Shock Caused by Trauma One of the most common causes of circulatory shock is trauma to the body. Often the shock results simply from hemorrhage caused by the trauma, but it can also occur even without hemorrhage, because extensive contusion of the body can damage the capillaries sufficiently to allow excessive loss of plasma into the tissues. This results in greatly reduced plasma volume, with resultant hypovolemic shock. Various attempts have been made to implicate toxic factors released by the traumatized tissues as one of the causes of shock after trauma. However, crosstransfusion experiments into normal animals have failed to show significant toxic elements. In summary, traumatic shock seems to result mainly from hypovolemia, although there might also be a moderate degree of concomitant neurogenic shock caused by loss of vasomotor tone, as discussed next. 285 Neurogenic Shock—Increased Vascular Capacity Shock occasionally results without any loss of blood volume. Instead, the vascular capacity increases so much that even the normal amount of blood becomes incapable of filling the circulatory system adequately. One of the major causes of this is sudden loss of vasomotor tone throughout the body, resulting especially in massive dilation of the veins. The resulting condition is known as neurogenic shock. The role of vascular capacity in helping to regulate circulatory function was discussed in Chapter 15, where it was pointed out that either an increase in vascular capacity or a decrease in blood volume reduces the mean systemic filling pressure, which reduces venous return to the heart. Diminished venous return caused by vascular dilation is called venous pooling of blood. Causes of Neurogenic Shock. Some neurogenic factors that can cause loss of vasomotor tone include the following: 1. Deep general anesthesia often depresses the vasomotor center enough to cause vasomotor paralysis, with resulting neurogenic shock. 2. Spinal anesthesia, especially when this extends all the way up the spinal cord, blocks the sympathetic nervous outflow from the nervous system and can be a potent cause of neurogenic shock. 3. Brain damage is often a cause of vasomotor paralysis. Many patients who have had brain concussion or contusion of the basal regions of the brain develop profound neurogenic shock. Also, even though brain ischemia for a few minutes almost always causes extreme vasomotor stimulation, prolonged ischemia (lasting longer than 5 to 10 minutes) can cause the opposite effect—total inactivation of the vasomotor neurons in the brain stem, with consequent development of severe neurogenic shock. Anaphylactic Shock and Histamine Shock Anaphylaxis is an allergic condition in which the cardiac output and arterial pressure often decrease drastically. This is discussed in Chapter 34. It results primarily from an antigen-antibody reaction that takes place immediately after an antigen to which the person is sensitive enters the circulation. One of the principal effects is to cause the basophils in the blood and mast cells in the pericapillary tissues to release histamine or a histamine-like substance. The histamine causes (1) an increase in vascular capacity because of venous dilation, thus causing a marked decrease in venous return; (2) dilation of the arterioles, resulting in greatly reduced arterial pressure; and (3) greatly increased capillary permeability, with rapid loss of fluid and 286 Unit IV The Circulation protein into the tissue spaces. The net effect is a great reduction in venous return and sometimes such serious shock that the person dies within minutes. Intravenous injection of large amounts of histamine causes “histamine shock,” which has characteristics almost identical to those of anaphylactic shock. Septic Shock A condition that was formerly known by the popular name “blood poisoning” is now called septic shock by most clinicians. This refers to a bacterial infection widely disseminated to many areas of the body, with the infection being borne through the blood from one tissue to another and causing extensive damage. There are many varieties of septic shock because of the many types of bacterial infections that can cause it and because infection in different parts of the body produces different effects. Septic shock is extremely important to the clinician, because other than cardiogenic shock, septic shock is the most frequent cause of shock-related death in the modern hospital. Some of the typical causes of septic shock include the following: 1. Peritonitis caused by spread of infection from the uterus and fallopian tubes, sometimes resulting from instrumental abortion performed under unsterile conditions. 2. Peritonitis resulting from rupture of the gastrointestinal system, sometimes caused by intestinal disease and sometimes by wounds. 3. Generalized bodily infection resulting from spread of a skin infection such as streptococcal or staphylococcal infection. 4. Generalized gangrenous infection resulting specifically from gas gangrene bacilli, spreading first through peripheral tissues and finally by way of the blood to the internal organs, especially the liver. 5. Infection spreading into the blood from the kidney or urinary tract, often caused by colon bacilli. Special Features of Septic Shock. Because of the multiple types of septic shock, it is difficult to categorize this condition. Some features often observed are: 1. High fever. 2. Often marked vasodilation throughout the body, especially in the infected tissues. 3. High cardiac output in perhaps half of patients, caused by arteriolar dilation in the infected tissues and by high metabolic rate and vasodilation elsewhere in the body, resulting from bacterial toxin stimulation of cellular metabolism and from high body temperature. 4. Sludging of the blood, caused by red cell agglutination in response to degenerating tissues. 5. Development of micro–blood clots in widespread areas of the body, a condition called disseminated intravascular coagulation. Also, this causes the blood clotting factors to be used up, so that hemorrhaging occurs in many tissues, especially in the gut wall of the intestinal tract. In early stages of septic shock, the patient usually does not have signs of circulatory collapse but only signs of the bacterial infection. As the infection becomes more severe, the circulatory system usually becomes involved either because of direct extension of the infection or secondarily as a result of toxins from the bacteria, with resultant loss of plasma into the infected tissues through deteriorating blood capillary walls. There finally comes a point at which deterioration of the circulation becomes progressive in the same way that progression occurs in all other types of shock. The end stages of septic shock are not greatly different from the end stages of hemorrhagic shock, even though the initiating factors are markedly different in the two conditions. Physiology of Treatment in Shock Replacement Therapy Blood and Plasma Transfusion. If a person is in shock caused by hemorrhage, the best possible therapy is usually transfusion of whole blood. If the shock is caused by plasma loss, the best therapy is administration of plasma; when dehydration is the cause, administration of an appropriate electrolyte solution can correct the shock. Whole blood is not always available, such as under battlefield conditions. Plasma can usually substitute adequately for whole blood because it increases the blood volume and restores normal hemodynamics. Plasma cannot restore a normal hematocrit, but the human body can usually stand a decrease in hematocrit to about half of normal before serious consequences result, if cardiac output is adequate. Therefore, in emergency conditions, it is reasonable to use plasma in place of whole blood for treatment of hemorrhagic or most other types of hypovolemic shock. Sometimes plasma is unavailable. In these instances, various plasma substitutes have been developed that perform almost exactly the same hemodynamic functions as plasma. One of these is dextran solution. Dextran Solution as a Plasma Substitute. The principal requirement of a truly effective plasma substitute is that it remain in the circulatory system—that is, not filter through the capillary pores into the tissue spaces. In addition, the solution must be nontoxic and must contain appropriate electrolytes to prevent derangement of the body’s extracellular fluid electrolytes on administration. To remain in the circulation, the plasma substitute must contain some substance that has a large enough molecular size to exert colloid osmotic pressure. One of the most satisfactory substances developed for this Chapter 24 Circulatory Shock and Physiology of Its Treatment purpose is dextran, a large polysaccharide polymer of glucose. Certain bacteria secrete dextran as a byproduct of their growth, and commercial dextran can be manufactured using a bacterial culture procedure. By varying the growth conditions of the bacteria, the molecular weight of the dextran can be controlled to the desired value. Dextrans of appropriate molecular size do not pass through the capillary pores and, therefore, can replace plasma proteins as colloid osmotic agents. Few toxic reactions have been observed when using purified dextran to provide colloid osmotic pressure; therefore, solutions containing this substance have proved to be a satisfactory substitute for plasma in most fluid replacement therapy. Treatment of Shock with Sympathomimetic Drugs—Sometimes Useful, Sometimes Not 287 the tissues, giving the patient oxygen to breathe can be of benefit in many instances. However, this frequently is far less beneficial than one might expect, because the problem in most types of shock is not inadequate oxygenation of the blood by the lungs but inadequate transport of the blood after it is oxygenated. Treatment with Glucocorticoids (Adrenal Cortex Hormones That Control Glucose Metabolism). Glucocorticoids are fre- quently given to patients in severe shock for several reasons: (1) experiments have shown empirically that glucocorticoids frequently increase the strength of the heart in the late stages of shock; (2) glucocorticoids stabilize lysosomes in tissue cells and thereby prevent release of lysosomal enzymes into the cytoplasm of the cells, thus preventing deterioration from this source; and (3) glucocorticoids might aid in the metabolism of glucose by the severely damaged cells. Circulatory Arrest A sympathomimetic drug is a drug that mimics sympathetic stimulation. These drugs include norepinephrine, epinephrine, and a large number of long-acting drugs that have the same effect as epinephrine and norepinephrine. In two types of shock, sympathomimetic drugs have proved to be especially beneficial. The first of these is neurogenic shock, in which the sympathetic nervous system is severely depressed. Administering a sympathomimetic drug takes the place of the diminished sympathetic actions and can often restore full circulatory function. The second type of shock in which sympathomimetic drugs are valuable is anaphylactic shock, in which excess histamine plays a prominent role. The sympathomimetic drugs have a vasoconstrictor effect that opposes the vasodilating effect of histamine. Therefore, either norepinephrine or another sympathomimetic drug is often lifesaving. Sympathomimetic drugs have not proved to be very valuable in hemorrhagic shock. The reason is that in this type of shock, the sympathetic nervous system is almost always maximally activated by the circulatory reflexes already; so much norepinephrine and epinephrine are already circulating in the blood that sympathomimetic drugs have essentially no additional beneficial effect. Other Therapy Treatment by the Head-Down Position. When the pressure falls too low in most types of shock, especially in hemorrhagic and neurogenic shock, placing the patient with the head at least 12 inches lower than the feet helps tremendously in promoting venous return, thereby also increasing cardiac output. This headdown position is the first essential step in the treatment of many types of shock. Oxygen Therapy. Because the major deleterious effect of most types of shock is too little delivery of oxygen to A condition closely allied to circulatory shock is circulatory arrest, in which all blood flow stops. This occurs frequently on the surgical operating table as a result of cardiac arrest or ventricular fibrillation. Ventricular fibrillation can usually be stopped by strong electroshock of the heart, the basic principles of which are described in Chapter 13. Cardiac arrest often results from too little oxygen in the anesthetic gaseous mixture or from a depressant effect of the anesthesia itself. A normal cardiac rhythm can usually be restored by removing the anesthetic and immediately applying cardiopulmonary resuscitation procedures, while at the same time supplying the patient’s lungs with adequate quantities of ventilatory oxygen. Effect of Circulatory Arrest on the Brain A special problem in circulatory arrest is to prevent detrimental effects in the brain as a result of the arrest. In general, more than 5 to 8 minutes of total circulatory arrest can cause at least some degree of permanent brain damage in more than half of patients. Circulatory arrest for as long as 10 to 15 minutes almost always permanently destroys significant amounts of mental power. For many years, it was taught that this detrimental effect on the brain was caused by the acute cerebral hypoxia that occurs during circulatory arrest. However, experiments have shown that if blood clots are prevented from occurring in the blood vessels of the brain, this will also prevent most of the early deterioration of the brain during circulatory arrest. For instance, in animal experiments performed by Crowell, all the blood was removed from the animal’s blood vessels at the beginning of circulatory arrest and then replaced at the end of circulatory arrest so that no intravascular blood clotting could occur. In this 288 Unit IV The Circulation experiment, the brain was usually able to withstand up to 30 minutes of circulatory arrest without permanent brain damage.Also, administration of heparin or streptokinase (to prevent blood coagulation) before cardiac arrest was shown to increase the survivability of the brain up to two to four times longer than usual. It is likely that the severe brain damage that occurs from circulatory arrest is caused mainly by permanent blockage of many small blood vessels by blood clots, thus leading to prolonged ischemia and eventual death of the neurons. References Annane D, Sebille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862, 2002. Burry LD, Wax RS: Role of corticosteroids in septic shock. Ann Pharmacother 38:464, 2004. Creteur J, Vincent JL: Hemoglobin solutions. Crit Care Med 31(12 Suppl):S698, 2003. Crowell JW, Guyton AC: Evidence favoring a cardiac mechanism in irreversible hemorrhagic shock. Am J Physiol 201:893, 1961. Crowell JW, Smith EE: Oxygen deficit and irreversible hemorrhagic shock. Am J Physiol 206:313, 1964. de Jonge E, Levi M: Effects of different plasma substitutes on blood coagulation: a comparative review. Crit Care Med 29:1261, 2001. Goodnough LT, Shander A: Evolution in alternatives to blood transfusion. Hematol J 4:87, 2003. Granger DN, Stokes KY, Shigematsu T, et al: Splanchnic ischaemia-reperfusion injury: mechanistic insights provided by mutant mice. Acta Physiol Scand 173:83, 2001. Guyton AC, Jones CE, Coleman TG: Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: WB Saunders, 1973. Ledgerwood AM, Lucas CE: A review of studies on the effects of hemorrhagic shock and resuscitation on the coagulation profile. J Trauma 54(5 Suppl):S68, 2003. Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546, 2003. McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP: Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ 327:1332, 2003. Proctor KG: Blood substitutes and experimental models of trauma. J Trauma 54(5 Suppl):S106, 2003. Rivers E, Nguyen B, Havstad S, et al: The Early GoalDirected Therapy Collaborative Group. Early goaldirected therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368, 2001. Toh CH, Dennis M: Disseminated intravascular coagulation: old disease, new hope. BMJ 327:974, 2003. Wernly JA: Ischemia, reperfusion, and the role of surgery in the treatment of cardiogenic shock secondary to acute myocardial infarction: an interpretative review. J Surg Res 117:6, 2004. Wilson M, Davis DP, Coimbra R: Diagnosis and monitoring of hemorrhagic shock during the initial resuscitation of multiple trauma patients: a review. J Emerg Med 24:413, 2003. U N I The Body Fluids and Kidneys 25. The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema 26. Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control 27. Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate 28. Regulation of Extracellular Fluid Osmolarity and Sodium Concentration 29. Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume 30. Regulation of Acid-Base Balance 31. Kidney Diseases and Diuretics T V C H A P T E R 2 5 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema The maintenance of a relatively constant volume and a stable composition of the body fluids is essential for homeostasis, as discussed in Chapter 1. Some of the most common and important problems in clinical medicine arise because of abnormalities in the control systems that maintain this constancy of the body fluids. In this chapter and in the following chapters on the kidneys, we discuss the overall regulation of body fluid volume, constituents of the extracellular fluid, acid-base balance, and control of fluid exchange between extracellular and intracellular compartments. Fluid Intake and Output Are Balanced During Steady-State Conditions The relative constancy of the body fluids is remarkable because there is continuous exchange of fluid and solutes with the external environment as well as within the different compartments of the body. For example, there is a highly variable fluid intake that must be carefully matched by equal output from the body to prevent body fluid volumes from increasing or decreasing. Daily Intake of Water Water is added to the body by two major sources: (1) it is ingested in the form of liquids or water in the food, which together normally add about 2100 ml/day to the body fluids, and (2) it is synthesized in the body as a result of oxidation of carbohydrates, adding about 200 ml/day. This provides a total water intake of about 2300 ml/day (Table 25–1). Intake of water, however, is highly variable among different people and even within the same person on different days, depending on climate, habits, and level of physical activity. Daily Loss of Body Water Insensible Water Loss. Some of the water losses cannot be precisely regulated. For example, there is a continuous loss of water by evaporation from the respiratory tract and diffusion through the skin, which together account for about 700 ml/day of water loss under normal conditions. This is termed insensible water loss because we are not consciously aware of it, even though it occurs continually in all living humans. The insensible water loss through the skin occurs independently of sweating and is present even in people who are born without sweat glands; the average water loss by diffusion through the skin is about 300 to 400 ml/day. This loss is minimized by the cholesterol-filled cornified layer of the skin, which provides a barrier against excessive loss by diffusion. When the cornified layer becomes 291 The Body Fluids and Kidneys Table 25–1 Daily Intake and Output of Water (ml/day) Normal Prolonged, Heavy Exercise Intake Fluids ingested From metabolism Total intake 2100 200 2300 ? 200 ? Output Insensible—skin Insensible—lungs Sweat Feces Urine Total output 350 350 100 100 1400 2300 350 650 5000 100 500 6600 denuded, as occurs with extensive burns, the rate of evaporation can increase as much as 10-fold, to 3 to 5 L/day. For this reason, burn victims must be given large amounts of fluid, usually intravenously, to balance fluid loss. Insensible water loss through the respiratory tract averages about 300 to 400 ml/day. As air enters the respiratory tract, it becomes saturated with moisture, to a vapor pressure of about 47 mm Hg, before it is expelled. Because the vapor pressure of the inspired air is usually less than 47 mm Hg, water is continuously lost through the lungs with respiration. In cold weather, the atmospheric vapor pressure decreases to nearly 0, causing an even greater loss of water from the lungs as the temperature decreases. This explains the dry feeling in the respiratory passages in cold weather. Fluid Loss in Sweat. The amount of water lost by sweating is highly variable, depending on physical activity and environmental temperature. The volume of sweat normally is about 100 ml/day, but in very hot weather or during heavy exercise, water loss in sweat occasionally increases to 1 to 2 L/hour. This would rapidly deplete the body fluids if intake were not also increased by activating the thirst mechanism discussed in Chapter 29. OUTPUT •Kidneys •Lungs •Feces •Sweat •Skin INTAKE Plasma 3.0 L Capillary membrane Interstitial fluid 11.0 L Lymphatics Unit V Extracellular fluid (14.0 L) 292 Cell membrane Intracellular fluid 28.0 L Figure 25–1 Summary of body fluid regulation, including the major body fluid compartments and the membranes that separate these compartments. The values shown are for an average 70-kilogram person. 20 L/day in a person who has been drinking tremendous amounts of water. This variability of intake is also true for most of the electrolytes of the body, such as sodium, chloride, and potassium. In some people, sodium intake may be as low as 20 mEq/day, whereas in others, sodium intake may be as high as 300 to 500 mEq/day. The kidneys are faced with the task of adjusting the excretion rate of water and electrolytes to match precisely the intake of these substances, as well as compensating for excessive losses of fluids and electrolytes that occur in certain disease states. In Chapters 26 through 30, we discuss the mechanisms that allow the kidneys to perform these remarkable tasks. Water Loss in Feces. Only a small amount of water (100 ml/day) normally is lost in the feces. This can increase to several liters a day in people with severe diarrhea. For this reason, severe diarrhea can be life threatening if not corrected within a few days. Water Loss by the Kidneys. The remaining water loss from the body occurs in the urine excreted by the kidneys. There are multiple mechanisms that control the rate of urine excretion. In fact, the most important means by which the body maintains a balance between water intake and output, as well as a balance between intake and output of most electrolytes in the body, is by controlling the rates at which the kidneys excrete these substances. For example, urine volume can be as low as 0.5 L/day in a dehydrated person or as high as Body Fluid Compartments The total body fluid is distributed mainly between two compartments: the extracellular fluid and the intracellular fluid (Figure 25–1). The extracellular fluid is divided into the interstitial fluid and the blood plasma. There is another small compartment of fluid that is referred to as transcellular fluid. This compartment includes fluid in the synovial, peritoneal, pericardial, and intraocular spaces, as well as the cerebrospinal fluid; it is usually considered to be a specialized type of extracellular fluid, although in some cases, its composition may differ markedly from that of the plasma or interstitial fluid. All the transcellular fluids together constitute about 1 to 2 liters. Chapter 25 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema In the average 70-kilogram adult human, the total body water is about 60 per cent of the body weight, or about 42 liters. This percentage can change, depending on age, gender, and degree of obesity. As a person grows older, the percentage of total body weight that is fluid gradually decreases. This is due in part to the fact that aging is usually associated with an increased percentage of the body weight being fat, which decreases the percentage of water in the body. Because women normally have more body fat than men, they contain slightly less water than men in proportion to their body weight. Therefore, when discussing the “average” body fluid compartments, we should realize that variations exist, depending on age, gender, and percentage of body fat. Intracellular Fluid Compartment About 28 of the 42 liters of fluid in the body are inside the 75 trillion cells and are collectively called the intracellular fluid. Thus, the intracellular fluid constitutes about 40 per cent of the total body weight in an “average” person. The fluid of each cell contains its individual mixture of different constituents, but the concentrations of these substances are similar from one cell to another. In fact, the composition of cell fluids is remarkably similar even in different animals, ranging from the most primitive microorganisms to humans. For this reason, the intracellular fluid of all the different cells together is considered to be one large fluid compartment. Extracellular Fluid Compartment All the fluids outside the cells are collectively called the extracellular fluid. Together these fluids account for about 20 per cent of the body weight, or about 14 liters in a normal 70-kilogram adult. The two largest compartments of the extracellular fluid are the interstitial fluid, which makes up more than three fourths of the extracellular fluid, and the plasma, which makes up almost one fourth of the extracellular fluid, or about 3 liters. The plasma is the noncellular part of the blood; it exchanges substances continuously with the interstitial fluid through the pores of the capillary membranes. These pores are highly permeable to almost all solutes in the extracellular fluid except the proteins. Therefore, the extracellular fluids are constantly mixing, so that the plasma and interstitial fluids have about the same composition except for proteins, which have a higher concentration in the plasma. Blood Volume Blood contains both extracellular fluid (the fluid in plasma) and intracellular fluid (the fluid in the red blood cells). However, blood is considered to be a separate fluid compartment because it is contained in a 293 chamber of its own, the circulatory system. The blood volume is especially important in the control of cardiovascular dynamics. The average blood volume of adults is about 7 per cent of body weight, or about 5 liters. About 60 per cent of the blood is plasma and 40 per cent is red blood cells, but these percentages can vary considerably in different people, depending on gender, weight, and other factors. Hematocrit (Packed Red Cell Volume). The hematocrit is the fraction of the blood composed of red blood cells, as determined by centrifuging blood in a “hematocrit tube” until the cells become tightly packed in the bottom of the tube. It is impossible to completely pack the red cells together; therefore, about 3 to 4 per cent of the plasma remains entrapped among the cells, and the true hematocrit is only about 96 per cent of the measured hematocrit. In men, the measured hematocrit is normally about 0.40, and in women, it is about 0.36. In severe anemia, the hematocrit may fall as low as 0.10, a value that is barely sufficient to sustain life. Conversely, there are some conditions in which there is excessive production of red blood cells, resulting in polycythemia. In these conditions, the hematocrit can rise to 0.65. Constituents of Extracellular and Intracellular Fluids Comparisons of the composition of the extracellular fluid, including the plasma and interstitial fluid, and the intracellular fluid are shown in Figures 25–2 and 25–3 and in Table 25–2. Ionic Composition of Plasma and Interstitial Fluid Is Similar Because the plasma and interstitial fluid are separated only by highly permeable capillary membranes, their ionic composition is similar. The most important difference between these two compartments is the higher concentration of protein in the plasma; because the capillaries have a low permeability to the plasma proteins, only small amounts of proteins are leaked into the interstitial spaces in most tissues. Because of the Donnan effect, the concentration of positively charged ions (cations) is slightly greater (about 2 per cent) in the plasma than in the interstitial fluid. The plasma proteins have a net negative charge and, therefore, tend to bind cations, such as sodium and potassium ions, thus holding extra amounts of these cations in the plasma along with the plasma proteins. Conversely, negatively charged ions (anions) tend to have a slightly higher concentration in the interstitial fluid compared with the plasma, because the negative charges of the plasma proteins repel the negatively charged anions. For practical purposes, however, the concentration of ions in the 294 Unit V Anions 100 50 100 Mg++ Cl- Cholesterol – 150 mg/dl Protein Ca++ K+ HCO3- Na+ PO –––4 and organic anions mEq/L 50 0 Phospholipids – 280 mg/dl EXTRACELLULAR Cations INTRACELLULAR 150 The Body Fluids and Kidneys Neutral fat – 125 mg/dl Glucose – 100 mg/dl Urea – 15 mg/dl Lactic acid – 10 mg/dl Uric acid – 3 mg/dl Creatinine – 1.5 mg/dl Bilirubin – 0.5 mg/dl Bile salts – trace 150 Figure 25–2 Major cations and anions of the intracellular and extracellular fluids. The concentrations of Ca++ and Mg++ represent the sum of these two ions. The concentrations shown represent the total of free ions and complexed ions. Figure 25–3 Nonelectrolytes of the plasma. Table 25–2 Osmolar Substances in Extracellular and Intracellular Fluids + Na K+ Ca++ Mg+ Cl– HCO3– HPO4–, H2PO4– SO4– Phosphocreatine Carnosine Amino acids Creatine Lactate Adenosine triphosphate Hexose monophosphate Glucose Protein Urea Others Total mOsm/L Corrected osmolar activity (mOsm/L) Total osmotic pressure at 37∞C (mm Hg) Plasma (mOsm/L H2O) Interstitial (mOsm/L H2O) Intracellular (mOsm/L H2O) 142 4.2 1.3 0.8 108 24 2 0.5 139 4.0 1.2 0.7 108 28.3 2 0.5 2 0.2 1.2 2 0.2 1.2 14 140 0 20 4 10 11 1 45 14 8 9 1.5 5 3.7 5.6 1.2 4 4.8 301.8 282.0 5443 5.6 0.2 4 3.9 300.8 281.0 5423 4 4 10 301.2 281.0 5423 Chapter 25 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema interstitial fluid and in the plasma is considered to be about equal. Referring again to Figure 25–2, one can see that the extracellular fluid, including the plasma and the interstitial fluid, contains large amounts of sodium and chloride ions, reasonably large amounts of bicarbonate ions, but only small quantities of potassium, calcium, magnesium, phosphate, and organic acid ions. The composition of extracellular fluid is carefully regulated by various mechanisms, but especially by the kidneys, as discussed later. This allows the cells to remain continually bathed in a fluid that contains the proper concentration of electrolytes and nutrients for optimal cell function. Important Constituents of the Intracellular Fluid 295 Indicator Mass A = Volume A x Concentration A Indicator Mass A = Indicator Mass B Indicator Mass B = Volume B x Concentration B Volume B = Indicator Mass B / Concentration B The intracellular fluid is separated from the extracellular fluid by a cell membrane that is highly permeable to water but not to most of the electrolytes in the body. In contrast to the extracellular fluid, the intracellular fluid contains only small quantities of sodium and chloride ions and almost no calcium ions. Instead, it contains large amounts of potassium and phosphate ions plus moderate quantities of magnesium and sulfate ions, all of which have low concentrations in the extracellular fluid. Also, cells contain large amounts of protein, almost four times as much as in the plasma. Measurement of Fluid Volumes in the Different Body Fluid Compartments—The Indicator-Dilution Principle The volume of a fluid compartment in the body can be measured by placing an indicator substance in the compartment, allowing it to disperse evenly throughout the compartment’s fluid, and then analyzing the extent to which the substance becomes diluted. Figure 25–4 shows this “indicator-dilution” method of measuring the volume of a fluid compartment, which is based on the principle of conservation of mass. This means that the total mass of a substance after dispersion in the fluid compartment will be the same as the total mass injected into the compartment. In the example shown in Figure 25–4, a small amount of dye or other substance contained in the syringe is injected into a chamber, and the substance is allowed to disperse throughout the chamber until it becomes mixed in equal concentrations in all areas. Then a sample of fluid containing the dispersed substance is removed and the concentration is analyzed chemically, photoelectrically, or by other means. If none of the substance leaks out of the compartment, the total mass of substance in the compartment (Volume B ¥ Concentration B) will equal the total mass of the substance injected (Volume A ¥ Concentration A). By simple rearrangement of the equa- Figure 25–4 Indicator-dilution method for measuring fluid volumes. tion, one can calculate the unknown volume of chamber B as Volume B = Volume A ¥ Concentration A Concentration B Note that all one needs to know for this calculation is (1) the total amount of substance injected into the chamber (the numerator of the equation) and (2) the concentration of the fluid in the chamber after the substance has been dispersed (the denominator). For example, if 1 milliliter of a solution containing 10 mg/ml of dye is dispersed into chamber B and the final concentration in the chamber is 0.01 milligram for each milliliter of fluid, the unknown volume of the chamber can be calculated as follows: Volume B = 1 ml ¥ 10 mg ml = 1000 ml 0.01 mg ml This method can be used to measure the volume of virtually any compartment in the body as long as (1) the indicator disperses evenly throughout the compartment, (2) the indicator disperses only in the compartment that is being measured, and (3) the indicator is not metabolized or excreted. Several substances can be used to measure the volume of each of the different body fluids. Determination of Volumes of Specific Body Fluid Compartments Measurement of Total Body Water. Radioactive water (tritium, 3H2O) or heavy water (deuterium, 2H2O) can be used to measure total body water. These forms of water mix with the total body water within a few hours after being injected into the blood, and the dilution 296 Unit V The Body Fluids and Kidneys Table 25–3 Measurement of Body Fluid Volumes Volume Indicators Total body water 3 Extracellular fluid 22 Intracellular fluid (Calculated as Total body water – Extracellular fluid volume) Plasma volume 125 Blood volume 51 Interstitial fluid (Calculated as Extracellular fluid volume - Plasma volume) H2O, 2H2O, antipyrine Na, 125I-iothalamate, thiosulfate, inulin I-albumin, Evans blue dye (T-1824) Cr-labeled red blood cells, or calculated as Blood volume = Plasma volume/ (1 - Hematocrit) From Guyton AC, Hall JE: Human Physiology and Mechanisms of Disease, 6th ed. Philadelphia: WB Saunders, 1997. principle can be used to calculate total body water (Table 25–3). Another substance that has been used to measure total body water is antipyrine, which is very lipid soluble and can rapidly penetrate cell membranes and distribute itself uniformly throughout the intracellular and extracellular compartments. volume can also be calculated if one knows the hematocrit (the fraction of the total blood volume composed of cells), using the following equation: Total blood volume = Plasma volume 1 - Hematocrit For example, if plasma volume is 3 liters and hematocrit is 0.40, total blood volume would be calculated as 3 liters = 5 liters 1 - 0.4 Another way to measure blood volume is to inject into the circulation red blood cells that have been labeled with radioactive material. After these mix in the circulation, the radioactivity of a mixed blood sample can be measured, and the total blood volume can be calculated using the dilution principle. A substance frequently used to label the red blood cells is radioactive chromium (51Cr), which binds tightly with the red blood cells. Regulation of Fluid Exchange and Osmotic Equilibrium Between Intracellular and Extracellular Fluid Measurement of Extracellular Fluid Volume. The volume of extracellular fluid can be estimated using any of several substances that disperse in the plasma and interstitial fluid but do not readily permeate the cell membrane. They include radioactive sodium, radioactive chloride, radioactive iothalamate, thiosulfate ion, and inulin. When any one of these substances is injected into the blood, it usually disperses almost completely throughout the extracellular fluid within 30 to 60 minutes. Some of these substances, however, such as radioactive sodium, may diffuse into the cells in small amounts. Therefore, one frequently speaks of the sodium space or the inulin space, instead of calling the measurement the true extracellular fluid volume. of Intracellular Volume. The intracellular volume cannot be measured directly. However, it can be calculated as Calculation Intracellular volume = Total body water – Extracellular volume Measurement of Plasma Volume. To measure plasma volume, a substance must be used that does not readily penetrate capillary membranes but remains in the vascular system after injection. One of the most commonly used substances for measuring plasma volume is serum albumin labeled with radioactive iodine (125I-albumin). Also, dyes that avidly bind to the plasma proteins, such as Evans blue dye (also called T-1824), can be used to measure plasma volume. Calculation of Interstitial Fluid Volume. Interstitial fluid volume cannot be measured directly, but it can be calculated as Interstitial fluid volume = Extracellular fluid volume – Plasma volume Measurement of Blood Volume. If one measures plasma volume using the methods described earlier, blood A frequent problem in treating seriously ill patients is maintaining adequate fluids in one or both of the intracellular and extracellular compartments. As discussed in Chapter 16 and later in this chapter, the relative amounts of extracellular fluid distributed between the plasma and interstitial spaces are determined mainly by the balance of hydrostatic and colloid osmotic forces across the capillary membranes. The distribution of fluid between intracellular and extracellular compartments, in contrast, is determined mainly by the osmotic effect of the smaller solutes— especially sodium, chloride, and other electrolytes— acting across the cell membrane. The reason for this is that the cell membranes are highly permeable to water but relatively impermeable to even small ions such as sodium and chloride. Therefore, water moves across the cell membrane rapidly, so that the intracellular fluid remains isotonic with the extracellular fluid. In the next section, we discuss the interrelations between intracellular and extracellular fluid volumes and the osmotic factors that can cause shifts of fluid between these two compartments. Basic Principles of Osmosis and Osmotic Pressure The basic principles of osmosis and osmotic pressure were presented in Chapter 4. Therefore, we review here only the most important aspects of these principles as they apply to volume regulation. Osmosis is the net diffusion of water across a selectively permeable membrane from a region of high water concentration to one that has a lower water concentration. When a solute is added to pure water, this reduces Chapter 25 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema the concentration of water in the mixture. Thus, the higher the solute concentration in a solution, the lower the water concentration. Further, water diffuses from a region of low solute concentration (high water concentration) to one with a high solute concentration (low water concentration). Because cell membranes are relatively impermeable to most solutes but highly permeable to water (i.e., selectively permeable), whenever there is a higher concentration of solute on one side of the cell membrane, water diffuses across the membrane toward the region of higher solute concentration. Thus, if a solute such as sodium chloride is added to the extracellular fluid, water rapidly diffuses from the cells through the cell membranes into the extracellular fluid until the water concentration on both sides of the membrane becomes equal. Conversely, if a solute such as sodium chloride is removed from the extracellular fluid, water diffuses from the extracellular fluid through the cell membranes and into the cells. The rate of diffusion of water is called the rate of osmosis. Relation Between Moles and Osmoles. Because the water concentration of a solution depends on the number of solute particles in the solution, a concentration term is needed to describe the total concentration of solute particles, regardless of their exact composition. The total number of particles in a solution is measured in osmoles. One osmole (osm) is equal to 1 mole (mol) (6.02 ¥ 1023) of solute particles. Therefore, a solution containing 1 mole of glucose in each liter has a concentration of 1 osm/L. If a molecule dissociates into two ions (giving two particles), such as sodium chloride ionizing to give chloride and sodium ions, then a solution containing 1 mol/L will have an osmolar concentration of 2 osm/L. Likewise, a solution that contains 1 mole of a molecule that dissociates into three ions, such as sodium sulfate (Na2SO4), will contain 3 osm/L. Thus, the term osmole refers to the number of osmotically active particles in a solution rather than to the molar concentration. In general, the osmole is too large a unit for expressing osmotic activity of solutes in the body fluids. The term milliosmole (mOsm), which equals 1/1000 osmole, is commonly used. Osmolality and Osmolarity. The osmolal concentration of a solution is called osmolality when the concentration is expressed as osmoles per kilogram of water; it is called osmolarity when it is expressed as osmoles per liter of solution. In dilute solutions such as the body fluids, these two terms can be used almost synonymously because the differences are small. In most cases, it is easier to express body fluid quantities in liters of fluid rather than in kilograms of water. Therefore, most of the calculations used clinically and the calculations expressed in the next several chapters are based on osmolarities rather than osmolalities. Osmotic Pressure. Osmosis of water molecules across a selectively permeable membrane can be opposed by applying a pressure in the direction opposite that of 297 the osmosis. The precise amount of pressure required to prevent the osmosis is called the osmotic pressure. Osmotic pressure, therefore, is an indirect measurement of the water and solute concentrations of a solution. The higher the osmotic pressure of a solution, the lower the water concentration and the higher the solute concentration of the solution. Relation Between Osmotic Pressure and Osmolarity. The osmotic pressure of a solution is directly proportional to the concentration of osmotically active particles in that solution. This is true regardless of whether the solute is a large molecule or a small molecule. For example, one molecule of albumin with a molecular weight of 70,000 has the same osmotic effect as one molecule of glucose with a molecular weight of 180. One molecule of sodium chloride, however, has two osmotically active particles, Na+ and Cl–, and therefore has twice the osmotic effect of either an albumin molecule or a glucose molecule. Thus, the osmotic pressure of a solution is proportional to its osmolarity, a measure of the concentration of solute particles. Expressed mathematically, according to van’t Hoff’s law, osmotic pressure (p) can be calculated as p = CRT where C is the concentration of solutes in osmoles per liter, R is the ideal gas constant, and T is the absolute temperature in degrees kelvin (273° + centigrade°). If p is expressed in millimeters of mercury (mm Hg), the unit of pressure commonly used for biological fluids, and T is normal body temperature (273° + 37° = 310° kelvin), the value of p calculates to be about 19,300 mm Hg for a solution having a concentration of 1 osm/L. This means that for a concentration of 1 mOsm/L, p is equal to 19.3 mm Hg. Thus, for each milliosmole concentration gradient across the cell membrane, 19.3 mm Hg osmotic pressure is exerted. Calculation of the Osmolarity and Osmotic Pressure of a Solution. Using van’t Hoff’s law, one can calculate the potential osmotic pressure of a solution, assuming that the cell membrane is impermeable to the solute. For example, the osmotic pressure of a 0.9 per cent sodium chloride solution is calculated as follows: A 0.9 per cent solution means that there is 0.9 gram of sodium chloride per 100 milliliters of solution, or 9 g/L. Because the molecular weight of sodium chloride is 58.5 g/mol, the molarity of the solution is 9 g/L divided by 58.5 g/mol, or about 0.154 mol/L. Because each molecule of sodium chloride is equal to 2 osmoles, the osmolarity of the solution is 0.154 ¥ 2, or 0.308 osm/L. Therefore, the osmolarity of this solution is 308 mOsm/L. The potential osmotic pressure of this solution would therefore be 308 mOsm/L ¥ 19.3 mm Hg/mOsm/L, or 5944 mm Hg. This calculation is only an approximation, because sodium and chloride ions do not behave entirely independently in solution because of interionic attraction between them. One can correct for these deviations from the predictions of van’t Hoff’s law by using a correction factor called the osmotic coefficient. For 298 Unit V The Body Fluids and Kidneys sodium chloride, the osmotic coefficient is about 0.93. Therefore, the actual osmolarity of a 0.9 per cent sodium chloride solution is 308 ¥ 0.93, or about 286 mOsm/L. For practical reasons, the osmotic coefficients of different solutes are sometimes neglected in determining the osmolarity and osmotic pressures of physiologic solutions. A Osmolarity of the Body Fluids. Turning back to Table 25–2, B note the approximate osmolarity of the various osmotically active substances in plasma, interstitial fluid, and intracellular fluid. Note that about 80 per cent of the total osmolarity of the interstitial fluid and plasma is due to sodium and chloride ions, whereas for intracellular fluid, almost half the osmolarity is due to potassium ions, and the remainder is divided among many other intracellular substances. As shown in Table 25–2, the total osmolarity of each of the three compartments is about 300 mOsm/L, with the plasma being about 1 mOsm/L greater than that of the interstitial and intracellular fluids. The slight difference between plasma and interstitial fluid is caused by the osmotic effects of the plasma proteins, which maintain about 20 mm Hg greater pressure in the capillaries than in the surrounding interstitial spaces, as discussed in Chapter 16. 280 mOsm/L C ISOTONIC No change 200 mOsm/L 360 mOsm/L HYPOTONIC Cell swells HYPERTONIC Cell shrinks Figure 25–5 Effects of isotonic (A), hypertonic (B), and hypotonic (C) solutions on cell volume. Corrected Osmolar Activity of the Body Fluids. At the bottom of Table 25–2 are shown corrected osmolar activities of plasma, interstitial fluid, and intracellular fluid.The reason for these corrections is that molecules and ions in solution exert interionic and intermolecular attraction or repulsion from one solute molecule to the next, and these two effects can cause, respectively, a slight decrease or an increase in the osmotic “activity” of the dissolved substance. potential osmotic pressure that can develop across the cell membrane is more than 5400 mm Hg. This demonstrates the large force that can move water across the cell membrane when the intracellular and extracellular fluids are not in osmotic equilibrium. As a result of these forces, relatively small changes in the concentration of impermeant solutes in the extracellular fluid can cause large changes in cell volume. Total Osmotic Pressure Exerted by the Body Fluids. Table Isotonic, Hypotonic, and Hypertonic Fluids. The effects of 25–2 also shows the total osmotic pressure in millimeters of mercury that would be exerted by each of the different fluids if it were placed on one side of the cell membrane with pure water on the other side. Note that this total pressure averages about 5443 mm Hg for plasma, which is 19.3 times the corrected osmolarity of 282 mOsm/L for plasma. different concentrations of impermeant solutes in the extracellular fluid on cell volume are shown in Figure 25–5. If a cell is placed in a solution of impermeant solutes having an osmolarity of 282 mOsm/L, the cells will not shrink or swell because the water concentration in the intracellular and extracellular fluids is equal and the solutes cannot enter or leave the cell. Such a solution is said to be isotonic because it neither shrinks nor swells the cells. Examples of isotonic solutions include a 0.9 per cent solution of sodium chloride or a 5 per cent glucose solution. These solutions are important in clinical medicine because they can be infused into the blood without the danger of upsetting osmotic equilibrium between the intracellular and extracellular fluids. If a cell is placed into a hypotonic solution that has a lower concentration of impermeant solutes (less than 282 mOsm/L), water will diffuse into the cell, causing it to swell; water will continue to diffuse into the cell, diluting the intracellular fluid while also concentrating the extracellular fluid until both solutions have about the same osmolarity. Solutions of sodium chloride with a concentration of less than 0.9 per cent are hypotonic and cause cells to swell. Osmotic Equilibrium Is Maintained Between Intracellular and Extracellular Fluids Large osmotic pressures can develop across the cell membrane with relatively small changes in the concentrations of solutes in the extracellular fluid. As discussed earlier, for each milliosmole concentration gradient of an impermeant solute (one that will not permeate the cell membrane), about 19.3 mm Hg osmotic pressure is exerted across the cell membrane. If the cell membrane is exposed to pure water and the osmolarity of intracellular fluid is 282 mOsm/L, the Chapter 25 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema If a cell is placed in a hypertonic solution having a higher concentration of impermeant solutes, water will flow out of the cell into the extracellular fluid, concentrating the intracellular fluid and diluting the extracellular fluid. In this case, the cell will shrink until the two concentrations become equal. Sodium chloride solutions of greater than 0.9 per cent are hypertonic. Isosmotic, Hyperosmotic, and Hypo-osmotic Fluids. The terms isotonic, hypotonic, and hypertonic refer to whether solutions will cause a change in cell volume. The tonicity of solutions depends on the concentration of impermeant solutes. Some solutes, however, can permeate the cell membrane. Solutions with an osmolarity the same as the cell are called isosmotic, regardless of whether the solute can penetrate the cell membrane. The terms hyperosmotic and hypo-osmotic refer to solutions that have a higher or lower osmolarity, respectively, compared with the normal extracellular fluid, without regard for whether the solute permeates the cell membrane. Highly permeating substances, such as urea, can cause transient shifts in fluid volume between the intracellular and extracellular fluids, but given enough time, the concentrations of these substances eventually become equal in the two compartments and have little effect on intracellular volume under steady-state conditions. Osmotic Equilibrium Between Intracellular and Extracellular Fluids Is Rapidly Attained. The transfer of fluid across the cell membrane occurs so rapidly that any differences in osmolarities between these two compartments are usually corrected within seconds or, at the most, minutes. This rapid movement of water across the cell membrane does not mean that complete equilibrium occurs between the intracellular and extracellular compartments throughout the whole body within the same short period. The reason for this is that fluid usually enters the body through the gut and must be transported by the blood to all tissues before complete osmotic equilibrium can occur. It usually takes about 30 minutes to achieve osmotic equilibrium everywhere in the body after drinking water. Volume and Osmolality of Extracellular and Intracellular Fluids in Abnormal States Some of the different factors that can cause extracellular and intracellular volumes to change markedly are ingestion of water, dehydration, intravenous infusion of different types of solutions, loss of large amounts of fluid from the gastrointestinal tract, and loss of abnormal amounts of fluid by sweating or through the kidneys. One can calculate both the changes in intracellular and extracellular fluid volumes and the types of therapy that should be instituted if the following basic principles are kept in mind: 299 1. Water moves rapidly across cell membranes; therefore, the osmolarities of intracellular and extracellular fluids remain almost exactly equal to each other except for a few minutes after a change in one of the compartments. 2. Cell membranes are almost completely impermeable to many solutes; therefore, the number of osmoles in the extracellular or intracellular fluid generally remains constant unless solutes are added to or lost from the extracellular compartment. With these basic principles in mind, we can analyze the effects of different abnormal fluid conditions on extracellular and intracellular fluid volumes and osmolarities. Effect of Adding Saline Solution to the Extracellular Fluid If an isotonic saline solution is added to the extracellular fluid compartment, the osmolarity of the extracellular fluid does not change; therefore, no osmosis occurs through the cell membranes. The only effect is an increase in extracellular fluid volume (Figure 25–6A). The sodium and chloride largely remain in the extracellular fluid because the cell membrane behaves as though it were virtually impermeable to the sodium chloride. If a hypertonic solution is added to the extracellular fluid, the extracellular osmolarity increases and causes osmosis of water out of the cells into the extracellular compartment (see Figure 25–6B). Again, almost all the added sodium chloride remains in the extracellular compartment, and fluid diffuses from the cells into the extracellular space to achieve osmotic equilibrium. The net effect is an increase in extracellular volume (greater than the volume of fluid added), a decrease in intracellular volume, and a rise in osmolarity in both compartments. If a hypotonic solution is added to the extracellular fluid, the osmolarity of the extracellular fluid decreases and some of the extracellular water diffuses into the cells until the intracellular and extracellular compartments have the same osmolarity (see Figure 25–6C). Both the intracellular and the extracellular volumes are increased by the addition of hypotonic fluid, although the intracellular volume increases to a greater extent. Calculation of Fluid Shifts and Osmolarities After Infusion of Hypertonic Saline. We can calculate the sequential effects of infusing different solutions on extracellular and intracellular fluid volumes and osmolarities. For example, if 2 liters of a hypertonic 3.0 per cent sodium chloride solution are infused into the extracellular fluid compartment of a 70-kilogram patient whose initial plasma osmolarity is 280 mOsm/L, what would be the intracellular and extracellular fluid volumes and osmolarities after osmotic equilibrium? The first step is to calculate the initial conditions, including the volume, concentration, and total 300 Unit V Intracellular fluid The Body Fluids and Kidneys Extracellular fluid Normal State A. Add Isotonic NaCl Osmolarity 300 200 100 0 10 20 30 Volume (liters) 40 Figure 25–6 C. Add Hypotonic NaCl B. Add Hypertonic NaCl milliosmoles in each compartment. Assuming that extracellular fluid volume is 20 per cent of body weight and intracellular fluid volume is 40 per cent of body weight, the following volumes and concentrations can be calculated. Step 1. Initial Conditions Extracellular fluid Intracellular fluid Total body fluid Volume (Liters) Concentration (mOsm/L) Total (mOsm) 14 28 42 280 280 280 3,920 7,840 11,760 Next, we calculate the total milliosmoles added to the extracellular fluid in 2 liters of 3.0 per cent sodium chloride. A 3.0 per cent solution means that there are 3.0 g/100 ml, or 30 grams of sodium chloride per liter. Because the molecular weight of sodium chloride is about 58.5 g/mol, this means that there is about 0.513 mole of sodium chloride per liter of solution. For 2 liters of solution, this would be 1.026 mole of sodium chloride. Because 1 mole of sodium chloride is about equal to 2 osmoles (sodium chloride has two osmotically active particles per mole), the net effect of adding 2 liters of this solution is to add 2051 milliosmoles of sodium chloride to the extracellular fluid. In Step 2, we calculate the instantaneous effect of adding 2051 milliosmoles of sodium chloride to the extracellular fluid along with 2 liters of volume. There would be no change in the intracellular fluid concentration or volume, and there would be no osmotic equilibrium. In the extracellular fluid, however, there Effect of adding isotonic, hypertonic, and hypotonic solutions to the extracellular fluid after osmotic equilibrium. The normal state is indicated by the solid lines, and the shifts from normal are shown by the shaded areas. The volumes of intracellular and extracellular fluid compartments are shown in the abscissa of each diagram, and the osmolarities of these compartments are shown on the ordinates. would be an additional 2051 milliosmoles of total solute, yielding a total of 5791 milliosmoles. Because the extracellular compartment now has 16 liters of volume, the concentration can be calculated by dividing 5791 milliosmoles by 16 liters to yield a concentration of 373 mOsm/L. Thus, the following values would occur instantly after adding the solution. Step 2. Instantaneous Effect of Adding 2 Liters of 3.0 Per Cent Sodium Chloride Volume (Liters) Extracellular fluid Intracellular fluid Total body fluid 16 28 44 Concentration (mOsm/L) Total (mOsm) 373 280 No equilibrium 5,971 7,840 13,811 In the third step, we calculate the volumes and concentrations that would occur within a few minutes after osmotic equilibrium develops. In this case, the concentrations in the intracellular and extracellular fluid compartments would be equal and can be calculated by dividing the total milliosmoles in the body, 13,811, by the total volume, which is now 44 liters. This yields a concentration of 313.9 mOsm/L. Therefore, all the body fluid compartments will have this same concentration after osmotic equilibrium. Assuming that no solute or water has been lost from the body and that there is no movement of sodium chloride into or out of the cells, we then calculate the volumes of the intracellular and extracellular compartments. The intracellular fluid volume is calculated by dividing the total milliosmoles in the intracellular fluid (7840) by Chapter 25 301 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema the concentration (313.9 mOsm/L), to yield a volume of 24.98 liters. Extracellular fluid volume is calculated by dividing the total milliosmoles in extracellular fluid (5971) by the concentration (313.9 mOsm/L), to yield a volume of 19.02 liters. Again, these calculations are based on the assumption that the sodium chloride added to the extracellular fluid remains there and does not move into the cells. Step 3. Effect of Adding 2 Liters of 3.0 Per Cent Sodium Chloride After Osmotic Equilibrium Extracellular fluid Intracellular fluid Total body fluid Volume (Liters) Concentration (mOsm/L) Total (mOsm) 19.02 24.98 44.0 313.9 313.9 313.9 5,971 7,840 13,811 Thus, one can see from this example that adding 2 liters of a hypertonic sodium chloride solution causes more than a 5-liter increase in extracellular fluid volume while decreasing intracellular fluid volume by almost 3 liters. This method of calculating changes in intracellular and extracellular fluid volumes and osmolarities can be applied to virtually any clinical problem of fluid volume regulation. The reader should be familiar with such calculations because an understanding of the mathematical aspects of osmotic equilibrium between intracellular and extracellular fluid compartments is essential for understanding almost all fluid abnormalities of the body and their treatment. Glucose and Other Solutions Administered for Nutritive Purposes Many types of solutions are administered intravenously to provide nutrition to people who cannot otherwise take adequate amounts of nutrition. Glucose solutions are widely used, and amino acid and homogenized fat solutions are used to a lesser extent. When these solutions are administered, their concentrations of osmotically active substances are usually adjusted nearly to isotonicity, or they are given slowly enough that they do not upset the osmotic equilibrium of the body fluids. After the glucose or other nutrients are metabolized, an excess of water often remains, especially if additional fluid is ingested. Ordinarily, the kidneys excrete this in the form of a very dilute urine. The net result, therefore, is the addition of only nutrients to the body. Clinical Abnormalities of Fluid Volume Regulation: Hyponatremia and Hypernatremia The primary measurement that is readily available to the clinician for evaluating a patient’s fluid status is the plasma sodium concentration. Plasma osmolarity is not routinely measured, but because sodium and its associated anions (mainly chloride) account for more than 90 per cent of the solute in the extracellular fluid, plasma sodium concentration is a reasonable indicator of plasma osmolarity under many conditions. When plasma sodium concentration is reduced more than a few milliequivalents below normal (about 142 mEq/L), a person is said to have hyponatremia. When plasma sodium concentration is elevated above normal, a person is said to have hypernatremia. Causes of Hyponatremia: Excess Water or Loss of Sodium Decreased plasma sodium concentration can result from loss of sodium chloride from the extracellular fluid or addition of excess water to the extracellular fluid (Table 25–4). A primary loss of sodium chloride usually results in hypo-osmotic dehydration and is associated with decreased extracellular fluid volume. Conditions that can cause hyponatremia owing to loss of sodium chloride include diarrhea and vomiting. Overuse of diuretics that inhibit the ability of the kidneys to conserve sodium and certain types of sodium-wasting kidney diseases can also cause modest degrees of hyponatremia. Finally, Addison’s disease, which results from decreased secretion of the hormone aldosterone, impairs the ability of the kidneys to reabsorb sodium and can cause a modest degree of hyponatremia. Hyponatremia can also be associated with excess water retention, which dilutes the sodium in the extracellular fluid, a condition that is referred to as hypoosmotic overhydration. For example, excessive secretion of antidiuretic hormone, which causes the kidney Table 25–4 Abnormalities of Body Fluid Volume Regulation: Hyponatremia and Hypernatremia Abnormality Cause Hypo-osmotic dehydration Hypo-osmotic overhydration Hyper-osmotic dehydration Hyper-osmotic overhydration Adrenal insufficiency; overuse of diuretics Excess ADH; bronchogenic tumor Diabetes insipidus; excessive sweating Cushing’s disease; primary aldosteronism ADH, antidiuretic hormone. Plasma Na+ Concentration Extracellular Fluid Volume Intracellular Fluid Volume Ø Ø ≠ ≠ Ø ≠ Ø ≠ ≠ ≠ Ø Ø 302 Unit V The Body Fluids and Kidneys tubules to reabsorb more water, can lead to hyponatremia and overhydration. Causes of Hypernatremia: Water Loss or Excess Sodium Increased plasma sodium concentration, which also causes increased osmolarity, can be due to either loss of water from the extracellular fluid, which concentrates the sodium ions, or excess sodium in the extracellular fluid. When there is primary loss of water from the extracellular fluid, this results in hyperosmotic dehydration. This condition can occur from an inability to secrete antidiuretic hormone, which is needed for the kidneys to conserve water. As a result of lack of antidiuretic hormone, the kidneys excrete large amounts of dilute urine (a disorder referred to as diabetes insipidus), causing dehydration and increased concentration of sodium chloride in the extracellular fluid. In certain types of renal diseases, the kidneys cannot respond to antidiuretic hormone, also causing a type of nephrogenic diabetes insipidus. A more common cause of hypernatremia associated with decreased extracellular fluid volume is dehydration caused by water intake that is less than water loss, as can occur with sweating during prolonged, heavy exercise. Hypernatremia can also occur as a result of excessive sodium chloride added to the extracellular fluid. This often results in hyperosmotic overhydration because excess extracellular sodium chloride is usually associated with at least some degree of water retention by the kidneys as well. For example, excessive secretion of the sodium-retaining hormone aldosterone can cause a mild degree of hypernatremia and overhydration. The reason that the hypernatremia is not more severe is that increased aldosterone secretion causes the kidneys to reabsorb greater amounts of water as well as sodium. Thus, in analyzing abnormalities of plasma sodium concentration and deciding on proper therapy, one should first determine whether the abnormality is caused by a primary loss or gain of sodium or a primary loss or gain of water. Edema: Excess Fluid in the Tissues Edema refers to the presence of excess fluid in the body tissues. In most instances, edema occurs mainly in the extracellular fluid compartment, but it can involve intracellular fluid as well. Intracellular Edema Two conditions are especially prone to cause intracellular swelling: (1) depression of the metabolic systems of the tissues, and (2) lack of adequate nutrition to the cells. For example, when blood flow to a tissue is decreased, the delivery of oxygen and nutrients is reduced. If the blood flow becomes too low to maintain normal tissue metabolism, the cell membrane ionic pumps become depressed. When this occurs, sodium ions that normally leak into the interior of the cell can no longer be pumped out of the cells, and the excess sodium ions inside the cells cause osmosis of water into the cells. Sometimes this can increase intracellular volume of a tissue area—even of an entire ischemic leg, for example—to two to three times normal. When this occurs, it is usually a prelude to death of the tissue. Intracellular edema can also occur in inflamed tissues. Inflammation usually has a direct effect on the cell membranes to increase their permeability, allowing sodium and other ions to diffuse into the interior of the cell, with subsequent osmosis of water into the cells. Extracellular Edema Extracellular fluid edema occurs when there is excess fluid accumulation in the extracellular spaces. There are two general causes of extracellular edema: (1) abnormal leakage of fluid from the plasma to the interstitial spaces across the capillaries, and (2) failure of the lymphatics to return fluid from the interstitium back into the blood. The most common clinical cause of interstitial fluid accumulation is excessive capillary fluid filtration. Factors That Can Increase Capillary Filtration To understand the causes of excessive capillary filtration, it is useful to review the determinants of capillary filtration discussed in Chapter 16. Mathematically, capillary filtration rate can be expressed as Filtration = Kf ¥ (Pc – Pif – pc + pif), where Kf is the capillary filtration coefficient (the product of the permeability and surface area of the capillaries), Pc is the capillary hydrostatic pressure, Pif is the interstitial fluid hydrostatic pressure, pc is the capillary plasma colloid osmotic pressure, and pif is the interstitial fluid colloid osmotic pressure. From this equation, one can see that any one of the following changes can increase the capillary filtration rate: ∑ Increased capillary filtration coefficient. ∑ Increased capillary hydrostatic pressure. ∑ Decreased plasma colloid osmotic pressure. Lymphatic Blockage Causes Edema When lymphatic blockage occurs, edema can become especially severe because plasma proteins that leak into the interstitium have no other way to be removed. The rise in protein concentration raises the colloid osmotic pressure of the interstitial fluid, which draws even more fluid out of the capillaries. Blockage of lymph flow can be especially severe with infections of the lymph nodes, such as occurs with infection by filaria nematodes. Blockage of the lymph vessels can occur in certain types of cancer or after surgery in which lymph vessels are removed or obstructed. For example, large numbers of lymph vessels are removed during radical mastectomy, impairing removal of fluid from the breast and arm areas and causing edema and swelling of the tissue Chapter 25 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema spaces. A few lymph vessels eventually regrow after this type of surgery, so that the interstitial edema is usually temporary. Summary of Causes of Extracellular Edema A large number of conditions can cause fluid accumulation in the interstitial spaces by the abnormal leaking of fluid from the capillaries or by preventing the lymphatics from returning fluid from the interstitium back to the circulation. The following is a partial list of conditions that can cause extracellular edema by these two types of abnormalities: I. Increased capillary pressure A. Excessive kidney retention of salt and water 1. Acute or chronic kidney failure 2. Mineralocorticoid excess B. High venous pressure and venous constriction 1. Heart failure 2. Venous obstruction 3. Failure of venous pumps (a) Paralysis of muscles (b) Immobilization of parts of the body (c) Failure of venous valves C. Decreased arteriolar resistance 1. Excessive body heat 2. Insufficiency of sympathetic nervous system 3. Vasodilator drugs II. Decreased plasma proteins A. Loss of proteins in urine (nephrotic syndrome) B. Loss of protein from denuded skin areas 1. Burns 2. Wounds C. Failure to produce proteins 1. Liver disease (e.g., cirrhosis) 2. Serious protein or caloric malnutrition III. Increased capillary permeability A. Immune reactions that cause release of histamine and other immune products B. Toxins C. Bacterial infections D. Vitamin deficiency, especially vitamin C E. Prolonged ischemia F. Burns IV. Blockage of lymph return A. Cancer B. Infections (e.g., filaria nematodes) C. Surgery D. Congenital absence or abnormality of lymphatic vessels Edema Caused by Heart Failure. One of the most serious and most common causes of edema is heart failure. In heart failure, the heart fails to pump blood normally from the veins into the arteries; this raises venous pressure and capillary pressure, causing increased capillary filtration. In addition, the arterial pressure tends to fall, causing decreased excretion of salt and water by the kidneys, which increases blood volume and further raises capillary hydrostatic pressure to cause still more edema. Also, diminished blood flow to the kidneys stimulates secretion of renin, causing increased formation of angiotensin II and increased secretion of aldosterone, both of which cause additional salt and water retention by the kidneys. Thus, in untreated heart failure, all these 303 factors acting together cause serious generalized extracellular edema. In patients with left-sided heart failure but without significant failure of the right side of the heart, blood is pumped into the lungs normally by the right side of the heart but cannot escape easily from the pulmonary veins to the left side of the heart because this part of the heart has been greatly weakened. Consequently, all the pulmonary vascular pressures, including pulmonary capillary pressure, rise far above normal, causing serious and life-threatening pulmonary edema. When untreated, fluid accumulation in the lungs can rapidly progress, causing death within a few hours. Edema Caused by Decreased Kidney Excretion of Salt and Water. As discussed earlier, most sodium chloride added to the blood remains in the extracellular compartment, and only small amounts enter the cells. Therefore, in kidney diseases that compromise urinary excretion of salt and water, large amounts of sodium chloride and water are added to the extracellular fluid. Most of this salt and water leaks from the blood into the interstitial spaces, but some remains in the blood. The main effects of this are to cause (1) widespread increases in interstitial fluid volume (extracellular edema) and (2) hypertension because of the increase in blood volume, as explained in Chapter 19. As an example, children who develop acute glomerulonephritis, in which the renal glomeruli are injured by inflammation and therefore fail to filter adequate amounts of fluid, also develop serious extracellular fluid edema in the entire body; along with the edema, these children usually develop severe hypertension. Edema Caused by Decreased Plasma Proteins. A reduction in plasma concentration of proteins because of either failure to produce normal amounts of proteins or leakage of proteins from the plasma causes the plasma colloid osmotic pressure to fall. This leads to increased capillary filtration throughout the body as well as extracellular edema. One of the most important causes of decreased plasma protein concentration is loss of proteins in the urine in certain kidney diseases, a condition referred to as nephrotic syndrome. Multiple types of renal diseases can damage the membranes of the renal glomeruli, causing the membranes to become leaky to the plasma proteins and often allowing large quantities of these proteins to pass into the urine. When this loss exceeds the ability of the body to synthesize proteins, a reduction in plasma protein concentration occurs. Serious generalized edema occurs when the plasma protein concentration falls below 2.5 g/100 ml. Cirrhosis of the liver is another condition that causes a reduction in plasma protein concentration. Cirrhosis means development of large amounts of fibrous tissue among the liver parenchymal cells. One result is failure of these cells to produce sufficient plasma proteins, leading to decreased plasma colloid osmotic pressure and the generalized edema that goes with this condition. Another way that liver cirrhosis causes edema is that the liver fibrosis sometimes compresses the abdominal portal venous drainage vessels as they pass through the liver before emptying back into the general circulation. Blockage of this portal venous outflow raises capillary hydrostatic pressure throughout the gastrointestinal area and further increases filtration of fluid out of the plasma into the intra-abdominal areas. When this The Body Fluids and Kidneys Safety Factor Caused by Low Compliance of the Interstitium in the Negative Pressure Range In Chapter 16, we noted that interstitial fluid hydrostatic pressure in most loose subcutaneous tissues of the body is slightly less than atmospheric pressure, averaging about –3 mm Hg. This slight suction in the tissues helps hold the tissues together. Figure 25–7 shows the approximate relations between different levels of interstitial fluid pressure and interstitial fluid volume, as extrapolated to the human being from animal studies. Note in Figure 25–7 that as long as the interstitial fluid pressure is in the negative range, small changes in interstitial fluid volume are associated with relatively large changes in interstitial fluid hydrostatic pressure. Therefore, in the negative pressure range, the compliance of the tissues, defined as the change in volume per millimeter of mercury pressure change, is low. How does the low compliance of the tissues in the negative pressure range act as a safety factor against edema? To answer this question, recall the determinants of capillary filtration discussed previously. When interstitial fluid hydrostatic pressure increases, this increased pressure tends to oppose further capillary filtration. Therefore, as long as the interstitial fluid hydrostatic pressure is in the negative pressure range, small increases in interstitial fluid volume cause relatively large increases in interstitial fluid hydrostatic pressure, opposing further filtration of fluid into the tissues. Because the normal interstitial fluid hydrostatic pressure is –3 mm Hg, the interstitial fluid hydrostatic pressure must increase by about 3 mm Hg before large amounts of fluid will begin to accumulate in the tissues. Therefore, the safety factor against edema is a change of interstitial fluid pressure of about 3 mm Hg. Once interstitial fluid pressure rises above 0 mm Hg, the compliance of the tissues increases markedly, allowing large amounts of fluid to accumulate in the tissues with negative interstitial fluid pressure, virtually all the fluid in the interstitium is in gel form. That is, the fluid is bound in a proteoglycan meshwork so that there are virtually no “free” fluid spaces larger than a few hundredths of a micrometer in diameter. The importance of the gel is that it prevents fluid from flowing easily through the tissues because of impediment from the “brush pile” of trillions of proteoglycan filaments. Also, when the interstitial fluid pressure falls to very negative values, the gel does not contract greatly because the meshwork of proteoglycan filaments offers an elastic resistance to compression. In the negative fluid pressure range, the interstitial fluid volume does not change greatly, regardless of whether the degree of suction is only a few millimeters of mercury negative pressure or 10 to 20 mm Hg negative pressure. In other words, the compliance of the tissues is very low in the negative pressure range. 60 56 Free fluid Gel fluid 52 48 44 id Even though many disturbances can cause edema, usually the abnormality must be severe before serious edema develops. The reason for this is that three major safety factors prevent excessive fluid accumulation in the interstitial spaces: (1) low compliance of the interstitium when interstitial fluid pressure is in the negative pressure range, (2) the ability of lymph flow to increase 10- to 50-fold, and (3) washdown of interstitial fluid protein concentration, which reduces interstitial fluid colloid osmotic pressure as capillary filtration increases. Importance of Interstitial Gel in Preventing Fluid Accumulation in the Interstitium. Note in Figure 25–7 that in normal ial flu Safety Factors That Normally Prevent Edema tissues with relatively small additional increases in interstitial fluid hydrostatic pressure. Thus, in the positive tissue pressure range, this safety factor against edema is lost because of the large increase in compliance of the tissues. 40 36 terstit occurs, the combined effects of decreased plasma protein concentration and high portal capillary pressures cause transudation of large amounts of fluid and protein into the abdominal cavity, a condition referred to as ascites. 32 Total in Unit V Interstitial fluid volume (liters) 304 28 24 (High compliance) 20 Normal 16 12 8 (Low compliance) 4 0 2 4 -10 -8 -6 -4 -2 0 Interstitial free fluid pressure (mm Hg) 6 Figure 25–7 Relation between interstitial fluid hydrostatic pressure and interstitial fluid volumes, including total volume, free fluid volume, and gel fluid volume, for loose tissues such as skin. Note that significant amounts of free fluid occur only when the interstitial fluid pressure becomes positive. (Modified from Guyton AC, Granger HJ, Taylor AE: Interstitial fluid pressure. Physiol Rev 51:527, 1971.) Chapter 25 The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema By contrast, when interstitial fluid pressure rises to the positive pressure range, there is a tremendous accumulation of free fluid in the tissues. In this pressure range, the tissues are compliant, allowing large amounts of fluid to accumulate with relatively small additional increases in interstitial fluid hydrostatic pressure. Most of the extra fluid that accumulates is “free fluid” because it pushes the brush pile of proteoglycan filaments apart. Therefore, the fluid can flow freely through the tissue spaces because it is not in gel form. When this occurs, the edema is said to be pitting edema because one can press the thumb against the tissue area and push the fluid out of the area. When the thumb is removed, a pit is left in the skin for a few seconds until the fluid flows back from the surrounding tissues. This type of edema is distinguished from nonpitting edema, which occurs when the tissue cells swell instead of the interstitium or when the fluid in the interstitium becomes clotted with fibrinogen so that it cannot move freely within the tissue spaces. Importance of the Proteoglycan Filaments as a “Spacer” for the Cells and in Preventing Rapid Flow of Fluid in the Tissues. The proteoglycan filaments, along with much larger collagen fibrils in the interstitial spaces, act as a “spacer” between the cells. Nutrients and ions do not diffuse readily through cell membranes; therefore, without adequate spacing between the cells, these nutrients, electrolytes, and cell waste products could not be rapidly exchanged between the blood capillaries and cells located at a distance from one another. The proteoglycan filaments also prevent fluid from flowing too easily through the tissue spaces. If it were not for the proteoglycan filaments, the simple act of a person standing up would cause large amounts of interstitial fluid to flow from the upper body to the lower body. When too much fluid accumulates in the interstitium, as occurs in edema, this extra fluid creates large channels that allow the fluid to flow readily through the interstitium. Therefore, when severe edema occurs in the legs, the edema fluid often can be decreased by simply elevating the legs. Even though fluid does not flow easily through the tissues in the presence of the compacted proteoglycan filaments, different substances within the fluid can diffuse through the tissues at least 95 per cent as easily as they normally diffuse. Therefore, the usual diffusion of nutrients to the cells and the removal of waste products from the cells are not compromised by the proteoglycan filaments of the interstitium. Increased Lymph Flow as a Safety Factor Against Edema A major function of the lymphatic system is to return to the circulation the fluid and proteins filtered from the capillaries into the interstitium. Without this continuous return of the filtered proteins and fluid to the blood, the plasma volume would be rapidly depleted, and interstitial edema would occur. The lymphatics act as a safety factor against edema because lymph flow can increase 10- to 50-fold when fluid begins to accumulate in the tissues. This allows the lymphatics to carry away large amounts of fluid and proteins in response to increased capillary filtration, preventing the interstitial pressure from rising into the positive pressure range. The safety factor 305 caused by increased lymph flow has been calculated to be about 7 mm Hg. “Washdown” of the Interstitial Fluid Protein as a Safety Factor Against Edema As increased amounts of fluid are filtered into the interstitium, the interstitial fluid pressure increases, causing increased lymph flow. In most tissues, the protein concentration of the interstitium decreases as lymph flow is increased, because larger amounts of protein are carried away than can be filtered out of the capillaries; the reason for this is that the capillaries are relatively impermeable to proteins, compared with the lymph vessels. Therefore, the proteins are “washed out” of the interstitial fluid as lymph flow increases. Because the interstitial fluid colloid osmotic pressure caused by the proteins tends to draw fluid out of the capillaries, decreasing the interstitial fluid proteins lowers the net filtration force across the capillaries and tends to prevent further accumulation of fluid. The safety factor from this effect has been calculated to be about 7 mm Hg. Summary of Safety Factors That Prevent Edema Putting together all the safety factors against edema, we find the following: 1. The safety factor caused by low tissue compliance in the negative pressure range is about 3 mm Hg. 2. The safety factor caused by increased lymph flow is about 7 mm Hg. 3. The safety factor caused by washdown of proteins from the interstitial spaces is about 7 mm Hg. Therefore, the total safety factor against edema is about 17 mm Hg. This means that the capillary pressure in a peripheral tissue could theoretically rise by 17 mm Hg, or approximately double the normal value, before marked edema would occur. Fluids in the “Potential Spaces” of the Body Perhaps the best way to describe a “potential space” is to list some examples: pleural cavity, pericardial cavity, peritoneal cavity, and synovial cavities, including both the joint cavities and the bursae. Virtually all these potential spaces have surfaces that almost touch each other, with only a thin layer of fluid in between, and the surfaces slide over each other. To facilitate the sliding, a viscous proteinaceous fluid lubricates the surfaces. Fluid Is Exchanged Between the Capillaries and the Potential Spaces. The surface membrane of a potential space usually does not offer significant resistance to the passage of fluids, electrolytes, or even proteins, which all move back and forth between the space and the interstitial fluid in the surrounding tissue with relative ease. Therefore, each potential space is in reality a 306 Unit V The Body Fluids and Kidneys large tissue space. Consequently, fluid in the capillaries adjacent to the potential space diffuses not only into the interstitial fluid but also into the potential space. Lymphatic Vessels Drain Protein from the Potential Spaces. Proteins collect in the potential spaces because of leakage out of the capillaries, similar to the collection of protein in the interstitial spaces throughout the body. The protein must be removed through lymphatics or other channels and returned to the circulation. Each potential space is either directly or indirectly connected with lymph vessels. In some cases, such as the pleural cavity and peritoneal cavity, large lymph vessels arise directly from the cavity itself. Edema Fluid in the Potential Spaces Is Called “Effusion.” When edema occurs in the subcutaneous tissues adjacent to the potential space, edema fluid usually collects in the potential space as well, and this fluid is called effusion. Thus, lymph blockage or any of the multiple abnormalities that can cause excessive capillary filtration can cause effusion in the same way that interstitial edema is caused.The abdominal cavity is especially prone to collect effusion fluid, and in this instance, the effusion is called ascites. In serious cases, 20 liters or more of ascitic fluid can accumulate. The other potential spaces, such as the pleural cavity, pericardial cavity, and joint spaces, can become seriously swollen when there is generalized edema. Also, injury or local infection in any one of the cavities often blocks the lymph drainage, causing isolated swelling in the cavity. The dynamics of fluid exchange in the pleural cavity are discussed in detail in Chapter 38. These dynamics are mainly representative of all the other potential spaces as well. It is especially interesting that the normal fluid pressure in most or all of the potential spaces in the nonedematous state is negative in the same way that this pressure is negative (subatmospheric) in loose subcutaneous tissue. For instance, the interstitial fluid hydrostatic pressure is normally about –7 to –8 mm Hg in the pleural cavity, –3 to –5 mm Hg in the joint spaces, and –5 to –6 mm Hg in the pericardial cavity. References Amiry-Moghaddam M, Ottersen OP: The molecular basis of water transport in the brain. Nat Rev Neurosci 4:991, 2003. Aukland K: Why don’t our feet swell in the upright position? News Physiol Sci 9:214, 1994. Basnyat B, Murdoch DR: High-altitude illness. Lancet 361:1967, 2003. Cho S, Atwood JE: Peripheral edema. Am J Med 113:580, 2002. Decaux G, Soupart A: Treatment of symptomatic hyponatremia. Am J Med Sci 326:25, 2003. Drake RE, Doursout MF: Pulmonary edema and elevated left atrial pressure: four hours and beyond. News Physiol Sci 17:223, 2002. Gashev AA: Physiologic aspects of lymphatic contractile function: current perspectives. Ann N Y Acad Sci 979:178, 2002. Guyton AC, Granger HJ, Taylor AE: Interstitial fluid pressure. Physiol Rev 51:527, 1971. Guyton AC, Taylor AE, Granger HJ: Circulatory Physiology II: Dynamics and Control of the Body Fluids. Philadelphia: WB Saunders, 1975. Halperin ML, Bohn D: Clinical approach to disorders of salt and water balance: emphasis on integrative physiology. Crit Care Clin 18:249, 2002. Jussila L, Alitalo K: Vascular growth factors and lymphangiogenesis. Physiol Rev 82:673, 2002. Matthay MA, Folkesson HG, Clerici C: Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 82:569, 2002. Michel CC: Exchange of fluid and solutes across microvascular walls. In Seldin DW, Giebisch G (eds): The Kidney— Physiology & Pathophysiology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000. Moritz ML, Ayus JC: Disorders of water metabolism in children: hyponatremia and hypernatremia. Pediatr Rev 23:371, 2002. Saaristo A, Karkkainen MJ, Alitalo K: Insights into the molecular pathogenesis and targeted treatment of lymphedema. Ann N Y Acad Sci 979:94, 2002. Winaver J, Abassi Z, Green J, Skorecki KL: Control of extracellular fluid volume and the pathophysiology of edema formation. In Brenner BM, Rector FC (eds): The Kidney, 6th ed. Philadelphia: WB Saunders, 2000. C H A P T E R 2 6 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control Multiple Functions of the Kidneys in Homeostasis Most people are familiar with one important function of the kidneys—to rid the body of waste materials that are either ingested or produced by metabolism. A second function that is especially critical is to control the volume and composition of the body fluids. For water and virtually all electrolytes in the body, the balance between intake (due to ingestion or metabolic production) and output (due to excretion or metabolic consumption) is maintained in large part by the kidneys. This regulatory function of the kidneys maintains the stable environment of the cells necessary for them to perform their various activities. The kidneys perform their most important functions by filtering the plasma and removing substances from the filtrate at variable rates, depending on the needs of the body. Ultimately, the kidneys “clear” unwanted substances from the filtrate (and therefore from the blood) by excreting them in the urine while returning substances that are needed back to the blood. Although this chapter and the next few chapters focus mainly on the control of renal excretion, it is important to recognize that the kidneys serve multiple functions, including the following: ∑ Excretion of metabolic waste products and foreign chemicals ∑ Regulation of water and electrolyte balances ∑ Regulation of body fluid osmolality and electrolyte concentrations ∑ Regulation of arterial pressure ∑ Regulation of acid-base balance ∑ Secretion, metabolism, and excretion of hormones ∑ Gluconeogenesis Excretion of Metabolic Waste Products, Foreign Chemicals, Drugs, and Hormone Metabolites. The kidneys are the primary means for eliminating waste products of metabolism that are no longer needed by the body. These products include urea (from the metabolism of amino acids), creatinine (from muscle creatine), uric acid (from nucleic acids), end products of hemoglobin breakdown (such as bilirubin), and metabolites of various hormones. These waste products must be eliminated from the body as rapidly as they are produced. The kidneys also eliminate most toxins and other foreign substances that are either produced by the body or ingested, such as pesticides, drugs, and food additives. Regulation of Water and Electrolyte Balances. For maintenance of homeostasis, excretion of water and electrolytes must precisely match intake. If intake exceeds excretion, the amount of that substance in the body will increase. If intake is less than excretion, the amount of that substance in the body will decrease. Intake of water and many electrolytes is governed mainly by a person’s eating and drinking habits, requiring the kidneys to adjust their excretion rates to match the intake of various substances. Figure 26–1 shows the response of the kidneys to a sudden 10-fold increase in sodium intake from a low level of 30 mEq/day to a high level of 300 mEq/day. Within 2 to 3 days after raising the 307 308 Unit V The Body Fluids and Kidneys Regulation of Acid-Base Balance. The kidneys contribute to acid-base regulation, along with the lungs and body fluid buffers, by excreting acids and by regulating the body fluid buffer stores. The kidneys are the only means of eliminating from the body certain types of acids, such as sulfuric acid and phosphoric acid, generated by the metabolism of proteins. Extracellular fluid volume (Liters) Sodium intake and excretion (mEq/day) Sodium retention 300 Intake 200 Excretion 100 Sodium loss 0 15 10 5 -4 -2 0 2 4 6 8 Time (days) 10 12 14 Figure 26–1 Effect of increasing sodium intake 10-fold (from 30 to 300 mEq/ day) on urinary sodium excretion and extracellular fluid volume. The shaded areas represent the net sodium retention or the net sodium loss, determined from the difference between sodium intake and sodium excretion. Regulation of Erythrocyte Production. The kidneys secrete erythropoietin, which stimulates the production of red blood cells, as discussed in Chapter 32. One important stimulus for erythropoietin secretion by the kidneys is hypoxia. The kidneys normally account for almost all the erythropoietin secreted into the circulation. In people with severe kidney disease or who have had their kidneys removed and have been placed on hemodialysis, severe anemia develops as a result of decreased erythropoietin production. Regulation of 1,25–Dihydroxyvitamin D3 Production. The kidneys produce the active form of vitamin D, 1,25dihydroxyvitamin D3 (calcitriol), by hydroxylating this vitamin at the “number 1” position. Calcitriol is essential for normal calcium deposition in bone and calcium reabsorption by the gastrointestinal tract. As discussed in Chapter 79, calcitriol plays an important role in calcium and phosphate regulation. Glucose Synthesis. The kidneys synthesize glucose from sodium intake, renal excretion also increases to about 300 mEq/day, so that a balance between intake and output is re-established. However, during the 2 to 3 days of renal adaptation to the high sodium intake, there is a modest accumulation of sodium that raises extracellular fluid volume slightly and triggers hormonal changes and other compensatory responses that signal the kidneys to increase their sodium excretion. The capacity of the kidneys to alter sodium excretion in response to changes in sodium intake is enormous. Experimental studies have shown that in many people, sodium intake can be increased to 1500 mEq/ day (more than 10 times normal) or decreased to 10 mEq/day (less than one tenth normal) with relatively small changes in extracellular fluid volume or plasma sodium concentration. This is also true for water and for most other electrolytes, such as chloride, potassium, calcium, hydrogen, magnesium, and phosphate ions. In the next few chapters, we discuss the specific mechanisms that permit the kidneys to perform these amazing feats of homeostasis. Regulation of Arterial Pressure. As discussed in Chapter 19, the kidneys play a dominant role in long-term regulation of arterial pressure by excreting variable amounts of sodium and water. The kidneys also contribute to short-term arterial pressure regulation by secreting vasoactive factors or substances, such as renin, that lead to the formation of vasoactive products (e.g., angiotensin II). amino acids and other precursors during prolonged fasting, a process referred to as gluconeogenesis. The kidneys’ capacity to add glucose to the blood during prolonged periods of fasting rivals that of the liver. With chronic kidney disease or acute failure of the kidneys, these homeostatic functions are disrupted, and severe abnormalities of body fluid volumes and composition rapidly occur. With complete renal failure, enough potassium, acids, fluid, and other substances accumulate in the body to cause death within a few days, unless clinical interventions such as hemodialysis are initiated to restore, at least partially, the body fluid and electrolyte balances. Physiologic Anatomy of the Kidneys General Organization of the Kidneys and Urinary Tract The two kidneys lie on the posterior wall of the abdomen, outside the peritoneal cavity (Figure 26–2). Each kidney of the adult human weighs about 150 grams and is about the size of a clenched fist. The medial side of each kidney contains an indented region called the hilum through which pass the renal artery and vein, lymphatics, nerve supply, and ureter, which carries the final urine from the kidney to the bladder, where it is stored until emptied. The kidney is surrounded by a tough, fibrous capsule that protects its delicate inner structures. Chapter 26 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control 309 Minor calyx Major calyx Nephron (enlarged) Papilla Renal cortex Renal medulla Kidney Renal pelvis Renal pyramid Renal artery Capsule Ureter Figure 26–2 General organization of the kidneys and the urinary system. Ureter Kidney Bladder Urethra If the kidney is bisected from top to bottom, the two major regions that can be visualized are the outer cortex and the inner region referred to as the medulla. The medulla is divided into multiple cone-shaped masses of tissue called renal pyramids. The base of each pyramid originates at the border between the cortex and medulla and terminates in the papilla, which projects into the space of the renal pelvis, a funnel-shaped continuation of the upper end of the ureter. The outer border of the pelvis is divided into open-ended pouches called major calyces that extend downward and divide into minor calyces, which collect urine from the tubules of each papilla. The walls of the calyces, pelvis, and ureter contain contractile elements that propel the urine toward the bladder, where urine is stored until it is emptied by micturition, discussed in later in this chapter. much lower hydrostatic pressure in the peritubular capillaries (about 13 mm Hg) permits rapid fluid reabsorption. By adjusting the resistance of the afferent and efferent arterioles, the kidneys can regulate the hydrostatic pressure in both the glomerular and the peritubular capillaries, thereby changing the rate of Interlobar arteries Renal artery Arcuate arteries Segmental arteries Interlobular arterioles Renal Blood Supply Blood flow to the two kidneys is normally about 22 per cent of the cardiac output, or 1100 ml/min. The renal artery enters the kidney through the hilum and then branches progressively to form the interlobar arteries, arcuate arteries, interlobular arteries (also called radial arteries) and afferent arterioles, which lead to the glomerular capillaries, where large amounts of fluid and solutes (except the plasma proteins) are filtered to begin urine formation (Figure 26–3). The distal ends of the capillaries of each glomerulus coalesce to form the efferent arteriole, which leads to a second capillary network, the peritubular capillaries, that surrounds the renal tubules. The renal circulation is unique in that it has two capillary beds, the glomerular and peritubular capillaries, which are arranged in series and separated by the efferent arterioles, which help regulate the hydrostatic pressure in both sets of capillaries. High hydrostatic pressure in the glomerular capillaries (about 60 mm Hg) causes rapid fluid filtration, whereas a Efferent Bowman's arteriole capsule Glomerulus Juxtaglomerular apparatus Afferent arteriole Proximal tubule Cortical collecting tubule Distal tubule Arcuate artery Arcuate vein Loop of Henle Peritubular capillaries Collecting duct Figure 26–3 Section of the human kidney showing the major vessels that supply the blood flow to the kidney and schematic of the microcirculation of each nephron. 310 Unit V The Body Fluids and Kidneys glomerular filtration, tubular reabsorption, or both in response to body homeostatic demands. The peritubular capillaries empty into the vessels of the venous system, which run parallel to the arteriolar vessels and progressively form the interlobular vein, arcuate vein, interlobar vein, and renal vein, which leaves the kidney beside the renal artery and ureter. The Nephron Is the Functional Unit of the Kidney Each kidney in the human contains about 1 million nephrons, each capable of forming urine. The kidney cannot regenerate new nephrons.Therefore, with renal injury, disease, or normal aging, there is a gradual decrease in nephron number. After age 40, the number of functioning nephrons usually decreases about 10 per cent every 10 years; thus, at age 80, many people have 40 per cent fewer functioning nephrons than they did at age 40. This loss is not life threatening because adaptive changes in the remaining nephrons allow them to excrete the proper amounts of water, electrolytes, and waste products, as discussed in Chapter 31. Each nephron contains (1) a tuft of glomerular capillaries called the glomerulus, through which large amounts of fluid are filtered from the blood, and (2) a long tubule in which the filtered fluid is converted into urine on its way to the pelvis of the kidney (see Figure 26–3). The glomerulus contains a network of branching and anastomosing glomerular capillaries that, compared with other capillaries, have high hydrostatic pressure (about 60 mm Hg). The glomerular capillaries are covered by epithelial cells, and the total glomerulus is encased in Bowman’s capsule. Fluid filtered from the glomerular capillaries flows into Bowman’s capsule and then into the proximal tubule, which lies in the cortex of the kidney (Figure 26–4). From the proximal tubule, fluid flows into the loop of Henle, which dips into the renal medulla. Each loop consists of a descending and an ascending limb. The walls of the descending limb and the lower end of the ascending limb are very thin and therefore are called the thin segment of the loop of Henle. After the ascending limb of the loop has returned partway back to the cortex, its wall becomes much thicker, and it is referred to as the thick segment of the ascending limb. At the end of the thick ascending limb is a short segment, which is actually a plaque in its wall, known as the macula densa. As we discuss later, the macula densa plays an important role in controlling nephron function. Beyond the macula densa, fluid enters the distal tubule, which, like the proximal tubule, lies in the renal cortex. This is followed by the connecting tubule and the cortical collecting tubule, which lead to the cortical collecting duct. The initial parts of 8 to 10 cortical collecting ducts join to form a single larger collecting duct that runs downward into the medulla and becomes the medullary collecting duct. The collecting ducts merge to form progressively larger ducts that Proximal tubule Distal tubule Cortex Connecting tubule Bowman's capsule Macula densa Cortical collecting tubule Loop of Henle: Thick segment of ascending limb Thin segment of ascending limb Medulla Medullary collecting tubule Descending limb Collecting duct Figure 26–4 Basic tubular segments of the nephron. The relative lengths of the different tubular segments are not drawn to scale. eventually empty into the renal pelvis through the tips of the renal papillae. In each kidney, there are about 250 of the very large collecting ducts, each of which collects urine from about 4000 nephrons. Regional Differences in Nephron Structure: Cortical and Juxtamedullary Nephrons. Although each nephron has all the components described earlier, there are some differences, depending on how deep the nephron lies within the kidney mass. Those nephrons that have glomeruli located in the outer cortex are called cortical nephrons; they have short loops of Henle that penetrate only a short distance into the medulla (Figure 26–5). About 20 to 30 per cent of the nephrons have glomeruli that lie deep in the renal cortex near the medulla and are called juxtamedullary nephrons. These nephrons have long loops of Henle that dip deeply into the medulla, in some cases all the way to the tips of the renal papillae. The vascular structures supplying the juxtamedullary nephrons also differ from those supplying the cortical nephrons. For the cortical nephrons, the entire tubular system is surrounded by an extensive network of peritubular capillaries. For the juxtamedullary nephrons, long efferent arterioles extend from the glomeruli down into the outer medulla and then divide into specialized peritubular capillaries called vasa recta that extend downward into the medulla, lying side by side with the loops of Henle. Like the loops of Henle, the vasa recta return toward the cortex and empty into the cortical veins. This specialized network of capillaries in the medulla plays an essential role in the formation of a concentrated urine. Chapter 26 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control Micturition Cortex Micturition is the process by which the urinary bladder empties when it becomes filled. This involves two main steps: First, the bladder fills progressively until the tension in its walls rises above a threshold level; this elicits the second step, which is a nervous reflex called the micturition reflex that empties the bladder or, if this fails, at least causes a conscious desire to urinate. Efferent arteriole Afferent arteriole Cortical nephron Juxtamedullary nephron Outer zone Interlobar artery vein Thick loop of Henle Inner zone Medulla Interlobar artery vein Vasa recta Collecting duct Thin loop of Henle Duct of Bellini Figure 26–5 Schematic of relations between blood vessels and tubular structures and differences between cortical and juxtamedullary nephrons. 311 Although the micturition reflex is an autonomic spinal cord reflex, it can also be inhibited or facilitated by centers in the cerebral cortex or brain stem. Physiologic Anatomy and Nervous Connections of the Bladder The urinary bladder, shown in Figure 26–6, is a smooth muscle chamber composed of two main parts: (1) the body, which is the major part of the bladder in which urine collects, and (2) the neck, which is a funnel-shaped extension of the body, passing inferiorly and anteriorly into the urogenital triangle and connecting with the urethra. The lower part of the bladder neck is also called the posterior urethra because of its relation to the urethra. The smooth muscle of the bladder is called the detrusor muscle. Its muscle fibers extend in all directions and, when contracted, can increase the pressure in the bladder to 40 to 60 mm Hg. Thus, contraction of the detrusor muscle is a major step in emptying the bladder. Smooth muscle cells of the detrusor muscle fuse with one another so that low-resistance electrical pathways exist from one muscle cell to the other. Therefore, an action potential can spread throughout the detrusor muscle, from one muscle cell to the next, to cause contraction of the entire bladder at once. On the posterior wall of the bladder, lying immediately above the bladder neck, is a small triangular area called the trigone. At the lowermost apex of the trigone, the bladder neck opens into the posterior urethra, and the two ureters enter the bladder at the uppermost angles of the trigone. The trigone can be identified by the fact that its mucosa, the inner lining of the bladder, is smooth, in contrast to the remaining bladder mucosa, which is folded to form rugae. Each ureter, as it enters the bladder, courses obliquely through the detrusor muscle and then passes another 1 to 2 centimeters beneath the bladder mucosa before emptying into the bladder. Ureter L1 L2 L3 L4 L5 S1 S2 S3 S4 Sympathetics Parasympathetics Pudendal Figure 26–6 Urinary bladder and its innervation. Body Trigone Bladder neck (posterior urethra) External sphincter 312 Unit V The Body Fluids and Kidneys The bladder neck (posterior urethra) is 2 to 3 centimeters long, and its wall is composed of detrusor muscle interlaced with a large amount of elastic tissue. The muscle in this area is called the internal sphincter. Its natural tone normally keeps the bladder neck and posterior urethra empty of urine and, therefore, prevents emptying of the bladder until the pressure in the main part of the bladder rises above a critical threshold. Beyond the posterior urethra, the urethra passes through the urogenital diaphragm, which contains a layer of muscle called the external sphincter of the bladder. This muscle is a voluntary skeletal muscle, in contrast to the muscle of the bladder body and bladder neck, which is entirely smooth muscle. The external sphincter muscle is under voluntary control of the nervous system and can be used to consciously prevent urination even when involuntary controls are attempting to empty the bladder. Innervation of the Bladder The principal nerve supply of the bladder is by way of the pelvic nerves, which connect with the spinal cord through the sacral plexus, mainly connecting with cord segments S-2 and S-3. Coursing through the pelvic nerves are both sensory nerve fibers and motor nerve fibers. The sensory fibers detect the degree of stretch in the bladder wall. Stretch signals from the posterior urethra are especially strong and are mainly responsible for initiating the reflexes that cause bladder emptying. The motor nerves transmitted in the pelvic nerves are parasympathetic fibers. These terminate on ganglion cells located in the wall of the bladder. Short postganglionic nerves then innervate the detrusor muscle. In addition to the pelvic nerves, two other types of innervation are important in bladder function. Most important are the skeletal motor fibers transmitted through the pudendal nerve to the external bladder sphincter. These are somatic nerve fibers that innervate and control the voluntary skeletal muscle of the sphincter. Also, the bladder receives sympathetic innervation from the sympathetic chain through the hypogastric nerves, connecting mainly with the L-2 segment of the spinal cord. These sympathetic fibers stimulate mainly the blood vessels and have little to do with bladder contraction. Some sensory nerve fibers also pass by way of the sympathetic nerves and may be important in the sensation of fullness and, in some instances, pain. Transport of Urine from the Kidney Through the Ureters and into the Bladder Urine that is expelled from the bladder has essentially the same composition as fluid flowing out of the collecting ducts; there are no significant changes in the composition of urine as it flows through the renal calyces and ureters to the bladder. Urine flowing from the collecting ducts into the renal calyces stretches the calyces and increases their inherent pacemaker activity, which in turn initiates peristaltic contractions that spread to the renal pelvis and then downward along the length of the ureter, thereby forcing urine from the renal pelvis toward the bladder. The walls of the ureters contain smooth muscle and are innervated by both sympathetic and parasympathetic nerves as well as by an intramural plexus of neurons and nerve fibers that extends along the entire length of the ureters. As with other visceral smooth muscle, peristaltic contractions in the ureter are enhanced by parasympathetic stimulation and inhibited by sympathetic stimulation. The ureters enter the bladder through the detrusor muscle in the trigone region of the bladder, as shown in Figure 26–6. Normally, the ureters course obliquely for several centimeters through the bladder wall. The normal tone of the detrusor muscle in the bladder wall tends to compress the ureter, thereby preventing backflow of urine from the bladder when pressure builds up in the bladder during micturition or bladder compression. Each peristaltic wave along the ureter increases the pressure within the ureter so that the region passing through the bladder wall opens and allows urine to flow into the bladder. In some people, the distance that the ureter courses through the bladder wall is less than normal, so that contraction of the bladder during micturition does not always lead to complete occlusion of the ureter. As a result, some of the urine in the bladder is propelled backward into the ureter, a condition called vesicoureteral reflux. Such reflux can lead to enlargement of the ureters and, if severe, can increase the pressure in the renal calyces and structures of the renal medulla, causing damage to these regions. Pain Sensation in the Ureters, and the Ureterorenal Reflex. The ureters are well supplied with pain nerve fibers. When a ureter becomes blocked (e.g., by a ureteral stone), intense reflex constriction occurs, associated with severe pain. Also, the pain impulses cause a sympathetic reflex back to the kidney to constrict the renal arterioles, thereby decreasing urine output from the kidney. This effect is called the ureterorenal reflex and is important for preventing excessive flow of fluid into the pelvis of a kidney with a blocked ureter. Filling of the Bladder and Bladder Wall Tone; the Cystometrogram Figure 26–7 shows the approximate changes in intravesicular pressure as the bladder fills with urine. When there is no urine in the bladder, the intravesicular pressure is about 0, but by the time 30 to 50 milliliters of urine has collected, the pressure rises to 5 to 10 centimeters of water. Additional urine—200 to 300 milliliters—can collect with only a small additional rise in pressure; this constant level of pressure is caused by intrinsic tone of the bladder wall itself. Beyond 300 to 400 milliliters, collection of more urine in the bladder causes the pressure to rise rapidly. Superimposed on the tonic pressure changes during filling of the bladder are periodic acute increases in pressure that last from a few seconds to more than a minute. The pressure peaks may rise only a few centimeters of water or may rise to more than 100 Chapter 26 Intravesical pressure (centimeters of water) 40 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control Micturition contractions 30 20 10 gram stometro Basal cy 0 0 100 200 300 400 Volume (milliliters) Figure 26–7 Normal cystometrogram, showing also acute pressure waves (dashed spikes) caused by micturition reflexes. centimeters of water. These pressure peaks are called micturition waves in the cystometrogram and are caused by the micturition reflex. Micturition Reflex Referring again to Figure 26–7, one can see that as the bladder fills, many superimposed micturition contractions begin to appear, as shown by the dashed spikes. They are the result of a stretch reflex initiated by sensory stretch receptors in the bladder wall, especially by the receptors in the posterior urethra when this area begins to fill with urine at the higher bladder pressures. Sensory signals from the bladder stretch receptors are conducted to the sacral segments of the cord through the pelvic nerves and then reflexively back again to the bladder through the parasympathetic nerve fibers by way of these same nerves. When the bladder is only partially filled, these micturition contractions usually relax spontaneously after a fraction of a minute, the detrusor muscles stop contracting, and pressure falls back to the baseline. As the bladder continues to fill, the micturition reflexes become more frequent and cause greater contractions of the detrusor muscle. Once a micturition reflex begins, it is “self-regenerative.” That is, initial contraction of the bladder activates the stretch receptors to cause a greater increase in sensory impulses to the bladder and posterior urethra, which causes a further increase in reflex contraction of the bladder; thus, the cycle is repeated again and again until the bladder has reached a strong degree of contraction. Then, after a few seconds to more than a minute, the self-regenerative reflex begins to fatigue and the regenerative cycle of the micturition reflex ceases, permitting the bladder to relax. 313 Thus, the micturition reflex is a single complete cycle of (1) progressive and rapid increase of pressure, (2) a period of sustained pressure, and (3) return of the pressure to the basal tone of the bladder. Once a micturition reflex has occurred but has not succeeded in emptying the bladder, the nervous elements of this reflex usually remain in an inhibited state for a few minutes to 1 hour or more before another micturition reflex occurs. As the bladder becomes more and more filled, micturition reflexes occur more and more often and more and more powerfully. Once the micturition reflex becomes powerful enough, it causes another reflex, which passes through the pudendal nerves to the external sphincter to inhibit it. If this inhibition is more potent in the brain than the voluntary constrictor signals to the external sphincter, urination will occur. If not, urination will not occur until the bladder fills still further and the micturition reflex becomes more powerful. Facilitation or Inhibition of Micturition by the Brain The micturition reflex is a completely autonomic spinal cord reflex, but it can be inhibited or facilitated by centers in the brain. These centers include (1) strong facilitative and inhibitory centers in the brain stem, located mainly in the pons, and (2) several centers located in the cerebral cortex that are mainly inhibitory but can become excitatory. The micturition reflex is the basic cause of micturition, but the higher centers normally exert final control of micturition as follows: 1. The higher centers keep the micturition reflex partially inhibited, except when micturition is desired. 2. The higher centers can prevent micturition, even if the micturition reflex occurs, by continual tonic contraction of the external bladder sphincter until a convenient time presents itself. 3. When it is time to urinate, the cortical centers can facilitate the sacral micturition centers to help initiate a micturition reflex and at the same time inhibit the external urinary sphincter so that urination can occur. Voluntary urination is usually initiated in the following way: First, a person voluntarily contracts his or her abdominal muscles, which increases the pressure in the bladder and allows extra urine to enter the bladder neck and posterior urethra under pressure, thus stretching their walls. This stimulates the stretch receptors, which excites the micturition reflex and simultaneously inhibits the external urethral sphincter. Ordinarily, all the urine will be emptied, with rarely more than 5 to 10 milliliters left in the bladder. Abnormalities of Micturition Atonic Bladder Caused by Destruction of Sensory Nerve Fibers. Micturition reflex contraction cannot occur if the sensory nerve fibers from the bladder to the spinal cord 314 Unit V The Body Fluids and Kidneys are destroyed, thereby preventing transmission of stretch signals from the bladder. When this happens, a person loses bladder control, despite intact efferent fibers from the cord to the bladder and despite intact neurogenic connections within the brain. Instead of emptying periodically, the bladder fills to capacity and overflows a few drops at a time through the urethra.This is called overflow incontinence. A common cause of atonic bladder is crush injury to the sacral region of the spinal cord. Certain diseases can also cause damage to the dorsal root nerve fibers that enter the spinal cord. For example, syphilis can cause constrictive fibrosis around the dorsal root nerve fibers, destroying them. This condition is called tabes dorsalis, and the resulting bladder condition is called tabetic bladder. Afferent arteriole Uninhibited Neurogenic Bladder Caused by Lack of Inhibitory Signals from the Brain. Another abnormality of micturi- tion is the so-called uninhibited neurogenic bladder, which results in frequent and relatively uncontrolled micturition. This condition derives from partial damage in the spinal cord or the brain stem that interrupts most of the inhibitory signals. Therefore, facilitative impulses passing continually down the cord keep the sacral centers so excitable that even a small quantity of urine elicits an uncontrollable micturition reflex, thereby promoting frequent urination. Urine Formation Results from Glomerular Filtration, Tubular Reabsorption, and Tubular Secretion The rates at which different substances are excreted in the urine represent the sum of three renal processes, shown in Figure 26–8: (1) glomerular filtration, (2) reabsorption of substances from the renal tubules into the blood, and (3) secretion of substances from the blood into the renal tubules. Expressed mathematically, Urinary excretion rate = Filtration rate - Reabsorption rate + Secretion rate 1. Filtration 2. Reabsorption 3. Secretion 4. Excretion Glomerular capillaries Bowman's capsule 1 2 Peritubular capillaries 3 Automatic Bladder Caused by Spinal Cord Damage Above the Sacral Region. If the spinal cord is damaged above the sacral region but the sacral cord segments are still intact, typical micturition reflexes can still occur. However, they are no longer controlled by the brain. During the first few days to several weeks after the damage to the cord has occurred, the micturition reflexes are suppressed because of the state of “spinal shock” caused by the sudden loss of facilitative impulses from the brain stem and cerebrum. However, if the bladder is emptied periodically by catheterization to prevent bladder injury caused by overstretching of the bladder, the excitability of the micturition reflex gradually increases until typical micturition reflexes return; then, periodic (but unannounced) bladder emptying occurs. Some patients can still control urination in this condition by stimulating the skin (scratching or tickling) in the genital region, which sometimes elicits a micturition reflex. Efferent arteriole 4 Renal vein Urinary excretion Excretion = Filtration – Reabsorption + Secretion Figure 26–8 Basic kidney processes that determine the composition of the urine. Urinary excretion rate of a substance is equal to the rate at which the substance is filtered minus its reabsorption rate plus the rate at which it is secreted from the peritubular capillary blood into the tubules. Urine formation begins when a large amount of fluid that is virtually free of protein is filtered from the glomerular capillaries into Bowman’s capsule. Most substances in the plasma, except for proteins, are freely filtered, so that their concentration in the glomerular filtrate in Bowman’s capsule is almost the same as in the plasma. As filtered fluid leaves Bowman’s capsule and passes through the tubules, it is modified by reabsorption of water and specific solutes back into the blood or by secretion of other substances from the peritubular capillaries into the tubules. Figure 26–9 shows the renal handling of four hypothetical substances. The substance shown in panel A is freely filtered by the glomerular capillaries but is neither reabsorbed nor secreted. Therefore, its excretion rate is equal to the rate at which it was filtered. Certain waste products in the body, such as creatinine, are handled by the kidneys in this manner, allowing excretion of essentially all that is filtered. In panel B, the substance is freely filtered but is also partly reabsorbed from the tubules back into the blood. Therefore, the rate of urinary excretion is less than the rate of filtration at the glomerular capillaries. In this case, the excretion rate is calculated as the filtration rate minus the reabsorption rate. This is typical for many of the electrolytes of the body. In panel C, the substance is freely filtered at the glomerular capillaries but is not excreted into the Chapter 26 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control A. Filtration only B. Filtration, partial reabsorption Substance B Substance A Urine Urine C. Filtration, complete D. Filtration, secretion reabsorption Substance D Substance C Urine Urine Figure 26–9 Renal handling of four hypothetical substances. A, The substance is freely filtered but not reabsorbed. B, The substance is freely filtered, but part of the filtered load is reabsorbed back in the blood. C, The substance is freely filtered but is not excreted in the urine because all the filtered substance is reabsorbed from the tubules into the blood. D, The substance is freely filtered and is not reabsorbed but is secreted from the peritubular capillary blood into the renal tubules. urine because all the filtered substance is reabsorbed from the tubules back into the blood. This pattern occurs for some of the nutritional substances in the blood, such as amino acids and glucose, allowing them to be conserved in the body fluids. The substance in panel D is freely filtered at the glomerular capillaries and is not reabsorbed, but additional quantities of this substance are secreted from the peritubular capillary blood into the renal tubules. This pattern often occurs for organic acids and bases, permitting them to be rapidly cleared from the blood and excreted in large amounts in the urine. The excretion rate in this case is calculated as filtration rate plus tubular secretion rate. For each substance in the plasma, a particular combination of filtration, reabsorption, and secretion occurs. The rate at which the substance is excreted in the urine depends on the relative rates of these three basic renal processes. 315 Filtration, Reabsorption, and Secretion of Different Substances In general, tubular reabsorption is quantitatively more important than tubular secretion in the formation of urine, but secretion plays an important role in determining the amounts of potassium and hydrogen ions and a few other substances that are excreted in the urine. Most substances that must be cleared from the blood, especially the end products of metabolism such as urea, creatinine, uric acid, and urates, are poorly reabsorbed and are therefore excreted in large amounts in the urine. Certain foreign substances and drugs are also poorly reabsorbed but, in addition, are secreted from the blood into the tubules, so that their excretion rates are high. Conversely, electrolytes, such as sodium ions, chloride ions, and bicarbonate ions, are highly reabsorbed, so that only small amounts appear in the urine. Certain nutritional substances, such as amino acids and glucose, are completely reabsorbed from the tubules and do not appear in the urine even though large amounts are filtered by the glomerular capillaries. Each of the processes—glomerular filtration, tubular reabsorption, and tubular secretion—is regulated according to the needs of the body. For example, when there is excess sodium in the body, the rate at which sodium is filtered increases and a smaller fraction of the filtered sodium is reabsorbed, resulting in increased urinary excretion of sodium. For most substances, the rates of filtration and reabsorption are extremely large relative to the rates of excretion.Therefore, subtle adjustments of filtration or reabsorption can lead to relatively large changes in renal excretion. For example, an increase in glomerular filtration rate (GFR) of only 10 per cent (from 180 to 198 L/day) would raise urine volume 13-fold (from 1.5 to 19.5 L/day) if tubular reabsorption remained constant. In reality, changes in glomerular filtration and tubular reabsorption usually act in a coordinated manner to produce the necessary changes in renal excretion. Why Are Large Amounts of Solutes Filtered and Then Reabsorbed by the Kidneys? One might question the wisdom of filtering such large amounts of water and solutes and then reabsorbing most of these substances. One advantage of a high GFR is that it allows the kidneys to rapidly remove waste products from the body that depend primarily on glomerular filtration for their excretion. Most waste products are poorly reabsorbed by the tubules and, therefore, depend on a high GFR for effective removal from the body. A second advantage of a high GFR is that it allows all the body fluids to be filtered and processed by the kidney many times each day. Because the entire plasma volume is only about 3 liters, whereas the GFR is about 180 L/day, the entire plasma can be filtered and processed about 60 times each day. This high GFR allows the kidneys to precisely and rapidly control the volume and composition of the body fluids. 316 Unit V The Body Fluids and Kidneys Glomerular Filtration—The First Step in Urine Formation Proximal tubule Podocytes Composition of the Glomerular Filtrate Urine formation begins with filtration of large amounts of fluid through the glomerular capillaries into Bowman’s capsule. Like most capillaries, the glomerular capillaries are relatively impermeable to proteins, so that the filtered fluid (called the glomerular filtrate) is essentially protein-free and devoid of cellular elements, including red blood cells. The concentrations of other constituents of the glomerular filtrate, including most salts and organic molecules, are similar to the concentrations in the plasma. Exceptions to this generalization include a few low-molecular-weight substances, such as calcium and fatty acids, that are not freely filtered because they are partially bound to the plasma proteins. Almost one half of the plasma calcium and most of the plasma fatty acids are bound to proteins, and these bound portions are not filtered through the glomerular capillaries. Capillary loops Bowman's space A As in other capillaries, the GFR is determined by (1) the balance of hydrostatic and colloid osmotic forces acting across the capillary membrane and (2) the capillary filtration coefficient (Kf), the product of the permeability and filtering surface area of the capillaries. The glomerular capillaries have a much higher rate of filtration than most other capillaries because of a high glomerular hydrostatic pressure and a large Kf. In the average adult human, the GFR is about 125 ml/min, or 180 L/day. The fraction of the renal plasma flow that is filtered (the filtration fraction) averages about 0.2; this means that about 20 per cent of the plasma flowing through the kidney is filtered through the glomerular capillaries. The filtration fraction is calculated as follows: Filtration fraction = GFR/Renal plasma flow Glomerular Capillary Membrane The glomerular capillary membrane is similar to that of other capillaries, except that it has three (instead of the usual two) major layers: (1) the endothelium of the capillary, (2) a basement membrane, and (3) a layer of epithelial cells (podocytes) surrounding the outer surface of the capillary basement membrane (Figure 26–10). Together, these layers make up the filtration barrier, which, despite the three layers, filters several hundred times as much water and solutes as the usual capillary membrane. Even with this high rate of filtration, the glomerular capillary membrane normally prevents filtration of plasma proteins. Efferent arteriole Slit pores Epithelium Basement membrane Endothelium B GFR Is About 20 Per Cent of the Renal Plasma Flow Afferent arteriole Bowman's capsule Fenestrations Figure 26–10 A, Basic ultrastructure of the glomerular capillaries. B, Cross section of the glomerular capillary membrane and its major components: capillary endothelium, basement membrane, and epithelium (podocytes). The high filtration rate across the glomerular capillary membrane is due partly to its special characteristics. The capillary endothelium is perforated by thousands of small holes called fenestrae, similar to the fenestrated capillaries found in the liver. Although the fenestrations are relatively large, endothelial cells are richly endowed with fixed negative charges that hinder the passage of plasma proteins. Surrounding the endothelium is the basement membrane, which consists of a meshwork of collagen and proteoglycan fibrillae that have large spaces through which large amounts of water and small solutes can filter. The basement membrane effectively prevents filtration of plasma proteins, in part because of strong negative electrical charges associated with the proteoglycans. The final part of the glomerular membrane is a layer of epithelial cells that line the outer surface of the glomerulus. These cells are not continuous but have long footlike processes (podocytes) that encircle the outer surface of the capillaries (see Figure 26–10). The foot processes are separated by gaps called slit pores through which the glomerular filtrate moves. The epithelial cells, which also have negative charges, provide additional restriction to filtration of plasma proteins. Thus, all layers of the glomerular capillary wall provide a barrier to filtration of plasma proteins. Chapter 26 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control 317 Table 26–1 Filterability of Substances by Glomerular Capillaries Based on Molecular Weight Molecular Weight Filterability Water Sodium Glucose Inulin Myoglobin Albumin 18 23 180 5,500 17,000 69,000 1.0 1.0 1.0 1.0 0.75 0.005 Relative filterability Substance 1.0 Polycationic dextran Neutral dextran Polyanionic dextran 0.8 0.6 0.4 0.2 Filterability of Solutes Is Inversely Related to Their Size. The glomerular capillary membrane is thicker than most other capillaries, but it is also much more porous and therefore filters fluid at a high rate. Despite the high filtration rate, the glomerular filtration barrier is selective in determining which molecules will filter, based on their size and electrical charge. Table 26–1 lists the effect of molecular size on filterability of different molecules. A filterability of 1.0 means that the substance is filtered as freely as water; a filterability of 0.75 means that the substance is filtered only 75 per cent as rapidly as water. Note that electrolytes such as sodium and small organic compounds such as glucose are freely filtered. As the molecular weight of the molecule approaches that of albumin, the filterability rapidly decreases, approaching zero. Negatively Charged Large Molecules Are Filtered Less Easily Than Positively Charged Molecules of Equal Molecular Size. The molecular diameter of the plasma protein albumin is only about 6 nanometers, whereas the pores of the glomerular membrane are thought to be about 8 nanometers (80 angstroms). Albumin is restricted from filtration, however, because of its negative charge and the electrostatic repulsion exerted by negative charges of the glomerular capillary wall proteoglycans. Figure 26–11 shows how electrical charge affects the filtration of different molecular weight dextrans by the glomerulus. Dextrans are polysaccharides that can be manufactured as neutral molecules or with negative or positive charges. Note that for any given molecular radius, positively charged molecules are filtered much more readily than negatively charged molecules. Neutral dextrans are also filtered more readily than negatively charged dextrans of equal molecular weight. The reason for these differences in filterability is that the negative charges of the basement membrane and the podocytes provide an important means for restricting large negatively charged molecules, including the plasma proteins. In certain kidney diseases, the negative charges on the basement membrane are lost even before there are noticeable changes in kidney histology, a condition referred to as minimal change nephropathy. As a result of this loss of negative charges on the basement membranes, some of the lower-molecular-weight proteins, especially albumin, are filtered and appear 0 18 22 26 30 34 38 Effective molecular radius (A) 42 Figure 26–11 Effect of size and electrical charge of dextran on its filterability by the glomerular capillaries. A value of 1.0 indicates that the substance is filtered as freely as water, whereas a value of 0 indicates that it is not filtered. Dextrans are polysaccharides that can be manufactured as neutral molecules or with negative or positive charges and with varying molecular weights. in the urine, a condition known as proteinuria or albuminuria. Determinants of the GFR The GFR is determined by (1) the sum of the hydrostatic and colloid osmotic forces across the glomerular membrane, which gives the net filtration pressure, and (2) the glomerular capillary filtration coefficient, Kf. Expressed mathematically, the GFR equals the product of Kf and the net filtration pressure: GFR = Kf ¥ Net filtration pressure The net filtration pressure represents the sum of the hydrostatic and colloid osmotic forces that either favor or oppose filtration across the glomerular capillaries (Figure 26–12). These forces include (1) hydrostatic pressure inside the glomerular capillaries (glomerular hydrostatic pressure, PG), which promotes filtration; (2) the hydrostatic pressure in Bowman’s capsule (PB) outside the capillaries, which opposes filtration; (3) the colloid osmotic pressure of the glomerular capillary plasma proteins (pG), which opposes filtration; and (4) the colloid osmotic pressure of the proteins in Bowman’s capsule (pB), which promotes filtration. (Under normal conditions, the concentration of protein in the glomerular filtrate is so low that the colloid osmotic pressure of the Bowman’s capsule fluid is considered to be zero.) The GFR can therefore be expressed as GFR = Kf ¥ (PG – PB – pG + pB) 318 Unit V Afferent arteriole Glomerular Glomerular hydrostatic colloid osmotic pressure pressure (60 mm Hg) (32 mm Hg) The Body Fluids and Kidneys Efferent arteriole Bowman's capsule pressure (18 mm Hg) Net filtration pressure (10 mm Hg) = Glomerular hydrostatic – pressure (60 mm Hg) Bowman's capsule – pressure (18 mm Hg) Glomerular oncotic pressure (32 mm Hg) 4.2 ml/min/mm Hg, a value about 400 times as high as the Kf of most other capillary systems of the body; the average Kf of many other tissues in the body is only about 0.01 ml/min/mm Hg per 100 grams. This high Kf for the glomerular capillaries contributes tremendously to their rapid rate of fluid filtration. Although increased Kf raises GFR and decreased Kf reduces GFR, changes in Kf probably do not provide a primary mechanism for the normal day-to-day regulation of GFR. Some diseases, however, lower Kf by reducing the number of functional glomerular capillaries (thereby reducing the surface area for filtration) or by increasing the thickness of the glomerular capillary membrane and reducing its hydraulic conductivity. For example, chronic, uncontrolled hypertension and diabetes mellitus gradually reduce Kf by increasing the thickness of the glomerular capillary basement membrane and, eventually, by damaging the capillaries so severely that there is loss of capillary function. Figure 26–12 Summary of forces causing filtration by the glomerular capillaries. The values shown are estimates for healthy humans. Although the normal values for the determinants of GFR have not been measured directly in humans, they have been estimated in animals such as dogs and rats. Based on the results in animals, the approximate normal forces favoring and opposing glomerular filtration in humans are believed to be as follows (see Figure 26–12): Forces Favoring Filtration (mm Hg) Glomerular hydrostatic pressure Bowman’s capsule colloid osmotic pressure 60 0 Forces Opposing Filtration (mm Hg) Bowman’s capsule hydrostatic pressure Glomerular capillary colloid osmotic pressure 18 32 Net filtration pressure = 60 – 18 – 32 = +10 mm Hg Some of these values can change markedly under different physiologic conditions, whereas others are altered mainly in disease states, as discussed later. Increased Glomerular Capillary Filtration Coefficient Increases GFR The Kf is a measure of the product of the hydraulic conductivity and surface area of the glomerular capillaries. The Kf cannot be measured directly, but it is estimated experimentally by dividing the rate of glomerular filtration by net filtration pressure: Kf = GFR/Net filtration pressure Because total GFR for both kidneys is about 125 ml/ min and the net filtration pressure is 10 mm Hg, the normal Kf is calculated to be about 12.5 ml/min/mm Hg of filtration pressure. When Kf is expressed per 100 grams of kidney weight, it averages about Increased Bowman’s Capsule Hydrostatic Pressure Decreases GFR Direct measurements, using micropipettes, of hydrostatic pressure in Bowman’s capsule and at different points in the proximal tubule suggest that a reasonable estimate for Bowman’s capsule pressure in humans is about 18 mm Hg under normal conditions. Increasing the hydrostatic pressure in Bowman’s capsule reduces GFR, whereas decreasing this pressure raises GFR. However, changes in Bowman’s capsule pressure normally do not serve as a primary means for regulating GFR. In certain pathological states associated with obstruction of the urinary tract, Bowman’s capsule pressure can increase markedly, causing serious reduction of GFR. For example, precipitation of calcium or of uric acid may lead to “stones” that lodge in the urinary tract, often in the ureter, thereby obstructing outflow of the urinary tract and raising Bowman’s capsule pressure. This reduces GFR and eventually can damage or even destroy the kidney unless the obstruction is relieved. Increased Glomerular Capillary Colloid Osmotic Pressure Decreases GFR As blood passes from the afferent arteriole through the glomerular capillaries to the efferent arterioles, the plasma protein concentration increases about 20 per cent (Figure 26–13). The reason for this is that about one fifth of the fluid in the capillaries filters into Bowman’s capsule, thereby concentrating the glomerular plasma proteins that are not filtered. Assuming that the normal colloid osmotic pressure of plasma entering the glomerular capillaries is 28 mm Hg, this value usually rises to about 36 mm Hg Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control Normal 36 34 32 Filtration fraction 30 28 100 Distance along glomerular capillary 1400 Normal 60 800 Renal blood flow 0 Afferent end 0 Efferent end Glomerular filtration rate (ml/min) Increase in colloid osmotic pressure in plasma flowing through the glomerular capillary. Normally, about one fifth of the fluid in the glomerular capillaries filters into Bowman’s capsule, thereby concentrating the plasma proteins that are not filtered. Increases in the filtration fraction (glomerular filtration rate/renal plasma flow) increase the rate at which the plasma colloid osmotic pressure rises along the glomerular capillary; decreases in the filtration fraction have the opposite effect. 2000 100 1400 150 Normal 100 Glomerular filtration rate 50 Renal blood flow 0 800 200 0 by the time the blood reaches the efferent end of the capillaries. Therefore, the average colloid osmotic pressure of the glomerular capillary plasma proteins is midway between 28 and 36 mm Hg, or about 32 mm Hg. Thus, two factors that influence the glomerular capillary colloid osmotic pressure are (1) the arterial plasma colloid osmotic pressure and (2) the fraction of plasma filtered by the glomerular capillaries (filtration fraction). Increasing the arterial plasma colloid osmotic pressure raises the glomerular capillary colloid osmotic pressure, which in turn decreases GFR. Increasing the filtration fraction also concentrates the plasma proteins and raises the glomerular colloid osmotic pressure (see Figure 26–13). Because the filtration fraction is defined as GFR/renal plasma flow, the filtration fraction can be increased either by raising GFR or by reducing renal plasma flow. For example, a reduction in renal plasma flow with no initial change in GFR would tend to increase the filtration fraction, which would raise the glomerular capillary colloid osmotic pressure and tend to reduce GFR. For this reason, changes in renal blood flow can influence GFR independently of changes in glomerular hydrostatic pressure. With increasing renal blood flow, a lower fraction of the plasma is initially filtered out of the glomerular capillaries, causing a slower rise in the glomerular capillary colloid osmotic pressure and less inhibitory effect on GFR. Consequently, even with a constant glomerular hydrostatic pressure, a greater rate of blood flow into the glomerulus tends to increase GFR, and a lower rate of blood flow into the glomerulus tends to decrease GFR. 200 1 2 3 4 Efferent arteriolar resistance (X normal) 250 Figure 26–13 2000 Renal blood flow (ml/min) 38 Glomerular filtration rate 150 Filtration fraction 319 Renal blood flow (ml/min) Glomerular colloid osmotic pressure (mm Hg) 40 Glomerular filtration rate (ml/min) Chapter 26 1 2 3 4 Afferent arteriolar resistance (X normal) Figure 26–14 Effect of change in afferent arteriolar resistance or efferent arteriolar resistance on glomerular filtration rate and renal blood flow. Increased Glomerular Capillary Hydrostatic Pressure Increases GFR The glomerular capillary hydrostatic pressure has been estimated to be about 60 mm Hg under normal conditions. Changes in glomerular hydrostatic pressure serve as the primary means for physiologic regulation of GFR. Increases in glomerular hydrostatic pressure raise GFR, whereas decreases in glomerular hydrostatic pressure reduce GFR. Glomerular hydrostatic pressure is determined by three variables, each of which is under physiologic control: (1) arterial pressure, (2) afferent arteriolar resistance, and (3) efferent arteriolar resistance. Increased arterial pressure tends to raise glomerular hydrostatic pressure and, therefore, to increase GFR. (However, as discussed later, this effect is buffered by autoregulatory mechanisms that maintain a relatively constant glomerular pressure as blood pressure fluctuates.) Increased resistance of afferent arterioles reduces glomerular hydrostatic pressure and decreases GFR. Conversely, dilation of the afferent arterioles increases both glomerular hydrostatic pressure and GFR (Figure 26–14). 320 Unit V The Body Fluids and Kidneys Constriction of the efferent arterioles increases the resistance to outflow from the glomerular capillaries. This raises the glomerular hydrostatic pressure, and as long as the increase in efferent resistance does not reduce renal blood flow too much, GFR increases slightly (see Figure 26–14). However, because efferent arteriolar constriction also reduces renal blood flow, the filtration fraction and glomerular colloid osmotic pressure increase as efferent arteriolar resistance increases. Therefore, if the constriction of efferent arterioles is severe (more than about a threefold increase in efferent arteriolar resistance), the rise in colloid osmotic pressure exceeds the increase in glomerular capillary hydrostatic pressure caused by efferent arteriolar constriction. When this occurs, the net force for filtration actually decreases, causing a reduction in GFR. Thus, efferent arteriolar constriction has a biphasic effect on GFR. At moderate levels of constriction, there is a slight increase in GFR, but with severe constriction, there is a decrease in GFR. The primary cause of the eventual decrease in GFR is as follows: As efferent constriction becomes severe and as plasma protein concentration increases, there is a rapid, nonlinear increase in colloid osmotic pressure caused by the Donnan effect; the higher the protein concentration, the more rapidly the colloid osmotic pressure rises because of the interaction of ions bound to the plasma proteins, which also exert an osmotic effect, as discussed in Chapter 16. To summarize, constriction of afferent arterioles reduces GFR. However, the effect of efferent arteriolar constriction depends on the severity of the constriction; modest efferent constriction raises GFR, but severe efferent constriction (more than a threefold increase in resistance) tends to reduce GFR. Table 26–2 summarizes the factors that can decrease GFR. Table 26–2 Factors That Can Decrease the Glomerular Filtration Rate (GFR) Physical Determinants* Physiologic/Pathophysiologic Causes Ø Kf Æ Ø GFR Renal disease, diabetes mellitus, hypertension Urinary tract obstruction (e.g., kidney stones) Ø Renal blood flow, increased plasma proteins ≠ PB Æ Ø GFR ≠ pG Æ Ø GFR Ø PG Æ Ø GFR Ø AP Æ Ø PG Ø RE Æ Ø PG ≠ RA Æ Ø PG Ø Arterial pressure (has only small effect due to autoregulation) Ø Angiotensin II (drugs that block angiotensin II formation) ≠ Sympathetic activity, vasoconstrictor hormones (e.g., norepinephrine, endothelin) * Opposite changes in the determinants usually increase GFR. Kf, glomerular filtration coefficient; PB, Bowman’s capsule hydrostatic pressure; pG, glomerular capillary colloid osmotic pressure; PG, glomerular capillary hydrostatic pressure; AP, systemic arterial pressure; RE, efferent arteriolar resistance; RA, afferent arteriolar resistance. Renal Blood Flow In an average 70-kilogram man, the combined blood flow through both kidneys is about 1100 ml/min, or about 22 per cent of the cardiac output. Considering the fact that the two kidneys constitute only about 0.4 per cent of the total body weight, one can readily see that they receive an extremely high blood flow compared with other organs. As with other tissues, blood flow supplies the kidneys with nutrients and removes waste products. However, the high flow to the kidneys greatly exceeds this need. The purpose of this additional flow is to supply enough plasma for the high rates of glomerular filtration that are necessary for precise regulation of body fluid volumes and solute concentrations. As might be expected, the mechanisms that regulate renal blood flow are closely linked to the control of GFR and the excretory functions of the kidneys. Renal Blood Flow and Oxygen Consumption On a per gram weight basis, the kidneys normally consume oxygen at twice the rate of the brain but have almost seven times the blood flow of the brain. Thus, the oxygen delivered to the kidneys far exceeds their metabolic needs, and the arterial-venous extraction of oxygen is relatively low compared with that of most other tissues. A large fraction of the oxygen consumed by the kidneys is related to the high rate of active sodium reabsorption by the renal tubules. If renal blood flow and GFR are reduced and less sodium is filtered, less sodium is reabsorbed and less oxygen is consumed. Therefore, renal oxygen consumption varies in proportion to renal tubular sodium reabsorption, which in turn is closely related to GFR and the rate of sodium filtered (Figure 26–15). If glomerular filtration completely ceases, renal sodium reabsorption also ceases, and oxygen consumption decreases to about one fourth normal. This residual oxygen consumption reflects the basic metabolic needs of the renal cells. Determinants of Renal Blood Flow Renal blood flow is determined by the pressure gradient across the renal vasculature (the difference between renal artery and renal vein hydrostatic pressures), divided by the total renal vascular resistance: (Renal artery pressure - Renal vein pressure) Total renal vascular resistance Renal artery pressure is about equal to systemic arterial pressure, and renal vein pressure averages about 3 to 4 mm Hg under most conditions. As in other vascular beds, the total vascular resistance through the kidneys is determined by the sum of the resistances in the individual vasculature segments, including the arteries, arterioles, capillaries, and veins (Table 26–3). Chapter 26 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control 321 Table 26–3 Approximate Pressures and Vascular Resistances in the Circulation of a Normal Kidney Pressure in Vessel (mm Hg) Beginning End Vessel Renal artery Interlobar, arcuate, and interlobular arteries Afferent arteriole Glomerular capillaries Efferent arteriole Peritubular capillaries Interlobar, interlobular, and arcuate veins Renal vein 100 ~100 85 60 59 18 8 4 ~0 ~16 ~26 ~1 ~43 ~10 ~4 ~0 range between 80 and 170 mm Hg, a process called autoregulation. This capacity for autoregulation occurs through mechanisms that are completely intrinsic to the kidneys, as discussed later in this chapter. 3.0 Oxygen consumption (ml/min/100 gm kidney weight) 100 85 60 59 18 8 4 ~4 Per Cent of Total Renal Vascular Resistance 2.5 Blood Flow in the Vasa Recta of the Renal Medulla Is Very Low Compared with Flow in the Renal Cortex 2.0 1.5 1.0 0.5 Basal oxygen consumption 0 0 5 10 15 20 Sodium reabsorption (mEq/min per 100 g kidney weight) Figure 26–15 Relationship between oxygen consumption and sodium reabsorption in dog kidneys. (Kramer K, Deetjen P: Relation of renal oxygen consumption to blood supply and glomerular filtration during variations of blood pressure. Pflugers Arch Physiol 271:782, 1960.) Most of the renal vascular resistance resides in three major segments: interlobular arteries, afferent arterioles, and efferent arterioles. Resistance of these vessels is controlled by the sympathetic nervous system, various hormones, and local internal renal control mechanisms, as discussed later. An increase in the resistance of any of the vascular segments of the kidneys tends to reduce the renal blood flow, whereas a decrease in vascular resistance increases renal blood flow if renal artery and renal vein pressures remain constant. Although changes in arterial pressure have some influence on renal blood flow, the kidneys have effective mechanisms for maintaining renal blood flow and GFR relatively constant over an arterial pressure The outer part of the kidney, the renal cortex, receives most of the kidney’s blood flow. Blood flow in the renal medulla accounts for only 1 to 2 per cent of the total renal blood flow. Flow to the renal medulla is supplied by a specialized portion of the peritubular capillary system called the vasa recta. These vessels descend into the medulla in parallel with the loops of Henle and then loop back along with the loops of Henle and return to the cortex before emptying into the venous system. As discussed in Chapter 28, the vasa recta play an important role in allowing the kidneys to form a concentrated urine. Physiologic Control of Glomerular Filtration and Renal Blood Flow The determinants of GFR that are most variable and subject to physiologic control include the glomerular hydrostatic pressure and the glomerular capillary colloid osmotic pressure. These variables, in turn, are influenced by the sympathetic nervous system, hormones and autacoids (vasoactive substances that are released in the kidneys and act locally), and other feedback controls that are intrinsic to the kidneys. Sympathetic Nervous System Activation Decreases GFR Essentially all the blood vessels of the kidneys, including the afferent and the efferent arterioles, are richly innervated by sympathetic nerve fibers. Strong activation of the renal sympathetic nerves can constrict the renal arterioles and decrease renal blood flow and 322 Unit V The Body Fluids and Kidneys GFR. Moderate or mild sympathetic stimulation has little influence on renal blood flow and GFR. For example, reflex activation of the sympathetic nervous system resulting from moderate decreases in pressure at the carotid sinus baroreceptors or cardiopulmonary receptors has little influence on renal blood flow or GFR. The renal sympathetic nerves seem to be most important in reducing GFR during severe, acute disturbances lasting for a few minutes to a few hours, such as those elicited by the defense reaction, brain ischemia, or severe hemorrhage. In the healthy resting person, sympathetic tone appears to have little influence on renal blood flow. Hormonal and Autacoid Control of Renal Circulation There are several hormones and autacoids that can influence GFR and renal blood flow, as summarized in Table 26–4. Norepinephrine, Epinephrine, and Endothelin Constrict Renal Blood Vessels and Decrease GFR. Hormones that constrict afferent and efferent arterioles, causing reductions in GFR and renal blood flow, include norepinephrine and epinephrine released from the adrenal medulla. In general, blood levels of these hormones parallel the activity of the sympathetic nervous system; thus, norepinephrine and epinephrine have little influence on renal hemodynamics except under extreme conditions, such as severe hemorrhage. Another vasoconstrictor, endothelin, is a peptide that can be released by damaged vascular endothelial cells of the kidneys as well as by other tissues. The physiologic role of this autacoid is not completely understood. However, endothelin may contribute to hemostasis (minimizing blood loss) when a blood vessel is severed, which damages the endothelium and releases this powerful vasoconstrictor. Plasma endothelin levels also are increased in certain disease states associated with vascular injury, such as toxemia of pregnancy, acute renal failure, and chronic uremia, and may contribute to renal vasoconstriction and decreased GFR in some of these pathophysiologic conditions. Angiotensin II Constricts Efferent Arterioles. A powerful renal vasoconstrictor, angiotensin II, can be considered a circulating hormone as well as a locally produced autacoid because it is formed in the kidneys as well as in the systemic circulation. Because angiotensin II preferentially constricts efferent arterioles, increased angiotensin II levels raise glomerular hydrostatic pressure while reducing renal blood flow. It should be kept in mind that increased angiotensin II formation usually occurs in circumstances associated with decreased arterial pressure or volume depletion, which tend to decrease GFR. In these circumstances, the increased level of angiotensin II, by constricting efferent arterioles, helps prevent decreases in glomerular hydrostatic pressure and GFR; at the same time, though, the reduction in renal blood flow caused by efferent arteriolar constriction contributes to decreased flow through the peritubular capillaries, which in turn increases reabsorption of sodium and water, as discussed in Chapter 27. Thus, increased angiotensin II levels that occur with a low-sodium diet or volume depletion help preserve GFR and maintain normal excretion of metabolic waste products such as urea and creatinine that depend on glomerular filtration for their excretion; at the same time, the angiotensin II–induced constriction of efferent arterioles increases tubular reabsorption of sodium and water, which helps restore blood volume and blood pressure. This effect of angiotensin II in helping to “autoregulate” GFR is discussed in more detail later in this chapter. Endothelial-Derived Nitric Oxide Decreases Renal Vascular Resistance and Increases GFR. An autacoid that de- creases renal vascular resistance and is released by the vascular endothelium throughout the body is endothelial-derived nitric oxide. A basal level of nitric oxide production appears to be important for maintaining vasodilation of the kidneys. This allows the kidneys to excrete normal amounts of sodium and water. Therefore, administration of drugs that inhibit this normal formation of nitric oxide increases renal vascular resistance and decreases GFR and urinary sodium excretion, eventually causing high blood pressure. In some hypertensive patients, impaired nitric oxide production could be the cause of increased renal vasoconstriction and increased blood pressure. Prostaglandins and Bradykinin Tend to Increase GFR. Hor- Table 26–4 Hormones and Autacoids That Influence Glomerular Filtration Rate (GFR) Hormone or Autacoid Effect on GFR Norepinephrine Epinephrine Endothelin Angiotensin II Endothelial-derived nitric oxide Prostaglandins Ø Ø Ø ¨Æ (prevents Ø) ≠ ≠ mones and autacoids that cause vasodilation and increased renal blood flow and GFR include the prostaglandins (PGE2 and PGI2) and bradykinin. These substances are discussed in Chapter 17. Although these vasodilators do not appear to be of major importance in regulating renal blood flow or GFR in normal conditions, they may dampen the renal vasoconstrictor effects of the sympathetic nerves or angiotensin II, especially their effects to constrict the afferent arterioles. By opposing vasoconstriction of afferent arterioles, the prostaglandins may help prevent excessive reductions in GFR and renal blood flow. Under stressful Chapter 26 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control conditions, such as volume depletion or after surgery, the administration of nonsteroidal anti-inflammatory agents, such as aspirin, that inhibit prostaglandin synthesis may cause significant reductions in GFR. Autoregulation of GFR and Renal Blood Flow 1600 160 1200 120 800 80 400 0 Renal blood flow Glomerular filtration rate 40 0 Glomerular filtration rate (ml/min) Renal blood flow (ml/min) Feedback mechanisms intrinsic to the kidneys normally keep the renal blood flow and GFR relatively constant, despite marked changes in arterial blood pressure. These mechanisms still function in bloodperfused kidneys that have been removed from the body, independent of systemic influences. This relative constancy of GFR and renal blood flow is referred to as autoregulation (Figure 26–16). The primary function of blood flow autoregulation in most tissues other than the kidneys is to maintain the delivery of oxygen and nutrients at a normal level and to remove the waste products of metabolism, despite changes in the arterial pressure. In the kidneys, the normal blood flow is much higher than that required for these functions. The major function of autoregulation in the kidneys is to maintain a relatively constant GFR and to allow precise control of renal excretion of water and solutes. The GFR normally remains autoregulated (that is, remains relatively constant), despite considerable arterial pressure fluctuations that occur during a person’s usual activities. For instance, a decrease in Urine output (ml/min) 8 6 4 2 0 50 100 150 Arterial pressure (mm Hg) 200 Figure 26–16 Autoregulation of renal blood flow and glomerular filtration rate but lack of autoregulation of urine flow during changes in renal arterial pressure. 323 arterial pressure to as low as 75 mm Hg or an increase to as high as 160 mm Hg changes GFR only a few percentage points. In general, renal blood flow is autoregulated in parallel with GFR, but GFR is more efficiently autoregulated under certain conditions. Importance of GFR Autoregulation in Preventing Extreme Changes in Renal Excretion The autoregulatory mechanisms of the kidney are not 100 per cent perfect, but they do prevent potentially large changes in GFR and renal excretion of water and solutes that would otherwise occur with changes in blood pressure. One can understand the quantitative importance of autoregulation by considering the relative magnitudes of glomerular filtration, tubular reabsorption, and renal excretion and the changes in renal excretion that would occur without autoregulatory mechanisms. Normally, GFR is about 180 L/day and tubular reabsorption is 178.5 L/day, leaving 1.5 L/day of fluid to be excreted in the urine. In the absence of autoregulation, a relatively small increase in blood pressure (from 100 to 125 mm Hg) would cause a similar 25 per cent increase in GFR (from about 180 to 225 L/day). If tubular reabsorption remained constant at 178.5 L/ day, this would increase the urine flow to 46.5 L/day (the difference between GFR and tubular reabsorption)—a total increase in urine of more than 30-fold. Because the total plasma volume is only about 3 liters, such a change would quickly deplete the blood volume. But in reality, such a change in arterial pressure exerts much less of an effect on urine volume for two reasons: (1) renal autoregulation prevents large changes in GFR that would otherwise occur, and (2) there are additional adaptive mechanisms in the renal tubules that allow them to increase their reabsorption rate when GFR rises, a phenomenon referred to as glomerulotubular balance (discussed in Chapter 27). Even with these special control mechanisms, changes in arterial pressure still have significant effects on renal excretion of water and sodium; this is referred to as pressure diuresis or pressure natriuresis, and it is crucial in the regulation of body fluid volumes and arterial pressure, as discussed in Chapters 19 and 29. Role of Tubuloglomerular Feedback in Autoregulation of GFR To perform the function of autoregulation, the kidneys have a feedback mechanism that links changes in sodium chloride concentration at the macula densa with the control of renal arteriolar resistance. This feedback helps ensure a relatively constant delivery of sodium chloride to the distal tubule and helps prevent spurious fluctuations in renal excretion that would otherwise occur. In many circumstances, this feedback 324 Unit V The Body Fluids and Kidneys autoregulates renal blood flow and GFR in parallel. However, because this mechanism is specifically directed toward stabilizing sodium chloride delivery to the distal tubule, there are instances when GFR is autoregulated at the expense of changes in renal blood flow, as discussed later. The tubuloglomerular feedback mechanism has two components that act together to control GFR: (1) an afferent arteriolar feedback mechanism and (2) an efferent arteriolar feedback mechanism. These feedback mechanisms depend on special anatomical arrangements of the juxtaglomerular complex (Figure 26–17). The juxtaglomerular complex consists of macula densa cells in the initial portion of the distal tubule and juxtaglomerular cells in the walls of the afferent and efferent arterioles. The macula densa is a specialized group of epithelial cells in the distal tubules that comes in close contact with the afferent and efferent arterioles. The macula densa cells contain Golgi apparatus, which are intracellular secretory organelles directed toward the arterioles, suggesting that these cells may be secreting a substance toward the arterioles. Decreased Macula Densa Sodium Chloride Causes Dilation of Afferent Arterioles and Increased Renin Release. The macula densa cells sense changes in volume delivery to the distal tubule by way of signals that are not completely understood. Experimental studies suggest that decreased GFR slows the flow rate in the loop of Henle, causing increased reabsorption of sodium and chloride ions in the ascending loop of Henle, thereby reducing the concentration of sodium chloride at the macula densa cells. This decrease in sodium chloride concentration initiates a signal from the macula densa that has two effects (Figure 26–18): (1) it decreases resistance to blood flow in the afferent arterioles, which raises glomerular hydrostatic pressure and helps return GFR toward normal, and (2) it increases renin release from the juxtaglomerular cells of the afferent and efferent arterioles, which are the major storage sites for renin. Renin released from these cells then functions as an enzyme to increase the formation of angiotensin I, which is converted to angiotensin II. Finally, the angiotensin II constricts the efferent arterioles, thereby increasing glomerular hydrostatic pressure and returning GFR toward normal. These two components of the tubuloglomerular feedback mechanism, operating together by way of the special anatomical structure of the juxtaglomerular apparatus, provide feedback signals to both the afferent and the efferent arterioles for efficient autoregulation of GFR during changes in arterial pressure. When both of these mechanisms are functioning together, the GFR changes only a few percentage points, even with large fluctuations in arterial pressure between the limits of 75 and 160 mm Hg. Arterial pressure - Glomerular hydrostatic pressure Glomerular epithelium GFR Proximal NaCl reabsorption Juxtaglomerular cells Afferent arteriole Efferent arteriole - Macula densa NaCl Renin Angiotensin II Internal elastic lamina Macula densa Smooth muscle fiber Distal tubule Efferent arteriolar resistance Basement membrane Afferent arteriolar resistance Figure 26–18 Figure 26–17 Structure of the juxtaglomerular apparatus, demonstrating its possible feedback role in the control of nephron function. Macula densa feedback mechanism for autoregulation of glomerular hydrostatic pressure and glomerular filtration rate (GFR) during decreased renal arterial pressure. Chapter 26 Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control Blockade of Angiotensin II Formation Further Reduces GFR During Renal Hypoperfusion. As discussed earlier, a preferential constrictor action of angiotensin II on efferent arterioles helps prevent serious reductions in glomerular hydrostatic pressure and GFR when renal perfusion pressure falls below normal. The administration of drugs that block the formation of angiotensin II (angiotensin-converting enzyme inhibitors) or that block the action of angiotensin II (angiotensin II antagonists) causes greater reductions in GFR than usual when the renal arterial pressure falls below normal. Therefore, an important complication of using these drugs to treat patients who have hypertension because of renal artery stenosis (partial blockage of the renal artery) is a severe decrease in GFR that can, in some cases, cause acute renal failure. Nevertheless, angiotensin II–blocking drugs can be useful therapeutic agents in many patients with hypertension, congestive heart failure, and other conditions, as long as they are monitored to ensure that severe decreases in GFR do not occur. Myogenic Autoregulation of Renal Blood Flow and GFR Another mechanism that contributes to the maintenance of a relatively constant renal blood flow and GFR is the ability of individual blood vessels to resist stretching during increased arterial pressure, a phenomenon referred to as the myogenic mechanism. Studies of individual blood vessels (especially small arterioles) throughout the body have shown that they respond to increased wall tension or wall stretch by contraction of the vascular smooth muscle. Stretch of the vascular wall allows increased movement of calcium ions from the extracellular fluid into the cells, causing them to contract through the mechanisms discussed in Chapter 8. This contraction prevents overdistention of the vessel and at the same time, by raising vascular resistance, helps prevent excessive increases in renal blood flow and GFR when arterial pressure increases. Although the myogenic mechanism probably operates in most arterioles throughout the body, its importance in renal blood flow and GFR autoregulation has been questioned by some physiologists because this pressure-sensitive mechanism has no means of directly detecting changes in renal blood flow or GFR per se. Other Factors That Increase Renal Blood Flow and GFR: High Protein Intake and Increased Blood Glucose Although renal blood flow and GFR are relatively stable under most conditions, there are circumstances in which these variables change significantly. For example, a high protein intake is known to increase both renal blood flow and GFR. With a chronic high-protein diet, such as one that contains large amounts of meat, the increases in GFR and renal blood flow are due partly to growth of the kidneys. However, GFR and renal blood flow increase 20 to 30 per cent within 1 or 2 hours after a person eats a high-protein meal. 325 The exact mechanisms by which this occurs are still not completely understood, but one possible explanation is the following: A high-protein meal increases the release of amino acids into the blood, which are reabsorbed in the proximal tubule. Because amino acids and sodium are reabsorbed together by the proximal tubules, increased amino acid reabsorption also stimulates sodium reabsorption in the proximal tubules. This decreases sodium delivery to the macula densa, which elicits a tubuloglomerular feedback–mediated decrease in resistance of the afferent arterioles, as discussed earlier.The decreased afferent arteriolar resistance then raises renal blood flow and GFR. This increased GFR allows sodium excretion to be maintained at a nearly normal level while increasing the excretion of the waste products of protein metabolism, such as urea. A similar mechanism may also explain the marked increases in renal blood flow and GFR that occur with large increases in blood glucose levels in uncontrolled diabetes mellitus. Because glucose, like some of the amino acids, is also reabsorbed along with sodium in the proximal tubule, increased glucose delivery to the tubules causes them to reabsorb excess sodium along with glucose. This, in turn, decreases delivery of sodium chloride to the macula densa, activating a tubuloglomerular feedback–mediated dilation of the afferent arterioles and subsequent increases in renal blood flow and GFR. These examples demonstrate that renal blood flow and GFR per se are not the primary variables controlled by the tubuloglomerular feedback mechanism. The main purpose of this feedback is to ensure a constant delivery of sodium chloride to the distal tubule, where final processing of the urine takes place. Thus, disturbances that tend to increase reabsorption of sodium chloride at tubular sites before the macula densa tend to elicit increased renal blood flow and GFR, which helps return distal sodium chloride delivery toward normal so that normal rates of sodium and water excretion can be maintained (see Figure 26–18). An opposite sequence of events occurs when proximal tubular reabsorption is reduced. For example, when the proximal tubules are damaged (which can occur as a result of poisoning by heavy metals, such as mercury, or large doses of drugs, such as tetracyclines), their ability to reabsorb sodium chloride is decreased. As a consequence, large amounts of sodium chloride are delivered to the distal tubule and, without appropriate compensations, would quickly cause excessive volume depletion. One of the important compensatory responses appears to be a tubuloglomerular feedback–mediated renal vasoconstriction that occurs in response to the increased sodium chloride delivery to the macula densa in these circumstances. These examples again demonstrate the importance of this feedback mechanism in ensuring that the distal tubule receives the proper rate of delivery of sodium chloride, other tubular fluid solutes, and tubular fluid volume so that appropriate amounts of these substances are excreted in the urine. References Beeuwkes R III: The vascular organization of the kidney. Annu Rev Physiol 42:531, 1980. Bell PD, Lapointe JY, Peti-Peterdi J: Macula densa cell signaling. Annu Rev Physiol 65:481, 2003. 326 Unit V The Body Fluids and Kidneys Blantz RC, Deng A, Lortie M, et al: The complex role of nitric oxide in the regulation of glomerular ultrafiltration. Kidney Int 61:782, 2002. Cowley AW Jr, Mori T, Mattson D, Zou AP: Role of renal NO production in the regulation of medullary blood flow. Am J Physiol Regul Integr Comp Physiol 284:R1355, 2003. Davis MJ, Hill MA: Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 79:387, 1999. Deen WM, Lazzara MJ, Myers BD: Structural determinants of glomerular permeability. Am J Physiol Renal Physiol 281:F579, 2001. DiBona GF: Neural control of the kidney: past, present, and future. Hypertension 41:621, 2003. Hall JE: Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney. J Am Soc Nephrol 10 (Suppl 12):s258, 1999. Hall JE, Brands MW: The renin-angiotensin-aldosterone system: renal mechanisms and circulatory homeostasis. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 1009-1046. Haraldsson B, Sörensson J: Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier. News Physiol Sci 19:7, 2004. Kriz W, Kaissling B: Structural organization of the mammalian kidney. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 587-654. Navar LG, Kobori H, Prieto-Carrasquero M: Intrarenal angiotensin II and hypertension. Curr Hypertens Rep 5:135, 2003. Pallone TL, Zhang Z, Rhinehart K: Physiology of the renal medullary microcirculation. Am J Physiol Renal Physiol 284:F253, 2003. Roman RJ: P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82:131, 2002. Schnermann J, Levine DZ: Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide. Annu Rev Physiol 65:501, 2003. Whelton A: Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2-specific inhibitors. Am J Med 110 (Suppl 3A):33S, 2001. C H A P T E R 2 7 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Reabsorption and Secretion by the Renal Tubules As the glomerular filtrate enters the renal tubules, it flows sequentially through the successive parts of the tubule—the proximal tubule, the loop of Henle, the distal tubule, the collecting tubule, and, finally, the collecting duct—before it is excreted as urine. Along this course, some substances are selectively reabsorbed from the tubules back into the blood, whereas others are secreted from the blood into the tubular lumen. Eventually, the urine that is formed and all the substances in the urine represent the sum of three basic renal processes—glomerular filtration, tubular reabsorption, and tubular secretion—as follows: Urinary excretion = Glomerular filtration - Tubular reabsorption + Tubular secretion For many substances, reabsorption plays a much more important role than does secretion in determining the final urinary excretion rate. However, secretion accounts for significant amounts of potassium ions, hydrogen ions, and a few other substances that appear in the urine. Tubular Reabsorption Is Selective and Quantitatively Large Table 27–1 shows the renal handling of several substances that are all freely filtered in the kidneys and reabsorbed at variable rates. The rate at which each of these substances is filtered is calculated as Filtration = Glomerular filtration rate ¥ Plasma concentration This calculation assumes that the substance is freely filtered and not bound to plasma proteins. For example, if plasma glucose concentration is 1 g/L, the amount of glucose filtered each day is about 180 L/day ¥ 1 g/L, or 180 g/day. Because virtually none of the filtered glucose is normally excreted, the rate of glucose reabsorption is also 180 g/day. From Table 27–1, two things are immediately apparent. First, the processes of glomerular filtration and tubular reabsorption are quantitatively very large relative to urinary excretion for many substances. This means that a small change in glomerular filtration or tubular reabsorption can potentially cause a relatively large change in urinary excretion. For example, a 10 per cent decrease in tubular reabsorption, from 178.5 to 160.7 L/day, would increase urine volume from 1.5 to 19.3 L/day (almost a 13-fold increase) if the glomerular filtration rate (GFR) remained constant. In reality, however, changes in tubular reabsorption and glomerular filtration are closely coordinated, so that large fluctuations in urinary excretion are avoided. Second, unlike glomerular filtration, which is relatively nonselective (that is, essentially all solutes in the plasma are filtered except the plasma proteins or substances bound to them), tubular reabsorption is highly selective. Some substances, such as glucose and amino acids, are almost completely reabsorbed 327 328 Unit V The Body Fluids and Kidneys Table 27–1 Filtration, Reabsorption, and Excretion Rates of Different Substances by the Kidneys Glucose (g/day) Bicarbonate (mEq/day) Sodium (mEq/day) Chloride (mEq/day) Potassium (mEq/day) Urea (g/day) Creatinine (g/day) Amount Filtered Amount Reabsorbed Amount Excreted % of Filtered Load Reabsorbed 180 4,320 25,560 19,440 756 46.8 1.8 180 4,318 25,410 19,260 664 23.4 0 0 2 150 180 92 23.4 1.8 100 >99.9 99.4 99.1 87.8 50 0 from the tubules, so that the urinary excretion rate is essentially zero. Many of the ions in the plasma, such as sodium, chloride, and bicarbonate, are also highly reabsorbed, but their rates of reabsorption and urinary excretion are variable, depending on the needs of the body. Certain waste products, such as urea and creatinine, conversely, are poorly reabsorbed from the tubules and excreted in relatively large amounts. Therefore, by controlling the rate at which they reabsorb different substances, the kidneys regulate the excretion of solutes independently of one another, a capability that is essential for precise control of the composition of body fluids. In this chapter, we discuss the mechanisms that allow the kidneys to selectively reabsorb or secrete different substances at variable rates. Tubular Reabsorption Includes Passive and Active Mechanisms For a substance to be reabsorbed, it must first be transported (1) across the tubular epithelial membranes into the renal interstitial fluid and then (2) through the peritubular capillary membrane back into the blood (Figure 27–1). Thus, reabsorption of water and solutes includes a series of transport steps. Reabsorption across the tubular epithelium into the interstitial fluid includes active or passive transport by way of the same basic mechanisms discussed in Chapter 4 for transport across other membranes of the body. For instance, water and solutes can be transported either through the cell membranes themselves (transcellular route) or through the junctional spaces between the cells (paracellular route). Then, after absorption across the tubular epithelial cells into the interstitial fluid, water and solutes are transported the rest of the way through the peritubular capillary walls into the blood by ultrafiltration (bulk flow) that is mediated by hydrostatic and colloid osmotic forces. The peritubular capillaries behave very much like the venous ends of most other capillaries because there is a net reabsorptive force that moves the fluid and solutes from the interstitium into the blood. Peritubular capillary Tubular cells FILTRATION Lumen Paracellular path Bulk flow ATP Blood Active Passive (diffusion) Osmosis REABSORPTION Transcellular path Solutes H2O EXCRETION Figure 27–1 Reabsorption of filtered water and solutes from the tubular lumen across the tubular epithelial cells, through the renal interstitium, and back into the blood. Solutes are transported through the cells (transcellular route) by passive diffusion or active transport, or between the cells (paracellular route) by diffusion. Water is transported through the cells and between the tubular cells by osmosis. Transport of water and solutes from the interstitial fluid into the peritubular capillaries occurs by ultrafiltration (bulk flow). Active Transport Active transport can move a solute against an electrochemical gradient and requires energy derived from metabolism. Transport that is coupled directly to an energy source, such as the hydrolysis of adenosine triphosphate (ATP), is termed primary active transport. A good example of this is the sodium-potassium ATPase pump that functions throughout most parts of the renal tubule. Transport that is coupled indirectly to an energy source, such as that due to an ion gradient, is referred to as secondary active transport. Reabsorption of glucose by the renal tubule is an example of secondary active transport. Although solutes can be reabsorbed by active and/or passive mechanisms by the tubule, water is always reabsorbed by a passive Chapter 27 329 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate (nonactive) physical mechanism called osmosis, which means water diffusion from a region of low solute concentration (high water concentration) to one of high solute concentration (low water concentration). Peritubular capillary Tubular epithelial cells Na+ Solutes Can Be Transported Through Epithelial Cells or Between Cells. Renal tubular cells, like other epithelial cells, are held together by tight junctions. Lateral intercellular spaces lie behind the tight junctions and separate the epithelial cells of the tubule. Solutes can be reabsorbed or secreted across the cells by way of the transcellular pathway or between the cells by moving across the tight junctions and intercellular spaces by way of the paracellular pathway. Sodium is a substance that moves through both routes, although most of the sodium is transported through the transcellular pathway. In some nephron segments, especially the proximal tubule, water is also reabsorbed across the paracellular pathway, and substances dissolved in the water, especially potassium, magnesium, and chloride ions, are carried with the reabsorbed fluid between the cells. Primary Active Transport Through the Tubular Membrane Is Linked to Hydrolysis of ATP. The special importance of primary active transport is that it can move solutes against an electrochemical gradient. The energy for this active transport comes from the hydrolysis of ATP by way of membrane-bound ATPase; the ATPase is also a component of the carrier mechanism that binds and moves solutes across the cell membranes. The primary active transporters that are known include sodiumpotassium ATPase, hydrogen ATPase, hydrogenpotassium ATPase, and calcium ATPase. A good example of a primary active transport system is the reabsorption of sodium ions across the proximal tubular membrane, as shown in Figure 27–2. On the basolateral sides of the tubular epithelial cell, the cell membrane has an extensive sodium-potassium ATPase system that hydrolyzes ATP and uses the released energy to transport sodium ions out of the cell into the interstitium. At the same time, potassium is transported from the interstitium to the inside of the cell. The operation of this ion pump maintains low intracellular sodium and high intracellular potassium concentrations and creates a net negative charge of about -70 millivolts within the cell. This pumping of sodium out of the cell across the basolateral membrane of the cell favors passive diffusion of sodium across the luminal membrane of the cell, from the tubular lumen into the cell, for two reasons: (1) There is a concentration gradient favoring sodium diffusion into the cell because intracellular sodium concentration is low (12 mEq/L) and tubular fluid sodium concentration is high (140 mEq/L). (2) The negative, -70-millivolt, intracellular potential attracts the positive sodium ions from the tubular lumen into the cell. Active reabsorption of sodium by sodiumpotassium ATPase occurs in most parts of the tubule. In certain parts of the nephron, there are additional provisions for moving large amounts of sodium into the cell. In the proximal tubule, there is an extensive Tubular lumen ATP Na+ ATP K+ K+ (-70 mV) Basal channels Interstitial fluid Basement membrane Na+ (-3 mv) Tight junction Brush border (luminal membrane) Intercellular space Figure 27–2 Basic mechanism for active transport of sodium through the tubular epithelial cell. The sodium-potassium pump transports sodium from the interior of the cell across the basolateral membrane, creating a low intracellular sodium concentration and a negative intracellular electrical potential. The low intracellular sodium concentration and the negative electrical potential cause sodium ions to diffuse from the tubular lumen into the cell through the brush border. brush border on the luminal side of the membrane (the side that faces the tubular lumen) that multiplies the surface area about 20-fold. There are also sodium carrier proteins that bind sodium ions on the luminal surface of the membrane and release them inside the cell, providing facilitated diffusion of sodium through the membrane into the cell. These sodium carrier proteins are also important for secondary active transport of other substances, such as glucose and amino acids, as discussed later. Thus, the net reabsorption of sodium ions from the tubular lumen back into the blood involves at least three steps: 1. Sodium diffuses across the luminal membrane (also called the apical membrane) into the cell down an electrochemical gradient established by the sodium-potassium ATPase pump on the basolateral side of the membrane. 2. Sodium is transported across the basolateral membrane against an electrochemical gradient by the sodium-potassium ATPase pump. 3. Sodium, water, and other substances are reabsorbed from the interstitial fluid into the peritubular capillaries by ultrafiltration, a passive process driven by the hydrostatic and colloid osmotic pressure gradients. Secondary Active Reabsorption Through the Tubular Membrane. In secondary active transport, two or more substances interact with a specific membrane protein (a carrier molecule) and are transported together across the membrane. As one of the substances (for instance, sodium) diffuses down its electrochemical gradient, the energy released is used to drive another substance 330 Unit V Interstitial fluid Tubular cells The Body Fluids and Kidneys Tubular lumen Co-transport Glucose Glucose Na+ Na+ K+ K+ -70 mV ATP Na+ ATP Amino acids Amino acids Na+ Na+ -70 mV H+ Counter-transport Figure 27–3 Mechanisms of secondary active transport. The upper cell shows the co-transport of glucose and amino acids along with sodium ions through the apical side of the tubular epithelial cells, followed by facilitated diffusion through the basolateral membranes. The lower cell shows the counter-transport of hydrogen ions from the interior of the cell across the apical membrane and into the tubular lumen; movement of sodium ions into the cell, down an electrochemical gradient established by the sodium-potassium pump on the basolateral membrane, provides the energy for transport of the hydrogen ions from inside the cell into the tubular lumen. (for instance, glucose) against its electrochemical gradient. Thus, secondary active transport does not require energy directly from ATP or from other highenergy phosphate sources. Rather, the direct source of the energy is that liberated by the simultaneous facilitated diffusion of another transported substance down its own electrochemical gradient. Figure 27–3 shows secondary active transport of glucose and amino acids in the proximal tubule. In both instances, a specific carrier protein in the brush border combines with a sodium ion and an amino acid or a glucose molecule at the same time. These transport mechanisms are so efficient that they remove virtually all the glucose and amino acids from the tubular lumen. After entry into the cell, glucose and amino acids exit across the basolateral membranes by facilitated diffusion, driven by the high glucose and amino acid concentrations in the cell. Although transport of glucose against a chemical gradient does not directly use ATP, the reabsorption of glucose depends on energy expended by the primary active sodium-potassium ATPase pump in the basolateral membrane. Because of the activity of this pump, an electrochemical gradient for facilitated diffusion of sodium across the luminal membrane is maintained, and it is this downhill diffusion of sodium to the interior of the cell that provides the energy for the simultaneous uphill transport of glucose across the luminal membrane. Thus, this reabsorption of glucose is referred to as “secondary active transport” because glucose itself is reabsorbed uphill against a chemical gradient, but it is “secondary” to primary active transport of sodium. Another important point is that a substance is said to undergo “active” transport when at least one of the steps in the reabsorption involves primary or secondary active transport, even though other steps in the reabsorption process may be passive. For glucose reabsorption, secondary active transport occurs at the luminal membrane, but passive facilitated diffusion occurs at the basolateral membrane, and passive uptake by bulk flow occurs at the peritubular capillaries. Secondary Active Secretion into the Tubules. Some sub- stances are secreted into the tubules by secondary active transport. This often involves counter-transport of the substance with sodium ions. In countertransport, the energy liberated from the downhill movement of one of the substances (for example, sodium ions) enables uphill movement of a second substance in the opposite direction. One example of counter-transport, shown in Figure 27–3, is the active secretion of hydrogen ions coupled to sodium reabsorption in the luminal membrane of the proximal tubule. In this case, sodium entry into the cell is coupled with hydrogen extrusion from the cell by sodium-hydrogen counter-transport. This transport is mediated by a specific protein in the brush border of the luminal membrane. As sodium is carried to the interior of the cell, hydrogen ions are forced outward in the opposite direction into the tubular lumen. The basic principles of primary and secondary active transport are discussed in additional detail in Chapter 4. Pinocytosis—An Active Transport Mechanism for Reabsorption of Proteins. Some parts of the tubule, especially the proximal tubule, reabsorb large molecules such as proteins by pinocytosis. In this process, the protein attaches to the brush border of the luminal membrane, and this portion of the membrane then invaginates to the interior of the cell until it is completely pinched off and a vesicle is formed containing the protein. Once inside the cell, the protein is digested into its constituent amino acids, which are reabsorbed through the basolateral membrane into the interstitial fluid. Because pinocytosis requires energy, it is considered a form of active transport. Transport Maximum for Substances That Are Actively Reabsorbed. For most substances that are actively reab- sorbed or secreted, there is a limit to the rate at which the solute can be transported, often referred to as the transport maximum. This limit is due to saturation of the specific transport systems involved when the amount of solute delivered to the tubule (referred to as tubular load) exceeds the capacity of the carrier proteins and specific enzymes involved in the transport process. Chapter 27 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Glucose filtered load, reabsorption or excretion (mg/min) 900 800 700 Filtered load 600 Excretion 500 400 Transport maximum 300 Reabsorption Normal 200 100 331 nephrons have the same transport maximum for glucose, and some of the nephrons excrete glucose before others have reached their transport maximum. The overall transport maximum for the kidneys, which is normally about 375 mg/min, is reached when all nephrons have reached their maximal capacity to reabsorb glucose. The plasma glucose of a healthy person almost never becomes high enough to cause excretion of glucose in the urine, even after eating a meal. However, in uncontrolled diabetes mellitus, plasma glucose may rise to high levels, causing the filtered load of glucose to exceed the transport maximum and resulting in urinary glucose excretion. Some of the important transport maximums for substances actively reabsorbed by the tubules are as follows: Threshold Substance 0 0 100 200 300 400 500 600 700 800 Plasma glucose concentration (mg/100 ml) Figure 27–4 Relations among the filtered load of glucose, the rate of glucose reabsorption by the renal tubules, and the rate of glucose excretion in the urine. The transport maximum is the maximum rate at which glucose can be reabsorbed from the tubules. The threshold for glucose refers to the filtered load of glucose at which glucose first begins to be excreted in the urine. Glucose Phosphate Sulfate Amino acids Urate Lactate Plasma protein 375 mg/min 0.10 mM/min 0.06 mM/min 1.5 mM/min 15 mg/min 75 mg/min 30 mg/min Transport Maximums for Substances That Are Actively Secreted. Substances that are actively secreted also exhibit transport maximums as follows: Substance The glucose transport system in the proximal tubule is a good example. Normally, measurable glucose does not appear in the urine because essentially all the filtered glucose is reabsorbed in the proximal tubule. However, when the filtered load exceeds the capability of the tubules to reabsorb glucose, urinary excretion of glucose does occur. In the adult human, the transport maximum for glucose averages about 375 mg/min, whereas the filtered load of glucose is only about 125 mg/min (GFR ¥ plasma glucose = 125 ml/min ¥ 1 mg/ml). With large increases in GFR and/or plasma glucose concentration that increase the filtered load of glucose above 375 mg/ min, the excess glucose filtered is not reabsorbed and passes into the urine. Figure 27–4 shows the relation between plasma concentration of glucose, filtered load of glucose, tubular transport maximum for glucose, and rate of glucose loss in the urine. Note that when the plasma glucose concentration is 100 mg/100 mL and the filtered load is at its normal level, 125 mg/min, there is no loss of glucose in the urine. However, when the plasma concentration of glucose rises above about 200 mg/100 ml, increasing the filtered load to about 250 mg/min, a small amount of glucose begins to appear in the urine. This point is termed the threshold for glucose. Note that this appearance of glucose in the urine (at the threshold) occurs before the transport maximum is reached. One reason for the difference between threshold and transport maximum is that not all Transport Maximum Creatinine Para-aminohippuric acid Transport Maximum 16 mg/min 80 mg/min Substances That Are Actively Transported but Do Not Exhibit a Transport Maximum. The reason that actively trans- ported solutes often exhibit a transport maximum is that the transport carrier system becomes saturated as the tubular load increases. Substances that are passively reabsorbed do not demonstrate a transport maximum because their rate of transport is determined by other factors, such as (1) the electrochemical gradient for diffusion of the substance across the membrane, (2) the permeability of the membrane for the substance, and (3) the time that the fluid containing the substance remains within the tubule. Transport of this type is referred to as gradient-time transport because the rate of transport depends on the electrochemical gradient and the time that the substance is in the tubule, which in turn depends on the tubular flow rate. Some actively transported substances also have characteristics of gradient-time transport. An example is sodium reabsorption in the proximal tubule. The main reason that sodium transport in the proximal tubule does not exhibit a transport maximum is that other factors limit the reabsorption rate besides the maximum rate of active transport. For example, in the proximal tubules, the maximum transport capacity of the basolateral sodium-potassium ATPase pump is usually far greater than the actual rate of net sodium 332 Unit V The Body Fluids and Kidneys reabsorption. One of the reasons for this is that a significant amount of sodium transported out of the cell leaks back into the tubular lumen through the epithelial tight junctions. The rate at which this backleak occurs depends on several factors, including (1) the permeability of the tight junctions and (2) the interstitial physical forces, which determine the rate of bulk flow reabsorption from the interstitial fluid into the peritubular capillaries. Therefore, sodium transport in the proximal tubules obeys mainly gradienttime transport principles rather than tubular maximum transport characteristics. This means that the greater the concentration of sodium in the proximal tubules, the greater its reabsorption rate. Also, the slower the flow rate of tubular fluid, the greater the percentage of sodium that can be reabsorbed from the proximal tubules. In the more distal parts of the nephron, the epithelial cells have much tighter junctions and transport much smaller amounts of sodium. In these segments, sodium reabsorption exhibits a transport maximum similar to that for other actively transported substances. Furthermore, this transport maximum can be increased in response to certain hormones, such as aldosterone. Passive Water Reabsorption by Osmosis Is Coupled Mainly to Sodium Reabsorption When solutes are transported out of the tubule by either primary or secondary active transport, their concentrations tend to decrease inside the tubule while increasing in the renal interstitium. This creates a concentration difference that causes osmosis of water in the same direction that the solutes are transported, from the tubular lumen to the renal interstitium. Some parts of the renal tubule, especially the proximal tubule, are highly permeable to water, and water reabsorption occurs so rapidly that there is only a small concentration gradient for solutes across the tubular membrane. A large part of the osmotic flow of water occurs through the so-called tight junctions between the epithelial cells as well as through the cells themselves. The reason for this, as already discussed, is that the junctions between the cells are not as tight as their name would imply, and they allow significant diffusion of water and small ions. This is especially true in the proximal tubules, which have a high permeability for water and a smaller but significant permeability to most ions, such as sodium, chloride, potassium, calcium, and magnesium. As water moves across the tight junctions by osmosis, it can also carry with it some of the solutes, a process referred to as solvent drag. And because the reabsorption of water, organic solutes, and ions is coupled to sodium reabsorption, changes in sodium reabsorption significantly influence the reabsorption of water and many other solutes. In the more distal parts of the nephron, beginning in the loop of Henle and extending through the col- lecting tubule, the tight junctions become far less permeable to water and solutes, and the epithelial cells also have a greatly decreased membrane surface area. Therefore, water cannot move easily across the tubular membrane by osmosis. However, antidiuretic hormone (ADH) greatly increases the water permeability in the distal and collecting tubules, as discussed later. Thus, water movement across the tubular epithelium can occur only if the membrane is permeable to water, no matter how large the osmotic gradient. In the proximal tubule, the water permeability is always high, and water is reabsorbed as rapidly as the solutes. In the ascending loop of Henle, water permeability is always low, so that almost no water is reabsorbed, despite a large osmotic gradient. Water permeability in the last parts of the tubules—the distal tubules, collecting tubules, and collecting ducts—can be high or low, depending on the presence or absence of ADH. Reabsorption of Chloride, Urea, and Other Solutes by Passive Diffusion When sodium is reabsorbed through the tubular epithelial cell, negative ions such as chloride are transported along with sodium because of electrical potentials. That is, transport of positively charged sodium ions out of the lumen leaves the inside of the lumen negatively charged, compared with the interstitial fluid. This causes chloride ions to diffuse passively through the paracellular pathway. Additional reabsorption of chloride ions occurs because of a chloride concentration gradient that develops when water is reabsorbed from the tubule by osmosis, thereby concentrating the chloride ions in the tubular lumen (Figure 27–5). Thus, the active reabsorption of sodium is closely coupled to the passive reabsorption of chloride by way of an electrical potential and a chloride concentration gradient. Na+ reabsorption H2O reabsorption Lumen negative potential Luminal Clconcentration Passive Clreabsorption Luminal urea concentration Passive urea reabsorption Figure 27–5 Mechanisms by which water, chloride, and urea reabsorption are coupled with sodium reabsorption. Chapter 27 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Chloride ions can also be reabsorbed by secondary active transport. The most important of the secondary active transport processes for chloride reabsorption involves co-transport of chloride with sodium across the luminal membrane. Urea is also passively reabsorbed from the tubule, but to a much lesser extent than chloride ions. As water is reabsorbed from the tubules (by osmosis coupled to sodium reabsorption), urea concentration in the tubular lumen increases (see Figure 27–5). This creates a concentration gradient favoring the reabsorption of urea. However, urea does not permeate the tubule as readily as water. In some parts of the nephron, especially the inner medullary collecting duct, passive urea reabsorption is facilitated by specific urea transporters. Yet only about one half of the urea that is filtered by the glomerular capillaries is reabsorbed from the tubules. The remainder of the urea passes into the urine, allowing the kidneys to excrete large amounts of this waste product of metabolism. Another waste product of metabolism, creatinine, is an even larger molecule than urea and is essentially impermeant to the tubular membrane. Therefore, almost none of the creatinine that is filtered is reabsorbed, so that virtually all the creatinine filtered by the glomerulus is excreted in the urine. Reabsorption and Secretion Along Different Parts of the Nephron In the previous sections, we discussed the basic principles by which water and solutes are transported across the tubular membrane. With these generalizations in mind, we can now discuss the different characteristics of the individual tubular segments that enable them to perform their specific excretory functions. Only the tubular transport functions that are quantitatively most important are discussed, especially as they relate to the reabsorption of sodium, chloride, and water. In subsequent chapters, we discuss the reabsorption and secretion of other specific substances in different parts of the tubular system. Proximal Tubular Reabsorption Normally, about 65 per cent of the filtered load of sodium and water and a slightly lower percentage of filtered chloride are reabsorbed by the proximal tubule before the filtrate reaches the loops of Henle. These percentages can be increased or decreased in different physiologic conditions, as discussed later. Proximal Tubules Have a High Capacity for Active and Passive Reabsorption. The high capacity of the proximal tubule for reabsorption results from its special cellular characteristics, as shown in Figure 27–6. The proximal tubule epithelial cells are highly metabolic and have large numbers of mitochondria to support potent active transport processes. In addition, the proximal 333 65% Proximal tubule Na+, Cl-, HCO3-, K+, H2O, glucose, amino acids Isosmotic H+, organic acids, bases Figure 27–6 Cellular ultrastructure and primary transport characteristics of the proximal tubule. The proximal tubules reabsorb about 65 per cent of the filtered sodium, chloride, bicarbonate, and potassium and essentially all the filtered glucose and amino acids. The proximal tubules also secrete organic acids, bases, and hydrogen ions into the tubular lumen. tubular cells have an extensive brush border on the luminal (apical) side of the membrane as well as an extensive labyrinth of intercellular and basal channels, all of which together provide an extensive membrane surface area on the luminal and basolateral sides of the epithelium for rapid transport of sodium ions and other substances. The extensive membrane surface of the epithelial brush border is also loaded with protein carrier molecules that transport a large fraction of the sodium ions across the luminal membrane linked by way of the cotransport mechanism with multiple organic nutrients such as amino acids and glucose. The remainder of the sodium is transported from the tubular lumen into the cell by counter-transport mechanisms, which reabsorb sodium while secreting other substances into the tubular lumen, especially hydrogen ions. As discussed in Chapter 30, the secretion of hydrogen ions into the tubular lumen is an important step in the removal of bicarbonate ions from the tubule (by combining H+ _ with the HCO3 to form H2CO3, which then dissociates into H2O and CO2). Although the sodium-potassium ATPase pump provides the major force for reabsorption of sodium, chloride, and water throughout the proximal tubule, there are some differences in the mechanisms by which sodium and chloride are transported through the luminal side of the early and late portions of the proximal tubular membrane. In the first half of the proximal tubule, sodium is reabsorbed by co-transport along with glucose, amino acids, and other solutes. But in the second half of the proximal tubule, little glucose and amino acids remain to be reabsorbed. Instead, sodium is now reabsorbed mainly with chloride ions. The second half of the proximal tubule has a relatively high concentration of chloride (around 140 mEq/L) compared with the early 334 Unit V The Body Fluids and Kidneys Secretion of Organic Acids and Bases by the Proximal Tubule. 5.0 Tubular fluid / plasma concentration Creatinine 2.0 Cl- Urea 1.0 Na+ Osmolality 0.5 HCO3- 0.2 0.1 Glucose 0.05 Amino acids 0.01 0 20 40 60 80 % Total proximal tubule length 100 Figure 27–7 Changes in concentrations of different substances in tubular fluid along the proximal convoluted tubule relative to the concentrations of these substances in the plasma and in the glomerular filtrate. A value of 1.0 indicates that the concentration of the substance in the tubular fluid is the same as the concentration in the plasma. Values below 1.0 indicate that the substance is reabsorbed more avidly than water, whereas values above 1.0 indicate that the substance is reabsorbed to a lesser extent than water or is secreted into the tubules. proximal tubule (about 105 mEq/L) because when sodium is reabsorbed, it preferentially carries with it glucose, bicarbonate, and organic ions in the early proximal tubule, leaving behind a solution that has a higher concentration of chloride. In the second half of the proximal tubule, the higher chloride concentration favors the diffusion of this ion from the tubule lumen through the intercellular junctions into the renal interstitial fluid. Concentrations of Solutes Along the Proximal Tubule. Figure 27–7 summarizes the changes in concentrations of various solutes along the proximal tubule. Although the amount of sodium in the tubular fluid decreases markedly along the proximal tubule, the concentration of sodium (and the total osmolarity) remains relatively constant because water permeability of the proximal tubules is so great that water reabsorption keeps pace with sodium reabsorption. Certain organic solutes, such as glucose, amino acids, and bicarbonate, are much more avidly reabsorbed than water, so that their concentrations decrease markedly along the length of the proximal tubule. Other organic solutes that are less permeant and not actively reabsorbed, such as creatinine, increase their concentration along the proximal tubule. The total solute concentration, as reflected by osmolarity, remains essentially the same all along the proximal tubule because of the extremely high permeability of this part of the nephron to water. The proximal tubule is also an important site for secretion of organic acids and bases such as bile salts, oxalate, urate, and catecholamines. Many of these substances are the end products of metabolism and must be rapidly removed from the body. The secretion of these substances into the proximal tubule plus filtration into the proximal tubule by the glomerular capillaries and the almost total lack of reabsorption by the tubules, all combined, contribute to rapid excretion in the urine. In addition to the waste products of metabolism, the kidneys secrete many potentially harmful drugs or toxins directly through the tubular cells into the tubules and rapidly clear these substances from the blood. In the case of certain drugs, such as penicillin and salicylates, the rapid clearance by the kidneys creates a problem in maintaining a therapeutically effective drug concentration. Another compound that is rapidly secreted by the proximal tubule is para-aminohippuric acid (PAH). PAH is secreted so rapidly that the average person can clear about 90 per cent of the PAH from the plasma flowing through the kidneys and excrete it in the urine. For this reason, the rate of PAH clearance can be used to estimate the renal plasma flow, as discussed later. Solute and Water Transport in the Loop of Henle The loop of Henle consists of three functionally distinct segments: the thin descending segment, the thin ascending segment, and the thick ascending segment. The thin descending and thin ascending segments, as their names imply, have thin epithelial membranes with no brush borders, few mitochondria, and minimal levels of metabolic activity (Figure 27–8). The descending part of the thin segment is highly permeable to water and moderately permeable to most solutes, including urea and sodium. The function of this nephron segment is mainly to allow simple diffusion of substances through its walls. About 20 per cent of the filtered water is reabsorbed in the loop of Henle, and almost all of this occurs in the thin descending limb. The ascending limb, including both the thin and the thick portions, is virtually impermeable to water, a characteristic that is important for concentrating the urine. The thick segment of the loop of Henle, which begins about halfway up the ascending limb, has thick epithelial cells that have high metabolic activity and are capable of active reabsorption of sodium, chloride, and potassium (see Figure 27–8). About 25 per cent of the filtered loads of sodium, chloride, and potassium are reabsorbed in the loop of Henle, mostly in the thick ascending limb. Considerable amounts of other ions, such as calcium, bicarbonate, and magnesium, are also reabsorbed in the thick ascending loop of Henle. The thin segment of the ascending limb has a much lower reabsorptive capacity than the thick segment, Chapter 27 335 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Renal interstitial fluid Thin descending loop of Henle Tubular lumen (+8 mV) Tubular cells Na+, K+ Mg++, Ca++ Paracellular diffusion H2O Na+ Na+ K+ ATP H+ Cl- 25% K+ Na+ 2Cl- K+ Thick ascending loop of Henle Loop diuretics • Furosemide • Ethacrynic acid • Bumetanide Na+, Cl-, K+, HCO3-, Mg++ Ca++, Hypoosmotic Figure 27–9 H+ Figure 27–8 Cellular ultrastructure and transport characteristics of the thin descending loop of Henle (top) and the thick ascending segment of the loop of Henle (bottom). The descending part of the thin segment of the loop of Henle is highly permeable to water and moderately permeable to most solutes but has few mitochondria and little or no active reabsorption. The thick ascending limb of the loop of Henle reabsorbs about 25 per cent of the filtered loads of sodium, chloride, and potassium, as well as large amounts of calcium, bicarbonate, and magnesium. This segment also secretes hydrogen ions into the tubular lumen. and the thin descending limb does not reabsorb significant amounts of any of these solutes. An important component of solute reabsorption in the thick ascending limb is the sodium-potassium ATPase pump in the epithelial cell basolateral membranes. As in the proximal tubule, the reabsorption of other solutes in the thick segment of the ascending loop of Henle is closely linked to the reabsorptive capability of the sodium-potassium ATPase pump, which maintains a low intracellular sodium concentration. The low intracellular sodium concentration in turn provides a favorable gradient for movement of sodium from the tubular fluid into the cell. In the thick ascending loop, movement of sodium across the luminal membrane is mediated primarily by a 1-sodium, 2-chloride, 1-potassium co-transporter (Figure 27–9). This co-transport protein carrier in the luminal membrane uses the potential energy released by downhill diffusion of sodium into the cell to drive the reabsorption of potassium into the cell against a concentration gradient. Mechanisms of sodium, chloride, and potassium transport in the thick ascending loop of Henle. The sodium-potassium ATPase pump in the basolateral cell membrane maintains a low intracellular sodium concentration and a negative electrical potential in the cell. The 1-sodium, 2-chloride, 1-potassium co-transporter in the luminal membrane transports these three ions from the tubular lumen into the cells, using the potential energy released by diffusion of sodium down an electrochemical gradient into the cells. Sodium is also transported into the tubular cell by sodium-hydrogen counter-transport. The positive charge (+8 mV) of the tubular lumen relative to the interstitial fluid forces cations such as Mg++ and Ca++ to diffuse from the lumen to the interstitial fluid via the paracellular pathway. The thick ascending limb of the loop of Henle is the site of action of the powerful “loop” diuretics furosemide, ethacrynic acid, and bumetanide, all of which inhibit the action of the sodium 2-chloride, potassium co-transporter. These diuretics are discussed in Chapter 31. There is also significant paracellular reabsorption of cations, such as Mg++, Ca++, Na+, and K+, in the thick ascending limb owing to the slight positive charge of the tubular lumen relative to the interstitial fluid. Although the 1-sodium, 2-chloride, 1-potassium cotransporter moves equal amounts of cations and anions into the cell, there is a slight backleak of potassium ions into the lumen, creating a positive charge of about +8 millivolts in the tubular lumen. This positive charge forces cations such as Mg++ and Ca++ to diffuse from the tubular lumen through the paracellular space and into the interstitial fluid. The thick ascending limb also has a sodiumhydrogen counter-transport mechanism in its luminal cell membrane that mediates sodium reabsorption and hydrogen secretion in this segment. The thick segment of the ascending loop of Henle is virtually impermeable to water. Therefore, most of the water delivered to this segment remains in the tubule, 336 Unit V The Body Fluids and Kidneys despite reabsorption of large amounts of solute. The tubular fluid in the ascending limb becomes very dilute as it flows toward the distal tubule, a feature that is important in allowing the kidneys to dilute or concentrate the urine under different conditions, as we discuss much more fully in Chapter 28. Distal Tubule The thick segment of the ascending limb of the loop of Henle empties into the distal tubule. The very first portion of the distal tubule forms part of the juxtaglomerular complex that provides feedback control of GFR and blood flow in this same nephron. The next part of the distal tubule is highly convoluted and has many of the same reabsorptive characteristics of the thick segment of the ascending limb of the loop of Henle. That is, it avidly reabsorbs most of the ions, including sodium, potassium, and chloride, but is virtually impermeable to water and urea. For this reason, it is referred to as the diluting segment because it also dilutes the tubular fluid. Approximately 5 percent of the filtered load of sodium chloride is reabsorbed in the early distal tubule. The sodium-chloride co-transporter moves sodium chloride from the tubular lumen into the cell, and the sodium-potassium ATPase pump transports sodium out of the cell across the basolateral membrane (Figure 27–10). Chloride diffuses out of the cell into the renal interstitial fluid through chloride channels in the basolateral membrane. The thiazide diuretics, which are widely used to treat disorders such as hypertension and heart failure, inhibit the sodiumchloride co-transporter. Renal interstitial fluid Tubular cells Late Distal Tubule and Cortical Collecting Tubule The second half of the distal tubule and the subsequent cortical collecting tubule have similar functional characteristics. Anatomically, they are composed of two distinct cell types, the principal cells and the intercalated cells (Figure 27–11). The principal cells reabsorb sodium and water from the lumen and secrete potassium ions into the lumen. The intercalated cells reabsorb potassium ions and secrete hydrogen ions into the tubular lumen. Principal Cells Reabsorb Sodium and Secrete Potassium. Sodium reabsorption and potassium secretion by the principal cells depend on the activity of a sodiumpotassium ATPase pump in each cell’s basolateral membrane (Figure 27–12). This pump maintains a low sodium concentration inside the cell and, therefore, favors sodium diffusion into the cell through special Early distal tubule Na+, Cl-, Ca++, Mg++ Late distal tubule and collecting tubule Principal Na+, Clcells Tubular lumen (-10mV) K+ (+ADH) H2O H+ Na+ K+ ATP Na+ Intercalated cells - K+ HCO3- ClCl- Figure 27–11 Thiazide diuretics: Figure 27–10 Mechanism of sodium chloride transport in the early distal tubule. Sodium and chloride are transported from the tubular lumen into the cell by a co-transporter that is inhibited by thiazide diuretics. Sodium is pumped out of the cell by sodium-potassium ATPase and chloride diffuses into the interstitial fluid via chloride channels. Cellular ultrastructure and transport characteristics of the early distal tubule and the late distal tubule and collecting tubule. The early distal tubule has many of the same characteristics as the thick ascending loop of Henle and reabsorbs sodium, chloride, calcium, and magnesium but is virtually impermeable to water and urea. The late distal tubules and cortical collecting tubules are composed of two distinct cell types, the principal cells and the intercalated cells. The principal cells reabsorb sodium from the lumen and secrete potassium ions into the lumen.The intercalated cells reabsorb potassium and bicarbonate ions from the lumen and secrete hydrogen ions into the lumen. The reabsorption of water from this tubular segment is controlled by the concentration of antidiuretic hormone. Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Chapter 27 Renal interstitial fluid Tubular lumen (-50 mV) Tubular cells K+ Na+ K+ Na+ ATP - - Cl- Aldosterone antagonists • Spironolactone • Eplerenone Na+ channel blockers • Amiloride • Triamterene Figure 27–12 Mechanism of sodium chloride reabsorption and potassium secretion in the late distal tubules and cortical collecting tubules. Sodium enters the cell through special channels and is transported out of the cell by the sodium-potassium ATPase pump. Aldosterone antagonists compete with aldosterone for binding sites in the cell and therefore inhibit the effects of aldosterone to stimulate sodium reabsorption and potassium secretion. Sodium channel blockers directly inhibit the entry of sodium into the sodium channels. channels. The secretion of potassium by these cells from the blood into the tubular lumen involves two steps: (1) Potassium enters the cell because of the sodium-potassium ATPase pump, which maintains a high intracellular potassium concentration, and then (2) once in the cell, potassium diffuses down its concentration gradient across the luminal membrane into the tubular fluid. The principal cells are the primary sites of action of the potassium-sparing diuretics, including spironolactone, eplerenone, amiloride, and triamterene. Aldosterone antagonists compete with aldosterone for receptor sites in the principal cells and therefore inhibit the stimulatory effects of aldosterone on sodium reabsorption and potassium secretion. Sodium channel blockers directly inhibit the entry of sodium into the sodium channels of the luminal membranes and therefore reduce the amount of sodium that can be transported across the basolateral membranes by the sodium-potassium ATPase pump. This, in turn, decreases transport of potassium into the cells and ultimately reduces potassium secretion into the tubular fluid. For this reason the sodium channel blockers as well as the aldosterone antagonists decrease urinary excretion of potassium and act as potassium-sparing diuretics. Intercalated Cells Avidly Secrete Hydrogen and Reabsorb Bicarbonate and Potassium Ions. Hydrogen ion secretion by the intercalated cells is mediated by a hydrogenATPase transport mechanism. Hydrogen is generated in this cell by the action of carbonic anhydrase on water and carbon dioxide to form carbonic acid, which 337 then dissociates into hydrogen ions and bicarbonate ions. The hydrogen ions are then secreted into the tubular lumen, and for each hydrogen ion secreted, a bicarbonate ion becomes available for reabsorption across the basolateral membrane. A more detailed discussion of this mechanism is presented in Chapter 30. The intercalated cells can also reabsorb potassium ions. The functional characteristics of the late distal tubule and cortical collecting tubule can be summarized as follows: 1. The tubular membranes of both segments are almost completely impermeable to urea, similar to the diluting segment of the early distal tubule; thus, almost all the urea that enters these segments passes on through and into the collecting duct to be excreted in the urine, although some reabsorption of urea occurs in the medullary collecting ducts. 2. Both the late distal tubule and the cortical collecting tubule segments reabsorb sodium ions, and the rate of reabsorption is controlled by hormones, especially aldosterone. At the same time, these segments secrete potassium ions from the peritubular capillary blood into the tubular lumen, a process that is also controlled by aldosterone and by other factors such as the concentration of potassium ions in the body fluids. 3. The intercalated cells of these nephron segments avidly secrete hydrogen ions by an active hydrogen-ATPase mechanism. This process is different from the secondary active secretion of hydrogen ions by the proximal tubule because it is capable of secreting hydrogen ions against a large concentration gradient, as much as 1000 to 1. This is in contrast to the relatively small gradient (4- to 10-fold) for hydrogen ions that can be achieved by secondary active secretion in the proximal tubule. Thus, the intercalated cells play a key role in acid-base regulation of the body fluids. 4. The permeability of the late distal tubule and cortical collecting duct to water is controlled by the concentration of ADH, which is also called vasopressin. With high levels of ADH, these tubular segments are permeable to water, but in the absence of ADH, they are virtually impermeable to water. This special characteristic provides an important mechanism for controlling the degree of dilution or concentration of the urine. Medullary Collecting Duct Although the medullary collecting ducts reabsorb less than 10 per cent of the filtered water and sodium, they are the final site for processing the urine and, therefore, play an extremely important role in determining the final urine output of water and solutes. The epithelial cells of the collecting ducts are nearly cuboidal in shape with smooth surfaces and relatively Unit V - 5 Cl 100.0 3 - 10.0 ine tin ea r C lin Cl Inu Urea K and Na 5.0 2.0 1.0 0.20 0.10 ein cids Whether a solute will become concentrated in the tubular fluid is determined by the relative degree of reabsorption of that solute versus the reabsorption of water. If a greater percentage of water is reabsorbed, the substance becomes more concentrated. If a greater percentage of the solute is reabsorbed, the substance becomes more diluted. Figure 27–14 shows the degree of concentration of several substances in the different tubular segments. All the values in this figure represent the tubular fluid concentration divided by the plasma concentration of HCO3 Prot Summary of Concentrations of Different Solutes in the Different Tubular Segments no a 0.05 Cl Na 0.02 few mitochondria (Figure 27–13). Special characteristics of this tubular segment are as follows: 1. The permeability of the medullary collecting duct to water is controlled by the level of ADH. With high levels of ADH, water is avidly reabsorbed into the medullary interstitium, thereby reducing the urine volume and concentrating most of the solutes in the urine. 2. Unlike the cortical collecting tubule, the medullary collecting duct is permeable to urea. Therefore, some of the tubular urea is reabsorbed into the medullary interstitium, helping to raise the osmolality in this region of the kidneys and contributing to the kidneys’ overall ability to form a concentrated urine. 3. The medullary collecting duct is capable of secreting hydrogen ions against a large concentration gradient, as also occurs in the cortical collecting tubule. Thus, the medullary collecting duct also plays a key role in regulating acid-base balance. K 0.50 Ami Cellular ultrastructure and transport characteristics of the medullary collecting duct. The medullary collecting ducts actively reabsorb sodium and secrete hydrogen ions and are permeable to urea, which is reabsorbed in these tubular segments. The reabsorption of water in medullary collecting ducts is controlled by the concentration of antidiuretic hormone. 20.0 ose Gluc Figure 27–13 Tubular fluid/plasma concentration HCO 12 PAH Urea H+ 5 50.0 to H) D (+A H 2O 40 58 +, Na to 1 Medullary collecting duct The Body Fluids and Kidneys to 338 Proximal tubule Loop of Henle Distal tubule Collecting tubule Figure 27–14 Changes in average concentrations of different substances at different points in the tubular system relative to the concentration of that substance in the plasma and in the glomerular filtrate. A value of 1.0 indicates that the concentration of the substance in the tubular fluid is the same as the concentration of that substance in the plasma. Values below 1.0 indicate that the substance is reabsorbed more avidly than water, whereas values above 1.0 indicate that the substance is reabsorbed to a lesser extent than water or is secreted into the tubules. a substance. If plasma concentration of the substance is assumed to be constant, any change in the ratio of tubular fluid/plasma concentration rate reflects changes in tubular fluid concentration. As the filtrate moves along the tubular system, the concentration rises to progressively greater than 1.0 if more water is reabsorbed than solute, or if there has been a net secretion of the solute into the tubular fluid. If the concentration ratio becomes progressively less than 1.0, this means that relatively more solute has been reabsorbed than water. The substances represented at the top of Figure 27–14, such as creatinine, become highly concentrated in the urine. In general, these substances are not needed by the body, and the kidneys have become adapted to reabsorb them only slightly or not at all, or even to secrete them into the tubules, thereby excreting especially great quantities into the urine. Conversely, the substances represented toward the bottom of the figure, such as glucose and amino acids, are all strongly reabsorbed; these are all substances that the body needs to conserve, and almost none of them are lost in the urine. Chapter 27 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Tubular Fluid /Plasma Inulin Concentration Ratio Can Be Used to Measure Water Reabsorption by the Renal Tubules. Inulin, 339 a polysaccharide used to measure GFR, is not reabsorbed or secreted by the renal tubules. Changes in inulin concentration at different points along the renal tubule, therefore, reflect changes in the amount of water present in the tubular fluid. For example, the tubular fluid/plasma concentration ratio for inulin rises to about 3.0 at the end of the proximal tubules, indicating that inulin concentration in the tubular fluid is 3 times greater than in the plasma and in the glomerular filtrate. Since inulin is not secreted or reabsorbed from the tubules, a tubular fluid/plasma concentration ratio of 3.0 means that only one third of the water that was filtered remains in the renal tubule and that two thirds of the filtered water has been reabsorbed as the fluid passes through the proximal tubule. At the end of the collecting ducts, the tubular fluid/plasma inulin concentration ratio rises to about 125 (see Figure 27–14), indicating that only 1/125 of the filtered water remains in the tubule and that more than 99% has been reabsorbed. are not fully understood but may be due partly to changes in physical forces in the tubule and surrounding renal interstitium, as discussed later. It is clear that the mechanisms for glomerulotubular balance can occur independently of hormones and can be demonstrated in completely isolated kidneys or even in completely isolated proximal tubular segments. The importance of glomerulotubular balance is that it helps to prevent overloading of the distal tubular segments when GFR increases. Glomerulotubular balance acts as a second line of defense to buffer the effects of spontaneous changes in GFR on urine output. (The first line of defense, discussed earlier, includes the renal autoregulatory mechanisms, especially tubuloglomerular feedback, which help prevent changes in GFR.) Working together, the autoregulatory and glomerulotubular balance mechanisms prevent large changes in fluid flow in the distal tubules when the arterial pressure changes or when there are other disturbances that would otherwise wreak havoc with the maintenance of sodium and volume homeostasis. Regulation of Tubular Reabsorption Peritubular Capillary and Renal Interstitial Fluid Physical Forces Because it is essential to maintain a precise balance between tubular reabsorption and glomerular filtration, there are multiple nervous, hormonal, and local control mechanisms that regulate tubular reabsorption, just as there are for control of glomerular filtration. An important feature of tubular reabsorption is that reabsorption of some solutes can be regulated independently of others, especially through hormonal control mechanisms. Hydrostatic and colloid osmotic forces govern the rate of reabsorption across the peritubular capillaries, just as these physical forces control filtration in the glomerular capillaries. Changes in peritubular capillary reabsorption can in turn influence the hydrostatic and colloid osmotic pressures of the renal interstitium and, ultimately, reabsorption of water and solutes from the renal tubules. Glomerulotubular Balance—The Ability of the Tubules to Increase Reabsorption Rate in Response to Increased Tubular Load One of the most basic mechanisms for controlling tubular reabsorption is the intrinsic ability of the tubules to increase their reabsorption rate in response to increased tubular load (increased tubular inflow). This phenomenon is referred to as glomerulotubular balance. For example, if GFR is increased from 125 ml/ min to 150 ml/min, the absolute rate of proximal tubular reabsorption also increases from about 81 ml/ min (65 per cent of GFR) to about 97.5 ml/min (65 per cent of GFR). Thus, glomerulotubular balance refers to the fact that the total rate of reabsorption increases as the filtered load increases, even though the percentage of GFR reabsorbed in the proximal tubule remains relatively constant at about 65 per cent. Some degree of glomerulotubular balance also occurs in other tubular segments, especially the loop of Henle. The precise mechanisms responsible for this Normal Values for Physical Forces and Reabsorption Rate. As the glomerular filtrate passes through the renal tubules, more than 99 per cent of the water and most of the solutes are normally reabsorbed. Fluid and electrolytes are reabsorbed from the tubules into the renal interstitium and from there into the peritubular capillaries. The normal rate of peritubular capillary reabsorption is about 124 ml/min. Reabsorption across the peritubular capillaries can be calculated as Reabsorption = Kf ¥ Net reabsorptive force The net reabsorptive force represents the sum of the hydrostatic and colloid osmotic forces that either favor or oppose reabsorption across the peritubular capillaries. These forces include (1) hydrostatic pressure inside the peritubular capillaries (peritubular hydrostatic pressure [Pc]), which opposes reabsorption; (2) hydrostatic pressure in the renal interstitium (Pif) outside the capillaries, which favors reabsorption; (3) colloid osmotic pressure of the peritubular capillary plasma proteins (pc), which favors reabsorption; and (4) colloid osmotic pressure of the proteins in the renal interstitium (pif), which opposes reabsorption. Figure 27–15 shows the approximate normal forces that favor and oppose peritubular reabsorption. 340 Unit V Peritubular capillary Pc 13 mm Hg πc 32 mm Hg Interstitial fluid Tubular cells The Body Fluids and Kidneys Tubular lumen Pif 6 mm Hg πif 15 mm Hg Bulk flow H2O H2O + 10 mm Hg Na Net reabsorption pressure ATP Na+ Figure 27–15 Summary of the hydrostatic and colloid osmotic forces that determine fluid reabsorption by the peritubular capillaries. The numerical values shown are estimates of the normal values for humans. The net reabsorptive pressure is normally about 10 mm Hg, causing fluid and solutes to be reabsorbed into the peritubular capillaries as they are transported across the renal tubular cells. ATP, adenosine triphosphate; Pc, peritubular capillary hydrostatic pressure; Pif, interstitial fluid hydrostatic pressure; pc, peritubular capillary colloid osmotic pressure; pif, interstitial fluid colloid osmotic pressure. Because the normal peritubular capillary pressure averages about 13 mm Hg and renal interstitial fluid hydrostatic pressure averages 6 mm Hg, there is a positive hydrostatic pressure gradient from the peritubular capillary to the interstitial fluid of about 7 mm Hg, which opposes fluid reabsorption. This is more than counterbalanced by the colloid osmotic pressures that favor reabsorption. The plasma colloid osmotic pressure, which favors reabsorption, is about 32 mm Hg, and the colloid osmotic pressure of the interstitium, which opposes reabsorption, is 15 mm Hg, causing a net colloid osmotic force of about 17 mm Hg, favoring reabsorption. Therefore, subtracting the net hydrostatic forces that oppose reabsorption (7 mm Hg) from the net colloid osmotic forces that favor reabsorption (17 mm Hg) gives a net reabsorptive force of about 10 mm Hg. This is a high value, similar to that found in the glomerular capillaries, but in the opposite direction. The other factor that contributes to the high rate of fluid reabsorption in the peritubular capillaries is a large filtration coefficient (Kf) because of the high hydraulic conductivity and large surface area of the capillaries. Because the reabsorption rate is normally about 124 ml/min and net reabsorption pressure is 10 mm Hg, Kf normally is about 12.4 ml/min/mm Hg. Regulation of Peritubular Capillary Physical Forces. The two determinants of peritubular capillary reabsorption that are directly influenced by renal hemodynamic changes are the hydrostatic and colloid osmotic pressures of the peritubular capillaries. The peritubular capillary hydrostatic pressure is influenced by the arterial pressure and resistances of the afferent and efferent arterioles. (1) Increases in arterial pressure tend to raise peritubular capillary hydrostatic pressure and decrease reabsorption rate. This effect is buffered to some extent by autoregulatory mechanisms that maintain relatively constant renal blood flow as well as relatively constant hydrostatic pressures in the renal blood vessels. (2) Increase in resistance of either the afferent or the efferent arterioles reduces peritubular capillary hydrostatic pressure and tends to increase reabsorption rate. Although constriction of the efferent arterioles increases glomerular capillary hydrostatic pressure, it lowers peritubular capillary hydrostatic pressure. The second major determinant of peritubular capillary reabsorption is the colloid osmotic pressure of the plasma in these capillaries; raising the colloid osmotic pressure increases peritubular capillary reabsorption. The colloid osmotic pressure of peritubular capillaries is determined by (1) the systemic plasma colloid osmotic pressure; increasing the plasma protein concentration of systemic blood tends to raise peritubular capillary colloid osmotic pressure, thereby increasing reabsorption; and (2) the filtration fraction; the higher the filtration fraction, the greater the fraction of plasma filtered through the glomerulus and, consequently, the more concentrated the protein becomes in the plasma that remains behind. Thus, increasing the filtration fraction also tends to increase the peritubular capillary reabsorption rate. Because filtration fraction is defined as the ratio of GFR/renal plasma flow, increased filtration fraction can occur as a result of increased GFR or decreased renal plasma flow. Some renal vasoconstrictors, such as angiotensin II, increase peritubular capillary reabsorption by decreasing renal plasma flow and increasing filtration fraction, as discussed later. Changes in the peritubular capillary Kf can also influence the reabsorption rate because Kf is a measure of the permeability and surface area of the capillaries. Increases in Kf raise reabsorption, whereas decreases in Kf lower peritubular capillary reabsorption. Kf remains relatively constant in most physiologic conditions. Table 27–2 summarizes the factors that can influence the peritubular capillary reabsorption rate. Renal Interstitial Hydrostatic and Colloid Osmotic Pressures. Ultimately, changes in peritubular capillary physical forces influence tubular reabsorption by changing the physical forces in the renal interstitium surrounding the tubules. For example, a decrease in the reabsorptive force across the peritubular capillary membranes, caused by either increased peritubular capillary hydrostatic pressure or decreased peritubular capillary colloid osmotic pressure, reduces the uptake of fluid and solutes from the interstitium into the peritubular capillaries. This in turn raises renal interstitial fluid hydrostatic pressure and decreases interstitial fluid colloid osmotic pressure because of dilution of the proteins in the renal interstitium. These changes then decrease the net reabsorption of fluid from the renal tubules into the interstitium, especially in the proximal tubules. Chapter 27 341 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Normal Table 27–2 Factors That Can Influence Peritubular Capillary Reabsorption ≠ Pc Æ Ø Reabsorption • Ø RA Æ ≠ Pc • Ø RE Æ ≠ Pc • ≠ Arterial Pressure Æ ≠ Pc ≠ pc Æ ≠ Reabsorption • ≠ pA Æ ≠ pc • ≠ FF Æ ≠ pc ≠ Kf Æ ≠ Reabsorption Peritubular capillary Interstitial fluid Tubular cells Pc πc Net reabsorption ATP Pc, peritubular capillary hydrostatic pressure; RA and RE, afferent and efferent arteriolar resistances, respectively; pc, peritubular capillary colloid osmotic pressure; pA, arterial plasma colloid osmotic pressure; FF, filtration fraction; Kf, peritubular capillary filtration coefficient. The mechanisms by which changes in interstitial fluid hydrostatic and colloid osmotic pressures influence tubular reabsorption can be understood by examining the pathways through which solute and water are reabsorbed (Figure 27–16). Once the solutes enter the intercellular channels or renal interstitium by active transport or passive diffusion, water is drawn from the tubular lumen into the interstitium by osmosis. And once the water and solutes are in the interstitial spaces, they can either be swept up into the peritubular capillaries or diffuse back through the epithelial junctions into the tubular lumen. The so-called tight junctions between the epithelial cells of the proximal tubule are actually leaky, so that considerable amounts of sodium can diffuse in both directions through these junctions. With the normal high rate of peritubular capillary reabsorption, the net movement of water and solutes is into the peritubular capillaries with little backleak into the lumen of the tubule. However, when peritubular capillary reabsorption is reduced, there is increased interstitial fluid hydrostatic pressure and a tendency for greater amounts of solute and water to backleak into the tubular lumen, thereby reducing the rate of net reabsorption (refer again to Figure 27–16). The opposite is true when there is increased peritubular capillary reabsorption above the normal level. An initial increase in reabsorption by the peritubular capillaries tends to reduce interstitial fluid hydrostatic pressure and raise interstitial fluid colloid osmotic pressure. Both of these forces favor movement of fluid and solutes out of the tubular lumen and into the interstitium; therefore, backleak of water and solutes into the tubular lumen is reduced, and net tubular reabsorption increases. Thus, through changes in the hydrostatic and colloid osmotic pressures of the renal interstitium, the uptake of water and solutes by the peritubular capillaries is closely matched to the net reabsorption of water and solutes from the tubular lumen into the interstitium. Therefore, in general, forces that increase peritubular capillary reabsorption also increase reabsorption from the renal tubules. Conversely, hemodynamic changes that inhibit peritubular capillary reabsorption also inhibit tubular reabsorption of water and solutes. Lumen ATP Backleak Decreased reabsorption Pc πc ATP Decreased net reabsorption ATP Increased backleak Figure 27–16 Proximal tubular and peritubular capillary reabsorption under normal conditions (top) and during decreased peritubular capillary reabsorption (bottom) caused by either increasing peritubular capillary hydrostatic pressure (Pc) or decreasing peritubular capillary colloid osmotic pressure (pc). Reduced peritubular capillary reabsorption, in turn, decreases the net reabsorption of solutes and water by increasing the amounts of solutes and water that leak back into the tubular lumen through the tight junctions of the tubular epithelial cells, especially in the proximal tubule. Effect of Arterial Pressure on Urine Output—The Pressure-Natriuresis and Pressure-Diuresis Mechanisms Even small increases in arterial pressure often cause marked increases in urinary excretion of sodium and water, phenomena that are referred to as pressure natriuresis and pressure diuresis. Because of the autoregulatory mechanisms described in Chapter 26, increasing the arterial pressure between the limits of 75 and 160 mm Hg usually has only a small effect on renal blood flow and GFR. The slight increase in GFR that does occur contributes in part to the effect of increased arterial pressure on urine output. When GFR autoregulation is impaired, as often occurs in kidney disease, increases in arterial pressure cause much larger increases in GFR. 342 Unit V The Body Fluids and Kidneys A second effect of increased renal arterial pressure that raises urine output is that it decreases the percentage of the filtered load of sodium and water that is reabsorbed by the tubules. The mechanisms responsible for this effect include a slight increase in peritubular capillary hydrostatic pressure, especially in the vasa recta of the renal medulla, and a subsequent increase in the renal interstitial fluid hydrostatic pressure. As discussed earlier, an increase in the renal interstitial fluid hydrostatic pressure enhances backleak of sodium into the tubular lumen, thereby reducing the net reabsorption of sodium and water and further increasing the rate of urine output when renal arterial pressure rises. A third factor that contributes to the pressurenatriuresis and pressure-diuresis mechanisms is reduced angiotensin II formation. Angiotensin II itself increases sodium reabsorption by the tubules; it also stimulates aldosterone secretion, which further increases sodium reabsorption. Therefore, decreased angiotensin II formation contributes to the decreased tubular sodium reabsorption that occurs when arterial pressure is increased. Hormonal Control of Tubular Reabsorption Precise regulation of body fluid volumes and solute concentrations requires the kidneys to excrete different solutes and water at variable rates, sometimes independently of one another. For example, when potassium intake is increased, the kidneys must excrete more potassium while maintaining normal excretion of sodium and other electrolytes. Likewise, when sodium intake is changed, the kidneys must appropriately adjust urinary sodium excretion without major changes in excretion of other electrolytes. Several hormones in the body provide this specificity of tubular reabsorption for different electrolytes and water. Table 27–3 summarizes some of the most important hormones for regulating tubular reabsorption, their principal sites of action on the renal tubule, and their effects on solute and water excretion. Some of these hormones are discussed in more detail in Chapters 28 and 29, but we briefly review their renal tubular actions in the next few paragraphs. Aldosterone Increases Sodium Reabsorption and Increases Potassium Secretion. Aldosterone, secreted by the zona glomerulosa cells of the adrenal cortex, is an important regulator of sodium reabsorption and potassium secretion by the renal tubules. The primary site of aldosterone action is on the principal cells of the cortical collecting tubule. The mechanism by which aldosterone increases sodium reabsorption while at the same time increasing potassium secretion is by stimulating the sodium-potassium ATPase pump on the basolateral side of the cortical collecting tubule membrane. Aldosterone also increases the sodium permeability of the luminal side of the membrane. The cellular mechanisms of aldosterone action are discussed in Chapter 77. In the absence of aldosterone, as occurs with adrenal destruction or malfunction (Addison’s disease), there is marked loss of sodium from the body and accumulation of potassium. Conversely, excess aldosterone secretion, as occurs in patients with adrenal tumors (Conn’s syndrome) is associated with sodium retention and potassium depletion. Although day-to-day regulation of sodium balance can be maintained as long as minimal levels of aldosterone are present, the inability to appropriately adjust aldosterone secretion greatly impairs the regulation of renal potassium excretion and potassium concentration of the body fluids. Thus, aldosterone is even more important as a regulator of potassium concentration than it is for sodium concentration. Angiotensin II Increases Sodium and Water Reabsorption. Angiotensin II is perhaps the body’s most powerful sodium-retaining hormone. As discussed in Chapter 19, angiotensin II formation increases in circumstances associated with low blood pressure and/or low extracellular fluid volume, such as during hemorrhage or loss of salt and water from the body fluids. The increased formation of angiotensin II helps to return blood pressure and extracellular volume toward normal by increasing sodium and water reabsorption from the renal tubules through three main effects: 1. Angiotensin II stimulates aldosterone secretion, which in turn increases sodium reabsorption. 2. Angiotensin II constricts the efferent arterioles, which has two effects on peritubular capillary dynamics that raise sodium and water Table 27–3 Hormones That Regulate Tubular Reabsorption Hormone Site of Action Effects Aldosterone Angiotensin II Collecting tubule and duct Proximal tubule, thick ascending loop of Henle/distal tubule, collecting tubule Distal tubule/collecting tubule and duct Distal tubule/collecting tubule and duct Proximal tubule, thick ascending loop of Henle/distal tubule ≠ NaCl, H2O reabsorption, ≠ K+ secretion ≠ NaCl, H2O reabsorption, ≠ H+ secretion Antidiuretic hormone Atrial natriuretic peptide Parathyroid hormone ≠ H2O reabsorption Ø NaCl reabsorption Ø PO4- - - reabsorption, ≠ Ca++ reabsorption Chapter 27 343 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate reabsorption. First, efferent arteriolar constriction reduces peritubular capillary hydrostatic pressure, which increases net tubular reabsorption, especially from the proximal tubules. Second, efferent arteriolar constriction, by reducing renal blood flow, raises filtration fraction in the glomerulus and increases the concentration of proteins and the colloid osmotic pressure in the peritubular capillaries; this increases the reabsorptive force at the peritubular capillaries and raises tubular reabsorption of sodium and water. 3. Angiotensin II directly stimulates sodium reabsorption in the proximal tubules, the loops of Henle, the distal tubules, and the collecting tubules. One of the direct effects of angiotensin II is to stimulate the sodium-potassium ATPase pump on the tubular epithelial cell basolateral membrane. A second effect is to stimulate sodium-hydrogen exchange in the luminal membrane, especially in the proximal tubule. Thus, angiotensin II stimulates sodium transport across both the luminal and the basolateral surfaces of the epithelial cell membrane in the tubules. These multiple actions of angiotensin II cause marked sodium retention by the kidneys when angiotensin II levels are increased. ADH Increases Water Reabsorption. The most important renal action of ADH is to increase the water permeability of the distal tubule, collecting tubule, and collecting duct epithelia. This effect helps the body to conserve water in circumstances such as dehydration. In the absence of ADH, the permeability of the distal tubules and collecting ducts to water is low, causing the kidneys to excrete large amounts of dilute urine. Thus, the actions of ADH play a key role in controlling the degree of dilution or concentration of the urine, as discussed further in Chapters 28 and 75. ADH binds to specific V2 receptors in the late distal tubules, collecting tubules, and collecting ducts, increasing the formation of cyclic AMP and activating protein kinases. This, in turn, stimulates the movement of an intracellular protein, called aquaporin-2 (AQP2), to the luminal side of the cell membranes. The molecules of AQP-2 cluster together and fuse with the cell membrane by exocytosis to form water channels that permit rapid diffusion of water through the cells. There are other aquaporins, AQP-3 and AQP-4, in the basolateral side of the cell membrane that provide a path for water to rapidly exit the cells, although these are not believed to be regulated by ADH. Chronic increases in ADH levels also increase the formation of AQP-2 protein in the renal tubular cells by stimulating AQP-2 gene transcription. When the concentration of ADH decreases, the molecules of AQP-2 are shuttled back to the cell cytoplasm, thereby removing the water channels from the luminal membrane and reducing water permeability. Atrial Natriuretic Peptide Decreases Sodium and Water Reabsorption. Specific cells of the cardiac atria, when distended because of plasma volume expansion, secrete a peptide called atrial natriuretic peptide. Increased levels of this peptide in turn inhibit the reabsorption of sodium and water by the renal tubules, especially in the collecting ducts. This decreased sodium and water reabsorption increases urinary excretion, which helps to return blood volume back toward normal. Parathyroid Hormone Increases Calcium Reabsorption. Parathyroid hormone is one of the most important calcium-regulating hormones in the body. Its principal action in the kidneys is to increase tubular reabsorption of calcium, especially in the distal tubules and perhaps also in the loops of Henle. Parathyroid hormone also has other actions, including inhibition of phosphate reabsorption by the proximal tubule and stimulation of magnesium reabsorption by the loop of Henle, as discussed in Chapter 29. Sympathetic Nervous System Activation Increases Sodium Reabsorption Activation of the sympathetic nervous system can decrease sodium and water excretion by constricting the renal arterioles, thereby reducing GFR. Sympathetic activation also increases sodium reabsorption in the proximal tubule, the thick ascending limb of the loop of Henle, and perhaps in more distal parts of the renal tubule. And finally, sympathetic nervous system stimulation increases renin release and angiotensin II formation, which adds to the overall effect to increase tubular reabsorption and decrease renal excretion of sodium. Use of Clearance Methods to Quantify Kidney Function The rates at which different substances are “cleared” from the plasma provide a useful way of quantitating the effectiveness with which the kidneys excrete various substances (Table 27–4). By definition, the renal clearance of a substance is the volume of plasma that is completely cleared of the substance by the kidneys per unit time. This concept is somewhat abstract because there is no single volume of plasma that is completely cleared of a substance. However, renal clearance provides a useful way of quantifying the excretory function of the kidneys and, as discussed later, can be used to quantify the rate at which blood flows through the kidneys as well as the basic functions of the kidneys: glomerular filtration, tubular reabsorption, and tubular secretion. To illustrate the clearance principle, consider the following example: If the plasma passing through the kidneys contains 1 milligram of a substance in each milliliter and if 1 milligram of this substance is also excreted into the urine each minute, then 1 ml/min of the plasma is “cleared” of the substance. Thus, 344 Unit V The Body Fluids and Kidneys Table 27–4 Use of Clearance to Quantify Kidney Function Term Equation Units Us ¥ V Ps Uinulin ¥ V GFR = Pinulin Cs = Clearance rate (Cs) Glomerular filtration rate (GFR) ml/min Cs C inulin Clearance ratio Clearance ratio = Effective renal plasma flow (ERPF) ERPF = C PAH = Renal plasma flow (RPF) RPF = Renal blood flow (RBF) RBF = Excretion rate Excretion rate = Us ¥ V Reabsorption rate = Filtered load - Excretion rate = (GFR ¥ Ps) - (Us ¥ V) Secretion rate = Excretion rate - Filtered load Reabsorption rate Secretion rate None UPAH ¥ V PPAH ml/min (UPAH ¥ V PPAH ) C PAH = EPAH (PPAH - VPAH ) PPAH UPAH ¥ VPAH = PPAH - VPAH RPF 1 - Hematocrit ml/min ml/min mg/min, mmol/min, or mEq/min mg/min, mmol/min, or mEq/min mg/min, mmol/min, or mEq/min S, a substance; U, urine concentration; V, urine flow rate; P, plasma concentration; PAH, para-aminohippuric acid; PPAH, renal arterial PAH concentration; EPAH, PAH extraction ratio; VPAH, renal venous PAH concentration. clearance refers to the volume of plasma that would be necessary to supply the amount of substance excreted in the urine per unit time. Stated mathematically, Cs ¥ Ps = Us ¥ V, where Cs is the clearance rate of a substance s, Ps is the plasma concentration of the substance, Us is the urine concentration of that substance, and V is the urine flow rate. Rearranging this equation, clearance can be expressed as Cs = Us ¥ V Ps Thus, renal clearance of a substance is calculated from the urinary excretion rate (Us ¥ V) of that substance divided by its plasma concentration. Inulin Clearance Can Be Used to Estimate GFR If a substance is freely filtered (filtered as freely as water) and is not reabsorbed or secreted by the renal tubules, then the rate at which that substance is excreted in the urine (Us ¥ V) is equal to the filtration rate of the substance by the kidneys (GFR ¥ Ps). Thus, GFR ¥ Ps = Us ¥ V The GFR, therefore, can be calculated as the clearance of the substance as follows: GFR = Us ¥ V = Cs Ps A substance that fits these criteria is inulin, a polysaccharide molecule with a molecular weight of about 5200. Inulin, which is not produced in the body, is found in the roots of certain plants and must be administered intravenously to a patient to measure GFR. Figure 27–17 shows the renal handling of inulin. In this example, the plasma concentration is 1 mg/ml, urine concentration is 125 mg/ml, and urine flow rate is 1 ml/ min. Therefore, 125 mg/min of inulin passes into the urine. Then, inulin clearance is calculated as the urine excretion rate of inulin divided by the plasma concentration, which yields a value of 125 ml/min. Thus, 125 milliliters of plasma flowing through the kidneys must be filtered to deliver the inulin that appears in the urine. Inulin is not the only substance that can be used for determining GFR. Other substances that have been used clinically to estimate GFR include radioactive iothalamate and creatinine. Creatinine Clearance and Plasma Creatinine Concentration Can Be Used to Estimate GFR Creatinine is a by-product of muscle metabolism and is cleared from the body fluids almost entirely by glomerular filtration. Therefore, the clearance of creatinine can also be used to assess GFR. Because measurement of creatinine clearance does not require intravenous infusion into the patient, this method is much more widely used than inulin clearance for estimating GFR clinically. However, creatinine clearance is not a perfect marker of GFR because a small amount of it is secreted by the tubules, so that the amount of creatinine excreted slightly exceeds the amount filtered. There is normally a slight error in measuring plasma creatinine that leads to an overestimate of the plasma creatinine Chapter 27 345 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Pinulin = 1 mg/ml GFR (ml/min) 100 Amount filtered = Amount excreted GFR x Pinulin = Uinulin x V Uinulin x V 0 Pinulin GFR = 125 ml/min Uinulin = 125 mg/ml Serum creatinine concentration (mg/dl) GFR = 50 2 1 0 Figure 27–17 Measurement of glomerular filtration rate (GFR) from the renal clearance of inulin. Inulin is freely filtered by the glomerular capillaries but is not reabsorbed by the renal tubules. Pinulin, plasma inulin concentration; Uinulin, urine inulin concentration; V, urine flow rate. concentration, and fortuitously, these two errors tend to cancel each other. Therefore, creatinine clearance provides a reasonable estimate of GFR. In some cases, it may not be practical to collect urine in a patient for measuring creatinine clearance (CCr). An approximation of changes in GFR, however, can be obtained by simply measuring plasma creatinine concentration (PCr), which is inversely proportional to GFR: GFR ª CCr = UCr ¥ V PCr If GFR suddenly decreases by 50%, the kidneys will transiently filter and excrete only half as much creatinine, causing accumulation of creatinine in the body fluids and raising plasma concentration. Plasma concentration of creatinine will continue to rise until the filtered load of creatinine (PCr ¥ GFR) and creatinine excretion (UCr ¥ V) return to normal and a balance between creatinine production and creatinine excretion is reestablished. This will occur when plasma creatinine increases to approximately twice normal, as shown in Figure 27–18. If GFR falls to one-fourth normal, plasma creatinine would increase to about 4 times normal, and a decrease of GFR to one-eighth normal would raise plasma creatinine to 8 times normal. Thus, under steadystate conditions, the creatinine excretion rate equals the rate of creatinine production, despite reductions in GFR. However, this normal rate of creatinine excretion occurs at the expense of elevated plasma creatinine concentration, as shown in Figure 27–19. PAH Clearance Can Be Used to Estimate Renal Plasma Flow Theoretically, if a substance is completely cleared from the plasma, the clearance rate of that substance is equal Creatinine production and renal excretion (g/day) V = 1 ml/min Positive balance Production 2 Excretion GFR x PCreatinine 1 0 0 1 2 Days 3 4 Figure 27–18 Effect of reducing glomerular filtration rate (GRF) by 50 per cent on serum creatinine concentration and on creatinine excretion rate when the production rate of creatinine remains constant. PCreatinine, plasma creatinine concentration. to the total renal plasma flow. In other words, the amount of the substance delivered to the kidneys in the blood (renal plasma flow ¥ Ps) would be equal to the amount excreted in the urine (Us ¥ V). Thus, renal plasma flow (RPF) could be calculated as RPF = Us ¥ V = Cs Ps Because the GFR is only about 20 per cent of the total plasma flow, a substance that is completely cleared from the plasma must be excreted by tubular secretion as well as glomerular filtration (Figure 27–20). There is no known substance that is completely cleared by the kidneys. One substance, however, PAH, is about 90 per cent cleared from the plasma. Therefore, the clearance of PAH can be used as an approximation of renal plasma flow. To be more accurate, one can correct for the percentage of PAH that is still in the blood when it leaves the kidneys. The percentage of PAH removed from the blood is known as the extraction ratio of PAH and averages about 90 per cent in normal kidneys. In diseased kidneys, this extraction ratio may be reduced 346 Unit V The Body Fluids and Kidneys PPAH = 0.01 mg/ml Plasma creatinine concentration (mg/100 ml) 14 12 10 Renal plasma flow UPAH x V = PPAH 8 6 4 2 Renal venous PAH = 0.001 mg/ml Normal 25 50 75 100 125 Glomerular filtration rate (ml/min) Figure 27–19 Approximate relationship between glomerular filtration rate (GFR) and plasma creatinine concentration under steady-state conditions. Decreasing GFR by 50 per cent will increase plasma creatinine to twice normal if creatinine production by the body remains constant. because of inability of damaged tubules to secrete PAH into the tubular fluid. The calculation of RPF can be demonstrated by the following example: Assume that the plasma concentration of PAH is 0.01 mg/ml, urine concentration is 5.85 mg/ml, and urine flow rate is 1 ml/min. PAH clearance can be calculated from the rate of urinary PAH excretion (5.85 mg/ml ¥ 1 ml/min) divided by the plasma PAH concentration (0.01 mg/ml). Thus, clearance of PAH calculates to be 585 ml/min. If the extraction ratio for PAH is 90 per cent, the actual renal plasma flow can be calculated by dividing 585 ml/min by 0.9, yielding a value of 650 ml/min. Thus, total renal plasma flow can be calculated as Total renal plasma flow = Clearance of PAH/Extraction ratio of PAH The extraction ratio (EPAH) is calculated as the difference between the renal arterial PAH (PPAH) and renal venous PAH (VPAH) concentrations, divided by the renal arterial PAH concentration: EPAH = UPAH = 5.85 mg/ml 150 PPAH - VPAH PPAH One can calculate the total blood flow through the kidneys from the total renal plasma flow and hematocrit (the percentage of red blood cells in the blood). If the hematocrit is 0.45 and the total renal plasma flow is 650 ml/min, the total blood flow through both kidneys is 650/(1 - 0.45), or 1182 ml/min. V = 1 ml/min Figure 27–20 Measurement of renal plasma flow from the renal clearance of paraaminohippuric acid (PAH). PAH is freely filtered by the glomerular capillaries and is also secreted from the peritubular capillary blood into the tubular lumen. The amount of PAH in the plasma of the renal artery is about equal to the amount of PAH excreted in the urine. Therefore, the renal plasma flow can be calculated from the clearance of PAH (CPAH). To be more accurate, one can correct for the percentage of PAH that is still in the blood when it leaves the kidneys. PPAH, arterial plasma PAH concentration; UPAH, urine PAH concentration; V, urine flow rate. Filtration Fraction Is Calculated from GFR Divided by Renal Plasma Flow To calculate the filtration fraction, which is the fraction of plasma that filters through the glomerular membrane, one must first know the renal plasma flow (PAH clearance) and the GFR (inulin clearance). If renal plasma flow is 650 ml/min and GFR is 125 ml/min, the filtration fraction (FF) is calculated as FF = GFR/RPF = 125/650 = 0.19 Calculation of Tubular Reabsorption or Secretion from Renal Clearances If the rates of glomerular filtration and renal excretion of a substance are known, one can calculate whether there is a net reabsorption or a net secretion of that substance by the renal tubules. For example, if the rate of excretion of the substance (Us ¥ V) is less than the filtered load of the substance (GFR ¥ Ps), then some of the substance must have been reabsorbed from the renal tubules. Conversely, if the excretion rate of the substance is greater than its filtered load, then the rate at which it appears in the urine represents the sum of the rate of glomerular filtration plus tubular secretion. The following example demonstrates the calculation of tubular reabsorption. Assume the following laboratory values for a patient were obtained: Chapter 27 Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate Urine flow rate = 1 ml/min Urine concentration of sodium (UNa) = 70 mEq/L = 70 mEq/ml Plasma sodium concentration = 140 mEq/L = 140 mEq/ml GFR (inulin clearance) = 100 ml/min In this example, the filtered sodium load is GFR ¥ PNa, or 100 ml/min ¥ 140 mEq/ml = 14,000 mEq/min. Urinary sodium excretion (UNa ¥ urine flow rate) is 70 mEq/min. Therefore, tubular reabsorption of sodium is the difference between the filtered load and urinary excretion, or 14,000 mEq/min - 70 mEq/min = 13,930 mEq/min. Comparisons of Inulin Clearance with Clearances of Different Solutes. The following generalizations can be made by comparing the clearance of a substance with the clearance of inulin, a measure of GFR: (1) if the clearance rate of the substance equals that of inulin, the substance is only filtered and not reabsorbed or secreted; (2) if the clearance rate of a substance is less than inulin clearance, the substance must have been reabsorbed by the nephron tubules; and (3) if the clearance rate of a substance is greater than that of inulin, the substance must be secreted by the nephron tubules. Listed below are the approximate clearance rates for some of the substances normally handled by the kidneys: Substance Clearance Rate (ml/min) Glucose Sodium Chloride Potassium Phosphate Inulin Creatinine 0 0.9 1.3 12.0 25.0 125.0 140.0 References Aronson PS: Ion exchangers mediating NaCl transport in the renal proximal tubule. Cell Biochem Biophys 36:147, 2002. Benos DJ, Fuller CM, Shlyonsky VG, et al: Amiloridesensitive Na+ channels: insights and outlooks. News Physiol Sci 12:55, 1997. 347 Féraille E, Doucet A: Sodium-potassium-adenosinetriphosphatase–dependent sodium transport in the kidney: Hormonal control. Physiol Rev 81:345, 2001. Granger JP, Alexander BT, Llinas M: Mechanisms of pressure natriuresis. Curr Hypertens Rep 4:152, 2002. Hall JE, Brands MW: The renin-angiotensin-aldosterone system: renal mechanisms and circulatory homeostasis. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000. Humphreys MH, Valentin J-P: Natriuretic hormonal agents. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000. Kellenberger S, Schild L: Epithelial sodium channel/ degenerin family of ion channels: A variety of functions for a shared structure. Physiol Rev 82:735, 2002. Nielsen S, Frøkiær J, Marples D, et al: Aquaporins in the kidney: from molecules to medicine. Physiol Rev 82:205, 2002. Palmer LG, Frindt G: Aldosterone and potassium secretion by the cortical collecting duct. Kidney Int 57:1324, 2000. Rahn KH, Heidenreich S, Bruckner D: How to assess glomerular function and damage in humans. J Hypertens 17:309, 1999. Reeves WB, Andreoli TE: Sodium chloride transport in the loop of Henle, distal convoluted tubule and collecting duct. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000. Reilly RF, Ellison DH: Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol Rev 80:277, 2000. Rossier BC, Praderv S, Schild L, Hummler E: Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu Rev Physiol 64:877, 2002. Russell JM: Sodium-potassium-chloride cotransport. Physiol Rev 80:211, 2000. Schafer JA: Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct. Am J Physiol Renal Physiol 283:F221, 2002. Weinstein AM: Mathematical models of renal fluid and electrolyte transport: acknowledging our uncertainty. Am J Physiol Renal Physiol 284:F871, 2003. Wright EM: Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol 280:F10, 2001. C H A P T E R 2 8 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration For the cells of the body to function properly, they must be bathed in extracellular fluid with a relatively constant concentration of electrolytes and other solutes. The total concentration of solutes in the extracellular fluid—and therefore the osmolarity—is determined by the amount of solute divided by the volume of the extracellular fluid. Thus, to a large extent, extracellular fluid sodium concentration and osmolarity are regulated by the amount of extracellular water. The body water in turn is controlled by (1) fluid intake, which is regulated by factors that determine thirst, and (2) renal excretion of water, which is controlled by multiple factors that influence glomerular filtration and tubular reabsorption. In this chapter, we discuss specifically (1) the mechanisms that cause the kidneys to eliminate excess water by excreting a dilute urine; (2) the mechanisms that cause the kidneys to conserve water by excreting a concentrated urine; (3) the renal feedback mechanisms that control the extracellular fluid sodium concentration and osmolarity; and (4) the thirst and salt appetite mechanisms that determine the intakes of water and salt, which also help to control extracellular fluid volume, osmolarity, and sodium concentration. The Kidneys Excrete Excess Water by Forming a Dilute Urine The normal kidney has tremendous capability to vary the relative proportions of solutes and water in the urine in response to various challenges. When there is excess water in the body and body fluid osmolarity is reduced, the kidney can excrete urine with an osmolarity as low as 50 mOsm/L, a concentration that is only about one sixth the osmolarity of normal extracellular fluid. Conversely, when there is a deficit of water and extracellular fluid osmolarity is high, the kidney can excrete urine with a concentration of 1200 to 1400 mOsm/L. Equally important, the kidney can excrete a large volume of dilute urine or a small volume of concentrated urine without major changes in rates of excretion of solutes such as sodium and potassium. This ability to regulate water excretion independently of solute excretion is necessary for survival, especially when fluid intake is limited. Antidiuretic Hormone Controls Urine Concentration There is a powerful feedback system for regulating plasma osmolarity and sodium concentration that operates by altering renal excretion of water independently of the rate of solute excretion. A primary effector of this feedback is antidiuretic hormone (ADH), also called vasopressin. When osmolarity of the body fluids increases above normal (that is, the solutes in the body fluids become too concentrated), the posterior pituitary gland secretes more ADH, which increases the permeability of the distal tubules and collecting ducts to water, as discussed in Chapter 27. This allows large amounts of water to be reabsorbed and decreases urine volume but does not 348 Chapter 28 349 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration markedly alter the rate of renal excretion of the solutes. When there is excess water in the body and extracellular fluid osmolarity is reduced, the secretion of ADH by the posterior pituitary decreases, thereby reducing the permeability of the distal tubule and collecting ducts to water, which causes large amounts of dilute urine to be excreted. Thus, the rate of ADH secretion determines, to a large extent, whether the kidney excretes a dilute or a concentrated urine. Renal Mechanisms for Excreting a Dilute Urine When there is a large excess of water in the body, the kidney can excrete as much as 20 L/day of dilute urine, with a concentration as low as 50 mOsm/L. The kidney performs this impressive feat by continuing to reabsorb solutes while failing to reabsorb large amounts of water in the distal parts of the nephron, including the late distal tubule and the collecting ducts. Figure 28–1 shows the approximate renal responses in a human after ingestion of 1 liter of water. Note that urine volume increases to about six times normal within 45 minutes after the water has been drunk. However, the total amount of solute excreted remains relatively constant because the urine formed becomes very dilute and urine osmolarity decreases from 600 to about 100 mOsm/L. Thus, after ingestion of excess water, the kidney rids the body of the excess water but does not excrete excess amounts of solutes. When the glomerular filtrate is initially formed, its osmolarity is about the same as that of plasma (300 mOsm/L). To excrete excess water, it is necessary to dilute the filtrate as it passes along the tubule. This is achieved by reabsorbing solutes to a greater extent than water, as shown in Figure 28–2, but this occurs only in certain segments of the tubular system as follows. Tubular Fluid Remains Isosmotic in the Proximal Tubule. As fluid flows through the proximal tubule, solutes and water are reabsorbed in equal proportions, so that little change in osmolarity occurs; that is, the proximal tubule fluid remains isosmotic to the plasma, with an osmolarity of about 300 mOsm/L.As fluid passes down the descending loop of Henle, water is reabsorbed by osmosis and the tubular fluid reaches equilibrium with the surrounding interstitial fluid of the renal medulla, which is very hypertonic—about two to four times the osmolarity of the original glomerular filtrate. Therefore, the tubular fluid becomes more concentrated as it flows into the inner medulla. Tubular Fluid Becomes Dilute in the Ascending Loop of Henle. Drink 1.0 L H2O Urine osmolarity Plasma osmolarity 400 NaCl 0 300 300 6 Urine flow rate (ml/min) Urinary solute excretion (mOsm/min) NaCl H2O 100 300 4 100 Cortex NaCl 2 0 1.2 400 0.6 400 NaCl H 2O 400 70 Medulla Osmolarity (mOsm/L) 800 In the ascending limb of the loop of Henle, especially in the thick segment, sodium, potassium, and chloride are avidly reabsorbed. However, this portion of the tubular segment is impermeable to water, even in NaCl 0 0 60 120 Time (minutes) 180 600 600 600 50 Figure 28–2 Figure 28–1 Water diuresis in a human after ingestion of 1 liter of water. Note that after water ingestion, urine volume increases and urine osmolarity decreases, causing the excretion of a large volume of dilute urine; however, the total amount of solute excreted by the kidneys remains relatively constant. These responses of the kidneys prevent plasma osmolarity from decreasing markedly during excess water ingestion. Formation of a dilute urine when antidiuretic hormone (ADH) levels are very low. Note that in the ascending loop of Henle, the tubular fluid becomes very dilute. In the distal tubules and collecting tubules, the tubular fluid is further diluted by the reabsorption of sodium chloride and the failure to reabsorb water when ADH levels are very low. The failure to reabsorb water and continued reabsorption of solutes lead to a large volume of dilute urine. (Numerical values are in milliosmoles per liter.) 350 Unit V The Body Fluids and Kidneys the presence of large amounts of ADH. Therefore, the tubular fluid becomes more dilute as it flows up the ascending loop of Henle into the early distal tubule, with the osmolarity decreasing progressively to about 100 mOsm/L by the time the fluid enters the early distal tubular segment. Thus, regardless of whether ADH is present or absent, fluid leaving the early distal tubular segment is hypo-osmotic, with an osmolarity of only about one third the osmolarity of plasma. Tubular Fluid in Distal and Collecting Tubules Is Further Diluted in the Absence of ADH. As the dilute fluid in the early distal tubule passes into the late distal convoluted tubule, cortical collecting duct, and collecting duct, there is additional reabsorption of sodium chloride. In the absence of ADH, this portion of the tubule is also impermeable to water, and the additional reabsorption of solutes causes the tubular fluid to become even more dilute, decreasing its osmolarity to as low as 50 mOsm/L.The failure to reabsorb water and the continued reabsorption of solutes lead to a large volume of dilute urine. To summarize, the mechanism for forming a dilute urine is to continue reabsorbing solutes from the distal segments of the tubular system while failing to reabsorb water. In healthy kidneys, fluid leaving the ascending loop of Henle and early distal tubule is always dilute, regardless of the level of ADH. In the absence of ADH, the urine is further diluted in the late distal tubule and collecting ducts, and a large volume of dilute urine is excreted. The Kidneys Conserve Water by Excreting a Concentrated Urine The ability of the kidney to form a urine that is more concentrated than plasma is essential for survival of mammals that live on land, including humans. Water is continuously lost from the body through various routes, including the lungs by evaporation into the expired air, the gastrointestinal tract by way of the feces, the skin through evaporation and perspiration, and the kidneys through the excretion of urine. Fluid intake is required to match this loss, but the ability of the kidney to form a small volume of concentrated urine minimizes the intake of fluid required to maintain homeostasis, a function that is especially important when water is in short supply. When there is a water deficit in the body, the kidney forms a concentrated urine by continuing to excrete solutes while increasing water reabsorption and decreasing the volume of urine formed. The human kidney can produce a maximal urine concentration of 1200 to 1400 mOsm/L, four to five times the osmolarity of plasma. Some desert animals, such as the Australian hopping mouse, can concentrate urine to as high as 10,000 mOsm/L. This allows the mouse to survive in the desert without drinking water; sufficient water can be obtained through the food ingested and water produced in the body by metabolism of the food. Animals adapted to aquatic environments, such as the beaver, have minimal urine concentrating ability; they can concentrate the urine to only about 500 mOsm/L. Obligatory Urine Volume The maximal concentrating ability of the kidney dictates how much urine volume must be excreted each day to rid the body of waste products of metabolism and ions that are ingested. A normal 70-kilogram human must excrete about 600 milliosmoles of solute each day. If maximal urine concentrating ability is 1200 mOsm/L, the minimal volume of urine that must be excreted, called the obligatory urine volume, can be calculated as 600 mOsm day = 0.5 L day 1200 mOsm L This minimal loss of volume in the urine contributes to dehydration, along with water loss from the skin, respiratory tract, and gastrointestinal tract, when water is not available to drink. The limited ability of the human kidney to concentrate the urine to a maximal concentration of 1200 mOsm/L explains why severe dehydration occurs if one attempts to drink seawater. Sodium chloride concentration in the oceans averages about 3.0 to 3.5 per cent, with an osmolarity between about 1000 and 1200 mOsm/L. Drinking 1 liter of seawater with a concentration of 1200 mOsm/L would provide a total sodium chloride intake of 1200 milliosmoles. If maximal urine concentrating ability is 1200 mOsm/L, the amount of urine volume needed to excrete 1200 milliosmoles would be 1200 milliosmoles divided by 1200 mOsm/L, or 1.0 liter. Why then does drinking seawater cause dehydration? The answer is that the kidney must also excrete other solutes, especially urea, which contribute about 600 mOsm/L when the urine is maximally concentrated. Therefore, the maximum concentration of sodium chloride that can be excreted by the kidneys is about 600 mOsm/L. Thus, for every liter of seawater drunk, 2 liters of urine volume would be required to rid the body of 1200 milliosmoles of sodium chloride ingested in addition to other solutes such as urea. This would result in a net fluid loss of 1 liter for every liter of seawater drunk, explaining the rapid dehydration that occurs in shipwreck victims who drink seawater. However, a shipwreck victim’s pet Australian hopping mouse could drink with impunity all the seawater it wanted. Requirements for Excreting a Concentrated Urine—High ADH Levels and Hyperosmotic Renal Medulla The basic requirements for forming a concentrated urine are (1) a high level of ADH, which increases the permeability of the distal tubules and collecting ducts to water, thereby allowing these tubular segments to avidly reabsorb water, and (2) a high osmolarity of the renal medullary interstitial fluid, which provides the osmotic gradient necessary for water reabsorption to occur in the presence of high levels of ADH. Chapter 28 351 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration The renal medullary interstitium surrounding the collecting ducts normally is very hyperosmotic, so that when ADH levels are high, water moves through the tubular membrane by osmosis into the renal interstitium; from there it is carried away by the vasa recta back into the blood. Thus, the urine concentrating ability is limited by the level of ADH and by the degree of hyperosmolarity of the renal medulla. We discuss the factors that control ADH secretion later, but for now, what is the process by which renal medullary interstitial fluid becomes hyperosmotic? This process involves the operation of the countercurrent mechanism. The countercurrent mechanism depends on the special anatomical arrangement of the loops of Henle and the vasa recta, the specialized peritubular capillaries of the renal medulla. In the human, about 25 per cent of the nephrons are juxtamedullary nephrons, with loops of Henle and vasa recta that go deeply into the medulla before returning to the cortex. Some of the loops of Henle dip all the way to the tips of the renal papillae that project from the medulla into the renal pelvis. Paralleling the long loops of Henle are the vasa recta, which also loop down into the medulla before returning to the renal cortex. And finally, the collecting ducts, which carry urine through the hyperosmotic renal medulla before it is excreted, also play a critical role in the countercurrent mechanism. Countercurrent Mechanism Produces a Hyperosmotic Renal Medullary Interstitium The osmolarity of interstitial fluid in almost all parts of the body is about 300 mOsm/L, which is similar to the plasma osmolarity. (As discussed in Chapter 25, the corrected osmolar activity, which accounts for intermolecular attraction and repulsion, is about 282 mOsm/L.) The osmolarity of the interstitial fluid in the medulla of the kidney is much higher, increasing progressively to about 1200 to 1400 mOsm/L in the pelvic tip of the medulla. This means that the renal medullary interstitium has accumulated solutes in great excess of water. Once the high solute concentration in the medulla is achieved, it is maintained by a balanced inflow and outflow of solutes and water in the medulla. The major factors that contribute to the buildup of solute concentration into the renal medulla are as follows: 1. Active transport of sodium ions and co-transport of potassium, chloride, and other ions out of the thick portion of the ascending limb of the loop of Henle into the medullary interstitium 2. Active transport of ions from the collecting ducts into the medullary interstitium 3. Facilitated diffusion of large amounts of urea from the inner medullary collecting ducts into the medullary interstitium 4. Diffusion of only small amounts of water from the medullary tubules into the medullary interstitium, Table 28–1 Summary of Tubule Characteristics—Urine Concentration Proximal tubule Thin descending limb Thin ascending limb Thick ascending limb Distal tubule Cortical collecting tubule Inner medullary collecting duct Permeability NaCl Urea Active NaCl Transport H2O ++ 0 0 ++ + + ++ ++ 0 0 +ADH +ADH + + + 0 0 0 + + + 0 0 0 + +ADH 0 ++ADH 0, minimal level of active transport or permeability; +, moderate level of active transport or permeability; ++, high level of active transport or permeability; +ADH, permeability to water or urea is increased by ADH. far less than the reabsorption of solutes into the medullary interstitium Special Characteristics of Loop of Henle That Cause Solutes to Be Trapped in the Renal Medulla. The transport character- istics of the loops of Henle are summarized in Table 28–1, along with the characteristics of the proximal tubules, distal tubules, cortical collecting tubules, and inner medullary collecting ducts. The most important cause of the high medullary osmolarity is active transport of sodium and cotransport of potassium, chloride, and other ions from the thick ascending loop of Henle into the interstitium. This pump is capable of establishing about a 200milliosmole concentration gradient between the tubular lumen and the interstitial fluid. Because the thick ascending limb is virtually impermeable to water, the solutes pumped out are not followed by osmotic flow of water into the interstitium. Thus, the active transport of sodium and other ions out of the thick ascending loop adds solutes in excess of water to the renal medullary interstitium. There is some passive reabsorption of sodium chloride from the thin ascending limb of Henle’s loop, which is also impermeable to water, adding further to the high solute concentration of the renal medullary interstitium. The descending limb of Henle’s loop, in contrast to the ascending limb, is very permeable to water, and the tubular fluid osmolarity quickly becomes equal to the renal medullary osmolarity. Therefore, water diffuses out of the descending limb of Henle’s loop into the interstitium, and the tubular fluid osmolarity gradually rises as it flows toward the tip of the loop of Henle. Steps Involved in Causing Hyperosmotic Renal Medullary Interstitium. With these characteristics of the loop of Henle in mind, let us now discuss how the renal medulla becomes hyperosmotic. First, assume that the loop of Henle is filled with fluid with a concentration of 300 mOsm/L, the same as that leaving the proximal tubule (Figure 28–3, step 1). Next, the active pump of the thick ascending limb on the loop of Henle is turned on, reducing the concentration inside the tubule and 352 1 Unit V 300 300 300 300 300 300 300 300 300 300 300 300 5 150 400 500 300 400 500 300 200 300 400 200 400 300 150 350 400 300 300 300 300 6 200 3 400 400 200 400 400 200 400 400 4 350 150 500 500 300 500 300 Repeat Steps 4-6 300 300 200 300 400 200 400 400 400 400 200 150 350 500 200 300 200 300 2 The Body Fluids and Kidneys 7 400 400 300 300 100 700 700 500 1000 1000 800 1200 1200 1000 Figure 28–3 Countercurrent multiplier system in the loop of Henle for producing a hyperosmotic renal medulla. (Numerical values are in milliosmoles per liter.) raising the interstitial concentration; this pump establishes a 200-mOsm/L concentration gradient between the tubular fluid and the interstitial fluid (step 2). The limit to the gradient is about 200 mOsm/L because paracellular diffusion of ions back into the tubule eventually counterbalances transport of ions out of the lumen when the 200-mOsm/L concentration gradient is achieved. Step 3 is that the tubular fluid in the descending limb of the loop of Henle and the interstitial fluid quickly reach osmotic equilibrium because of osmosis of water out of the descending limb. The interstitial osmolarity is maintained at 400 mOsm/L because of continued transport of ions out of the thick ascending loop of Henle. Thus, by itself, the active transport of sodium chloride out of the thick ascending limb is capable of establishing only a 200-mOsm/L concentration gradient, much less than that achieved by the countercurrent system. Step 4 is additional flow of fluid into the loop of Henle from the proximal tubule, which causes the hyperosmotic fluid previously formed in the descending limb to flow into the ascending limb. Once this fluid is in the ascending limb, additional ions are pumped into the interstitium, with water remaining behind, until a 200-mOsm/L osmotic gradient is established, with the interstitial fluid osmolarity rising to 500 mOsm/L (step 5). Then, once again, the fluid in the descending limb reaches equilibrium with the hyperosmotic medullary interstitial fluid (step 6), and as the hyperosmotic tubular fluid from the descending limb of the loop of Henle flows into the ascending limb, still more solute is continuously pumped out of the tubules and deposited into the medullary interstitium. These steps are repeated over and over, with the net effect of adding more and more solute to the medulla in excess of water; with sufficient time, this process gradually traps solutes in the medulla and multiplies the concentration gradient established by the active pumping of ions out of the thick ascending loop of Henle, eventually raising the interstitial fluid osmolarity to 1200 to 1400 mOsm/L as shown in step 7. Thus, the repetitive reabsorption of sodium chloride by the thick ascending loop of Henle and continued inflow of new sodium chloride from the proximal tubule into the loop of Henle is called the countercurrent multiplier. The sodium chloride reabsorbed from the ascending loop of Henle keeps adding to the newly arrived sodium chloride, thus “multiplying” its concentration in the medullary interstitium. Role of Distal Tubule and Collecting Ducts in Excreting a Concentrated Urine When the tubular fluid leaves the loop of Henle and flows into the distal convoluted tubule in the renal cortex, the fluid is dilute, with an osmolarity of only about 100 mOsm/L (Figure 28–4). The early distal Chapter 28 NaCl H2O Regulation of Extracellular Fluid Osmolarity and Sodium Concentration 300 100 300 Urea Contributes to Hyperosmotic Renal Medullary Interstitium and to a Concentrated Urine H2O NaCl Urea 300 Cortex NaCl 600 NaCl H2O 1200 1200 600 600 H2O NaCl Urea 1200 1200 Medulla 600 353 Figure 28–4 Formation of a concentrated urine when antidiuretic hormone (ADH) levels are high. Note that the fluid leaving the loop of Henle is dilute but becomes concentrated as water is absorbed from the distal tubules and collecting tubules. With high ADH levels, the osmolarity of the urine is about the same as the osmolarity of the renal medullary interstitial fluid in the papilla, which is about 1200 mOsm/L. (Numerical values are in milliosmoles per liter.) tubule further dilutes the tubular fluid because this segment, like the ascending loop of Henle, actively transports sodium chloride out of the tubule but is relatively impermeable to water. As fluid flows into the cortical collecting tubule, the amount of water reabsorbed is critically dependent on the plasma concentration of ADH. In the absence of ADH, this segment is almost impermeable to water and fails to reabsorb water but continues to reabsorb solutes and further dilutes the urine. When there is a high concentration of ADH, the cortical collecting tubule becomes highly permeable to water, so that large amounts of water are now reabsorbed from the tubule into the cortex interstitium, where it is swept away by the rapidly flowing peritubular capillaries. The fact that these large amounts of water are reabsorbed into the cortex, rather than into the renal medulla, helps to preserve the high medullary interstitial fluid osmolarity. As the tubular fluid flows along the medullary collecting ducts, there is further water reabsorption from the tubular fluid into the interstitium, but the total amount of water is relatively small compared with that added to the cortex interstitium. The reabsorbed water is quickly carried away by the vasa recta into the venous blood. When high levels of ADH are present, the collecting ducts become permeable to water, so that the fluid at the end of the collecting ducts has essentially the same osmolarity as the interstitial fluid of the renal medulla—about 1200 mOsm/L (see Figure 28–3). Thus, by reabsorbing as much water as possible, the kidneys form a highly concentrated urine, excreting normal amounts of solutes in the urine while adding water back to the extracellular fluid and compensating for deficits of body water. Thus far, we have considered only the contribution of sodium chloride to the hyperosmotic renal medullary interstitium. However, urea contributes about 40 to 50 per cent of the osmolarity (500-600 mOsm/L) of the renal medullary interstitium when the kidney is forming a maximally concentrated urine. Unlike sodium chloride, urea is passively reabsorbed from the tubule. When there is water deficit and blood concentrations of ADH are high, large amounts of urea are passively reabsorbed from the inner medullary collecting ducts into the interstitium. The mechanism for reabsorption of urea into the renal medulla is as follows: As water flows up the ascending loop of Henle and into the distal and cortical collecting tubules, little urea is reabsorbed because these segments are impermeable to urea (see Table 28–1). In the presence of high concentrations of ADH, water is reabsorbed rapidly from the cortical collecting tubule and the urea concentration increases rapidly because urea is not very permeant in this part of the tubule. Then, as the tubular fluid flows into the inner medullary collecting ducts, still more water reabsorption takes place, causing an even higher concentration of urea in the fluid. This high concentration of urea in the tubular fluid of the inner medullary collecting duct causes urea to diffuse out of the tubule into the renal interstitium. This diffusion is greatly facilitated by specific urea transporters. One of these urea transporters, UT-AI, is activated by ADH, increasing transport of urea out of the inner medullary collecting duct even more when ADH levels are elevated. The simultaneous movement of water and urea out of the inner medullary collecting ducts maintains a high concentration of urea in the tubular fluid and, eventually, in the urine, even though urea is being reabsorbed. The fundamental role of urea in contributing to urine concentrating ability is evidenced by the fact that people who ingest a high-protein diet, yielding large amounts of urea as a nitrogenous “waste” product, can concentrate their urine much better than people whose protein intake and urea production are low. Malnutrition is associated with a low urea concentration in the medullary interstitium and considerable impairment of urine concentrating ability. Recirculation of Urea from Collecting Duct to Loop of Henle Contributes to Hyperosmotic Renal Medulla. A person usually excretes about 20 to 50 per cent of the filtered load of urea. In general, the rate of urea excretion is determined mainly by two factors: (1) the concentration of urea in the plasma and (2) the glomerular filtration rate (GFR). In patients with renal disease who have large reductions of GFR, the plasma urea concentration increases markedly, returning the filtered urea load and urea excretion rate to the normal level (equal to the rate of urea production), despite the reduced GFR. 354 Unit V The Body Fluids and Kidneys 100% remaining 4.5 Urea Urea 4.5 Cortex 50% remaining Outer H2O medulla 100% remaining 7 30 30 15 Urea Inner medulla Urea 300 300 500 550 20% remaining Figure 28–5 Recirculation of urea absorbed from the medullary collecting duct into the interstitial fluid. This urea diffuses into the thin loop of Henle, and then passes through the distal tubules, and finally passes back into the collecting duct. The recirculation of urea helps to trap urea in the renal medulla and contributes to the hyperosmolarity of the renal medulla. The heavy dark lines, from the thick ascending loop of Henle to the medullary collecting ducts, indicate that these segments are not very permeable to urea. (Numerical values are in milliosmoles per liter of urea during antidiuresis, when large amounts of antidiuretic hormone are present. Percentages of the filtered load of urea that remain in the tubules are indicated in the boxes.) In the proximal tubule, 40 to 50 per cent of the filtered urea is reabsorbed, but even so, the tubular fluid urea concentration increases because urea is not nearly as permeant as water.The concentration of urea continues to rise as the tubular fluid flows into the thin segments of the loop of Henle, partly because of water reabsorption out of the descending loop of Henle but also because of some secretion of urea into the thin loop of Henle from the medullary interstitium (Figure 28–5). The thick limb of the loop of Henle, the distal tubule, and the cortical collecting tubule are all relatively impermeable to urea, and very little urea reabsorption occurs in these tubular segments. When the kidney is forming a concentrated urine and high levels of ADH are present, the reabsorption of water from the distal tubule and cortical collecting tubule further raises the tubular fluid concentration of urea. And as this urea flows into the inner medullary collecting duct, the high tubular fluid concentration of urea and specific urea transporters cause urea to diffuse into the medullary interstitium. A moderate share of the urea that moves into the medullary interstitium eventually diffuses into the thin loop of Henle, so that it passes upward through the ascending loop of Henle, the distal tubule, the cortical collecting tubule, and back down into the medullary collecting duct again. In this way, urea can recirculate through these terminal parts of the tubular system several times before it is excreted. Each time around the circuit contributes to a higher concentration of urea. This urea recirculation provides an additional mechanism for forming a hyperosmotic renal medulla. Because urea is one of the most abundant waste products that must be excreted by the kidneys, this mechanism for concentrating urea before it is excreted is essential to the economy of the body fluid when water is in short supply. When there is excess water in the body and low levels of ADH, the inner medullary collecting ducts have a much lower permeability to both water and urea, and more urea is excreted in the urine. Countercurrent Exchange in the Vasa Recta Preserves Hyperosmolarity of the Renal Medulla Blood flow must be provided to the renal medulla to supply the metabolic needs of the cells in this part of the kidney. Without a special medullary blood flow system, the solutes pumped into the renal medulla by the countercurrent multiplier system would be rapidly dissipated. There are two special features of the renal medullary blood flow that contribute to the preservation of the high solute concentrations: 1. The medullary blood flow is low, accounting for less than 5 per cent of the total renal blood flow. This sluggish blood flow is sufficient to supply the metabolic needs of the tissues but helps to minimize solute loss from the medullary interstitium. 2. The vasa recta serve as countercurrent exchangers, minimizing washout of solutes from the medullary interstitium. The countercurrent exchange mechanism operates as follows (Figure 28–6): Blood enters and leaves the medulla by way of the vasa recta at the boundary of the cortex and renal medulla. The vasa recta, like other capillaries, are highly permeable to solutes in the blood, except for the plasma proteins. As blood descends into the medulla toward the papillae, it becomes progressively more concentrated, partly by solute entry from the interstitium and partly by loss of water into the interstitium. By the time the blood reaches the tips of the vasa recta, it has a concentration of about 1200 mOsm/L, the same as that of the medullary interstitium. As blood ascends back toward the cortex, it becomes progressively less concentrated as solutes diffuse back out into the medullary interstitium and as water moves into the vasa recta. Thus, although there is a large amount of fluid and solute exchange across the vasa recta, there is little net dilution of the concentration of the interstitial fluid at each level of the renal medulla because of the U shape Chapter 28 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration Vasa recta mOsm/L Interstitium mOsm/L 300 350 Solute 600 H2O 600 600 300 Solute 600 Solute 800 H2O 800 800 Solute H2O 1000 1000 Solute 900 Solute 1000 1200 1200 355 Summary of Urine Concentrating Mechanism and Changes in Osmolarity in Different Segments of the Tubules The changes in osmolarity and volume of the tubular fluid as it passes through the different parts of the nephron are shown in Figure 28–7. Proximal Tubule. About 65 per cent of the filtered electrolytes are reabsorbed in the proximal tubule. However, the tubular membranes are highly permeable to water, so that whenever solutes are reabsorbed, water also diffuses through the tubular membrane by osmosis. Therefore, the osmolarity of the fluid remains about the same as the glomerular filtrate, 300 mOsm/L. Figure 28–6 Countercurrent exchange in the vasa recta. Plasma flowing down the descending limb of the vasa recta becomes more hyperosmotic because of diffusion of water out of the blood and diffusion of solutes from the renal interstitial fluid into the blood. In the ascending limb of the vasa recta, solutes diffuse back into the interstitial fluid and water diffuses back into the vasa recta. Large amounts of solutes would be lost from the renal medulla without the U shape of the vasa recta capillaries. (Numerical values are in milliosmoles per liter.) of the vasa recta capillaries, which act as countercurrent exchangers. Thus, the vasa recta do not create the medullary hyperosmolarity, but they do prevent it from being dissipated. The U-shaped structure of the vessels minimizes loss of solute from the interstitium but does not prevent the bulk flow of fluid and solutes into the blood through the usual colloid osmotic and hydrostatic pressures that favor reabsorption in these capillaries. Thus, under steady-state conditions, the vasa recta carry away only as much solute and water as is absorbed from the medullary tubules, and the high concentration of solutes established by the countercurrent mechanism is maintained. Increased Medullary Blood Flow Can Reduce Urine Concentrating Ability. Certain vasodilators can markedly increase renal medullary blood flow, thereby “washing out” some of the solutes from the renal medulla and reducing maximum urine concentrating ability. Large increases in arterial pressure can also increase the blood flow of the renal medulla to a greater extent than in other regions of the kidney and tend to wash out the hyperosmotic interstitium, thereby reducing urine concentrating ability. As discussed earlier, maximum concentrating ability of the kidney is determined not only by the level of ADH but also by the osmolarity of the renal medulla interstitial fluid. Even with maximal levels of ADH, urine concentrating ability will be reduced if medullary blood flow increases enough to reduce the hyperosmolarity in the renal medulla. Descending Loop of Henle. As fluid flows down the descending loop of Henle, water is absorbed into the medulla. The descending limb is highly permeable to water but much less permeable to sodium chloride and urea. Therefore, the osmolarity of the fluid flowing through the descending loop gradually increases until it is equal to that of the surrounding interstitial fluid, which is about 1200 mOsm/L when the blood concentration of ADH is high. When a dilute urine is being formed, owing to low ADH concentrations, the medullary interstitial osmolarity is less than 1200 mOsm/L; consequently, the descending loop tubular fluid osmolarity also becomes less concentrated. This is due partly to the fact that less urea is absorbed into the medullary interstitium from the collecting ducts when ADH levels are low and the kidney is forming a large volume of dilute urine. Thin Ascending Loop of Henle. The thin ascending limb is essentially impermeable to water but reabsorbs some sodium chloride. Because of the high concentration of sodium chloride in the tubular fluid, owing to water removal from the descending loop of Henle, there is some passive diffusion of sodium chloride from the thin ascending limb into the medullary interstitium. Thus, the tubular fluid becomes more dilute as the sodium chloride diffuses out of the tubule and water remains in the tubule. Some of the urea absorbed into the medullary interstitium from the collecting ducts also diffuses into the ascending limb, thereby returning the urea to the tubular system and helping to prevent its washout from the renal medulla. This urea recycling is an additional mechanism that contributes to the hyperosmotic renal medulla. Thick Ascending Loop of Henle. The thick part of the ascending loop of Henle is also virtually impermeable to water, but large amounts of sodium, chloride, potassium, and other ions are actively transported from the tubule into the medullary interstitium. Therefore, fluid in the thick ascending limb of the loop of Henle becomes very dilute, falling to a concentration of about 100 mOsm/L. 356 Unit V 600 Medullary Cortical Late distal Diluting segment 900 Effect of ADH 0.2 ml 25 ml 1200 Osmolarity (mOsm/L) The Body Fluids and Kidneys Figure 28–7 8 ml 300 125 ml 44 ml 200 100 0 25 ml Proximal tubule Loop of Henle 20 ml Distal tubule Collecting tubule and duct Early Distal Tubule. The early distal tubule has properties similar to those of the thick ascending loop of Henle, so that further dilution of the tubular fluid occurs as solutes are reabsorbed while water remains in the tubule. Late Distal Tubule and Cortical Collecting Tubules. In the late distal tubule and cortical collecting tubules, the osmolarity of the fluid depends on the level of ADH. With high levels of ADH, these tubules are highly permeable to water, and significant amounts of water are reabsorbed. Urea, however, is not very permeant in this part of the nephron, resulting in increased urea concentration as water is reabsorbed. This allows most of the urea delivered to the distal tubule and collecting tubule to pass into the inner medullary collecting ducts, from which it is eventually reabsorbed or excreted in the urine. In the absence of ADH, little water is reabsorbed in the late distal tubule and cortical collecting tubule; therefore, osmolarity decreases even further because of continued active reabsorption of ions from these segments. Inner Medullary Collecting Ducts. The concentration of fluid in the inner medullary collecting ducts also depends on (1) ADH and (2) the osmolarity of the medullary interstitium established by the countercurrent mechanism. In the presence of large amounts of ADH, these ducts are highly permeable to water, and water diffuses from the tubule into the interstitium until osmotic equilibrium is reached, with the tubular fluid having about the same concentration as the renal medullary interstitium (1200 to 1400 mOsm/L). Thus, a very concentrated but small volume of urine is produced when ADH levels are high. Because water reabsorption increases urea concentration in the tubular Urine Changes in osmolarity of the tubular fluid as it passes through the different tubular segments in the presence of high levels of antidiuretic hormone (ADH) and in the absence of ADH. (Numerical values indicate the approximate volumes in milliliters per minute or in osmolarities in milliosmoles per liter of fluid flowing along the different tubular segments.) fluid, and because the inner medullary collecting ducts have specific urea transporters that greatly facilitate diffusion, much of the highly concentrated urea in the ducts diffuses out of the tubular lumen into the medullary interstitium. This absorption of the urea into the renal medulla contributes to the high osmolarity of the medullary interstitium and the high concentrating ability of the kidney. There are several important points to consider that may not be obvious from this discussion. First, although sodium chloride is one of the principal solutes that contributes to the hyperosmolarity of the medullary interstitium, the kidney can, when needed, excrete a highly concentrated urine that contains little sodium chloride. The hyperosmolarity of the urine in these circumstances is due to high concentrations of other solutes, especially of waste products such as urea and creatinine. One condition in which this occurs is dehydration accompanied by low sodium intake. As discussed in Chapter 29, low sodium intake stimulates formation of the hormones angiotensin II and aldosterone, which together cause avid sodium reabsorption from the tubules while leaving the urea and other solutes to maintain the highly concentrated urine. Second, large quantities of dilute urine can be excreted without increasing the excretion of sodium. This is accomplished by decreasing ADH secretion, which reduces water reabsorption in the more distal tubular segments without significantly altering sodium reabsorption. And finally, we should keep in mind that there is an obligatory urine volume, which is dictated by the maximum concentrating ability of the kidney and the amount of solute that must be excreted. Therefore, if large amounts of solute must be excreted, they must be accompanied by the minimal amount of water Chapter 28 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration necessary to excrete them. For example, if 1200 milliosmoles of solute must be excreted each day, this requires at least 1 liter of urine if maximal urine concentrating ability is 1200 mOsm/L. Quantifying Renal Urine Concentration and Dilution: “Free Water” and Osmolar Clearances The process of concentrating or diluting the urine requires the kidneys to excrete water and solutes somewhat independently. When the urine is dilute, water is excreted in excess of solutes. Conversely, when the urine is concentrated, solutes are excreted in excess of water. The total clearance of solutes from the blood can be expressed as the osmolar clearance (Cosm); this is the volume of plasma cleared of solutes each minute, in the same way that clearance of a single substance is calculated: Cosm = Uosm ¥ V Posm where Uosm is the urine osmolarity, V is the urine flow rate, and Posm is the plasma osmolarity. For example, if plasma osmolarity is 300 mOsm/L, urine osmolarity is 600 mOsm/L, and urine flow rate is 1 ml/min (0.001 L/ min), the rate of osmolar excretion is 0.6 mOsm/min (600 mOsm/L ¥ 0.001 L/min) and osmolar clearance is 0.6 mOsm/min divided by 300 mOsm/L, or 0.002 L/min (2.0 ml/min). This means that 2 milliliters of plasma are being cleared of solute each minute. Relative Rates at Which Solutes and Water Are Excreted Can Be Assessed Using the Concept of “Free-Water Clearance.” Free- water clearance (CH2O) is calculated as the difference between water excretion (urine flow rate) and osmolar clearance: CH2O = V - Cosm = V - ( Uosm ¥ V ) (Posm ) Thus, the rate of free-water clearance represents the rate at which solute-free water is excreted by the kidneys. When free-water clearance is positive, excess water is being excreted by the kidneys; when free-water clearance is negative, excess solutes are being removed from the blood by the kidneys and water is being conserved. Using the example discussed earlier, if urine flow rate is 1 ml/min and osmolar clearance is 2 ml/min, free-water clearance would be -1 ml/min. This means that instead of water being cleared from the kidneys in excess of solutes, the kidneys are actually returning water back to the systemic circulation, as occurs during water deficits. Thus, whenever urine osmolarity is greater than plasma osmolarity, free-water clearance will be negative, indicating water conservation. When the kidneys are forming a dilute urine (that is, urine osmolarity is less than plasma osmolarity), freewater clearance will be a positive value, denoting that water is being removed from the plasma by the kidneys in excess of solutes. Thus, water free of solutes, called “free water,” is being lost from the body and the plasma is being concentrated when free-water clearance is positive. 357 Disorders of Urinary Concentrating Ability An impairment in the ability of the kidneys to concentrate or dilute the urine appropriately can occur with one or more of the following abnormalities: 1. Inappropriate secretion of ADH. Either too much or too little ADH secretion results in abnormal fluid handling by the kidneys. 2. Impairment of the countercurrent mechanism. A hyperosmotic medullary interstitium is required for maximal urine concentrating ability. No matter how much ADH is present, maximal urine concentration is limited by the degree of hyperosmolarity of the medullary interstitium. 3. Inability of the distal tubule, collecting tubule, and collecting ducts to respond to ADH. Failure to Produce ADH: “Central” Diabetes Insipidus. An inability to produce or release ADH from the posterior pituitary can be caused by head injuries or infections, or it can be congenital. Because the distal tubular segments cannot reabsorb water in the absence of ADH, this condition, called “central” diabetes insipidus, results in the formation of a large volume of dilute urine, with urine volumes that can exceed 15 L/day. The thirst mechanisms, discussed later in this chapter, are activated when excessive water is lost from the body; therefore, as long as the person drinks enough water, large decreases in body fluid water do not occur. The primary abnormality observed clinically in people with this condition is the large volume of dilute urine. However, if water intake is restricted, as can occur in a hospital setting when fluid intake is restricted or the patient is unconscious (for example, because of a head injury), severe dehydration can rapidly occur. The treatment for central diabetes insipidus is administration of a synthetic analog of ADH, desmopressin, which acts selectively on V2 receptors to increase water permeability in the late distal and collecting tubules. Desmopressin can be given by injection, as a nasal spray, or orally, and rapidly restores urine output toward normal. Inability of the Kidneys to Respond to ADH: “Nephrogenic” Diabetes Insipidus. There are circumstances in which normal or elevated levels of ADH are present but the renal tubular segments cannot respond appropriately. This condition is referred to as “nephrogenic” diabetes insipidus because the abnormality resides in the kidneys. This abnormality can be due to either failure of the countercurrent mechanism to form a hyperosmotic renal medullary interstitium or failure of the distal and collecting tubules and collecting ducts to respond to ADH. In either case, large volumes of dilute urine are formed, which tends to cause dehydration unless fluid intake is increased by the same amount as urine volume is increased. Many types of renal diseases can impair the concentrating mechanism, especially those that damage the renal medulla. Also, impairment of the function of the loop of Henle, as occurs with diuretics that inhibit electrolyte reabsorption by this segment, can compromise urine concentrating ability. And certain drugs, such as lithium (used to treat manic-depressive disorders) and tetracyclines (used as antibiotics), can impair the ability of the distal nephron segments to respond to ADH. 358 Unit V The Body Fluids and Kidneys Nephrogenic diabetes insipidus can be distinguished from central diabetes insipidus by administration of desmopressin, the synthetic analog of ADH. Lack of a prompt decrease in urine volume and an increase in urine osmolarity within 2 hours after injection of desmopressin is strongly suggestive of nephrogenic diabetes insipidus. The treatment for nephrogenic diabetes insipidus is to correct, if possible, the underlying renal disorder. The hypernatremia can also be attenuated by a low-sodium diet and administration of a diuretic that enhances renal sodium excretion, such as a thiazide diuretic. Control of Extracellular Fluid Osmolarity and Sodium Concentration Regulation of extracellular fluid osmolarity and sodium concentration are closely linked because sodium is the most abundant ion in the extracellular compartment. Plasma sodium concentration is normally regulated within close limits of 140 to 145 mEq/ L, with an average concentration of about 142 mEq/L. Osmolarity averages about 300 mOsm/L (about 282 mOsm/L when corrected for interionic attraction) and seldom changes more than ±2 to 3 per cent. As discussed in Chapter 25, these variables must be precisely controlled because they determine the distribution of fluid between the intracellular and extracellular compartments. Although multiple mechanisms control the amount of sodium and water excretion by the kidneys, two primary systems are especially involved in regulating the concentration of sodium and osmolarity of extracellular fluid: (1) the osmoreceptor-ADH system and (2) the thirst mechanism. Osmoreceptor-ADH Feedback System Figure 28–8 shows the basic components of the osmoreceptor-ADH feedback system for control of extracellular fluid sodium concentration and osmolarity. When osmolarity (plasma sodium concentration) increases above normal because of water deficit, for example, this feedback system operates as follows: 1. An increase in extracellular fluid osmolarity (which in practical terms means an increase in plasma sodium concentration) causes the special nerve cells called osmoreceptor cells, located in the anterior hypothalamus near the supraoptic nuclei, to shrink. 2. Shrinkage of the osmoreceptor cells causes them to fire, sending nerve signals to additional nerve cells in the supraoptic nuclei, which then relay Water deficit Estimating Plasma Osmolarity from Plasma Sodium Concentration Extracellular osmolarity In most clinical laboratories, plasma osmolarity is not routinely measured. However, because sodium and its associated anions account for about 94 per cent of the solute in the extracellular compartment, plasma osmolarity (Posm) can be roughly approximated as Osmoreceptors ADH secretion (posterior pituitary) Posm = 2.1 ¥ Plasma sodium concentration For instance, with a plasma sodium concentration of 142 mEq/L, the plasma osmolarity would be estimated from the formula above to be about 298 mOsm/L. To be more exact, especially in conditions associated with renal disease, the contribution of two other solutes, glucose and urea, should be included. Such estimates of plasma osmolarity are usually accurate within a few percentage points of those measured directly. Normally, sodium ions and associated anions (primarily bicarbonate and chloride) represent about 94 per cent of the extracellular osmoles, with glucose and urea contributing about 3 to 5 per cent of the total osmoles. However, because urea easily permeates most cell membranes, it exerts little effective osmotic pressure under steady-state conditions. Therefore, the sodium ions in the extracellular fluid and associated anions are the principal determinants of fluid movement across the cell membrane. Consequently, we can discuss the control of osmolarity and control of sodium ion concentration at the same time. Plasma ADH H2O permeability in distal tubules, collecting ducts H2O reabsorption H2O excreted Figure 28–8 Osmoreceptor-antidiuretic hormone (ADH) feedback mechanism for regulating extracellular fluid osmolarity in response to a water deficit. Chapter 28 359 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration these signals down the stalk of the pituitary gland to the posterior pituitary. 3. These action potentials conducted to the posterior pituitary stimulate the release of ADH, which is stored in secretory granules (or vesicles) in the nerve endings. 4. ADH enters the blood stream and is transported to the kidneys, where it increases the water permeability of the late distal tubules, cortical collecting tubules, and medullary collecting ducts. 5. The increased water permeability in the distal nephron segments causes increased water reabsorption and excretion of a small volume of concentrated urine. Thus, water is conserved in the body while sodium and other solutes continue to be excreted in the urine. This causes dilution of the solutes in the extracellular fluid, thereby correcting the initial excessively concentrated extracellular fluid. The opposite sequence of events occurs when the extracellular fluid becomes too dilute (hypo-osmotic). For example, with excess water ingestion and a decrease in extracellular fluid osmolarity, less ADH is formed, the renal tubules decrease their permeability for water, less water is reabsorbed, and a large volume of dilute urine is formed. This in turn concentrates the body fluids and returns plasma osmolarity toward normal. ADH Synthesis in Supraoptic and Paraventricular Nuclei of the Hypothalamus and ADH Release from the Posterior Pituitary Figure 28–9 shows the neuroanatomy of the hypothalamus and the pituitary gland, where ADH is synthesized and released. The hypothalamus contains two types of magnocellular (large) neurons that synthesize ADH in the supraoptic and paraventricular nuclei of the hypothalamus, about five sixths in the supraoptic nuclei and about one sixth in the paraventricular nuclei. Both of these nuclei have axonal extensions to the posterior pituitary. Once ADH is synthesized, it is transported down the axons of the neurons to their tips, terminating in the posterior pituitary gland. When the supraoptic and paraventricular nuclei are stimulated by increased osmolarity or other factors, nerve impulses pass down these nerve endings, changing their membrane permeability and increasing calcium entry. ADH stored in the secretory granules (also called vesicles) of the nerve endings is released in response to increased calcium entry. The released ADH is then carried away in the capillary blood of the posterior pituitary into the systemic circulation. Secretion of ADH in response to an osmotic stimulus is rapid, so that plasma ADH levels can increase severalfold within minutes, thereby providing a rapid means for altering renal excretion of water. A second neuronal area important in controlling osmolarity and ADH secretion is located along the Pituitary Osmoreceptors Baroreceptors Cardiopulmonary receptors Supraoptic neuron Paraventricular neuron Anterior lobe Posterior lobe ADH Urine: decreased flow and concentrated Figure 28–9 Neuroanatomy of the hypothalamus, where antidiuretic hormone (ADH) is synthesized, and the posterior pituitary gland, where ADH is released. anteroventral region of the third ventricle, called the AV3V region. At the upper part of this region is a structure called the subfornical organ, and at the inferior part is another structure called the organum vasculosum of the lamina terminalis. Between these two organs is the median preoptic nucleus, which has multiple nerve connections with the two organs as well as with the supraoptic nuclei and the blood pressure control centers in the medulla of the brain. Lesions of the AV3V region cause multiple deficits in the control of ADH secretion, thirst, sodium appetite, and blood pressure. Electrical stimulation of this region or stimulation by angiotensin II can alter ADH secretion, thirst, and sodium appetite. In the vicinity of the AV3V region and the supraoptic nuclei are neuronal cells that are excited by small increases in extracellular fluid osmolarity; hence, the term osmoreceptors has been used to describe these neurons. These cells send nerve signals to the supraoptic nuclei to control their firing and secretion of ADH. It is also likely that they induce thirst in response to increased extracellular fluid osmolarity. 360 Unit V The Body Fluids and Kidneys Both the subfornical organ and the organum vasculosum of the lamina terminalis have vascular supplies that lack the typical blood-brain barrier that impedes the diffusion of most ions from the blood into the brain tissue. This makes it possible for ions and other solutes to cross between the blood and the local interstitial fluid in this region. As a result, the osmoreceptors rapidly respond to changes in osmolarity of the extracellular fluid, exerting powerful control over the secretion of ADH and over thirst, as discussed later. ADH release is also controlled by cardiovascular reflexes that respond to decreases in blood pressure and/or blood volume, including (1) the arterial baroreceptor reflexes and (2) the cardiopulmonary reflexes, both of which are discussed in Chapter 18. These reflex pathways originate in high-pressure regions of the circulation, such as the aortic arch and carotid sinus, and in the low-pressure regions, especially in the cardiac atria. Afferent stimuli are carried by the vagus and glossopharyngeal nerves with synapses in the nuclei of the tractus solitarius. Projections from these nuclei relay signals to the hypothalamic nuclei that control ADH synthesis and secretion. Thus, in addition to increased osmolarity, two other stimuli increase ADH secretion: (1) decreased arterial pressure and (2) decreased blood volume. Whenever blood pressure and blood volume are reduced, such as occurs during hemorrhage, increased ADH secretion causes increased fluid reabsorption by the kidneys, helping to restore blood pressure and blood volume toward normal. Quantitative Importance of Cardiovascular Reflexes and Osmolarity in Stimulating ADH Secretion As shown in Figure 28–10, either a decrease in effective blood volume or an increase in extracellular fluid osmolarity stimulates ADH secretion. However, ADH is considerably more sensitive to small changes in osmolarity than to similar changes in blood volume. For example, a change in plasma osmolarity of only 1 per cent is sufficient to increase ADH levels. By contrast, after blood loss, plasma ADH levels do not change appreciably until blood volume is reduced by about 10 per cent. With further decreases in blood volume, ADH levels rapidly increase. Thus, with severe decreases in blood volume, the cardiovascular reflexes play a major role in stimulating ADH secretion. The usual day-to-day regulation of ADH secretion during simple dehydration is effected mainly by changes in plasma osmolarity. Decreased blood volume, however, PAVP = 1.3 e–0.17 vol. 50 45 40 Plasma ADH (pg/ml) Cardiovascular Reflex Stimulation of ADH Release by Decreased Arterial Pressure and/or Decreased Blood Volume Isotonic volume depletion Isovolemic osmotic increase 35 30 25 20 PAVP = 2.5 D Osm + 2.0 15 10 5 0 0 5 10 15 20 Per cent change Figure 28–10 The effect of increased plasma osmolarity or decreased blood volume on the level of plasma (P) antidiuretic hormone (ADH), also called arginine vasopressin (AVP). (Redrawn from Dunn FL, Brennan TJ, Nelson AE, Robertson GL: The role of blood osmolality and volume in regulating vasopressin secretion in the rat. J Clin Invest 52(12):3212, 1973. By copyright permission of the American Society of Clinical Investigation.) Table 28–2 Regulation of ADH Secretion Increase ADH Decrease ADH ≠ Plasma osmolarity Ø Blood volume Ø Blood pressure Ø Plasma osmolarity ≠ Blood volume ≠ Blood pressure Nausea Hypoxia Drugs: Morphine Nicotine Cyclophosphamide Drugs: Alcohol Clonidine (antihypertensive drug) Haloperidol (dopamine blocker) greatly enhances the ADH response to increased osmolarity. Other Stimuli for ADH Secretion ADH secretion can also be increased or decreased by other stimuli to the central nervous system as well as by various drugs and hormones, as shown in Table 28–2. For example, nausea is a potent stimulus for Chapter 28 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration ADH release, which may increase to as much as 100 times normal after vomiting. Also, drugs such as nicotine and morphine stimulate ADH release, whereas some drugs, such as alcohol, inhibit ADH release. The marked diuresis that occurs after ingestion of alcohol is due in part to inhibition of ADH release. Role of Thirst in Controlling Extracellular Fluid Osmolarity and Sodium Concentration The kidneys minimize fluid loss during water deficits through the osmoreceptor-ADH feedback system. Adequate fluid intake, however, is necessary to counterbalance whatever fluid loss does occur through sweating and breathing and through the gastrointestinal tract. Fluid intake is regulated by the thirst mechanism, which, together with the osmoreceptor-ADH mechanism, maintains precise control of extracellular fluid osmolarity and sodium concentration. Many of the same factors that stimulate ADH secretion also increase thirst, which is defined as the conscious desire for water. Central Nervous System Centers for Thirst Referring again to Figure 28–9, the same area along the anteroventral wall of the third ventricle that promotes ADH release also stimulates thirst. Located anterolaterally in the preoptic nucleus is another small area that, when stimulated electrically, causes immediate drinking that continues as long as the stimulation lasts. All these areas together are called the thirst center. The neurons of the thirst center respond to injections of hypertonic salt solutions by stimulating drinking behavior. These cells almost certainly function as osmoreceptors to activate the thirst mechanism, in the same way that the osmoreceptors stimulate ADH release. Increased osmolarity of the cerebrospinal fluid in the third ventricle has essentially the same effect to promote drinking. It is likely that the organum vasculosum of the lamina terminalis, which lies immediately beneath the ventricular surface at the inferior end of the AV3V region, is intimately involved in mediating this response. Stimuli for Thirst Table 28–3 summarizes some of the known stimuli for thirst. One of the most important is increased extracellular fluid osmolarity, which causes intracellular dehydration in the thirst centers, thereby stimulating the sensation of thirst. The value of this response is obvious: it helps to dilute extracellular fluids and returns osmolarity toward normal. 361 Table 28–3 Control of Thirst Increase Thirst Decrease Thirst ≠ Osmolarity Ø Blood volume Ø Blood pressure ≠ Angiotensin Ø Osmolarity ≠ Blood volume ≠ Blood pressure Ø Angiotensin II Dryness of mouth Gastric distention Decreases in extracellular fluid volume and arterial pressure also stimulate thirst by a pathway that is independent of the one stimulated by increased plasma osmolarity. Thus, blood volume loss by hemorrhage stimulates thirst even though there might be no change in plasma osmolarity. This probably occurs because of neutral input from cardiopulmonary and systemic arterial baroreceptors in the circulation. A third important stimulus for thirst is angiotensin II. Studies in animals have shown that angiotensin II acts on the subfornical organ and on the organum vasculosum of the lamina terminalis. These regions are outside the blood-brain barrier, and peptides such as angiotensin II diffuse into the tissues. Because angiotensin II is also stimulated by factors associated with hypovolemia and low blood pressure, its effect on thirst helps to restore blood volume and blood pressure toward normal, along with the other actions of angiotensin II on the kidneys to decrease fluid excretion. Dryness of the mouth and mucous membranes of the esophagus can elicit the sensation of thirst. As a result, a thirsty person may receive relief from thirst almost immediately after drinking water, even though the water has not been absorbed from the gastrointestinal tract and has not yet had an effect on extracellular fluid osmolarity. Gastrointestinal and pharyngeal stimuli influence thirst. For example, in animals that have an esophageal opening to the exterior so that water is never absorbed into the blood, partial relief of thirst occurs after drinking, although the relief is only temporary. Also, gastrointestinal distention may partially alleviate thirst; for instance, simple inflation of a balloon in the stomach can relieve thirst. However, relief of thirst sensations through gastrointestinal or pharyngeal mechanisms is short-lived; the desire to drink is completely satisfied only when plasma osmolarity and/or blood volume returns to normal. The ability of animals and humans to “meter” fluid intake is important because it prevents overhydration. After a person drinks water, 30 to 60 minutes may be required for the water to be reabsorbed and distributed throughout the body. If the thirst sensation were not temporarily relieved after drinking water, the person would continue to drink more and more, eventually leading to overhydration and excess dilution of 362 Unit V The Body Fluids and Kidneys the body fluids. Experimental studies have repeatedly shown that animals drink almost exactly the amount necessary to return plasma osmolarity and volume to normal. The kidneys must continually excrete at least some fluid, even in a dehydrated person, to rid the body of excess solutes that are ingested or produced by metabolism. Water is also lost by evaporation from the lungs and the gastrointestinal tract and by evaporation and sweating from the skin. Therefore, there is always a tendency for dehydration, with resultant increased extracellular fluid sodium concentration and osmolarity. When the sodium concentration increases only about 2 mEq/L above normal, the thirst mechanism is activated, causing a desire to drink water. This is called the threshold for drinking. Thus, even small increases in plasma osmolarity are normally followed by water intake, which restores extracellular fluid osmolarity and volume toward normal. In this way, the extracellular fluid osmolarity and sodium concentration are precisely controlled. Integrated Responses of Osmoreceptor-ADH and Thirst Mechanisms in Controlling Extracellular Fluid Osmolarity and Sodium Concentration In a healthy person, the osmoreceptor-ADH and thirst mechanisms work in parallel to precisely regulate extracellular fluid osmolarity and sodium concentration, despite the constant challenges of dehydration. Even with additional challenges, such as high salt intake, these feedback systems are able to keep plasma osmolarity reasonably constant. Figure 28–11 shows that an increase in sodium intake to as high as six times normal has only a small effect on plasma sodium concentration as long as the ADH and thirst mechanisms are both functioning normally. When either the ADH or the thirst mechanism fails, the other ordinarily can still control extracellular osmolarity and sodium concentration with reasonable effectiveness, as long as there is enough fluid intake to balance the daily obligatory urine volume and water losses caused by respiration, sweating, or gastrointestinal losses. However, if both the ADH and thirst mechanisms fail simultaneously, plasma sodium concentration and osmolarity are very poorly controlled; thus, when sodium intake is increased after blocking the total ADH-thirst system, relatively large changes in plasma sodium concentration do occur. In the absence of the ADH-thirst mechanisms, no other feedback mechanism is capable of adequately regulating plasma sodium concentration and osmolarity. Plasma sodium concentration (mEq/L) Threshold for Osmolar Stimulus of Drinking 152 ADH and thirst systems blocked 148 144 Normal 140 136 0 30 60 90 120 150 Sodium intake (mEq/day) 180 Figure 28–11 Effect of large changes in sodium intake on extracellular fluid sodium concentration in dogs under normal conditions (red line) and after the antidiuretic hormone (ADH) and thirst feedback systems had been blocked (blue line). Note that control of extracellular fluid sodium concentration is poor in the absence of these feedback systems. (Courtesy Dr. David B. Young.) Role of Angiotensin II and Aldosterone in Controlling Extracellular Fluid Osmolarity and Sodium Concentration As discussed in Chapter 27, both angiotensin II and aldosterone play an important role in regulating sodium reabsorption by the renal tubules. When sodium intake is low, increased levels of these hormones stimulate sodium reabsorption by the kidneys and, therefore, prevent large sodium losses, even though sodium intake may be reduced to as low as 10 per cent of normal. Conversely, with high sodium intake, decreased formation of these hormones permits the kidneys to excrete large amounts of sodium. Because of the importance of angiotensin II and aldosterone in regulating sodium excretion by the kidneys, one might mistakenly infer that they also play an important role in regulating extracellular fluid sodium concentration. Although these hormones increase the amount of sodium in the extracellular fluid, they also increase the extracellular fluid volume by increasing reabsorption of water along with the sodium. Therefore, angiotensin II and aldosterone have little effect on sodium concentration, except under extreme conditions. This relative unimportance of aldosterone in regulating extracellular fluid sodium concentration is shown by the experiment of Figure 28–12. This figure shows the effect on plasma sodium concentration of changing Plasma sodium concentration (mEq/L) Chapter 28 150 Regulation of Extracellular Fluid Osmolarity and Sodium Concentration Normal 140 Aldosterone system blocked 130 120 110 363 reasons for this is that large losses of sodium eventually cause severe volume depletion and decreased blood pressure, which can activate the thirst mechanism through the cardiovascular reflexes. This leads to a further dilution of the plasma sodium concentration, even though the increased water intake helps to minimize the decrease in body fluid volumes under these conditions. Thus, there are extreme situations in which plasma sodium concentration may change significantly, even with a functional ADH-thirst mechanism. Even so, the ADH-thirst mechanism is by far the most powerful feedback system in the body for controlling extracellular fluid osmolarity and sodium concentration. 100 0 30 60 90 120 150 180 210 Sodium intake (mEq/L) Salt-Appetite Mechanism for Controlling Extracellular Fluid Sodium Concentration and Volume Figure 28–12 Effect of large changes in sodium intake on extracellular fluid sodium concentration in dogs under normal conditions (red line) and after the aldosterone feedback system had been blocked (blue line). Note that sodium concentration is maintained relatively constant over this wide range of sodium intakes, with or without aldosterone feedback control. (Courtesy Dr. David B. Young.) sodium intake more than sixfold under two conditions: (1) under normal conditions and (2) after the aldosterone feedback system has been blocked by removing the adrenal glands and infusing the animals with aldosterone at a constant rate so that plasma levels could not change upward or downward. Note that when sodium intake was increased sixfold, plasma concentration changed only about 1 to 2 per cent in either case. This indicates that even without a functional aldosterone feedback system, plasma sodium concentration can be well regulated. The same type of experiment has been conducted after blocking angiotensin II formation, with the same result. There are two primary reasons why changes in angiotensin II and aldosterone do not have a major effect on plasma sodium concentration. First, as discussed earlier, angiotensin II and aldosterone increase both sodium and water reabsorption by the renal tubules, leading to increases in extracellular fluid volume and sodium quantity but little change in sodium concentrations. Second, as long as the ADH-thirst mechanism is functional, any tendency toward increased plasma sodium concentration is compensated for by increased water intake or increased plasma ADH secretion, which tends to dilute the extracellular fluid back toward normal. The ADH-thirst system far overshadows the angiotensin II and aldosterone systems for regulating sodium concentration under normal conditions. Even in patients with primary aldosteronism, who have extremely high levels of aldosterone, the plasma sodium concentration usually increases only about 3 to 5 mEq/L above normal. Under extreme conditions, caused by complete loss of aldosterone secretion because of adrenalectomy or in patients with Addison’s disease (severely impaired secretion or total lack of aldosterone), there is tremendous loss of sodium by the kidneys, which can lead to reductions in plasma sodium concentration. One of the Maintenance of normal extracellular fluid volume and sodium concentration requires a balance between sodium excretion and sodium intake. In modern civilizations, sodium intake is almost always greater than necessary for homeostasis. In fact, the average sodium intake for individuals in industrialized cultures eating processed foods usually ranges between 100 and 200 mEq/day, even though humans can survive and function normally on 10 to 20 mEq/day. Thus, most people eat far more sodium than is necessary for homeostasis, and there is evidence that our usual high sodium intake may contribute to cardiovascular disorders such as hypertension. Salt appetite is due in part to the fact that animals and humans like salt and eat it regardless of whether they are salt-deficient. There is also a regulatory component to salt appetite in which there is a behavioral drive to obtain salt when there is sodium deficiency in the body. This is particularly important in herbivores, which naturally eat a low-sodium diet, but salt craving may also be important in humans who have extreme deficiency of sodium, such as occurs in Addison’s disease. In this instance, there is deficiency of aldosterone secretion, which causes excessive loss of sodium in the urine and leads to decreased extracellular fluid volume and decreased sodium concentration; both of these changes elicit the desire for salt. In general, the two primary stimuli that are believed to increase salt appetite are (1) decreased extracellular fluid sodium concentration and (2) decreased blood volume or blood pressure, associated with circulatory insufficiency. These are the same major stimuli that elicit thirst. The neuronal mechanism for salt appetite is analogous to that of the thirst mechanism. Some of the same neuronal centers in the AV3V region of the brain seem to be involved, because lesions in this region frequently affect both thirst and salt appetite simultaneously in animals. Also, circulatory reflexes elicited by low blood pressure or decreased blood volume affect both thirst and salt appetite at the same time. References Cowley AW Jr, Mori T, Mattson D, Zou AP: Role of renal NO production in the regulation of medullary blood flow. Am J Physiol Regul Integr Comp Physiol 284:R1355, 2003. 364 Unit V The Body Fluids and Kidneys Dwyer TM, Schmidt-Nielsen B: The renal pelvis: machinery that concentrates urine in the papilla. News Physiol Sci 18:1, 2003. Edwards A, Delong MJ, Pallone TL: Interstitial water and solute recovery by inner medullary vasa recta. Am J Physiol Renal Physiol 278:F257, 2000. Fitzsimons JT: Angiotensin, thirst, and sodium appetite. Physiol Rev 78:583, 1998. Knepper MA, Saidel GM, Hascall VC, Dwyer T: Concentration of solutes in the renal inner medulla: interstitial hyaluronan as a mechano-osmotic transducer. Am J Physiol Renal Physiol 284:F433, 2003. Kozono D, Yasui M, King LS, Agre P: Aquaporin water channels: atomic structure molecular dynamics meet clinical medicine. J Clin Invest 109:1395, 2002. McKinley MJ, Johnson AK: The physiological regulation of thirst and fluid intake. News Physiol Sci 19:1, 2004. Morello JP, Bichet DG: Nephrogenic diabetes insipidus. Annu Rev Physiol 63:607, 2001. Nielsen S, Frokiaer J, Marples D, et al: Aquaporins in the kidney: from molecules to medicine. Physiol Rev 82:205, 2002. Pallone TL, Turner MR, Edwards A, Jamison RL: Countercurrent exchange in the renal medulla. Am J Physiol Regul Integr Comp Physiol 284:R1153, 2003. Robertson GL: Vasopressin. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000. Sands JM, Layton HE: Urine concentrating mechanism and its regulation. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000. Sands JM: Molecular mechanisms of urea transport. J Membrane Biol 191:149, 2003. Stricker EM, Sved AF: Controls of vasopressin secretion and thirst: similarities and dissimilarities in signals. Physiol Behav 77:731, 2002. Verbalis JG: Diabetes insipidus. Rev Endocr Metab Disord 4:177, 2003. C H A P T E R 2 9 Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume Regulation of Potassium Excretion and Potassium Concentration in Extracellular Fluid Extracellular fluid potassium concentration normally is regulated precisely at about 4.2 mEq/L, seldom rising or falling more than ± 0.3 mEq/L. This precise control is necessary because many cell functions are very sensitive to changes in extracellular fluid potassium concentration. For instance, an increase in plasma potassium concentration of only 3 to 4 mEq/L can cause cardiac arrhythmias, and higher concentrations can lead to cardiac arrest or fibrillation. A special difficulty in regulating extracellular potassium concentration is the fact that over 98 per cent of the total body potassium is contained in the cells and only 2 per cent in the extracellular fluid (Figure 29–1). For a 70-kilogram adult, who has about 28 liters of intracellular fluid (40 per cent of body weight) and 14 liters of extracellular fluid (20 per cent of body weight), about 3920 milliequivalents of potassium are inside the cells and only about 59 milliequivalents are in the extracellular fluid. Also, the potassium contained in a single meal is often as high as 50 milliequivalents, and the daily intake usually ranges between 50 and 200 mEq/day; therefore, failure to rapidly rid the extracellular fluid of the ingested potassium could cause life-threatening hyperkalemia (increased plasma potassium concentration). Likewise, a small loss of potassium from the extracellular fluid could cause severe hypokalemia (low plasma potassium concentration) in the absence of rapid and appropriate compensatory responses. Maintenance of potassium balance depends primarily on excretion by the kidneys because the amount excreted in the feces is only about 5 to 10 per cent of the potassium intake. Thus, the maintenance of normal potassium balance requires the kidneys to adjust their potassium excretion rapidly and precisely to wide variations in intake, as is also true for most other electrolytes. Control of potassium distribution between the extracellular and intracellular compartments also plays an important role in potassium homeostasis. Because over 98 per cent of the total body potassium is contained in the cells, they can serve as an overflow site for excess extracellular fluid potassium during hyperkalemia or as a source of potassium during hypokalemia. Thus, redistribution of potassium between the intra- and extracellular fluid compartments provides a first line of defense against changes in extracellular fluid potassium concentration. 365 366 Unit V The Body Fluids and Kidneys plasma potassium concentration after eating a meal is much greater than normal. Injections of insulin, however, can help to correct the hyperkalemia. K+ intake 100 mEq/day Extracellular fluid K+ Intracellular fluid K+ 4.2 mEq/L x 14 L 140 mEq/L x 28 L 59 m Eq 3920 mEq K+ output Urine 92 mEq/day Feces 8 mEq/day 100 mEq/day Aldosterone Increases Potassium Uptake into Cells. Increased potassium intake also stimulates secretion of aldosterone, which increases cell potassium uptake. Excess aldosterone secretion (Conn’s syndrome) is almost invariably associated with hypokalemia, due in part to movement of extracellular potassium into the cells. Conversely, patients with deficient aldosterone production (Addison’s disease) often have clinically significant hyperkalemia due to accumulation of potassium in the extracellular space as well as to renal retention of potassium. b-Adrenergic Stimulation Increases Cellular Uptake of Potassium. Figure 29–1 Normal potassium intake, distribution of potassium in the body fluids, and potassium output from the body. Table 29–1 Factors That Can Alter Potassium Distribution Between the Intra- and Extracellular Fluid + + Factors That Shift K into Cells (Decrease Extracellular [K+]) Factors That Shift K Out of Cells (Increase Extracellular [K+]) • • • • • Insulin deficiency (diabetes mellitus) • Aldosterone deficiency (Addison’s disease) • b-adrenergic blockade • Acidosis • Cell lysis • Strenuous exercise • Increased extracellular fluid osmolarity Insulin Aldosterone b-adrenergic stimulation Alkalosis Regulation of Internal Potassium Distribution After ingestion of a normal meal, extracellular fluid potassium concentration would rise to a lethal level if the ingested potassium did not rapidly move into the cells. For example, absorption of 40 milliequivalents of potassium (the amount contained in a meal rich in vegetables and fruit) into an extracellular fluid volume of 14 liters would raise plasma potassium concentration by about 2.9 mEq/L if all the potassium remained in the extracellular compartment. Fortunately, most of the ingested potassium rapidly moves into the cells until the kidneys can eliminate the excess. Table 29–1 summarizes some of the factors that can influence the distribution of potassium between the intra- and extracellular compartments. Insulin Stimulates Potassium Uptake into Cells. One of the most important factors that increase cell potassium uptake after a meal is insulin. In people who have insulin deficiency owing to diabetes mellitus, the rise in Increased secretion of catecholamines, especially epinephrine, can cause movement of potassium from the extracellular to the intracellular fluid, mainly by activation of b2-adrenergic receptors. Treatment of hypertension with b-adrenergic receptor blockers, such as propranolol, causes potassium to move out of the cells and creates a tendency toward hyperkalemia. Acid-Base Abnormalities Can Cause Changes in Potassium Distribution. Metabolic acidosis increases extracellular potas- sium concentration, in part by causing loss of potassium from the cells, whereas metabolic alkalosis decreases extracellular fluid potassium concentration. Although the mechanisms responsible for the effect of hydrogen ion concentration on potassium internal distribution are not completely understood, one effect of increased hydrogen ion concentration is to reduce the activity of the sodium-potassium adenosine triphosphatase (ATPase) pump. This in turn decreases cellular uptake of potassium and raises extracellular potassium concentration. Cell Lysis Causes Increased Extracellular Potassium Concentration. As cells are destroyed, the large amounts of potas- sium contained in the cells are released into the extracellular compartment. This can cause significant hyperkalemia if large amounts of tissue are destroyed, as occurs with severe muscle injury or with red blood cell lysis. Strenuous Exercise Can Cause Hyperkalemia by Releasing Potassium from Skeletal Muscle. During prolonged exercise, potassium is released from skeletal muscle into the extracellular fluid. Usually the hyperkalemia is mild, but it may be clinically significant after heavy exercise in patients treated with b-adrenergic blockers or in individuals with insulin deficiency. In rare instances, hyperkalemia after exercise may be severe enough to cause cardiac arrhythmias and sudden death. Increased Extracellular Fluid Osmolarity Causes Redistribution of Potassium from the Cells to Extracellular Fluid. Increased extracellular fluid osmolarity causes osmotic flow of water out of the cells. The cellular dehydration increases intracellular potassium concentration, thereby promoting diffusion of potassium out of the cells and increasing extracellular fluid potassium concentration. Decreased extracellular fluid osmolarity has the opposite effect. In diabetes mellitus, large increases in plasma glucose raise extracellular osmolarity, causing cell Chapter 29 367 Renal Regulation; Integration of Renal Mechanisms dehydration and movement of potassium from the cells into the extracellular fluid. Overview of Renal Potassium Excretion Potassium excretion is determined by the sum of three renal processes: (1) the rate of potassium filtration (GFR multiplied by the plasma potassium concentration), (2) the rate of potassium reabsorption by the tubules, and (3) the rate of potassium secretion by the tubules. The normal rate of potassium filtration is about 756 mEq/day (GFR, 180 L/day multiplied by plasma potassium, 4.2 mEq/L); this rate of filtration is usually relatively constant because of the autoregulatory mechanisms for GFR discussed previously and the precision with which plasma potassium concentration is regulated. Severe decreases in GFR in certain renal diseases, however, can cause serious potassium accumulation and hyperkalemia. Figure 29–2 summarizes the tubular handling of potassium under normal conditions. About 65 per cent of the filtered potassium is reabsorbed in the proximal tubule. Another 25 to 30 per cent of the filtered potassium is reabsorbed in the loop of Henle, especially in the thick ascending part where potassium is actively co-transported along with sodium and chloride. In both the proximal tubule and the loop of Henle, a relatively constant fraction of the filtered potassium load is reabsorbed. Changes in potassium reabsorption in these segments can influence potassium excretion, but most of the day-to-day variation of potassium excretion is not due to changes in reabsorption in the proximal tubule or loop of Henle. Most Daily Variation in Potassium Excretion Is Caused by Changes in Potassium Secretion in Distal and Collecting Tubules. The most important sites for regulating potas- sium excretion are the principal cells of the late distal tubules and cortical collecting tubules. In these tubular segments, potassium can at times be reabsorbed or at other times be secreted, depending on the needs of the body. With a normal potassium intake of 100 mEq/day, the kidneys must excrete about 92 mEq/day (the remaining 8 milliequivalents are lost in the feces). About one third (31 mEq/day) of this amount of potassium is secreted into the distal and collecting tubules. With high potassium intakes, the required extra excretion of potassium is achieved almost entirely by increasing the secretion of potassium into the distal and collecting tubules. In fact, with extremely high potassium diets, the rate of potassium excretion can exceed the amount of potassium in the glomerular filtrate, indicating a powerful mechanism for secreting potassium. When potassium intake is reduced below normal, the secretion rate of potassium in the distal and collecting tubules decreases, causing a reduction in urinary potassium secretion. With extreme reductions in potassium intake, there is net reabsorption of potassium in the distal segments of the nephron, and potassium excretion can fall to 1 per cent of the potassium in the glomerular filtrate (to less than 10 mEq/day). With potassium intakes below this level, severe hypokalemia can develop. Thus, most of the day-to-day regulation of potassium excretion occurs in the late distal and cortical collecting tubules, where potassium can be either reabsorbed or secreted, depending on the needs of the body. In the next section, we consider the basic mechanisms of potassium secretion and the factors that regulate this process. Potassium Secretion by Principal Cells of Late Distal and Cortical Collecting Tubules The cells in the late distal and cortical collecting tubules that secrete potassium are called principal cells 65% (491 mEq/day) 4% (31 mEq/day) 756 mEq/day (180 L/day x 4.2 mEq/L) Figure 29–2 Renal tubular sites of potassium reabsorption and secretion. Potassium is reabsorbed in the proximal tubule and in the ascending loop of Henle, so that only about 8 per cent of the filtered load is delivered to the distal tubule. Secretion of potassium into the late distal tubules and collecting ducts adds to the amount delivered, so that the daily excretion is about 12 per cent of the potassium filtered at the glomerular capillaries. The percentages indicate how much of the filtered load is reabsorbed or secreted into the different tubular segments. 27% (204 mEq/day) 12% (92 mEq/day) 368 Unit V Renal interstitial fluid Principal cells The Body Fluids and Kidneys Tubular lumen Na+ Na+ Na+ K+ ATP K+ K+ 0 mV -70 mV -50 mV Figure 29–3 Mechanisms of potassium secretion and sodium reabsorption by the principal cells of the late distal and collecting tubules. and make up about 90 per cent of the epithelial cells in these regions. Figure 29–3 shows the basic cellular mechanisms of potassium secretion by the principal cells. Secretion of potassium from the blood into the tubular lumen is a two-step process, beginning with uptake from the interstitium into the cell by the sodium-potassium ATPase pump in the basolateral membrane of the cell; this pump moves sodium out of the cell into the interstitium and at the same time moves potassium to the interior of the cell. The second step of the process is passive diffusion of potassium from the interior of the cell into the tubular fluid. The sodium-potassium ATPase pump creates a high intracellular potassium concentration, which provides the driving force for passive diffusion of potassium from the cell into the tubular lumen. The luminal membrane of the principal cells is highly permeable to potassium. One reason for this high permeability is that there are special channels that are specifically permeable to potassium ions, thus allowing these ions to diffuse across the membrane. Control of Potassium Secretion by Principal Cells. The primary factors that control potassium secretion by the principal cells of the late distal and cortical collecting tubules are (1) the activity of the sodium-potassium ATPase pump, (2) the electrochemical gradient for potassium secretion from the blood to the tubular lumen, and (3) the permeability of the luminal membrane for potassium. These three determinants of potassium secretion are in turn regulated by the factors discussed later. Intercalated Cells Can Reabsorb Potassium During Potassium Depletion. In circumstances associated with severe potassium depletion, there is a cessation of potassium secretion and actually a net reabsorption of potassium in the late distal and collecting tubules. This reabsorption occurs through the intercalated cells; although this reabsorptive process is not completely understood, one mechanism believed to contribute is a hydrogen-potassium ATPase transport mechanism located in the luminal membrane. This transporter reabsorbs potassium in exchange for hydrogen ions secreted into the tubular lumen, and the potassium then diffuses through the basolateral membrane of the cell into the blood. This transporter is necessary to allow potassium reabsorption during extracellular fluid potassium depletion, but under normal conditions it plays a small role in controlling the excretion of potassium. Summary of Factors That Regulate Potassium Secretion: Plasma Potassium Concentration, Aldosterone, Tubular Flow Rate, and Hydrogen Ion Concentration Because normal regulation of potassium excretion occurs mainly as a result of changes in potassium secretion by the principal cells of the late distal and collecting tubules, we will discuss the primary factors that influence secretion by these cells. The most important factors that stimulate potassium secretion by the principal cells include (1) increased extracellular fluid potassium concentration, (2) increased aldosterone, and (3) increased tubular flow rate. One factor that decreases potassium secretion is increased hydrogen ion concentration (acidosis). Increased Extracellular Fluid Potassium Concentration Stimulates Potassium Secretion. The rate of potassium secre- tion in the late distal and cortical collecting tubules is directly stimulated by increased extracellular fluid potassium concentration, leading to increases in potassium excretion, as shown in Figure 29–4. This effect is especially pronounced when extracellular fluid potassium concentration rises above about 4.1 mEq/L, slightly less than the normal concentration. Increased plasma potassium concentration, therefore, serves as one of the most important mechanisms for increasing potassium secretion and regulating extracellular fluid potassium ion concentration. There are three mechanisms by which increased extracellular fluid potassium concentration raises potassium secretion: (1) Increased extracellular fluid potassium concentration stimulates the sodiumpotassium ATPase pump, thereby increasing potassium uptake across the basolateral membrane. This in turn increases intracellular potassium ion concentration, causing potassium to diffuse across the luminal membrane into the tubule. (2) Increased extracellular potassium concentration increases the potassium gradient from the renal interstitial fluid to the interior of the epithelial cell; this reduces backleakage of potassium ions from inside the cells through the basolateral membrane. (3) Increased potassium concentration stimulates aldosterone secretion by the adrenal cortex, which further stimulates potassium secretion, as discussed next. Urinary potassium excretion (times normal) 4 369 Renal Regulation; Integration of Renal Mechanisms Effect of aldosterone Effect of extracellular K+ concentration 3 2 1 Approximate plasma aldosterone concentration (ng/100 ml plasma) Chapter 29 70 60 50 40 30 20 10 0 0 0 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 Serum potassium concentration (mEq/L) 1 2 3 4 5 Plasma aldosterone (times normal) 1 2 3 4 5 Extracellular potassium concentration (mEq/L) Figure 29–4 Figure 29–5 Effect of extracellular fluid potassium ion concentration on plasma aldosterone concentration. Note that small changes in potassium concentration cause large changes in aldosterone concentration. Effect of plasma aldosterone concentration (red line) and extracellular potassium ion concentration (black line) on the rate of urinary potassium excretion. These factors stimulate potassium secretion by the principal cells of the cortical collecting tubules. (Drawn from data in Young DB, Paulsen AW: Interrelated effects of aldosterone and plasma potassium on potassium excretion. Am J Physiol 244:F28, 1983.) 1 Ald. K+ concentration K+ 4 Aldosterone Stimulates Potassium Secretion. In Chapter 27, we discuss the fact that aldosterone stimulates active reabsorption of sodium ions by the principal cells of the late distal tubules and collecting ducts. This effect is mediated through a sodium-potassium ATPase pump that transports sodium outward through the basolateral membrane of the cell and into the blood at the same time that it pumps potassium into the cell. Thus, aldosterone also has a powerful effect to control the rate at which the principal cells secrete potassium. A second effect of aldosterone is to increase the permeability of the luminal membrane for potassium, further adding to the effectiveness of aldosterone in stimulating potassium secretion. Therefore, aldosterone has a powerful effect to increase potassium excretion, as shown in Figure 29–4. Increased Extracellular Potassium Ion Concentration Stimulates Aldosterone Secretion. In negative feedback control systems, the factor that is controlled usually has a feedback effect on the controller. In the case of the aldosterone-potassium control system, the rate of aldosterone secretion by the adrenal gland is controlled strongly by extracellular fluid potassium ion concentration. Figure 29–5 shows that an increase in plasma potassium concentration of about 3 mEq/L can increase plasma aldosterone concentration from nearly 0 to as high as 60 ng/100 ml, a concentration almost 10 times normal. Aldosterone concentration K+ excretion 3 + - K+ intake K+ excretion Ald. 2 Figure 29–6 Basic feedback mechanism for control of extracellular fluid potassium concentration by aldosterone (Ald.). The effect of potassium ion concentration to stimulate aldosterone secretion is part of a powerful feedback system for regulating potassium excretion, as shown in Figure 29–6. In this feedback system, an increase in plasma potassium concentration stimulates aldosterone secretion and, therefore, increases the blood level of aldosterone (block 1). The increase in blood aldosterone then causes a marked increase in potassium excretion by the kidneys (block 2). The increased potassium excretion then reduces the extracellular fluid potassium concentration back toward normal (blocks 3 and 4). Thus, this feedback mechanism acts synergistically with the direct effect of 370 Unit V The Body Fluids and Kidneys K+ intake Plasma K+ concentration Aldosterone K+ secretion Cortical collecting tubules K+ excretion Plasma potassium concentration (mEq/day) 4.8 4.6 4.4 Normal 4.2 Aldosterone system blocked 4.0 3.8 Figure 29–7 0 Primary mechanisms by which high potassium intake raises potassium excretion. Note that increased plasma potassium concentration directly raises potassium secretion by the cortical collecting tubules and indirectly increases potassium secretion by raising plasma aldosterone concentration. 30 60 90 120 150 180 210 Potassium intake (mEq/day) Figure 29–8 increased extracellular potassium concentration to elevate potassium excretion when potassium intake is raised (Figure 29–7). Effect of large changes in potassium intake on extracellular fluid potassium concentration under normal conditions (red line) and after the aldosterone feedback had been blocked (blue line). Note that after blockade of the aldosterone system, regulation of potassium concentration was greatly impaired. (Courtesy Dr. David B. Young.) Blockade of Aldosterone Feedback System Greatly Impairs Control of Potassium Concentration. In the absence of aldosterone secretion, as occurs in patients with Addison’s disease, renal secretion of potassium is impaired, thus causing extracellular fluid potassium concentration to rise to dangerously high levels. Conversely, with excess aldosterone secretion (primary aldosteronism), potassium secretion becomes greatly increased, causing potassium loss by the kidneys and thus leading to hypokalemia. The special quantitative importance of the aldosterone feedback system in controlling potassium concentration is shown in Figure 29–8. In this experiment, potassium intake was increased almost sevenfold in dogs under two conditions: (1) under normal conditions and (2) after the aldosterone feedback system had been blocked by removing the adrenal glands and placing the animals on a fixed rate of aldosterone infusion so that plasma aldosterone concentration could neither increase nor decrease. Note that in the normal animals, a sevenfold increase in potassium intake caused only a slight increase in potassium concentration, from 4.2 to 4.3 mEq/ L. Thus, when the aldosterone feedback system is functioning normally, potassium concentration is precisely controlled, despite large changes in potassium intake. When the aldosterone feedback system was blocked, the same increases in potassium intake caused a much larger increase in potassium concentration, from 3.8 to almost 4.7 mEq/L. Thus, control of potassium concentration is greatly impaired when the aldosterone feedback system is blocked. A similar impairment of potassium regulation is observed in humans with poorly functioning aldosterone feedback systems, such as occurs in patients with either primary aldosteronism (too much aldosterone) or Addison’s disease (too little aldosterone). Increased Distal Tubular Flow Rate Stimulates Potassium Secretion. A rise in distal tubular flow rate, as occurs with volume expansion, high sodium intake, or diuretic drug treatment, stimulates potassium secretion. Conversely, a decrease in distal tubular flow rate, as caused by sodium depletion, reduces potassium secretion. The mechanism for the effect of high-volume flow rate is as follows: When potassium is secreted into the tubular fluid, the luminal concentration of potassium increases, thereby reducing the driving force for potassium diffusion across the luminal membrane. With increased tubular flow rate, the secreted potassium is continuously flushed down the tubule, so that the rise in tubular potassium concentration becomes minimized. Therefore, net potassium secretion is stimulated by increased tubular flow rate. The effect of increased tubular flow rate is especially important in helping to preserve normal potassium excretion during changes in sodium intake. For example, with a high sodium intake, there is decreased aldosterone secretion, which by itself would tend to decrease the rate of potassium secretion and, therefore, reduce urinary excretion of potassium. However, the high distal tubular flow rate that occurs with a high sodium intake tends to increase potassium secretion Chapter 29 Renal Regulation; Integration of Renal Mechanisms to a loss of potassium, whereas acute acidosis leads to decreased potassium excretion. Na+ intake Aldosterone Proximal tubular Na+ reabsorption GFR Distal tubular flow rate - 371 K+ secretion Cortical collecting ducts + Unchanged K+ excretion Figure 29–9 Effect of high sodium intake on renal excretion of potassium. Note that a high-sodium diet decreases plasma aldosterone, which tends to decrease potassium secretion by the cortical collecting tubules. However, the high-sodium diet simultaneously increases fluid delivery to the cortical collecting duct, which tends to increase potassium secretion. The opposing effects of a highsodium diet counterbalance each other, so that there is little change in potassium excretion. (Figure 29–9), as discussed in the previous paragraph. Therefore, the two effects of high sodium intake, decreased aldosterone secretion and the high tubular flow rate, counterbalance each other, so that there is little change in potassium excretion. Likewise, with a low sodium intake, there is little change in potassium excretion because of the counterbalancing effects of increased aldosterone secretion and decreased tubular flow rate on potassium secretion. Acute Acidosis Decreases Potassium Secretion. Acute increases in hydrogen ion concentration of the extracellular fluid (acidosis) reduce potassium secretion, whereas decreased hydrogen ion concentration (alkalosis) increases potassium secretion. The primary mechanism by which increased hydrogen ion concentration inhibits potassium secretion is by reducing the activity of the sodium-potassium ATPase pump. This in turn decreases intracellular potassium concentration and subsequent passive diffusion of potassium across the luminal membrane into the tubule. With more prolonged acidosis, lasting over a period of several days, there is an increase in urinary potassium excretion. The mechanism for this effect is due in part to an effect of chronic acidosis to inhibit proximal tubular sodium chloride and water reabsorption, which increases distal volume delivery, thereby stimulating the secretion of potassium. This effect overrides the inhibitory effect of hydrogen ions on the sodiumpotassium ATPase pump. Thus, chronic acidosis leads Control of Renal Calcium Excretion and Extracellular Calcium Ion Concentration The mechanisms for regulating calcium ion concentration are discussed in detail in Chapter 79, along with the endocrinology of the calcium-regulating hormones parathyroid hormone (PTH) and calcitonin. Therefore, calcium ion regulation is discussed only briefly in this chapter. Extracellular fluid calcium ion concentration normally remains tightly controlled within a few percentage points of its normal level, 2.4 mEq/L. When calcium ion concentration falls to low levels (hypocalcemia), the excitability of nerve and muscle cells increases markedly and can in extreme cases result in hypocalcemic tetany. This is characterized by spastic skeletal muscle contractions. Hypercalcemia (increased calcium concentration) depresses neuromuscular excitability and can lead to cardiac arrhythmias. About 50 per cent of the total calcium in the plasma (5 mEq/L) exists in the ionized form, which is the form that has biological activity at cell membranes. The remainder is either bound to the plasma proteins (about 40 per cent) or complexed in the non-ionized form with anions such as phosphate and citrate (about 10 per cent). Changes in plasma hydrogen ion concentration can influence the degree of calcium binding to plasma proteins. With acidosis, less calcium is bound to the plasma proteins. Conversely, in alkalosis, a greater amount of calcium is bound to the plasma proteins. Therefore, patients with alkalosis are more susceptible to hypocalcemic tetany. As with other substances in the body, the intake of calcium must be balanced with the net loss of calcium over the long term. Unlike ions such as sodium and chloride, however, a large share of calcium excretion occurs in the feces. The usual rate of dietary calcium intake is about 1000 mg/day, with about 900 mg/day of calcium excreted in the feces. Under certain conditions, fecal calcium excretion can exceed calcium ingestion because calcium can also be secreted into the intestinal lumen. Therefore, the gastrointestinal tract and the regulatory mechanisms that influence intestinal calcium absorption and secretion play a major role in calcium homeostasis, as discussed in Chapter 79. Almost all the calcium in the body (99 per cent) is stored in the bone, with only about 1 per cent in the extracellular fluid and 0.1 per cent in the intracellular fluid. The bone, therefore, acts as a large reservoir for storing calcium and as a source of calcium when extracellular fluid calcium concentration tends to decrease. One of the most important regulators of bone uptake and release of calcium is PTH. When extracellular fluid 372 Unit V The Body Fluids and Kidneys [Ca++] Vitamin D3 activation PTH Intestinal Ca++ reabsorption Renal Ca++ reabsorption Ca++ release from bones Figure 29–10 Compensatory responses to decreased plasma ionized calcium concentration mediated by parathyroid hormone (PTH) and vitamin D. calcium concentration falls below normal, the parathyroid glands are directly stimulated by the low calcium levels to promote increased secretion of PTH. This hormone then acts directly on the bones to increase the resorption of bone salts (release of salts from the bones) and, therefore, to release large amounts of calcium into the extracellular fluid, thereby returning calcium levels back toward normal. When calcium ion concentration is elevated, PTH secretion decreases, so that almost no bone resorption now occurs; instead, excess calcium is deposited in the bones because of new bone formation. Thus, the day-to-day regulation of calcium ion concentration is mediated in large part by the effect of PTH on bone resorption. The bones, however, do not have an inexhaustible supply of calcium. Therefore, over the long term, the intake of calcium must be balanced with calcium excretion by the gastrointestinal tract and the kidneys. The most important regulator of calcium reabsorption at both of these sites is PTH. Thus, PTH regulates plasma calcium concentration through three main effects: (1) by stimulating bone resorption; (2) by stimulating activation of vitamin D, which then increases intestinal reabsorption of calcium; and (3) by directly increasing renal tubular calcium reabsorption (Figure 29–10). The control of gastrointestinal calcium reabsorption and calcium exchange in the bones is discussed elsewhere, and the remainder of this section focuses on the mechanisms that control renal calcium excretion. Control of Calcium Excretion by the Kidneys Because calcium is both filtered and reabsorbed in the kidneys but not secreted, the rate of renal calcium excretion is calculated as Renal calcium excretion = Calcium filtered - Calcium reabsorbed Only about 50 per cent of the plasma calcium is ionized, with the remainder being bound to the plasma proteins or complexed with anions such as phosphate. Therefore, only about 50 per cent of the plasma calcium can be filtered at the glomerulus. Normally, about 99 per cent of the filtered calcium is reabsorbed by the tubules, with only about 1 per cent of the filtered calcium being excreted. About 65 per cent of the filtered calcium is reabsorbed in the proximal tubule, 25 to 30 per cent is reabsorbed in the loop of Henle, and 4 to 9 per cent is reabsorbed in the distal and collecting tubules. This pattern of reabsorption is similar to that for sodium. As is true with the other ions, calcium excretion is adjusted to meet the body’s needs. With an increase in calcium intake, there is also increased renal calcium excretion, although much of the increase of calcium intake is eliminated in the feces. With calcium depletion, calcium excretion by the kidneys decreases as a result of enhanced tubular reabsorption. One of the primary controllers of renal tubular calcium reabsorption is PTH. With increased levels of PTH, there is increased calcium reabsorption in the thick ascending loops of Henle and distal tubules, which reduces urinary excretion of calcium. Conversely, reduction of PTH promotes calcium excretion by decreasing reabsorption in the loops of Henle and distal tubules. In the proximal tubule, calcium reabsorption usually parallels sodium and water reabsorption. Therefore, in instances of extracellular volume expansion or increased arterial pressure—both of which decrease proximal sodium and water reabsorption—there is also reduction in calcium reabsorption and, consequently, increased urinary excretion of calcium. Conversely, with extracellular volume contraction or decreased blood pressure, calcium excretion decreases primarily because of increased proximal tubular reabsorption. Another factor that influences calcium reabsorption is the plasma concentration of phosphate. An increase in plasma phosphate stimulates PTH, which increases calcium reabsorption by the renal tubules, thereby reducing calcium excretion. The opposite occurs with reduction in plasma phosphate concentration. Calcium reabsorption is also stimulated by metabolic acidosis and inhibited by metabolic alkalosis. Most of the effect of hydrogen ion concentration on calcium excretion results from changes in calcium reabsorption in the distal tubule. A summary of the factors that are known to influence calcium excretion by the renal tubules is shown in Table 29–2. Regulation of Renal Phosphate Excretion Phosphate excretion by the kidneys is controlled primarily by an overflow mechanism that can be explained as follows: The renal tubules have a normal transport maximum for reabsorbing phosphate of about 0.1 mM/min. When less than this amount of phosphate is present in the glomerular filtrate, Chapter 29 Renal Regulation; Integration of Renal Mechanisms Table 29–2 Factors That Alter Renal Calcium Excretion Ø Calcium Excretion ≠ Calcium Excretion ≠ Parathyroid hormone (PTH) Ø Extracellular fluid volume Ø Blood pressure ≠ Plasma phosphate Metabolic acidosis Vitamin D3 Ø PTH ≠ Extracellular fluid volume ≠ Blood pressure Ø Plasma phosphate Metabolic alkalosis essentially all the filtered phosphate is reabsorbed. When more than this is present, the excess is excreted. Therefore, phosphate normally begins to spill into the urine when its concentration in the extracellular fluid rises above a threshold of about 0.8 mM/L, which gives a tubular load of phosphate of about 0.1 mM/min, assuming a GFR of 125 ml/min. Because most people ingest large quantities of phosphate in milk products and meat, the concentration of phosphate is usually maintained above 1 mM/L, a level at which there is continual excretion of phosphate into the urine. Changes in tubular phosphate reabsorption can also influence phosphate excretion. For instance, a diet low in phosphate can, over time, increase the reabsorptive transport maximum for phosphate, thereby reducing the tendency for phosphate to spill over into the urine. PTH can play a significant role in regulating phosphate concentration through two effects: (1) PTH promotes bone resorption, thereby dumping large amounts of phosphate ions into the extracellular fluid from the bone salts, and (2) PTH decreases the transport maximum for phosphate by the renal tubules, so that a greater proportion of the tubular phosphate is lost in the urine. Thus, whenever plasma PTH is increased, tubular phosphate reabsorption is decreased and more phosphate is excreted. These interrelations among phosphate, PTH, and calcium are discussed in more detail in Chapter 79. Control of Renal Magnesium Excretion and Extracellular Magnesium Ion Concentration More than one half of the body’s magnesium is stored in the bones. Most of the rest resides within the cells, with less than 1 per cent located in the extracellular fluid. Although the total plasma magnesium concentration is about 1.8 mEq/L, more than one half of this is bound to plasma proteins. Therefore, the free ionized concentration of magnesium is only about 0.8 mEq/L. The normal daily intake of magnesium is about 250 to 300 mg/day, but only about one half of this intake is absorbed by the gastrointestinal tract. To maintain magnesium balance, the kidneys must excrete this absorbed magnesium, about one half the daily intake of magnesium, or 125 to 150 mg/day. The kidneys 373 normally excrete about 10 to 15 per cent of the magnesium in the glomerular filtrate. Renal excretion of magnesium can increase markedly during magnesium excess or can decrease to almost nil during magnesium depletion. Because magnesium is involved in many biochemical processes in the body, including activation of many enzymes, its concentration must be closely regulated. Regulation of magnesium excretion is achieved mainly by changing tubular reabsorption. The proximal tubule usually reabsorbs only about 25 per cent of the filtered magnesium. The primary site of reabsorption is the loop of Henle, where about 65 per cent of the filtered load of magnesium is reabsorbed. Only a small amount (usually less than 5 per cent) of the filtered magnesium is reabsorbed in the distal and collecting tubules. The mechanisms that regulate magnesium excretion are not well understood, but the following disturbances lead to increased magnesium excretion: (1) increased extracellular fluid magnesium concentration, (2) extracellular volume expansion, and (3) increased extracellular fluid calcium concentration. Integration of Renal Mechanisms for Control of Extracellular Fluid Extracellular fluid volume is determined mainly by the balance between intake and output of water and salt. In most cases, salt and fluid intakes are dictated by a person’s habits rather than by physiologic control mechanisms. Therefore, the burden of extracellular volume regulation is usually placed on the kidneys, which must adapt their excretion of salt and water to match intake of salt and water under steady-state conditions. In discussing the regulation of extracellular fluid volume, we also consider the factors that regulate the amount of sodium chloride in the extracellular fluid, because changes in extracellular fluid sodium chloride content usually cause parallel changes in extracellular fluid volume, provided the antidiuretic hormone (ADH)-thirst mechanisms are also operative. When the ADH-thirst mechanisms are functioning normally, a change in the amount of sodium chloride in the extracellular fluid is matched by a similar change in the amount of extracellular water, so that osmolality and sodium concentration are maintained relatively constant. Sodium Excretion Is Precisely Matched to Intake Under Steady-State Conditions An important consideration in overall control of sodium excretion—or excretion of any electrolyte, for that matter—is that under steady-state conditions, excretion by the kidneys is determined by intake. To 374 Unit V The Body Fluids and Kidneys maintain life, a person must, over the long term, excrete almost precisely the amount of sodium ingested. Therefore, even with disturbances that cause major changes in kidney function, balance between intake and output of sodium usually is restored within a few days. If disturbances of kidney function are not too severe, sodium balance may be achieved mainly by intrarenal adjustments with minimal changes in extracellular fluid volume or other systemic adjustments. But when perturbations to the kidneys are severe and intrarenal compensations are exhausted, systemic adjustments must be invoked, such as changes in blood pressure, changes in circulating hormones, and alterations of sympathetic nervous system activity. These adjustments are costly in terms of overall homeostasis because they cause other changes throughout the body that may, in the long run, be damaging. These compensations, however, are necessary because a sustained imbalance between fluid and electrolyte intake and excretion would quickly lead to accumulation or loss of electrolytes and fluid, causing cardiovascular collapse within a few days. Thus, one can view the systemic adjustments that occur in response to abnormalities of kidney function as a necessary tradeoff that brings electrolyte and fluid excretion back in balance with intake. Sodium Excretion Is Controlled by Altering Glomerular Filtration or Tubular Sodium Reabsorption Rates The two variables that influence sodium and water excretion are the rates of filtration and the rates of reabsorption: Excretion = Glomerular filtration - Tubular reabsorption GFR normally is about 180 L/day, tubular reabsorption is 178.5 L/day, and urine excretion is 1.5 L/day. Thus, small changes in GFR or tubular reabsorption potentially can cause large changes in renal excretion. For example, a 5 per cent increase in GFR (to 189 L/day) would cause a 9 L/day increase in urine volume, if tubular compensations did not occur; this would quickly cause catastrophic changes in body fluid volumes. Similarly, small changes in tubular reabsorption, in the absence of compensatory adjustments of GFR, would also lead to dramatic changes in urine volume and sodium excretion. Tubular reabsorption and GFR usually are regulated precisely, so that excretion by the kidneys can be exactly matched to intake of water and electrolytes. Even with disturbances that alter GFR or tubular reabsorption, changes in urinary excretion are minimized by various buffering mechanisms. For example, if the kidneys become greatly vasodilated and GFR increases (as can occur with certain drugs or high fever), this raises sodium chloride delivery to the tubules, which in turn leads to at least two intrarenal compensations: (1) increased tubular reabsorption of much of the extra sodium chloride filtered, called glomerulotubular balance, and (2) macula densa feedback, in which increased sodium chloride delivery to the distal tubule causes afferent arteriolar constriction and return of GFR toward normal. Likewise, abnormalities of tubular reabsorption in the proximal tubule or loop of Henle are partially compensated for by these same intrarenal feedbacks. Because neither of these two mechanisms operates perfectly to restore distal sodium chloride delivery all the way back to normal, changes in either GFR or tubular reabsorption can lead to significant changes in urine sodium and water excretion. When this happens, other feedback mechanisms come into play, such as changes in blood pressure and changes in various hormones, that eventually return sodium excretion to equal sodium intake. In the next few sections, we review how these mechanisms operate together to control sodium and water balance and in so doing act also to control extracellular fluid volume. We should keep in mind, however, that all these feedback mechanisms control renal excretion of sodium and water by altering either GFR or tubular reabsorption. Importance of Pressure Natriuresis and Pressure Diuresis in Maintaining Body Sodium and Fluid Balance One of the most basic and powerful mechanisms for control of blood volume and extracellular fluid volume, as well as for the maintenance of sodium and fluid balance, is the effect of blood pressure on sodium and water excretion—called the pressure natriuresis and pressure diuresis mechanisms, respectively. As discussed in Chapter 19, this feedback between the kidneys and the circulatory system also plays a dominant role in long-term blood pressure regulation. Pressure diuresis refers to the effect of increased blood pressure to raise urinary volume excretion, whereas pressure natriuresis refers to the rise in sodium excretion that occurs with elevated blood pressure. Because pressure diuresis and natriuresis usually occur in parallel, we refer to these mechanisms simply as “pressure natriuresis” in the following discussion. Figure 29–11 shows the effect of arterial pressure on urinary sodium output. Note that acute increases in blood pressure of 30 to 50 mm Hg cause a twofold to threefold increase in urinary sodium output. This effect is independent of changes in activity of the sympathetic nervous system or of various hormones, such as angiotensin II, ADH, or aldosterone, because pressure natriuresis can be demonstrated in an isolated kidney that has been removed from the influence of these factors. With chronic increases in blood pressure, the effectiveness of pressure natriuresis is greatly enhanced because the increased blood pressure also, after a short time delay, suppresses renin release and, therefore, decreases formation of angiotensin II and Chapter 29 aldosterone. As discussed previously, decreased levels of angiotensin II and aldosterone inhibit renal tubular reabsorption of sodium, thereby amplifying the direct effects of increased blood pressure to raise sodium and water excretion. Pressure Natriuresis and Diuresis Are Key Components of a Renal-Body Fluid Feedback for Regulating Body Fluid Volumes and Arterial Pressure Urinary sodium or volume output (times normal) The effect of increased blood pressure to raise urine output is part of a powerful feedback system that oper- 8 Chronic Acute 6 4 2 0 0 375 Renal Regulation; Integration of Renal Mechanisms 20 40 60 80 100 120 140 160 180 200 Arterial pressure (mm Hg) Figure 29–11 Acute and chronic effects of arterial pressure on sodium output by the kidneys (pressure natriuresis). Note that chronic increases in arterial pressure cause much greater increases in sodium output than those measured during acute increases in arterial pressure. ates to maintain balance between fluid intake and output, as shown in Figure 29–12. This is the same mechanism that is discussed in Chapter 19 for arterial pressure control. The extracellular fluid volume, blood volume, cardiac output, arterial pressure, and urine output are all controlled at the same time as separate parts of this basic feedback mechanism. During changes in sodium and fluid intake, this feedback mechanism helps to maintain fluid balance and to minimize changes in blood volume, extracellular fluid volume, and arterial pressure as follows: 1. An increase in fluid intake (assuming that sodium accompanies the fluid intake) above the level of urine output causes a temporary accumulation of fluid in the body. 2. As long as fluid intake exceeds urine output, fluid accumulates in the blood and interstitial spaces, causing parallel increases in blood volume and extracellular fluid volume. As discussed later, the actual increases in these variables are usually small because of the effectiveness of this feedback. 3. An increase in blood volume raises mean circulatory filling pressure. 4. An increase in mean circulatory filling pressure raises the pressure gradient for venous return. 5. An increased pressure gradient for venous return elevates cardiac output. 6. An increased cardiac output raises arterial pressure. 7. An increased arterial pressure increases urine output by way of pressure diuresis. The steepness of the normal pressure natriuresis relation indicates that only a slight increase in blood pressure is required to raise urinary excretion severalfold. 8. The increased fluid excretion balances the increased intake, and further accumulation of fluid is prevented. Nonrenal fluid loss Total peripheral resistance Rate of change of extracellular fluid volume Renal fluid excretion Arterial pressure Fluid intake Arterial pressure Extracellular fluid volume Blood volume Figure 29–12 Basic renal–body fluid feedback mechanism for control of blood volume, extracellular fluid volume, and arterial pressure. Solid lines indicate positive effects, and dashed lines indicate negative effects. Cardiac output Heart strength Venous return Mean circulatory filling pressure Vascular capacity 376 Unit V The Body Fluids and Kidneys 6 Blood volume (liters) Blood volume 5 Normal range 4 Death 3 2 1 0 0 1 2 3 4 5 6 7 Daily fluid intake (water and electrolytes) (L/day) 8 Figure 29–13 Approximate effect of changes in daily fluid intake on blood volume. Note that blood volume remains relatively constant in the normal range of daily fluid intakes. Thus, the renal-body fluid feedback mechanism operates to prevent continuous accumulation of salt and water in the body during increased salt and water intake. As long as kidney function is normal and the pressure diuresis mechanism is operating effectively, large changes in salt and water intake can be accommodated with only slight changes in blood volume, extracellular fluid volume, cardiac output, and arterial pressure. The opposite sequence of events occurs when fluid intake falls below normal. In this case, there is a tendency toward decreased blood volume and extracellular fluid volume, as well as reduced arterial pressure. Even a small decrease in blood pressure causes a large decrease in urine output, thereby allowing fluid balance to be maintained with minimal changes in blood pressure, blood volume, or extracellular fluid volume. The effectiveness of this mechanism in preventing large changes in blood volume is demonstrated in Figure 29–13, which shows that changes in blood volume are almost imperceptible despite large variations in daily intake of water and electrolytes, except when intake becomes so low that it is not sufficient to make up for fluid losses caused by evaporation or other inescapable losses. Precision of Blood Volume and Extracellular Fluid Volume Regulation By studying Figure 29–12, one can see why the blood volume remains almost exactly constant despite extreme changes in daily fluid intake. The reason for this is the following: (1) a slight change in blood volume causes a marked change in cardiac output, (2) a slight change in cardiac output causes a large change in blood pressure, and (3) a slight change in blood pressure causes a large change in urine output. These factors work together to provide effective feedback control of blood volume. The same control mechanisms operate whenever there is a loss of whole blood because of hemorrhage. In this case, fluid is retained by the kidneys, and other parallel processes occur to reconstitute the red blood cells and plasma proteins in the blood. If abnormalities of red blood cell volume remain, such as occurs when there is deficiency of erythropoietin or other factors needed to stimulate red blood cell production, the plasma volume will simply make up the difference, and the overall blood volume will return essentially to normal despite the low red blood cell mass. Distribution of Extracellular Fluid Between the Interstitial Spaces and Vascular System From Figure 29–12 it is apparent that blood volume and extracellular fluid volume are usually controlled in parallel with each other. Ingested fluid initially goes into the blood, but it rapidly becomes distributed between the interstitial spaces and the plasma. Therefore, blood volume and extracellular fluid volume usually are controlled simultaneously. There are circumstances, however, in which the distribution of extracellular fluid between the interstitial spaces and blood can vary greatly. As discussed in Chapter 25, the principal factors that can cause accumulation of fluid in the interstitial spaces include (1) increased capillary hydrostatic pressure, (2) decreased plasma colloid osmotic pressure, (3) increased permeability of the capillaries, and (4) obstruction of lymphatic vessels. In all these conditions, an unusually high proportion of the extracellular fluid becomes distributed to the interstitial spaces. Figure 29–14 shows the normal distribution of fluid between the interstitial spaces and the vascular system and the distribution that occurs in edema states. When small amounts of fluid accumulate in the blood as a result of either too much fluid intake or a decrease in renal output of fluid, about 20 to 30 per cent of it stays in the blood and increases the blood volume. The remainder is distributed to the interstitial spaces. When the extracellular fluid volume rises more than 30 to 50 per cent above normal, almost all the additional fluid goes into the interstitial spaces and little remains in the blood. This occurs because once the interstitial fluid pressure rises from its normally negative value to become positive, the tissue interstitial spaces become compliant, and large amounts of fluid then pour into the tissues without interstitial fluid pressure rising much more. In other words, the safety factor against edema, owing to a rising interstitial fluid pressure that counteracts fluid accumulation in the tissues, is lost once the tissues become highly compliant. Thus, under normal conditions, the interstitial spaces act as an “overflow” reservoir for excess fluid, Chapter 29 8 Renal Regulation; Integration of Renal Mechanisms Sympathetic Nervous System Control of Renal Excretion: Arterial Baroreceptor and Low-Pressure Stretch Receptor Reflexes Edema Blood volume (liters) 7 6 5 Normal value 4 3 Death 2 1 0 0 5 10 15 20 25 30 35 Extracellular fluid volume (liters) 377 40 Figure 29–14 Approximate relation between extracellular fluid volume and blood volume, showing a nearly linear relation in the normal range but also showing the failure of blood volume to continue rising when the extracellular fluid volume becomes excessive. When this occurs, the additional extracellular fluid volume resides in the interstitial spaces, and edema results. sometimes increasing in volume 10 to 30 liters. This causes edema, as explained in Chapter 25, but it also acts as an important overflow release valve for the circulation, protecting the cardiovascular system against dangerous overload that could lead to pulmonary edema and cardiac failure. To summarize, extracellular fluid volume and blood volume are controlled simultaneously, but the quantitative amounts of fluid distribution between the interstitium and the blood depend on the physical properties of the circulation and the interstitial spaces as well as on the dynamics of fluid exchange through the capillary membranes. Nervous and Hormonal Factors Increase the Effectiveness of Renal-Body Fluid Feedback Control In Chapter 27, we discuss the nervous and hormonal factors that influence GFR and tubular reabsorption and, therefore, renal excretion of salt and water. These nervous and hormonal mechanisms usually act in concert with the pressure natriuresis and pressure diuresis mechanisms, making them more effective in minimizing the changes in blood volume, extracellular fluid volume, and arterial pressure that occur in response to day-to-day challenges. However, abnormalities of kidney function or of the various nervous and hormonal factors that influence the kidneys can lead to serious changes in blood pressure and body fluid volumes, as discussed later. Because the kidneys receive extensive sympathetic innervation, changes in sympathetic activity can alter renal sodium and water excretion as well as regulation of extracellular fluid volume under some conditions. For example, when blood volume is reduced by hemorrhage, the pressures in the pulmonary blood vessels and other low-pressure regions of the thorax decrease, causing reflex activation of the sympathetic nervous system. This in turn increases renal sympathetic nerve activity, which has several effects to decrease sodium and water excretion: (1) constriction of the renal arterioles, with resultant decreased GFR; (2) increased tubular reabsorption of salt and water; and (3) stimulation of renin release and increased angiotensin II and aldosterone formation, both of which further increase tubular reabsorption. And if the reduction in blood volume is great enough to lower systemic arterial pressure, further activation of the sympathetic nervous system occurs because of decreased stretch of the arterial baroreceptors located in the carotid sinus and aortic arch. All these reflexes together play an important role in the rapid restitution of blood volume that occurs in acute conditions such as hemorrhage. Also, reflex inhibition of renal sympathetic activity may contribute to the rapid elimination of excess fluid in the circulation that occurs after eating a meal that contains large amounts of salt and water. Role of Angiotensin II In Controlling Renal Excretion One of the body’s most powerful controllers of sodium excretion is angiotensin II. Changes in sodium and fluid intake are associated with reciprocal changes in angiotensin II formation, and this in turn contributes greatly to the maintenance of body sodium and fluid balances. That is, when sodium intake is elevated above normal, renin secretion is decreased, causing decreased angiotensin II formation. Because angiotensin II has several important effects in increasing tubular reabsorption of sodium, as explained in Chapter 27, a reduced level of angiotensin II decreases tubular reabsorption of sodium and water, thus increasing the kidneys’ excretion of sodium and water. The net result is to minimize the rise in extracellular fluid volume and arterial pressure that would otherwise occur when sodium intake increases. Conversely, when sodium intake is reduced below normal, increased levels of angiotensin II cause sodium and water retention and oppose reductions in arterial blood pressure that would otherwise occur. Thus, changes in activity of the renin-angiotensin system act as a powerful amplifier of the pressure natriuresis mechanism for maintaining stable blood pressures and body fluid volumes. 378 Unit V Angiotensin blockade 12 Sodium intake and output (times normal) The Body Fluids and Kidneys Normal 10 High angiotensin II 8 6 Figure 29–15 4 2 0 60 80 100 120 Arterial pressure (mm Hg) Importance of Angiotensin II in Increasing Effectiveness of Pressure Natriuresis. The importance of angiotensin II in making the pressure natriuresis mechanism more effective is shown in Figure 29–15. Note that when the angiotensin control of natriuresis is fully functional, the pressure natriuresis curve is steep (normal curve), indicating that only minor changes in blood pressure are needed to increase sodium excretion when sodium intake is raised. In contrast, when angiotensin levels cannot be decreased in response to increased sodium intake (high angiotensin II curve), as occurs in some hypertensive patients who have impaired ability to decrease renin secretion, the pressure natriuresis curve is not nearly as steep. Therefore, when sodium intake is raised, much greater increases in arterial pressure are needed to increase sodium excretion and maintain sodium balance. For example, in most people, a 10-fold increase in sodium intake causes an increase of only a few millimeters of mercury in arterial pressure, whereas in subjects who cannot suppress angiotensin II formation appropriately in response to excess sodium, the same rise in sodium intake causes blood pressure to rise as much as 50 mm Hg. Thus, the inability to suppress angiotensin II formation when there is excess sodium reduces the slope of pressure natriuresis and makes arterial pressure very salt sensitive, as discussed in Chapter 19. The use of drugs to block the effects of angiotensin II has proved to be important clinically for improving the kidneys’ ability to excrete salt and water. When angiotensin II formation is blocked with an angiotensin-converting enzyme inhibitor (see Figure 29–15) or an angiotensin II receptor antagonist, the renal–pressure natriuresis curve is shifted to lower pressures; this indicates an enhanced ability of the kidneys to excrete sodium because normal levels of sodium excretion can now be maintained at reduced arterial pressures. This shift of pressure natriuresis provides the basis for the chronic blood pressure– 140 160 Effect of excessive angiotensin II formation and effect of blocking angiotensin II formation on the renal–pressure natriuresis curve. Note that high levels of angiotensin II formation decrease the slope of pressure natriuresis, making blood pressure very sensitive to changes in sodium intake. Blockade of angiotensin II formation shifts pressure natriuresis to lower blood pressures. lowering effects in hypertensive patients of the angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. Excessive Angiotensin II Does Not Cause Large Increases in Extracellular Fluid Volume Because Increased Arterial Pressure Counterbalances Angiotensin-Mediated Sodium Retention. Although angiotensin II is one of the most powerful sodium- and water-retaining hormones in the body, neither a decrease nor an increase in circulating angiotensin II has a large effect on extracellular fluid volume or blood volume. The reason for this is that with large increases in angiotensin II levels, as occurs with a renin-secreting tumor of the kidney, the high angiotensin II levels initially cause sodium and water retention by the kidneys and a small increase in extracellular fluid volume. This also initiates a rise in arterial pressure that quickly increases kidney output of sodium and water, thereby overcoming the sodium- and water-retaining effects of the angiotensin II and re-establishing a balance between intake and output of sodium at a higher blood pressure. Conversely, after blockade of angiotensin II formation, as occurs when an angiotensin-converting enzyme inhibitor is administered, there is initial loss of sodium and water, but the fall in blood pressure offsets this effect, and sodium excretion is once again restored to normal. Role of Aldosterone in Controlling Renal Excretion Aldosterone increases sodium reabsorption, especially in the cortical collecting tubules. The increased sodium reabsorption is also associated with increased water reabsorption and potassium secretion. Therefore, the net effect of aldosterone is to make the kidneys retain sodium and water but to increase potassium excretion in the urine. Chapter 29 Renal Regulation; Integration of Renal Mechanisms The function of aldosterone in regulating sodium balance is closely related to that described for angiotensin II.That is, with reduction in sodium intake, the increased angiotensin II levels that occur stimulate aldosterone secretion, which in turn contributes to the reduction in urinary sodium excretion and, therefore, to the maintenance of sodium balance. Conversely, with high sodium intake, suppression of aldosterone formation decreases tubular reabsorption, allowing the kidneys to excrete larger amounts of sodium. Thus, changes in aldosterone formation also aid the pressure natriuresis mechanism in maintaining sodium balance during variations in salt intake. During Chronic Oversecretion of Aldosterone, Kidneys “Escape” from Sodium Retention as Arterial Pressure Rises. Although aldosterone has powerful effects on sodium reabsorption, when there is excessive infusion of aldosterone or excessive formation of aldosterone, as occurs in patients with tumors of the adrenal gland (Conn’s syndrome), the increased sodium reabsorption and decreased sodium excretion by the kidneys are transient. After 1 to 3 days of sodium and water retention, the extracellular fluid volume rises by about 10 to 15 per cent and there is a simultaneous increase in arterial blood pressure. When the arterial pressure rises sufficiently, the kidneys “escape” from the sodium and water retention and thereafter excrete amounts of sodium equal to the daily intake, despite continued presence of high levels of aldosterone. The primary reason for the escape is the pressure natriuresis and diuresis that occur when the arterial pressure rises. In patients with adrenal insufficiency who do not secrete enough aldosterone (Addison’s disease), there is increased excretion of sodium and water, reduction in extracellular fluid volume, and a tendency toward low blood pressure. In the complete absence of aldosterone, the volume depletion may be severe unless the person is allowed to eat large amounts of salt and drink large amounts of water to balance the increased urine output of salt and water. Role of ADH in Controlling Renal Water Excretion As discussed in Chapter 28, ADH plays an important role in allowing the kidneys to form a small volume of concentrated urine while excreting normal amounts of salt. This effect is especially important during water deprivation, which strongly elevates plasma levels of ADH that in turn increase water reabsorption by the kidneys and help to minimize the decreases in extracellular fluid volume and arterial pressure that would otherwise occur. Water deprivation for 24 to 48 hours normally causes only a small decrease in extracellular fluid volume and arterial pressure. However, if the effects of ADH are blocked with a drug that antagonizes the action of ADH to promote water reabsorption in the distal and collecting tubules, the same period of water deprivation causes a substantial fall in both extracellular fluid volume and arterial pressure. 379 Conversely, when there is excess extracellular volume, decreased ADH levels reduce reabsorption of water by the kidneys, thus helping to rid the body of the excess volume. Excess ADH Secretion Usually Causes Only Small Increases in Extracellular Fluid Volume but Large Decreases in Sodium Concentration. Although ADH is important in regulating extracellular fluid volume, excessive levels of ADH seldom cause large increases in arterial pressure or extracellular fluid volume. Infusion of large amounts of ADH into animals initially causes renal retention of water and a 10 to 15 per cent increase in extracellular fluid volume. As the arterial pressure rises in response to this increased volume, much of the excess volume is excreted because of the pressure diuresis mechanism. After several days of ADH infusion, the blood volume and extracellular fluid volume are elevated no more than 5 to 10 per cent, and the arterial pressure is also elevated by less than 10 mm Hg. The same is true for patients with inappropriate ADH syndrome, in which ADH levels may be elevated severalfold. Thus, high levels of ADH do not cause major increases of either body fluid volume or arterial pressure, although high ADH levels can cause severe reductions in extracellular sodium ion concentration. The reason for this is that increased water reabsorption by the kidneys dilutes the extracellular sodium, and at the same time, the small increase in blood pressure that does occur causes loss of sodium from the extracellular fluid in the urine through pressure natriuresis. In patients who have lost their ability to secrete ADH because of destruction of the supraoptic nuclei, the urine volume may become 5 to 10 times normal. This is almost always compensated for by ingestion of enough water to maintain fluid balance. If free access to water is prevented, the inability to secrete ADH may lead to marked reductions in blood volume and arterial pressure. Role of Atrial Natriuretic Peptide in Controlling Renal Excretion Thus far, we have discussed mainly the role of sodiumand water-retaining hormones in controlling extracellular fluid volume. However, several different natriuretic hormones may also contribute to volume regulation. One of the most important of the natriuretic hormones is a peptide referred to as atrial natriuretic peptide (ANP), released by the cardiac atrial muscle fibers. The stimulus for release of this peptide appears to be overstretch of the atria, which can result from excess blood volume. Once released by the cardiac atria, ANP enters the circulation and acts on the kidneys to cause small increases in GFR and decreases in sodium reabsorption by the collecting ducts. These combined actions of ANP lead to increased excretion of salt and water, which helps to compensate for the excess blood volume. Changes in ANP levels probably help to minimize changes in blood volume during various disturbances, 380 Unit V The Body Fluids and Kidneys such as increased salt and water intake. However, excessive production of ANP or even complete lack of ANP does not cause major changes in blood volume because these effects can easily be overcome by small changes in blood pressure, acting through pressure natriuresis. For example, infusions of large amounts of ANP initially raise urine output of salt and water and cause slight decreases in blood volume. In less than 24 hours, this effect is overcome by a slight decrease in blood pressure that returns urine output toward normal, despite continued excess of ANP. Integrated Responses to Changes in Sodium Intake The integration of the different control systems that regulate sodium and fluid excretion under normal conditions can be summarized by examining the homeostatic responses to progressive increases in dietary sodium intake. As discussed previously, the kidneys have an amazing capability to match their excretion of salt and water to intakes that can range from as low as one tenth of normal to as high as 10 times normal. High Sodium Intake Suppresses Antinatriuretic Systems and Activates Natriuretic Systems. As sodium intake is increased, sodium output initially lags slightly behind intake. The time delay results in a small increase in the cumulative sodium balance, which causes a slight increase in extracellular fluid volume. It is mainly this small increase in extracellular fluid volume that triggers various mechanisms in the body to increase sodium excretion. These mechanisms include the following: 1. Activation of low pressure receptor reflexes that originate from the stretch receptors of the right atrium and the pulmonary blood vessels. Signals from the stretch receptors go to the brain stem and there inhibit sympathetic nerve activity to the kidneys to decrease tubular sodium reabsorption. This mechanism is most important in the first few hours—or perhaps the first day—after a large increase in salt and water intake. 2. Small increases in arterial pressure, caused by volume expansion, raise sodium excretion through pressure natriuresis. 3. Suppression of angiotensin II formation, caused by increased arterial pressure and extracellular fluid volume expansion, decreases tubular sodium reabsorption by eliminating the normal effect of angiotensin II to increase sodium reabsorption. Also, reduced angiotensin II decreases aldosterone secretion, thus further reducing tubular sodium reabsorption. 4. Stimulation of natriuretic systems, especially ANP, contributes further to increased sodium excretion. Thus, the combined activation of natriuretic systems and suppression of sodium- and water-retaining systems leads to an increase in sodium excretion when sodium intake is increased. The opposite changes take place when sodium intake is reduced below normal levels. Conditions That Cause Large Increases in Blood Volume and Extracellular Fluid Volume Despite the powerful regulatory mechanisms that maintain blood volume and extracellular fluid volume reasonably constant, there are abnormal conditions that can cause large increases in both of these variables. Almost all of these conditions result from circulatory abnormalities. Increased Blood Volume and Extracellular Fluid Volume Caused by Heart Diseases In congestive heart failure, blood volume may increase 15 to 20 per cent, and extracellular fluid volume sometimes increases by 200 per cent or more. The reason for this can be understood by re-examination of Figure 29–12. Initially, heart failure reduces cardiac output and, consequently, decreases arterial pressure. This in turn activates multiple sodium-retaining systems, especially the renin-angiotensin, aldosterone, and sympathetic nervous systems. In addition, the low blood pressure itself causes the kidneys to retain salt and water. Therefore, the kidneys retain volume in an attempt to return the arterial pressure and cardiac output toward normal. Indeed, if the heart failure is not too severe, the rise in blood volume can often return cardiac output and arterial pressure virtually all the way to normal, and sodium excretion will eventually increase back to normal, although there will remain excess extracellular fluid volume and blood volume to keep the weakened heart pumping adequately. However, if the heart is greatly weakened, arterial pressure will not be able to increase enough to restore urine output to normal. When this occurs, the kidneys continue to retain volume until the person develops severe circulatory congestion and eventually dies of pulmonary edema. In myocardial failure, heart valvular disease, and congenital abnormalities of the heart, an important circulatory compensation is an increase in blood volume, which helps to return cardiac output and blood pressure to normal. This allows even the weakened heart to maintain a life-sustaining level of cardiac output. Increased Blood Volume Caused by Increased Capacity of Circulation Any condition that increases vascular capacity will also cause the blood volume to increase to fill this extra capacity. An increase in vascular capacity initially reduces mean circulatory filling pressure (see Figure 29–12), which leads to decreased cardiac output and decreased arterial pressure. The fall in pressure causes salt and water retention by the kidneys until the blood Chapter 29 Renal Regulation; Integration of Renal Mechanisms volume increases sufficiently to fill the extra capacity. For example, in pregnancy the increased vascular capacity of the uterus, placenta, and other enlarged organs of the woman’s body regularly increases the blood volume 15 to 25 per cent. Similarly, in patients who have large varicose veins of the legs, which in rare instances may hold up to an extra liter of blood, the blood volume simply increases to fill the extra vascular capacity. In these cases, salt and water are retained by the kidneys until the total vascular bed is filled enough to raise blood pressure to the level required to balance renal output of fluid with daily intake of fluid. Conditions That Cause Large Increases in Extracellular Fluid Volume but with Normal Blood Volume There are several conditions in which extracellular fluid volume becomes markedly increased but blood volume remains normal or even slightly reduced. These conditions are usually initiated by leakage of fluid and protein into the interstitium, which tends to decrease the blood volume. The kidneys’ response to these conditions is similar to the response after hemorrhage. That is, the kidneys retain salt and water in an attempt to restore blood volume toward normal. Much of the extra fluid, however, leaks into the interstitium, causing further edema. 381 into the tissues of the body. The net result is massive fluid retention by the kidneys until tremendous extracellular edema occurs unless treatment is instituted to restore the plasma proteins. Liver Cirrhosis—Decreased Synthesis of Plasma Proteins by the Liver and Sodium Retention by the Kidneys A similar sequence of events occurs in cirrhosis of the liver as in nephrotic syndrome, except that in liver cirrhosis, the reduction in plasma protein concentration results from destruction of the liver cells, thus reducing the ability of the liver to synthesize enough plasma proteins. Cirrhosis is also associated with large amounts of fibrous tissue in the liver structure, which greatly impedes the flow of portal blood through the liver. This in turn raises capillary pressure throughout the portal vascular bed, which also contributes to the leakage of fluid and proteins into the peritoneal cavity, a condition called ascites. Once fluid and protein are lost from the circulation, the renal responses are similar to those observed in other conditions associated with decreased plasma volume. That is, the kidneys continue to retain salt and water until plasma volume and arterial pressure are restored to normal. In some cases, plasma volume may actually increase above normal because of increased vascular capacity in cirrhosis; the high pressures in the portal circulation can greatly distend veins and therefore increase vascular capacity. References Nephrotic Syndrome—Loss of Plasma Proteins in Urine and Sodium Retention by the Kidneys The general mechanisms that lead to extracellular edema are reviewed in Chapter 25. One of the most important clinical causes of edema is the so-called nephrotic syndrome. In nephrotic syndrome, the glomerular capillaries leak large amounts of protein into the filtrate and the urine because of an increased permeability of the glomerulus. Thirty to 50 grams of plasma protein can be lost in the urine each day, sometimes causing the plasma protein concentration to fall to less than one-third normal. As a consequence of the decreased plasma protein concentration, the plasma colloid osmotic pressure falls to low levels. This causes the capillaries all over the body to filter large amounts of fluid into the various tissues, which in turn causes edema and decreases the plasma volume. Renal sodium retention in nephrotic syndrome occurs through multiple mechanisms activated by leakage of protein and fluid from the plasma into the interstitial fluid, including activation of various sodiumretaining systems such as the renin-angiotensin system, aldosterone, and possibly the sympathetic nervous system. The kidneys continue to retain sodium and water until plasma volume is restored nearly to normal. However, because of the large amount of sodium and water retention, the plasma protein concentration becomes further diluted, causing still more fluid to leak Antunes-Rodrigues J, de Castro M, Elias LL, et al: Neuroendocrine control of body fluid metabolism. Physiol Rev 84:169, 2004. Cowley AW Jr: Long-term control of arterial pressure. Physiol Rev 72:231, 1992. Fitzsimmons JT: Physiology and pathophysiology of thirst and salt appetite. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 1153-1174. Giebisch GH: A trail of research on potassium. Kidney Int 62:1498, 2002. Giebisch G, Hebert SC, Wang WH: New aspects of renal potassium transport. Pflugers Arch 446:289, 2003. Granger JP, Alexander BT, Llinas M: Mechanisms of pressure natriuresis. Curr Hypertens Rep 4:15, 2002. Guise TA, Mundy GR: Disorders of calcium metabolism. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 1811-1840. Guyton AC: Blood pressure control—special role of the kidneys and body fluids. Science 252:1813, 1991. Hall JE, Brands MW: The renin-angiotensin-aldosterone system: renal mechanisms and circulatory homeostasis. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 1009-1046. Hall JE: Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney. J Am Soc Nephrol 10(Suppl 12):s258, 1999. 382 Unit V The Body Fluids and Kidneys Murer H, Hernando N, Forster I, Biber J: Regulation of Na/Pi transporter in the proximal tubule. Annu Rev Physiol 65:531, 2003. Rosa R, Epstein FH: Extrarenal potassium metabolism. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 1551-1574. Suki WN, Lederer ED, Rouse D: Renal transport of calcium magnesium and phosphate. In: Brenner BM (ed): The Kidney, 6th ed. Philadelphia: WB Saunders, 2000, pp 520574. Warnock DG. Renal genetic disorders related to K+ and Mg2+. Annu Rev Physiol 64:845, 2002. Young DB: Quantitative analysis of aldosterone’s role in potassium regulation. Am J Physiol 255: F811, 1988. Young DB: Analysis of long-term potassium regulation. Endocr Rev 6:24, 1985. C H A P T E R 3 0 Regulation of Acid-Base Balance Regulation of hydrogen ion (H+) balance is similar in some ways to the regulation of other ions in the body. For instance, to achieve homeostasis, there must be a balance between the intake or production of H+ and the net removal of H+ from the body.And, as is true for other ions, the kidneys play a key role in regulating H+ removal. However, precise control of extracellular fluid H+ concentration involves much more than simple elimination of H+ by the kidneys. There are also multiple acid-base buffering mechanisms involving the blood, cells, and lungs that are essential in maintaining normal H+ concentrations in both the extracellular and the intracellular fluid. In this chapter, the various mechanisms that contribute to the regulation of H+ concentration are discussed, with special emphasis on the control of renal H+ secretion and renal reabsorption, production, and excretion of bicarbonate ions (HCO3–), one of the key components of acid-base control systems in the body fluids. Hydrogen Ion Concentration Is Precisely Regulated Precise H+ regulation is essential because the activities of almost all enzyme systems in the body are influenced by H+ concentration. Therefore, changes in hydrogen concentration alter virtually all cell and body functions. Compared with other ions, the H+ concentration of the body fluids normally is kept at a low level. For example, the concentration of sodium in extracellular fluid (142 mEq/L) is about 3.5 million times as great as the normal concentration of H+, which averages only 0.00004 mEq/L. Equally important, the normal variation in H+ concentration in extracellular fluid is only about one millionth as great as the normal variation in sodium ion (Na+) concentration. Thus, the precision with which H+ is regulated emphasizes its importance to the various cell functions. Acids and Bases—Their Definitions and Meanings A hydrogen ion is a single free proton released from a hydrogen atom. Molecules containing hydrogen atoms that can release hydrogen ions in solutions are referred to as acids. An example is hydrochloric acid (HCl), which ionizes in water to form hydrogen ions (H+) and chloride ions (Cl–). Likewise, carbonic acid (H2CO3) ionizes in water to form H+ and bicarbonate ions (HCO3–). A base is an ion or a molecule that can accept an H+. For example, HCO3– is a base because it can combine with H+ to form H2CO3. Likewise, HPO4= is a base because it can accept an H+ to form H2PO4–. The proteins in the body also function as bases, because some of the amino acids that make up proteins have net negative charges that readily accept H+. The protein hemoglobin in the red blood cells and proteins in the other cells of the body are among the most important of the body’s bases. The terms base and alkali are often used synonymously. An alkali is a molecule formed by the combination of one or more of the alkaline metals—sodium, potassium, lithium, and so forth—with a highly basic ion such as a hydroxyl ion (OH–). 383 384 Unit V The Body Fluids and Kidneys The base portion of these molecules reacts quickly with H+ to remove it from solution; they are, therefore, typical bases. For similar reasons, the term alkalosis refers to excess removal of H+ from the body fluids, in contrast to the excess addition of H+, which is referred to as acidosis. Strong and Weak Acids and Bases. A strong acid is one that rapidly dissociates and releases especially large amounts of H+ in solution. An example is HCl. Weak acids have less tendency to dissociate their ions and, therefore, release H+ with less vigor. An example is H2CO3. A strong base is one that reacts rapidly and strongly with H+ and, therefore, quickly removes these from a solution. A typical example is OH–, which reacts with H+ to form water (H2O). A typical weak base is HCO3– because it binds with H+ much more weakly than does OH–. Most of the acids and bases in the extracellular fluid that are involved in normal acid-base regulation are weak acids and bases. The most important ones that we discuss in detail are H2CO3 and bicarbonate base. Normal Hydrogen Ion Concentration and pH of Body Fluids and Changes That Occur in Acidosis and Alkalosis. As dis- cussed earlier, the blood H+ concentration is normally maintained within tight limits around a normal value of about 0.00004 mEq/L (40 nEq/L). Normal variations are only about 3 to 5 nEq/L, but under extreme conditions, the H+ concentration can vary from as low as 10 nEq/L to as high as 160 nEq/L without causing death. Because H+ concentration normally is low, and because these small numbers are cumbersome, it is customary to express H+ concentration on a logarithm scale, using pH units. pH is related to the actual H+ concentration by the following formula (H+ concentration [H+] is expressed in equivalents per liter): pH = log 1 [H+ ] = - log [H+ ] For example, the normal [H+] is 40 nEq/L (0.00000004 Eq/L). Therefore, the normal pH is pH = –log [0.00000004] pH = 7.4 From this formula, one can see that pH is inversely related to the H+ concentration; therefore, a low pH corresponds to a high H+ concentration, and a high pH corresponds to a low H+ concentration. The normal pH of arterial blood is 7.4, whereas the pH of venous blood and interstitial fluids is about 7.35 because of the extra amounts of carbon dioxide (CO2) released from the tissues to form H2CO3 in these fluids (Table 30–1). Because the normal pH of arterial blood is 7.4, a person is considered to have acidosis when the pH falls below this value and to have alkalosis when the pH rises above 7.4. The lower limit of pH at which a person can live more than a few hours is about 6.8, and the upper limit is about 8.0. Intracellular pH usually is slightly lower than plasma pH because the metabolism of the cells produces acid, especially H2CO3. Depending on the type of cells, the pH of intracellular fluid has been estimated to range between 6.0 and 7.4. Hypoxia of the tissues and poor blood flow to the tissues can cause acid accumulation and decreased intracellular pH. Table 30–1 pH and H+ Concentration of Body Fluids H+ Concentration (mEq/L) pH Extracellular fluid Arterial blood Venous blood Interstitial fluid 4.0 ¥ 10–5 4.5 ¥ 10–5 4.5 ¥ 10–5 7.40 7.35 7.35 Intracellular fluid 1 ¥ 10–3 to 4 ¥ 10–5 6.0 to 7.4 Urine 3 ¥ 10–2 to 1 ¥ 10–5 4.5 to 8.0 Gastric HCl 160 0.8 The pH of urine can range from 4.5 to 8.0, depending on the acid-base status of the extracellular fluid. As discussed later, the kidneys play a major role in correcting abnormalities of extracellular fluid H+ concentration by excreting acids or bases at variable rates. An extreme example of an acidic body fluid is the HCl secreted into the stomach by the oxyntic (parietal) cells of the stomach mucosa, as discussed in Chapter 64. The H+ concentration in these cells is about 4 million times greater than the hydrogen concentration in blood, with a pH of 0.8. In the remainder of this chapter, we discuss the regulation of extracellular fluid H+ concentration. Defenses Against Changes in Hydrogen Ion Concentration: Buffers, Lungs, and Kidneys There are three primary systems that regulate the H+ concentration in the body fluids to prevent acidosis or alkalosis: (1) the chemical acid-base buffer systems of the body fluids, which immediately combine with acid or base to prevent excessive changes in H+ concentration; (2) the respiratory center, which regulates the removal of CO2 (and, therefore, H2CO3) from the extracellular fluid; and (3) the kidneys, which can excrete either acid or alkaline urine, thereby readjusting the extracellular fluid H+ concentration toward normal during acidosis or alkalosis. When there is a change in H+ concentration, the buffer systems of the body fluids react within a fraction of a second to minimize these changes. Buffer systems do not eliminate H+ from or add them to the body but only keep them tied up until balance can be reestablished. The second line of defense, the respiratory system, also acts within a few minutes to eliminate CO2 and, therefore, H2CO3 from the body. These first two lines of defense keep the H+ concentration from changing too much until the more slowly responding third line of defense, the kidneys, can eliminate the excess acid or base from the body. Although the kidneys are relatively slow to respond compared with the other defenses, over a period of hours to several days, they are by far the most powerful of the acid-base regulatory systems. 385 Regulation of Acid-Base Balance Now, putting the entire system together, we have the following: ææ æ æÆ H 2CO3 ¨ Æ H+ + HCO3– CO 2 + H 2O ¨ + Na+ æææÆ A buffer is any substance that can reversibly bind H+. The general form of the buffering reaction is æææÆ H Buffer Buffer + H + ¨ æææÆ In this example, a free H+ combines with the buffer to form a weak acid (H buffer) that can either remain as an unassociated molecule or dissociate back to buffer and H+. When the H+ concentration increases, the reaction is forced to the right, and more H+ binds to the buffer, as long as buffer is available. Conversely, when the H+ concentration decreases, the reaction shifts toward the left, and H+ is released from the buffer. In this way, changes in H+ concentration are minimized. The importance of the body fluid buffers can be quickly realized if one considers the low concentration of H+ in the body fluids and the relatively large amounts of acids produced by the body each day. For example, about 80 milliequivalents of hydrogen is either ingested or produced each day by metabolism, whereas the H+ concentration of the body fluids normally is only about 0.00004 mEq/L. Without buffering, the daily production and ingestion of acids would cause huge changes in body fluid H+ concentration. The action of acid-base buffers can perhaps best be explained by considering the buffer system that is quantitatively the most important in the extracellular fluid—the bicarbonate buffer system. Bicarbonate Buffer System The bicarbonate buffer system consists of a water solution that contains two ingredients: (1) a weak acid, H2CO3, and (2) a bicarbonate salt, such as NaHCO3. H2CO3 is formed in the body by the reaction of CO2 with H2O. Ï Ì Ó Buffering of Hydrogen Ions in the Body Fluids æææÆ Chapter 30 Because of the weak dissociation of H2CO3, the H+ concentration is extremely small. When a strong acid such as HCl is added to the bicarbonate buffer solution, the increased H+ released from the acid (HCl Æ H+ + Cl–) is buffered by HCO3–. ≠H+ + HCO3– Æ H2CO3 Æ CO2 + H2O As a result, more H2CO3 is formed, causing increased CO2 and H2O production. From these reactions, one can see that H+ from the strong acid HCl reacts with HCO3– to form the very weak acid H2CO3, which in turn forms CO2 and H2O. The excess CO2 greatly stimulates respiration, which eliminates the CO2 from the extracellular fluid. The opposite reactions take place when a strong base, such as sodium hydroxide (NaOH), is added to the bicarbonate buffer solution. NaOH + H2CO3 Æ NaHCO3 + H2O In this case, the OH– from the NaOH combines with H2CO3 to form additional HCO3–. Thus, the weak base NaHCO3 replaces the strong base NaOH. At the same time, the concentration of H2CO3 decreases (because it reacts with NaOH), causing more CO2 to combine with H2O to replace the H2CO3. CO 2 + H 2O æææÆ H 2CO3 æææÆ ≠HCO3 - + H + + + NaOH Na The net result, therefore, is a tendency for the CO2 levels in the blood to decrease, but the decreased CO2 in the blood inhibits respiration and decreases the rate of CO2 expiration. The rise in blood HCO3– that occurs is compensated for by increased renal excretion of HCO3–. carbonic anhydrase This reaction is slow, and exceedingly small amounts of H2CO3 are formed unless the enzyme carbonic anhydrase is present. This enzyme is especially abundant in the walls of the lung alveoli, where CO2 is released; carbonic anhydrase is also present in the epithelial cells of the renal tubules, where CO2 reacts with H2O to form H2CO3. H2CO3 ionizes weakly to form small amounts of H+ and HCO3–. H 2 CO 3 ¨ Æ H+ + HCO3 - æææÆ The second component of the system, bicarbonate salt, occurs predominantly as sodium bicarbonate (NaHCO3) in the extracellular fluid. NaHCO3 ionizes almost completely to form HCO3– and Na+, as follows: æÆ Na + + HCO3 NaHCO3 ææ ¨ Quantitative Dynamics of the Bicarbonate Buffer System All acids, including H2CO3, are ionized to some extent. From mass balance considerations, the concentrations of H+ and HCO3– are proportional to the concentration of H2CO3. H 2CO3 ¨ Æ æææÆ CO 2 + H 2O ¨ææ ææ H CO3 æ ææ æÆ 2 H + + HCO3 - For any acid, the concentration of the acid relative to its dissociated ions is defined by the dissociation constant K¢. K¢ = H+ ¥ HCO3 H 2CO3 (1) This equation indicates that in an H2CO3 solution, the amount of free H+ is equal to H+ = K ¢ ¥ H 2CO3 HCO3 - (2) 386 Unit V The Body Fluids and Kidneys The concentration of undissociated H2CO3 cannot be measured in solution because it rapidly dissociates into CO2 and H2O or to H+ and HCO3–. However, the CO2 dissolved in the blood is directly proportional to the amount of undissociated H2CO3. Therefore, equation 2 can be rewritten as H+ = K ¥ CO2 HCO3 - (3) The dissociation constant (K) for equation 3 is only about 1/400 of the dissociation constant (K¢) of equation 2 because the proportionality ratio between H2CO3 and CO2 is 1:400. Equation 3 is written in terms of the total amount of CO2 dissolved in solution. However, most clinical laboratories measure the blood CO2 tension (PCO2) rather than the actual amount of CO2. Fortunately, the amount of CO2 in the blood is a linear function of PCO2 times the solubility coefficient for CO2; under physiologic conditions, the solubility coefficient for CO2 is 0.03 mmol/mm Hg at body temperature.This means that 0.03 millimole of H2CO3 is present in the blood for each millimeter of mercury PCO2 measured. Therefore, equation 3 can be rewritten as H+ = K ¥ (0.03 ¥ Pco 2 ) HCO3 - (4) Henderson-Hasselbalch Equation. As discussed earlier, it is customary to express H+ concentration in pH units rather than in actual concentrations. Recall that pH is defined as pH = –log H+. The dissociation constant can be expressed in a similar manner. pK = –log K Therefore, we can express the H+ concentration in equation 4 in pH units by taking the negative logarithm of that equation, which yields - log H+ = - log pK - log (0.03 ¥ Pco 2 ) HCO3 - (5) toward alkalosis. An increase in PCO2 causes the pH to decrease, shifting the acid-base balance toward acidosis. The Henderson-Hasselbalch equation, in addition to defining the determinants of normal pH regulation and acid-base balance in the extracellular fluid, provides insight into the physiologic control of acid and base composition of the extracellular fluid. As discussed later, the bicarbonate concentration is regulated mainly by the kidneys, whereas the PCO2 in extracellular fluid is controlled by the rate of respiration. By increasing the rate of respiration, the lungs remove CO2 from the plasma, and by decreasing respiration, the lungs elevate PCO2. Normal physiologic acid-base homeostasis results from the coordinated efforts of both of these organs, the lungs and the kidneys, and acid-base disorders occur when one or both of these control mechanisms are impaired, thus altering either the bicarbonate concentration or the PCO2 of extracellular fluid. When disturbances of acid-base balance result from a primary change in extracellular fluid bicarbonate concentration, they are referred to as metabolic acid-base disorders. Therefore, acidosis caused by a primary decrease in bicarbonate concentration is termed metabolic acidosis, whereas alkalosis caused by a primary increase in bicarbonate concentration is called metabolic alkalosis. Acidosis caused by an increase in PCO2 is called respiratory acidosis, whereas alkalosis caused by a decrease in PCO2 is termed respiratory alkalosis. Bicarbonate Buffer System Titration Curve. Figure 30–1 shows the changes in pH of the extracellular fluid when the ratio of HCO3– to CO2 in extracellular fluid is altered. When the concentrations of these two components are equal, the right-hand portion of equation 8 becomes the log of 1, which is equal to 0. Therefore, when the two components of the buffer system are equal, the pH of the solution is the same as the pK (6.1) of the bicarbonate buffer system. When base is added to the system, part of the dissolved CO2 is converted into HCO3–, causing an increase in the ratio of HCO3– to CO2 and increasing the pH, as is evident from the HendersonHasselbalch equation. When acid is added, it is buffered Therefore, HCO3 - (6) Rather than work with a negative logarithm, we can change the sign of the logarithm and invert the numerator and denominator in the last term, using the law of logarithms to yield pH = pK + log HCO3 (0.03 ¥ Pco 2 ) (7) For the bicarbonate buffer system, the pK is 6.1, and equation 7 can be written as pH = 6.1 + log HCO3 0.03 ¥ Pco 2 (8) Equation 8 is the Henderson-Hasselbalch equation, and with it, one can calculate the pH of a solution if the molar concentration of HCO3– and the PCO2 are known. From the Henderson-Hasselbalch equation, it is apparent that an increase in HCO3– concentration causes the pH to rise, shifting the acid-base balance 0 100 Normal operating point in body 25 75 50 50 pK 25 75 Per cent of buffer in form of HCO3Base added (0.03 ¥ Pco 2 ) Acid added Per cent of buffer in form of H2CO3 and CO2 pH = pK - log 0 100 4 5 6 pH 7 8 Figure 30–1 Titration curve for bicarbonate buffer system showing the pH of extracellular fluid when the percentages of buffer in the form of HCO3– and CO2 (or H2CO3) are altered. Chapter 30 Regulation of Acid-Base Balance by HCO3–, which is then converted into dissolved CO2, decreasing the ratio of HCO3– to CO2 and decreasing the pH of the extracellular fluid. “Buffer Power” Is Determined by the Amount and Relative Concentrations of the Buffer Components. From the titration curve in Figure 30–1, several points are apparent. First, the pH of the system is the same as the pK when each of the components (HCO3– and CO2) constitutes 50 per cent of the total concentration of the buffer system. Second, the buffer system is most effective in the central part of the curve, where the pH is near the pK of the system. This means that the change in pH for any given amount of acid or base added to the system is least when the pH is near the pK of the system. The buffer system is still reasonably effective for 1.0 pH unit on either side of the pK, which for the bicarbonate buffer system extends from a pH of about 5.1 to 7.1 units. Beyond these limits, the buffering power rapidly diminishes. And when all the CO2 has been converted into HCO3– or when all the HCO3– has been converted into CO2, the system has no more buffering power. The absolute concentration of the buffers is also an important factor in determining the buffer power of a system. With low concentrations of the buffers, only a small amount of acid or base added to the solution changes the pH considerably. Bicarbonate Buffer System Is the Most Important Extracellular Buffer. From the titration curve shown in Figure 30–1, one would not expect the bicarbonate buffer system to be powerful, for two reasons: First, the pH of the extracellular fluid is about 7.4, whereas the pK of the bicarbonate buffer system is 6.1. This means that there is about 20 times as much of the bicarbonate buffer system in the form of HCO3– as in the form of dissolved CO2. For this reason, this system operates on the portion of the buffering curve where the slope is low and the buffering power is poor. Second, the concentrations of the two elements of the bicarbonate system, CO2 and HCO3–, are not great. Despite these characteristics, the bicarbonate buffer system is the most powerful extracellular buffer in the body. This apparent paradox is due mainly to the fact that the two elements of the buffer system, HCO3– and CO2, are regulated, respectively, by the kidneys and the lungs, as discussed later. As a result of this regulation, the pH of the extracellular fluid can be precisely controlled by the relative rate of removal and addition of HCO3– by the kidneys and the rate of removal of CO2 by the lungs. Phosphate Buffer System Although the phosphate buffer system is not important as an extracellular fluid buffer, it plays a major role in buffering renal tubular fluid and intracellular fluids. The main elements of the phosphate buffer system are H2PO4– and HPO4=. When a strong acid such as HCl is added to a mixture of these two substances, the hydrogen is accepted by the base HPO4= and converted to H2PO4–. 387 HCl + Na2HPO4 Æ NaH2PO4 + NaCl The result of this reaction is that the strong acid, HCl, is replaced by an additional amount of a weak acid, NaH2PO4, and the decrease in pH is minimized. When a strong base, such as NaOH, is added to the buffer system, the OH– is buffered by the H2PO4– to form additional amounts of HPO4= + H2O. NaOH + NaH2PO4 Æ Na2HPO4 + H2O In this case, a strong base, NaOH, is traded for a weak base, NaH2PO4, causing only a slight increase in pH. The phosphate buffer system has a pK of 6.8, which is not far from the normal pH of 7.4 in the body fluids; this allows the system to operate near its maximum buffering power. However, its concentration in the extracellular fluid is low, only about 8 per cent of the concentration of the bicarbonate buffer. Therefore, the total buffering power of the phosphate system in the extracellular fluid is much less than that of the bicarbonate buffering system. In contrast to its rather insignificant role as an extracellular buffer, the phosphate buffer is especially important in the tubular fluids of the kidneys, for two reasons: (1) phosphate usually becomes greatly concentrated in the tubules, thereby increasing the buffering power of the phosphate system, and (2) the tubular fluid usually has a considerably lower pH than the extracellular fluid does, bringing the operating range of the buffer closer to the pK (6.8) of the system. The phosphate buffer system is also important in buffering intracellular fluid because the concentration of phosphate in this fluid is many times that in the extracellular fluid. Also, the pH of intracellular fluid is lower than that of extracellular fluid and therefore is usually closer to the pK of the phosphate buffer system compared with the extracellular fluid. Proteins: Important Intracellular Buffers Proteins are among the most plentiful buffers in the body because of their high concentrations, especially within the cells. The pH of the cells, although slightly lower than in the extracellular fluid, nevertheless changes approximately in proportion to extracellular fluid pH changes. There is a slight amount of diffusion of H+ and HCO3– through the cell membrane, although these ions require several hours to come to equilibrium with the extracellular fluid, except for rapid equilibrium that occurs in the red blood cells. CO2, however, can rapidly diffuse through all the cell membranes. This diffusion of the elements of the bicarbonate buffer system causes the pH in intracellular fluid to change when there are changes in extracellular pH. For this reason, the buffer systems within the cells help prevent changes in the pH of extracellular fluid but may take several hours to become maximally effective. 388 Unit V The Body Fluids and Kidneys In the red blood cell, hemoglobin (Hb) is an important buffer, as follows: æææÆ HHb H+ + Hb ¨ æææÆ ¨ Approximately 60 to 70 per cent of the total chemical buffering of the body fluids is inside the cells, and most of this results from the intracellular proteins. However, except for the red blood cells, the slowness with which H+ and HCO3– move through the cell membranes often delays for several hours the maximum ability of the intracellular proteins to buffer extracellular acid-base abnormalities. In addition to the high concentration of proteins in the cells, another factor that contributes to their buffering power is the fact that the pKs of many of these protein systems are fairly close to 7.4. Isohydric Principle: All Buffers in a Common Solution Are in Equilibrium with the Same Hydrogen Ion Concentration We have been discussing buffer systems as though they operated individually in the body fluids. However, they all work together, because H+ is common to the reactions of all the systems. Therefore, whenever there is a change in H+ concentration in the extracellular fluid, the balance of all the buffer systems changes at the same time. This phenomenon is called the isohydric principle and is illustrated by the following formula: H+ = K1 ¥ HA1 HA 2 HA 3 = K2 ¥ = K3 ¥ A1 A2 A3 K1, K2, K3 are the dissociation constants of three respective acids, HA1, HA2, HA3, and A1, A2, A3 are the concentrations of the free negative ions that constitute the bases of the three buffer systems. The implication of this principle is that any condition that changes the balance of one of the buffer systems also changes the balance of all the others because the buffer systems actually buffer one another by shifting H+ back and forth between them. flowing blood transports it to the lungs, where it diffuses into the alveoli and then is transferred to the atmosphere by pulmonary ventilation. About 1.2 mol/ L of dissolved CO2 normally is in the extracellular fluid, corresponding to a Pco2 of 40 mm Hg. If the rate of metabolic formation of CO2 increases, the Pco2 of the extracellular fluid is likewise increased. Conversely, a decreased metabolic rate lowers the Pco2. If the rate of pulmonary ventilation is increased, CO2 is blown off from the lungs, and the Pco2 in the extracellular fluid decreases. Therefore, changes in either pulmonary ventilation or the rate of CO2 formation by the tissues can change the extracellular fluid Pco2. Increasing Alveolar Ventilation Decreases Extracellular Fluid Hydrogen Ion Concentration and Raises pH If the metabolic formation of CO2 remains constant, the only other factor that affects Pco2 in extracellular fluid is the rate of alveolar ventilation. The higher the alveolar ventilation, the lower the Pco2; conversely, the lower the alveolar ventilation rate, the higher the Pco2. As discussed previously, when CO2 concentration increases, the H2CO3 concentration and H+ concentration also increase, thereby lowering extracellular fluid pH. Figure 30–2 shows the approximate changes in blood pH that are caused by increasing or decreasing the rate of alveolar ventilation. Note that increasing alveolar ventilation to about twice normal raises the pH of the extracellular fluid by about 0.23. If the pH of the body fluids is 7.40 with normal alveolar ventilation, doubling the ventilation rate raises the pH to Respiratory Regulation of Acid-Base Balance The second line of defense against acid-base disturbances is control of extracellular fluid CO2 concentration by the lungs. An increase in ventilation eliminates CO2 from extracellular fluid, which, by mass action, reduces the H+ concentration. Conversely, decreased ventilation increases CO2, thus also increasing H+ concentration in the extracellular fluid. pH change in body fluids +0.3 +0.2 +0.1 0 Normal -0.1 -0.2 -0.3 -0.4 -0.5 0.5 1.0 1.5 2.0 Rate of alveolar ventilation (normal = 1) 2.5 Pulmonary Expiration of CO2 Balances Metabolic Formation of CO2 CO2 is formed continually in the body by intracellular metabolic processes. After it is formed, it diffuses from the cells into the interstitial fluids and blood, and the Figure 30–2 Change in extracellular fluid pH caused by increased or decreased rate of alveolar ventilation, expressed as times normal. Chapter 30 Regulation of Acid-Base Balance 389 about 7.63. Conversely, a decrease in alveolar ventilation to one fourth normal reduces the pH by 0.45. That is, if the pH is 7.4 at a normal alveolar ventilation, reducing the ventilation to one fourth normal reduces the pH to 6.95. Because the alveolar ventilation rate can change markedly, from as low as 0 to as high as 15 times normal, one can easily understand how much the pH of the body fluids can be changed by the respiratory system. Feedback Control of Hydrogen Ion Concentration by the Respiratory System. Because increased H+ concentration Increased Hydrogen Ion Concentration Stimulates Alveolar Ventilation That is, whenever the H+ concentration increases above normal, the respiratory system is stimulated, and alveolar ventilation increases. This decreases the PCO2 in extracellular fluid and reduces H+ concentration back toward normal. Conversely, if H+ concentration falls below normal, the respiratory center becomes depressed, alveolar ventilation decreases, and H+ concentration increases back toward normal. Alveolar ventilation (normal = 1) Not only does the alveolar ventilation rate influence H+ concentration by changing the Pco2 of the body fluids, but the H+ concentration affects the rate of alveolar ventilation. Thus, Figure 30–3 shows that the alveolar ventilation rate increases four to five times normal as the pH decreases from the normal value of 7.4 to the strongly acidic value of 7.0. Conversely, when plasma pH rises above 7.4, this causes a decrease in the ventilation rate. As one can see from the graph, the change in ventilation rate per unit pH change is much greater at reduced levels of pH (corresponding to elevated H+ concentration) compared with increased levels of pH. The reason for this is that as the alveolar ventilation rate decreases, owing to an increase in pH (decreased H+ concentration), the amount of oxygen added to the blood decreases and the partial pressure of oxygen (PO2) in the blood also decreases, which stimulates the ventilation rate. Therefore, the respiratory compensation for an increase in pH is not nearly as effective as the response to a marked reduction in pH. 4 ≠[H+] Æ ≠Alveolar ventilation Ø – ØPCO2 Efficiency of Respiratory Control of Hydrogen Ion Concentration. Respiratory control cannot return the H+ concentration all the way back to normal when a disturbance outside the respiratory system has altered pH. Ordinarily, the respiratory mechanism for controlling H+ concentration has an effectiveness between 50 and 75 per cent, corresponding to a feedback gain of 1 to 3. That is, if the H+ concentration is suddenly increased by adding acid to the extracellular fluid and pH falls from 7.4 to 7.0, the respiratory system can return the pH to a value of about 7.2 to 7.3. This response occurs within 3 to 12 minutes. Buffering Power of the Respiratory System. Respiratory reg- ulation of acid-base balance is a physiologic type of buffer system because it acts rapidly and keeps the H+ concentration from changing too much until the slowly responding kidneys can eliminate the imbalance. In general, the overall buffering power of the respiratory system is one to two times as great as the buffering power of all other chemical buffers in the extracellular fluid combined. That is, one to two times as much acid or base can normally be buffered by this mechanism as by the chemical buffers. Impairment of Lung Function Can Cause Respiratory Acidosis. 3 2 1 0 7.0 stimulates respiration, and because increased alveolar ventilation decreases the H+ concentration, the respiratory system acts as a typical negative feedback controller of H+ concentration. 7.1 7.2 7.3 7.4 pH of arterial blood 7.5 7.6 Figure 30–3 Effect of blood pH on the rate of alveolar ventilation. We have discussed thus far the role of the normal respiratory mechanism as a means of buffering changes in H+ concentration. However, abnormalities of respiration can also cause changes in H+ concentration. For example, an impairment of lung function, such as severe emphysema, decreases the ability of the lungs to eliminate CO2; this causes a buildup of CO2 in the extracellular fluid and a tendency toward respiratory acidosis. Also, the ability to respond to metabolic acidosis is impaired because the compensatory reductions in PCO2 that would normally occur by means of increased ventilation are blunted. In these circumstances, the kidneys represent the sole remaining physiologic mechanism for returning pH toward normal after the initial chemical buffering in the extracellular fluid has occurred. 390 Unit V The Body Fluids and Kidneys Renal Control of Acid-Base Balance body of the nonvolatile acids produced each day, for a total of 4400 milliequivalents of H+ secreted into the tubular fluid each day. When there is a reduction in the extracellular fluid H+ concentration (alkalosis), the kidneys fail to reabsorb all the filtered bicarbonate, thereby increasing the excretion of bicarbonate. Because HCO3– normally buffers hydrogen in the extracellular fluid, this loss of bicarbonate is the same as adding an H+ to the extracellular fluid. Therefore, in alkalosis, the removal of HCO3– raises the extracellular fluid H+ concentration back toward normal. In acidosis, the kidneys do not excrete bicarbonate into the urine but reabsorb all the filtered bicarbonate and produce new bicarbonate, which is added back to the extracellular fluid. This reduces the extracellular fluid H+ concentration back toward normal. Thus, the kidneys regulate extracellular fluid H + concentration through three fundamental mechanisms: (1) secretion of H +, (2) reabsorption of filtered HCO3-, and (3) production of new HCO3-. All these processes are accomplished through the same basic mechanism, as discussed in the next few sections. The kidneys control acid-base balance by excreting either an acidic or a basic urine. Excreting an acidic urine reduces the amount of acid in extracellular fluid, whereas excreting a basic urine removes base from the extracellular fluid. The overall mechanism by which the kidneys excrete acidic or basic urine is as follows: Large numbers of HCO3– are filtered continuously into the tubules, and if they are excreted into the urine, this removes base from the blood. Large numbers of H+ are also secreted into the tubular lumen by the tubular epithelial cells, thus removing acid from the blood. If more H+ is secreted than HCO3– is filtered, there will be a net loss of acid from the extracellular fluid. Conversely, if more HCO3– is filtered than H+ is secreted, there will be a net loss of base. As discussed previously, each day the body produces about 80 milliequivalents of nonvolatile acids, mainly from the metabolism of proteins.These acids are called nonvolatile because they are not H2CO3 and, therefore, cannot be excreted by the lungs. The primary mechanism for removal of these acids from the body is renal excretion. The kidneys must also prevent the loss of bicarbonate in the urine, a task that is quantitatively more important than the excretion of nonvolatile acids. Each day the kidneys filter about 4320 milliequivalents of bicarbonate (180 L/day ¥ 24 mEq/ L); under normal conditions, almost all this is reabsorbed from the tubules, thereby conserving the primary buffer system of the extracellular fluid. As discussed later, both the reabsorption of bicarbonate and the excretion of H+ are accomplished through the process of H+ secretion by the tubules. Because the HCO3– must react with a secreted H+ to form H2CO3 before it can be reabsorbed, 4320 milliequivalents of H+ must be secreted each day just to reabsorb the filtered bicarbonate. Then an additional 80 milliequivalents of H+ must be secreted to rid the Secretion of Hydrogen Ions and Reabsorption of Bicarbonate Ions by the Renal Tubules Hydrogen ion secretion and bicarbonate reabsorption occur in virtually all parts of the tubules except the descending and ascending thin limbs of the loop of Henle. Figure 30–4 summarizes bicarbonate reabsorption along the tubule. Keep in mind that for each bicarbonate reabsorbed, an H+ must be secreted. About 80 to 90 per cent of the bicarbonate reabsorption (and H+ secretion) occurs in the proximal tubule, so that only a small amount of bicarbonate flows into the distal tubules and collecting ducts. In the 85% (3672 mEq/day) 4320 mEq/day 10% (432 mEq/day) >4.9% (215 mEq/day) Figure 30–4 (1 mEq/day) Reabsorption of bicarbonate in different segments of the renal tubule. The percentages of the filtered load of bicarbonate absorbed by the various tubular segments are shown, as well as the number of milliequivalents reabsorbed per day under normal conditions. Regulation of Acid-Base Balance Chapter 30 thick ascending loop of Henle, another 10 per cent of the filtered bicarbonate is reabsorbed, and the remainder of the reabsorption takes place in the distal tubule and collecting duct. As discussed previously, the mechanism by which bicarbonate is reabsorbed also involves tubular secretion of H+, but different tubular segments accomplish this task differently. Hydrogen Ions Are Secreted by Secondary Active Transport in the Early Tubular Segments The epithelial cells of the proximal tubule, the thick segment of the ascending loop of Henle, and the early distal tubule all secrete H+ into the tubular fluid by sodium-hydrogen counter-transport, as shown in Figure 30–5. This secondary active secretion of H+ is coupled with the transport of Na+ into the cell at the luminal membrane by the sodium-hydrogen exchanger protein, and the energy for H+ secretion against a concentration gradient is derived from the sodium gradient favoring Na+ movement into the cell. This gradient is established by the sodium-potassium adenosine triphosphatase (ATPase) pump in the basolateral membrane. More than 90 per cent of the bicarbonate is reabsorbed in this manner, requiring about 3900 milliequivalents of H+ to be secreted each day by the tubules. This mechanism, however, does not establish a very high H+ concentration in the tubular fluid; the tubular fluid becomes very acidic only in the collecting tubules and collecting ducts. Figure 30–5 shows how the process of H+ secretion achieves bicarbonate reabsorption. The secretory Renal interstitial fluid Tubular cells Na+ K+ Tubular lumen Na+ + HCO3Na+ ATP HCO3- + H+ H+ H2CO3 H2CO3 CO2 H2O + CO2 Carbonic anhydrase CO2 + H2O Figure 30–5 Cellular mechanisms for (1) active secretion of hydrogen ions into the renal tubule; (2) tubular reabsorption of bicarbonate ions by combination with hydrogen ions to form carbonic acid, which dissociates to form carbon dioxide and water; and (3) sodium ion reabsorption in exchange for hydrogen ions secreted. This pattern of hydrogen ion secretion occurs in the proximal tubule, the thick ascending segment of the loop of Henle, and the early distal tubule. 391 process begins when CO2 either diffuses into the tubular cells or is formed by metabolism in the tubular epithelial cells. CO2, under the influence of the enzyme carbonic anhydrase, combines with H2O to form H2CO3, which dissociates into HCO3– and H+. The H+ is secreted from the cell into the tubular lumen by sodium-hydrogen counter-transport. That is, when an Na+ moves from the lumen of the tubule to the interior of the cell, it first combines with a carrier protein in the luminal border of the cell membrane; at the same time, an H+ in the interior of the cells combines with the carrier protein. The Na+ moves into the cell down a concentration gradient that has been established by the sodium-potassium ATPase pump in the basolateral membrane. The gradient for Na+ movement into the cell then provides the energy for moving H+ in the opposite direction from the interior of the cell to the tubular lumen. The HCO3– generated in the cell (when H+ dissociates from H2CO3) then moves downhill across the basolateral membrane into the renal interstitial fluid and the peritubular capillary blood. The net result is that for every H+ secreted into the tubular lumen, an HCO3– enters the blood. Filtered Bicarbonate Ions Are Reabsorbed by Interaction with Hydrogen Ions in the Tubules Bicarbonate ions do not readily permeate the luminal membranes of the renal tubular cells; therefore, HCO3– that is filtered by the glomerulus cannot be directly reabsorbed. Instead, HCO3– is reabsorbed by a special process in which it first combines with H+ to form H2CO3, which eventually becomes CO2 and H2O, as shown in Figure 30–5. This reabsorption of HCO3– is initiated by a reaction in the tubules between HCO3– filtered at the glomerulus and H+ secreted by the tubular cells. The H2CO3 formed then dissociates into CO2 and H2O. The CO2 can move easily across the tubular membrane; therefore, it instantly diffuses into the tubular cell, where it recombines with H2O, under the influence of carbonic anhydrase, to generate a new H2CO3 molecule. This H2CO3 in turn dissociates to form HCO3– and H+; the HCO3– then diffuses through the basolateral membrane into the interstitial fluid and is taken up into the peritubular capillary blood. The transport of HCO3 across the basolateral membrane is facilitated by two mechanisms: (1) Na+-HCO3– co-transport and (2) Cl–-HCO3– exchange. Thus, each time an H + is formed in the tubular epithelial cells, an HCO3- is also formed and released back into the blood. The net effect of these reactions is “reabsorption” of HCO3– from the tubules, although the HCO3– that actually enters the extracellular fluid is not the same as that filtered into the tubules. The reabsorption of filtered HCO3– does not result in net secretion of H+ because the secreted H+ combines with the filtered HCO3– and is therefore not excreted. 392 Unit V The Body Fluids and Kidneys Bicarbonate Ions Are “Titrated” Against Hydrogen Ions in the Tubules. Under normal conditions, the rate of tubular H+ secretion is about 4400 mEq/day, and the rate of filtration by HCO3– is about 4320 mEq/day. Thus, the quantities of these two ions entering the tubules are almost equal, and they combine with each other to form CO2 and H2O. Therefore, it is said that HCO3– and H+ normally “titrate” each other in the tubules. The titration process is not quite exact because there is usually a slight excess of H+ in the tubules to be excreted in the urine. This excess H+ (about 80 mEq/ day) rids the body of nonvolatile acids produced by metabolism. As discussed later, most of this H+ is not excreted as free H+ but rather in combination with other urinary buffers, especially phosphate and ammonia. When there is an excess of HCO3– over H+ in the urine, as occurs in metabolic alkalosis, the excess HCO3– cannot be reabsorbed; therefore, the excess HCO3– is left in the tubules and eventually excreted into the urine, which helps correct the metabolic alkalosis. In acidosis, there is excess H+ relative to HCO3–, causing complete reabsorption of the bicarbonate; the excess H+ passes into the urine. The excess H+ is buffered in the tubules by phosphate and ammonia and eventually excreted as salts. Thus, the basic mechanism by which the kidneys correct either acidosis or alkalosis is incomplete titration of H+ against HCO3–, leaving one or the other to pass into the urine and be removed from the extracellular fluid. Primary Active Secretion of Hydrogen Ions in the Intercalated Cells of Late Distal and Collecting Tubules Beginning in the late distal tubules and continuing through the remainder of the tubular system, the tubular epithelium secretes H+ by primary active transport. The characteristics of this transport are different from those discussed for the proximal tubule, loop of Henle, and early distal tubule. The mechanism for primary active H+ secretion is shown in Figure 30–6. It occurs at the luminal membrane of the tubular cell, where H+ is transported directly by a specific protein, a hydrogen-transporting ATPase. The energy required for pumping the H+ is derived from the breakdown of ATP to adenosine diphosphate. Primary active secretion of H+ occurs in a special type of cell called the intercalated cells of the late distal tubule and in the collecting tubules. Hydrogen ion secretion in these cells is accomplished in two steps: (1) the dissolved CO2 in this cell combines with H2O to form H2CO3, and (2) the H2CO3 then dissociates into HCO3–, which is reabsorbed into the blood, plus H+, which is secreted into the tubule by means of the hydrogen-ATPase mechanism. For each H+ secreted, an HCO3– is reabsorbed, similar to the process in the proximal tubules. The main difference is that H+ moves across the luminal membrane by an active H+ pump Renal interstitial fluid Tubular cells Cl- Cl- HCO3 + Tubular lumen ClH+ H+ ATP H2CO3 CO2 H2O + CO2 Carbonic anhydrase Figure 30–6 Primary active secretion of hydrogen ions through the luminal membrane of the intercalated epithelial cells of the late distal and collecting tubules. Note that one bicarbonate ion is absorbed for each hydrogen ion secreted, and a chloride ion is passively secreted along with the hydrogen ion. instead of by counter-transport, as occurs in the early parts of the nephron. Although the secretion of H+ in the late distal tubule and collecting tubules accounts for only about 5 per cent of the total H+ secreted, this mechanism is important in forming a maximally acidic urine. In the proximal tubules, H+ concentration can be increased only about threefold to fourfold, and the tubular fluid pH can be reduced to only about 6.7, although large amounts of H+ are secreted by this nephron segment. However, H+ concentration can be increased as much as 900-fold in the collecting tubules. This decreases the pH of the tubular fluid to about 4.5, which is the lower limit of pH that can be achieved in normal kidneys. Combination of Excess Hydrogen Ions with Phosphate and Ammonia Buffers in the Tubule—A Mechanism for Generating “New” Bicarbonate Ions When H+ is secreted in excess of the bicarbonate filtered into the tubular fluid, only a small part of the excess H+ can be excreted in the ionic form (H+) in the urine. The reason for this is that the minimal urine pH is about 4.5, corresponding to an H+ concentration of 10–4.5 mEq/L, or 0.03 mEq/L. Thus, for each liter of urine formed, a maximum of only about 0.03 milliequivalent of free H+ can be excreted. To excrete the 80 milliequivalents of nonvolatile acid formed by metabolism each day, about 2667 liters of urine would have to be excreted if the H+ remained free in solution. Chapter 30 393 Regulation of Acid-Base Balance The excretion of large amounts of H+ (on occasion as much as 500 mEq/day) in the urine is accomplished primarily by combining the H+ with buffers in the tubular fluid. The most important buffers are phosphate buffer and ammonia buffer. There are other weak buffer systems, such as urate and citrate, that are much less important. When H+ is titrated in the tubular fluid with HCO3–, this results in the reabsorption of one HCO3– for each H+ secreted, as discussed earlier. But when there are excess H+ in the urine, they combine with buffers other than HCO3–, and this results in the generation of new HCO3– that can also enter the blood. Thus, when there is excess H+ in the extracellular fluid, the kidneys not only reabsorb all the filtered HCO3– but also generate new HCO3–, thereby helping to replenish the HCO3– lost from the extracellular fluid in acidosis. In the next two sections, we discuss the mechanisms by which phosphate and ammonia buffers contribute to the generation of new HCO3–. Renal interstitial fluid Phosphate Buffer System Carries Excess Hydrogen Ions into the Urine and Generates New Bicarbonate HCO3- to the blood. This demonstrates one of the mechanisms by which the kidneys are able to replenish the extracellular fluid stores of HCO3–. Under normal conditions, much of the filtered phosphate is reabsorbed, and only about 30 to 40 mEq/day is available for buffering H+. Therefore, much of the buffering of excess H+ in the tubular fluid in acidosis occurs through the ammonia buffer system. The phosphate buffer system is composed of HPO4= and H2PO4–. Both become concentrated in the tubular fluid because of their relatively poor reabsorption and because of the reabsorption of water from the tubular fluid. Therefore, although phosphate is not an important extracellular fluid buffer, it is much more effective as a buffer in the tubular fluid. Another factor that makes phosphate important as a tubular buffer is the fact that the pK of this system is about 6.8. Under normal conditions, the urine is slightly acidic, and the urine pH is near the pK of the phosphate buffer system. Therefore, in the tubules, the phosphate buffer system normally functions near its most effective range of pH. Figure 30–7 shows the sequence of events by which H+ is excreted in combination with phosphate buffer and the mechanism by which new bicarbonate is added to the blood. The process of H+ secretion into the tubules is the same as described earlier. As long as there is excess HCO3– in the tubular fluid, most of the secreted H+ combines with HCO3–. However, once all the HCO3– has been reabsorbed and is no longer available to combine with H+, any excess H+ can combine with HPO4= and other tubular buffers. After the H+ combines with HPO4= to form H2PO4–, it can be excreted as a sodium salt (NaH2PO4), carrying with it the excess hydrogen. There is one important difference in this sequence of H+ excretion from that discussed previously. In this case, the HCO3– that is generated in the tubular cell and enters the peritubular blood represents a net gain of HCO3– by the blood, rather than merely a replacement of filtered HCO3–. Therefore, whenever an H + secreted into the tubular lumen combines with a buffer other than HCO3-, the net effect is addition of a new Na+ K+ HCO3- Tubular lumen Na+ + NaHPO4- Tubular cells Na+ ATP HCO3- + H+ H2CO3 CO2 H2O + CO2 Na+ H+ + NaHPO4- NaH2PO4 Carbonic anhydrase Figure 30–7 Buffering of secreted hydrogen ions by filtered phosphate (NaHPO4–). Note that a new bicarbonate ion is returned to the blood for each NaHPO4– that reacts with a secreted hydrogen ion. Excretion of Excess Hydrogen Ions and Generation of New Bicarbonate by the Ammonia Buffer System A second buffer system in the tubular fluid that is even more important quantitatively than the phosphate buffer system is composed of ammonia (NH3) and the ammonium ion (NH4+). Ammonium ion is synthesized from glutamine, which comes mainly from the metabolism of amino acids in the liver. The glutamine delivered to the kidneys is transported into the epithelial cells of the proximal tubules, thick ascending limb of the loop of Henle, and distal tubules (Figure 30–8). Once inside the cell, each molecule of glutamine is metabolized in a series of reactions to ultimately form two NH4+ and two HCO3–. The NH4+ is secreted into the tubular lumen by a counter-transport mechanism in exchange for sodium, which is reabsorbed. The HCO3– is transported across the basolateral membrane, along with the reabsorbed Na+, into the interstitial fluid and is taken up by the peritubular capillaries. Thus, for each molecule of glutamine metabolized in the proximal tubules, two NH4+ are secreted into the urine and two HCO3– are reabsorbed into the blood. The HCO3– generated by this process constitutes new bicarbonate. In the collecting tubules, the addition of NH4+ to the tubular fluids occurs through a different mechanism (Figure 30–9). Here, H+ is secreted by the tubular 394 Unit V Renal interstitial fluid Glutamine The Body Fluids and Kidneys Proximal tubular cells Tubular lumen Glutamine Glutamine Cl- 2HCO3- 2NH4+ NH4+ + Cl- NH4+ Na+ Na+ An increase in extracellular fluid H+ concentration stimulates renal glutamine metabolism and, therefore, increases the formation of NH4+ and new HCO3– to be used in H+ buffering; a decrease in H+ concentration has the opposite effect. Under normal conditions, the amount of H+ eliminated by the ammonia buffer system accounts for about 50 per cent of the acid excreted and 50 per cent of the new HCO3– generated by the kidneys. However, with chronic acidosis, the rate of NH4+ excretion can increase to as much as 500 mEq/day. Therefore, with chronic acidosis, the dominant mechanism by which acid is eliminated is excretion of NH4+. This also provides the most important mechanism for generating new bicarbonate during chronic acidosis. Figure 30–8 Production and secretion of ammonium ion (NH4+) by proximal tubular cells. Glutamine is metabolized in the cell, yielding NH4+ and bicarbonate. The NH4+ is secreted into the lumen by a sodium-NH4+ pump. For each glutamine molecule metabolized, two NH4+ are produced and secreted and two HCO3– are returned to the blood. Renal interstitial fluid Tubular lumen Collecting tubular cells Na+ ATP ClHCO3- + H+ H2CO3 CO2 NH3 NH3 K+ H2O + CO2 Carbonic anhydrase ATP H+ NH4+ + Cl- Figure 30–9 Buffering of hydrogen ion secretion by ammonia (NH3) in the collecting tubules. Ammonia diffuses into the tubular lumen, where it reacts with secreted hydrogen ions to form NH4+, which is then excreted. For each NH4+ excreted, a new HCO3– is formed in the tubular cells and returned to the blood. membrane into the lumen, where it combines with NH3 to form NH4+, which is then excreted. The collecting ducts are permeable to NH3, which can easily diffuse into the tubular lumen. However, the luminal membrane of this part of the tubules is much less permeable to NH4+; therefore, once the H+ has reacted with NH3 to form NH4+, the NH4+ is trapped in the tubular lumen and eliminated in the urine. For each NH4+ excreted, a new HCO3- is generated and added to the blood. Chronic Acidosis Increases NH4+ Excretion. One of the most important features of the renal ammonium-ammonia buffer system is that it is subject to physiologic control. Quantifying Renal Acid-Base Excretion Based on the principles discussed earlier, we can quantitate the kidneys’ net excretion of acid or net addition or elimination of bicarbonate from the blood as follows. Bicarbonate excretion is calculated as the urine flow rate multiplied by urinary bicarbonate concentration. This number indicates how rapidly the kidneys are removing HCO3– from the blood (which is the same as adding an H+ to the blood). In alkalosis, the loss of HCO3– helps return the plasma pH toward normal. The amount of new bicarbonate contributed to the blood at any given time is equal to the amount of H+ secreted that ends up in the tubular lumen with nonbicarbonate urinary buffers. As discussed previously, the primary sources of nonbicarbonate urinary buffers are NH4+ and phosphate. Therefore, the amount of HCO3– added to the blood (and H+ excreted by NH4+) is calculated by measuring NH4+ excretion (urine flow rate multiplied by urinary NH4+ concentration). The rest of the nonbicarbonate, non-NH4+ buffer excreted in the urine is measured by determining a value known as titratable acid. The amount of titratable acid in the urine is measured by titrating the urine with a strong base, such as NaOH, to a pH of 7.4, the pH of normal plasma, and the pH of the glomerular filtrate. This titration reverses the events that occurred in the tubular lumen when the tubular fluid was titrated by excreted H+. Therefore, the number of milliequivalents of NaOH required to return the urinary pH to 7.4 equals the number of milliequivalents of H+ added to the tubular fluid that combined with phosphate and other organic buffers. The titratable acid measurement does not include H+ in association with NH4+, because the pK of the ammonia-ammonium reaction is 9.2, and titration with NaOH to a pH of 7.4 does not remove the H+ from NH4+. Thus, the net acid excretion by the kidneys can be assessed as Net acid excretion = NH4+ excretion + Urinary titratable acid – Bicarbonate excretion Chapter 30 395 Regulation of Acid-Base Balance The reason we subtract bicarbonate excretion is that the loss of HCO3– is the same as the addition of H+ to the blood. To maintain acid-base balance, the net acid excretion must equal the nonvolatile acid production in the body. In acidosis, the net acid excretion increases markedly, especially because of increased NH4+ excretion, thereby removing acid from the blood. The net acid excretion also equals the rate of net HCO3– addition to the blood. Therefore, in acidosis, there is a net addition of HCO3– back to the blood as more NH4+ and urinary titratable acid are excreted. In alkalosis, titratable acid and NH4+ excretion drop to 0, whereas HCO3– excretion increases. Therefore, in alkalosis, there is a negative net acid secretion. This means that there is a net loss of HCO3– from the blood (which is the same as adding H+ to the blood) and that no new HCO3– is generated by the kidneys. Regulation of Renal Tubular Hydrogen Ion Secretion As discussed earlier, H+ secretion by the tubular epithelium is necessary for both HCO3– reabsorption and generation of new HCO3– associated with titratable acid formation. Therefore, the rate of H+ secretion must be carefully regulated if the kidneys are to effectively perform their functions in acid-base homeostasis. Under normal conditions, the kidney tubules must secrete at least enough H+ to reabsorb almost all the HCO3– that is filtered, and there must be enough H+ left over to be excreted as titratable acid or NH4+ to rid the body of the nonvolatile acids produced each day from metabolism. In alkalosis, tubular secretion of H+ must be reduced to a level that is too low to achieve complete HCO3– reabsorption, enabling the kidneys to increase HCO3– excretion. In this condition, titratable acid and ammonia are not excreted because there is no excess H+ available to combine with nonbicarbonate buffers; therefore, there is no new HCO3– added to the urine in alkalosis. During acidosis, the tubular H+ secretion must be increased sufficiently to reabsorb all the filtered HCO3– and still have enough H+ left over to excrete large amounts of NH4+ and titratable acid, thereby contributing large amounts of new HCO3– to the total body extracellular fluid. The most important stimuli for increasing H+ secretion by the tubules in acidosis are (1) an increase in PCO2 of the extracellular fluid and (2) an increase in H+ concentration of the extracellular fluid (decreased pH). The tubular cells respond directly to an increase in PCO2 of the blood, as occurs in respiratory acidosis, with an increase in the rate of H+ secretion as follows: The increased PCO2 raises the PCO2 of the tubular cells, causing increased formation of H+ in the tubular cells, which in turn stimulates the secretion of H+. The second factor that stimulates H+ secretion is an increase in extracellular fluid H+ concentration (decreased pH). Table 30–2 Factors That Increase or Decrease H+ Secretion and HCO3Reabsorption by the Renal Tubules Increase H+ Secretion and HCO3– Reabsorption Decrease H+ Secretion and HCO3– Reabsorption ≠ PCO2 Ø PCO2 ≠ H+, Ø HCO3– Ø H+, ≠ HCO3– Ø Extracellular fluid volume ≠ Extracellular fluid volume ≠ Angiotensin II Ø Angiotensin II ≠ Aldosterone Ø Aldosterone Hypokalemia Hyperkalemia A special factor that can increase H+ secretion under some pathophysiologic conditions is excessive aldosterone secretion. Aldosterone stimulates the secretion of H+ by the intercalated cells of the collecting duct. Therefore, oversecretion of aldosterone, as occurs in Conn’s syndrome, can cause excessive secretion of H+ into the tubular fluid and, consequently, increased amounts of bicarbonate added back to the blood. This usually causes alkalosis in patients with excessive aldosterone secretion. The tubular cells usually respond to a decrease in H+ concentration (alkalosis) by reducing H+ secretion. The decreased H+ secretion results from decreased extracellular PCO2, as occurs in respiratory alkalosis, or from a decrease in H+ concentration per se, as occurs in both respiratory and metabolic alkalosis. Table 30–2 summarizes the major factors that influence H+ secretion and HCO3– reabsorption. Some of these are not directly related to the regulation of acidbase balance. For example, H+ secretion is coupled to Na+ reabsorption by the Na+-H+ exchanger in the proximal tubule and thick ascending loop of Henle. Therefore, factors that stimulate Na+ reabsorption, such as decreased extracellular fluid volume, may also secondarily increase H+ secretion. Extracellular fluid volume depletion stimulates sodium reabsorption by the renal tubules and increases H+ secretion and HCO3– reabsorption through multiple mechanisms, including (1) increased angiotensin II levels, which directly stimulate the activity of the Na+-H+ exchanger in the renal tubules, and (2) increased aldosterone levels, which stimulate H+ secretion by the intercalated cells of the cortical collecting tubules. Therefore, extracellular fluid volume depletion tends to cause alkalosis due to excess H+ secretion and HCO3– reabsorption. Changes in plasma potassium concentration can also influence H+ secretion, with hypokalemia stimulating and hyperkalemia inhibiting H+ secretion in the proximal tubule. A decreased plasma potassium concentration tends to increase the H+ concentration in the renal tubular cells. This, in turn, stimulates H+ secretion and HCO3– reabsorption and leads to alkalosis. Hyperkalemia decreases H+ secretion and HCO3– reabsorption and tends to cause acidosis. 396 Unit V The Body Fluids and Kidneys Renal Correction of Acidosis— Increased Excretion of Hydrogen Ions and Addition of Bicarbonate Ions to the Extracellular Fluid Now that we have described the mechanisms by which the kidneys secrete H+ and reabsorb HCO3–, we can explain how the kidneys readjust the pH of the extracellular fluid when it becomes abnormal. Referring to equation 8, the HendersonHasselbalch equation, we can see that acidosis occurs when the ratio of HCO3– to CO2 in the extracellular fluid decreases, thereby decreasing pH. If this ratio decreases because of a fall in HCO3–, the acidosis is referred to as metabolic acidosis. If the pH falls because of an increase in PCO2, the acidosis is referred to as respiratory acidosis. Acidosis Decreases the Ratio of HCO3-/H+ in Renal Tubular Fluid Both respiratory and metabolic acidosis cause a decrease in the ratio of HCO3– to H+ in the renal tubular fluid. As a result, there is an excess of H+ in the renal tubules, causing complete reabsorption of HCO3– and still leaving additional H+ available to combine with the urinary buffers NH4+ and HPO4=. Thus, in acidosis, the kidneys reabsorb all the filtered HCO3– and contribute new HCO3– through the formation of NH4+ and titratable acid. In metabolic acidosis, an excess of H + over HCO3– occurs in the tubular fluid primarily because of decreased filtration of HCO3-. This decreased filtration of HCO3– is caused mainly by a decrease in the extracellular fluid concentration of HCO3–. In respiratory acidosis, the excess H+ in the tubular fluid is due mainly to the rise in extracellular fluid PCO2, which stimulates H+ secretion. As discussed previously, with chronic acidosis, regardless of whether it is respiratory or metabolic, there is an increase in the production of NH4+, which further contributes to the excretion of H+ and the addition of new HCO3– to the extracellular fluid. With severe chronic acidosis, as much as 500 mEq/day of H+ can be excreted in the urine, mainly in the form of NH4+; this, in turn, contributes up to 500 mEq/day of new HCO3– that is added to the blood. Thus, with chronic acidosis, the increased secretion of H+ by the tubules helps eliminate excess H+ from the body and increases the quantity of HCO3– in the extracellular fluid. This increases the bicarbonate part of the bicarbonate buffer system, which, in accordance with the Henderson-Hasselbalch equation, helps raise the extracellular pH and corrects the acidosis. If the acidosis is metabolically mediated, additional compensation by the lungs causes a reduction in PCO2, also helping to correct the acidosis. Table 30–3 summarizes the characteristics associated with respiratory and metabolic acidosis as well as Table 30–3 Characteristics of Primary Acid-Base Disturbances pH H+ PCO2 HCO3– Normal 7.4 40 mEq/L 40 mm Hg 24 mEq/L Respiratory acidosis Ø ≠ ≠≠ ≠ Respiratory alkalosis ≠ Ø ØØ Ø Metabolic acidosis Ø ≠ Ø ØØ Metabolic alkalosis ≠ Ø ≠ ≠≠ The primary event is indicated by the double arrows (≠≠ or ØØ). Note that respiratory acid-base disorders are initiated by an increase or decrease in PCO2, whereas metabolic disorders are initiated by an increase or decrease in HCO3–. respiratory and metabolic alkalosis, which are discussed in the next section. Note that in respiratory acidosis, there is a reduction in pH, an increase in extracellular fluid H+ concentration, and an increase in PCO2, which is the initial cause of the acidosis. The compensatory response is an increase in plasma HCO3-, caused by the addition of new bicarbonate to the extracellular fluid by the kidneys. The rise in HCO3– helps offset the increase in PCO2, thereby returning the plasma pH toward normal. In metabolic acidosis, there is also a decrease in pH and a rise in extracellular fluid H+ concentration. However, in this case, the primary abnormality is a decrease in plasma HCO3–. The primary compensations include increased ventilation rate, which reduces PCO2 , and renal compensation, which, by adding new bicarbonate to the extracellular fluid, helps minimize the initial fall in extracellular HCO3- concentration. Renal Correction of Alkalosis—Decreased Tubular Secretion of Hydrogen Ions and Increased Excretion of Bicarbonate Ions The compensatory responses to alkalosis are basically opposite to those that occur in acidosis. In alkalosis, the ratio of HCO3– to CO2 in the extracellular fluid increases, causing a rise in pH (a decrease in H+ concentration), as is evident from the HendersonHasselbalch equation. Alkalosis Increases the Ratio of HCO3-/H+ in Renal Tubular Fluid Regardless of whether the alkalosis is caused by metabolic or respiratory abnormalities, there is still an increase in the ratio of HCO3– to H+ in the renal tubular fluid. The net effect of this is an excess of HCO3– that cannot be reabsorbed from the tubules and is, therefore, excreted in the urine. Thus, in alkalosis, HCO3– is removed from the extracellular fluid by Chapter 30 Regulation of Acid-Base Balance renal excretion, which has the same effect as adding an H+ to the extracellular fluid. This helps return the H+ concentration and pH back toward normal. Table 30–3 shows the overall characteristics of respiratory and metabolic alkalosis. In respiratory alkalosis, there is an increase in extracellular fluid pH and a decrease in H+ concentration. The cause of the alkalosis is a decrease in plasma PCO2 , caused by hyperventilation. The reduction in PCO2 then leads to a decrease in the rate of H+ secretion by the renal tubules. The decrease in H+ secretion reduces the amount of H+ in the renal tubular fluid. Consequently, there is not enough H+ to react with all the HCO3– that is filtered. Therefore, the HCO3– that cannot react with H+ is not reabsorbed and is excreted in the urine. This results in a decrease in plasma HCO3– concentration and correction of the alkalosis. Therefore, the compensatory response to a primary reduction in PCO2 in respiratory alkalosis is a reduction in plasma HCO3- concentration, caused by increased renal excretion of HCO3-. In metabolic alkalosis, there is also an increase in plasma pH and a decrease in H+ concentration. The cause of metabolic alkalosis, however, is a rise in the extracellular fluid HCO3– concentration. This is partly compensated for by a reduction in the respiration rate, which increases PCO2 and helps return the extracellular fluid pH toward normal. In addition, the increase in HCO3– concentration in the extracellular fluid leads to an increase in the filtered load of HCO3–, which in turn causes an excess of HCO3– over H+ secreted in the renal tubular fluid. The excess HCO3– in the tubular fluid fails to be reabsorbed because there is no H+ to react with, and it is excreted in the urine. In metabolic alkalosis, the primary compensations are decreased ventilation, which raises PCO2 , and increased renal HCO3- excretion, which helps compensate for the initial rise in extracellular fluid HCO3concentration. Clinical Causes of Acid-Base Disorders Respiratory Acidosis Is Caused by Decreased Ventilation and Increased PCO2 From the previous discussion, it is obvious that any factor that decreases the rate of pulmonary ventilation also increases the PCO2 of extracellular fluid. This causes an increase in H2CO3 and H+ concentration, thus resulting in acidosis. Because the acidosis is caused by an abnormality in respiration, it is called respiratory acidosis. Respiratory acidosis can occur from pathological conditions that damage the respiratory centers or that decrease the ability of the lungs to eliminate CO2. For example, damage to the respiratory center in the medulla oblongata can lead to respiratory acidosis.Also, obstruction of the passageways of the respiratory tract, pneumonia, emphysema, or decreased pulmonary membrane surface area, as well as any factor that interferes with the exchange of gases between the blood and the alveolar air, can cause respiratory acidosis. 397 In respiratory acidosis, the compensatory responses available are (1) the buffers of the body fluids and (2) the kidneys, which require several days to compensate for the disorder. Respiratory Alkalosis Results from Increased Ventilation and Decreased PCO2 Respiratory alkalosis is caused by overventilation by the lungs. Rarely does this occur because of physical pathological conditions. However, a psychoneurosis can occasionally cause overbreathing to the extent that a person becomes alkalotic. A physiologic type of respiratory alkalosis occurs when a person ascends to high altitude. The low oxygen content of the air stimulates respiration, which causes excess loss of CO2 and development of mild respiratory alkalosis. Again, the major means for compensation are the chemical buffers of the body fluids and the ability of the kidneys to increase HCO3– excretion. Metabolic Acidosis Results from Decreased Extracellular Fluid Bicarbonate Concentration The term metabolic acidosis refers to all other types of acidosis besides those caused by excess CO2 in the body fluids. Metabolic acidosis can result from several general causes: (1) failure of the kidneys to excrete metabolic acids normally formed in the body, (2) formation of excess quantities of metabolic acids in the body, (3) addition of metabolic acids to the body by ingestion or infusion of acids, and (4) loss of base from the body fluids, which has the same effect as adding an acid to the body fluids. Some specific conditions that cause metabolic acidosis are the following. Renal Tubular Acidosis. This type of acidosis results from a defect in renal secretion of H+ or in reabsorption of HCO3–, or both. These disorders are generally of two types: (1) impairment of renal tubular HCO3– reabsorption, causing loss of HCO3– in the urine, or (2) inability of the renal tubular H+ secretory mechanism to establish a normal acidic urine, causing the excretion of an alkaline urine. In these cases, inadequate amounts of titratable acid and NH4+ are excreted, so that there is net accumulation of acid in the body fluids. Some causes of renal tubular acidosis include chronic renal failure, insufficient aldosterone secretion (Addison’s disease), and several hereditary and acquired disorders that impair tubular function, such as Fanconi’s syndrome. Diarrhea. Severe diarrhea is probably the most frequent cause of metabolic acidosis. The cause of this acidosis is the loss of large amounts of sodium bicarbonate into the feces. The gastrointestinal secretions normally contain large amounts of bicarbonate, and diarrhea results in the loss of HCO3– from the body, which has the same effect as losing large amounts of bicarbonate in the urine. This form of metabolic acidosis is particularly serious and can cause death, especially in young children. Vomiting of Intestinal Contents. Vomiting of gastric contents alone would cause loss of acid and a tendency 398 Unit V The Body Fluids and Kidneys toward alkalosis because the stomach secretions are highly acidic. However, vomiting large amounts from deeper in the gastrointestinal tract, which sometimes occurs, causes loss of bicarbonate and results in metabolic acidosis in the same way that diarrhea causes acidosis. Diabetes Mellitus. Diabetes mellitus is caused by lack of insulin secretion by the pancreas (type I diabetes) or by insufficient insulin secretion to compensate for decreased sensitivity to the effects of insulin (type II diabetes). In the absence of sufficient insulin, the normal use of glucose for metabolism is prevented. Instead, some of the fats are split into acetoacetic acid, and this is metabolized by the tissues for energy in place of glucose.With severe diabetes mellitus, blood acetoacetic acid levels can rise very high, causing severe metabolic acidosis. In an attempt to compensate for this acidosis, large amounts of acid are excreted in the urine, sometimes as much as 500 mmol/day. Ingestion of Acids. Rarely are large amounts of acids ingested in normal foods. However, severe metabolic acidosis occasionally results from the ingestion of certain acidic poisons. Some of these include acetylsalicylics (aspirin) and methyl alcohol (which forms formic acid when it is metabolized). Chronic Renal Failure. When kidney function declines markedly, there is a buildup of the anions of weak acids in the body fluids that are not being excreted by the kidneys. In addition, the decreased glomerular filtration rate reduces the excretion of phosphates and NH4+, which reduces the amount of bicarbonate added back to the body fluids. Thus, chronic renal failure can be associated with severe metabolic acidosis. Metabolic Alkalosis Is Caused by Increased Extracellular Fluid Bicarbonate Concentration When there is excess retention of HCO3– or loss of H+ from the body, this results in metabolic alkalosis. Metabolic alkalosis is not nearly as common as metabolic acidosis, but some of the causes of metabolic alkalosis are as follows. Administration of Diuretics (Except the Carbonic Anhydrase Inhibitors). All diuretics cause increased flow of fluid along the tubules, usually causing increased flow in the distal and collecting tubules. This leads to increased reabsorption of Na+ from these parts of the nephrons. Because the sodium reabsorption here is coupled with H+ secretion, the enhanced sodium reabsorption also leads to an increase in H+ secretion and an increase in bicarbonate reabsorption. These changes lead to the development of alkalosis, characterized by increased extracellular fluid bicarbonate concentration. Excess Aldosterone. When large amounts of aldosterone are secreted by the adrenal glands, a mild metabolic alkalosis develops. As discussed previously, aldosterone promotes extensive reabsorption of Na+ from the distal and collecting tubules and at the same time stimulates the secretion of H+ by the intercalated cells of the collecting tubules. This increased secretion of H+ leads to its increased excretion by the kidneys and, therefore, metabolic alkalosis. Vomiting of Gastric Contents. Vomiting of the gastric con- tents alone, without vomiting of the lower gastrointestinal contents, causes loss of the HCl secreted by the stomach mucosa. The net result is a loss of acid from the extracellular fluid and development of metabolic alkalosis. This type of alkalosis occurs especially in neonates who have pyloric obstruction caused by hypertrophied pyloric sphincter muscles. Ingestion of Alkaline Drugs. A common cause of metabolic alkalosis is ingestion of alkaline drugs, such as sodium bicarbonate, for the treatment of gastritis or peptic ulcer. Treatment of Acidosis or Alkalosis The best treatment for acidosis or alkalosis is to correct the condition that caused the abnormality. This is often difficult, especially in chronic diseases that cause impaired lung function or kidney failure. In these circumstances, various agents can be used to neutralize the excess acid or base in the extracellular fluid. To neutralize excess acid, large amounts of sodium bicarbonate can be ingested by mouth. The sodium bicarbonate is absorbed from the gastrointestinal tract into the blood and increases the bicarbonate portion of the bicarbonate buffer system, thereby increasing pH toward normal. Sodium bicarbonate can also be infused intravenously, but because of the potentially dangerous physiologic effects of such treatment, other substances are often used instead, such as sodium lactate and sodium gluconate. The lactate and gluconate portions of the molecules are metabolized in the body, leaving the sodium in the extracellular fluid in the form of sodium bicarbonate and thereby increasing the pH of the fluid toward normal. For the treatment of alkalosis, ammonium chloride can be administered by mouth. When the ammonium chloride is absorbed into the blood, the ammonia portion is converted by the liver into urea. This reaction liberates HCl, which immediately reacts with the buffers of the body fluids to shift the H+ concentration in the acidic direction. Ammonium chloride occasionally is infused intravenously, but NH4+ is highly toxic, and this procedure can be dangerous. Another substance used occasionally is lysine monohydrochloride. Clinical Measurements and Analysis of Acid-Base Disorders Appropriate therapy of acid-base disorders requires proper diagnosis. The simple acid-base disorders described previously can be diagnosed by analyzing three measurements from an arterial blood sample: pH, plasma bicarbonate concentration, and PCO2. The diagnosis of simple acid-base disorders involves several steps, as shown in Figure 30–10. By examining the pH, one can determine whether the disorder is acidosis or alkalosis. A pH less than 7.4 indicates acidosis, whereas a pH greater than 7.4 indicates alkalosis. Chapter 30 Regulation of Acid-Base Balance Complex Acid-Base Disorders and Use of the Acid-Base Nomogram for Diagnosis Arterial blood sample <7.4 pH? >7.4 Acidosis - HCO3 <24 mEq/L Pco2 >40 mm Hg Alkalosis - HCO3 >24 mEq/L Pco2 <40 mm Hg Respiratory Metabolic Respiratory Respiratory compensation Renal compensation Respiratory compensation Renal compensation Pco2 <40 mm Hg HCO3>24 mEq/L Pco2 >40 mm Hg HCO3<24 mEq/L Metabolic 399 Figure 30–10 Analysis of simple acid-base disorders. If the compensatory responses are markedly different from those shown at the bottom of the figure, one should suspect a mixed acid-base disorder. The second step is to examine the plasma PCO2 and HCO3– concentration. The normal value for PCO2 is about 40 mm Hg, and for HCO3–, it is 24 mEq/L. If the disorder has been characterized as acidosis and the plasma PCO2 is increased, there must be a respiratory component to the acidosis. After renal compensation, the plasma HCO3– concentration in respiratory acidosis would tend to increase above normal. Therefore, the expected values for a simple respiratory acidosis would be reduced plasma pH, increased PCO2 , and increased plasma HCO3– concentration after partial renal compensation. For metabolic acidosis, there would also be a decrease in plasma pH. However, with metabolic acidosis, the primary abnormality is a decrease in plasma HCO3– concentration. Therefore, if a low pH is associated with a low HCO3– concentration, there must be a metabolic component to the acidosis. In simple metabolic acidosis, the PCO2 is reduced because of partial respiratory compensation, in contrast to respiratory acidosis, in which PCO2 is increased. Therefore, in simple metabolic acidosis, one would expect to find a low pH, a low plasma HCO3- concentration, and a reduction in PCO2 after partial respiratory compensation. The procedures for categorizing the types of alkalosis involve the same basic steps. First, alkalosis implies that there is an increase in plasma pH. If the increase in pH is associated with decreased PCO2, there must be a respiratory component to the alkalosis. If the rise in pH is associated with increased HCO3–, there must be a metabolic component to the alkalosis. Therefore, in simple respiratory alkalosis, one would expect to find increased pH, decreased PCO2 , and decreased HCO3concentration in the plasma. In simple metabolic alkalosis, one would expect to find increased pH, increased plasma HCO3-, and increased PCO2. In some instances, acid-base disorders are not accompanied by appropriate compensatory responses. When this occurs, the abnormality is referred to as a mixed acid-base disorder. This means that there are two or more underlying causes for the acid-base disturbance. For example, a patient with low pH would be categorized as acidotic. If the disorder was metabolically mediated, this would also be accompanied by a low plasma HCO3– concentration and, after appropriate respiratory compensation, a low PCO2. However, if the low plasma pH and low HCO3– concentration are associated with elevated PCO2, one would suspect a respiratory component to the acidosis as well as a metabolic component. Therefore, this disorder would be categorized as a mixed acidosis. This could occur, for example, in a patient with acute HCO3– loss from the gastrointestinal tract because of diarrhea (metabolic acidosis) who also has emphysema (respiratory acidosis). A convenient way to diagnose acid-base disorders is to use an acid-base nomogram, as shown in Figure 30–11. This diagram can be used to determine the type of acidosis or alkalosis, as well as its severity. In this acid-base diagram, pH, HCO3– concentration, and PCO2 values intersect according to the Henderson-Hasselbalch equation. The central open circle shows normal values and the deviations that can still be considered within the normal range. The shaded areas of the diagram show the 95 per cent confidence limits for the normal compensations to simple metabolic and respiratory disorders. When using this diagram, one must assume that sufficient time has elapsed for a full compensatory response, which is 6 to 12 hours for the ventilatory compensations in primary metabolic disorders and 3 to 5 days for the metabolic compensations in primary respiratory disorders. If a value is within the shaded area, this suggests that there is a simple acid-base disturbance. Conversely, if the values for pH, bicarbonate, or PCO2 lie outside the shaded area, this suggests that there may be a mixed acid-base disorder. It is important to recognize that an acid-base value within the shaded area does not always mean that there is a simple acid-base disorder. With this reservation in mind, the acid-base diagrams can be used as a quick means of determining the specific type and severity of an acid-base disorder. For example, assume that the arterial plasma from a patient yields the following values: pH 7.30, plasma HCO3– concentration 12.0 mEq/L, and plasma PCO2 25 mm Hg. With these values, one can look at the diagram and find that this represents a simple metabolic acidosis, with appropriate respiratory compensation that reduces the PCO2 from its normal value of 40 mm Hg to 25 mm Hg. A second example would be a patient with the following values: pH 7.15, plasma HCO3– concentration 7 mEq/L, and plasma PCO2 50 mm Hg. In this example, the patient is acidotic, and there appears to be a metabolic component because the plasma HCO3– concentration is lower than the normal value of 24 mEq/L. However, the respiratory compensation that would normally reduce PCO2 is absent, and PCO2 is slightly increased above the normal value of 40 mm Hg. This is 400 Unit V 60 The Body Fluids and Kidneys 120 100 90 80 70 110 56 60 50 Arterial plasma [HCO3-] (mEq/L) 52 48 35 Pco2 (mm Hg) 44 32 Metabolic alkalosis Chronic respiratory acidosis 40 36 Acute respiratory acidosis 30 25 20 28 Normal 24 20 16 Acute respiratory alkalosis 15 10 12 Metabolic acidosis 8 4 0 7.00 40 7.10 7.20 Chronic respiratory alkalosis 7.30 7.40 7.50 Arterial blood pH consistent with a mixed acid-base disturbance consisting of metabolic acidosis as well as a respiratory component. The acid-base diagram serves as a quick way to assess the type and severity of disorders that may be contributing to abnormal pH, PCO2 , and plasma bicarbonate concentrations. In a clinical setting, the patient’s history and other physical findings also provide important clues concerning causes and treatment of the acidbase disorders. Use of Anion Gap to Diagnose Acid-Base Disorders The concentrations of anions and cations in plasma must be equal to maintain electrical neutrality. Therefore, there is no real “anion gap” in the plasma. However, only certain cations and anions are routinely measured in the clinical laboratory. The cation normally measured is Na+, and the anions are usually Cl– and HCO3–. The “anion gap” (which is only a diagnostic concept) is the difference between unmeasured anions and unmeasured cations, and is estimated as Plasma anion gap = [Na+] – [HCO3–] – [Cl–] = 144 – 24 – 108 = 10 mEq/L The anion gap will increase if unmeasured anions rise or if unmeasured cations fall. The most important unmeasured cations include calcium, magnesium, and potassium, and the major unmeasured anions are albumin, phosphate, sulfate, and other organic anions. Usually the unmeasured anions exceed the unmeasured cations, and the anion gap ranges between 8 and 16 mEq/L. The plasma anion gap is used mainly in diagnosing different causes of metabolic acidosis. In metabolic aci- Pco2 (mm Hg) 7.60 7.70 7.80 Figure 30–11 Acid-base nomogram showing arterial blood pH, arterial plasma HCO3–, and PCO2 values. The central open circle shows the approximate limits for acid-base status in normal people. The shaded areas in the nomogram show the approximate limits for the normal compensations caused by simple metabolic and respiratory disorders. For values lying outside the shaded areas, one should suspect a mixed acidbase disorder. (Adapted from Cogan MG, Rector FC Jr: AcidBase Disorders in the Kidney, 3rd ed. Philadelphia: WB Saunders, 1986.) Table 30–4 Metabolic Acidosis Associated with Normal or Increased Plasma Anion Gap Increased Anion Gap (Normochloremia) Normal Anion Gap (Hyperchloremia) Diabetes mellitus (ketoacidosis) Lactic acidosis Chronic renal failure Aspirin (acetylsalicylic acid) poisoning Methanol poisoning Ethylene glycol poisoning Starvation Diarrhea Renal tubular acidosis Carbonic anhydrase inhibitors Addison’s disease dosis, the plasma HCO3– is reduced. If the plasma sodium concentration is unchanged, the concentration of anions (either Cl– or an unmeasured anion) must increase to maintain electroneutrality. If plasma Cl– increases in proportion to the fall in plasma HCO3–, the anion gap will remain normal, and this is often referred to as hyperchloremic metabolic acidosis. If the decrease in plasma HCO3– is not accompanied by increased Cl–, there must be increased levels of unmeasured anions and therefore an increase in the calculated anion gap. Metabolic acidosis caused by excess nonvolatile acids (besides HCl), such as lactic acid or ketoacids, is associated with an increased plasma anion gap because the fall in HCO3– is not matched by an equal increase in Cl–. Some examples of metabolic acidosis associated with a normal or increased anion gap are shown in Table 30–4. By calculating the anion gap, one can narrow some of the potential causes of metabolic acidosis. Chapter 30 Regulation of Acid-Base Balance References Alpern RJ: Renal acidification mechanisms. In Brenner BM (ed): The Kidney, 6th ed. Philadelphia: WB Saunders, 2000, pp 455-519. Capasso G, Unwin R, Rizzo M, et al: Bicarbonate transport along the loop of Henle: molecular mechanisms and regulation. J Nephrol 15(Suppl 5):S88, 2002. Decoursey TE: Voltage-gated proton channels and other proton transfer pathways. Physiol Rev 83:475, 2003. Gennari FJ, Maddox DA: Renal regulation of acid-base homeostasis. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 2015-2054. Good DW: Ammonium transport by the thick ascending limb of Henle’s loop. Ann Rev Physiol 56:623, 1994. Igarashi I, Sekine T, Inatomi J, Seki G: Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis. J Am Soc Nephrol 13:2171, 2002. 401 Karet FE: Inherited distal renal tubular acidosis. J Am Soc Nephrol 13:2178, 2002. Laffey JG, Kavanagh BP: Hypocapnia. N Engl J Med 347:43, 2002. Lemann J Jr, Bushinsky DA, Hamm LL: Bone buffering of acid and base in humans. Am J Physiol Renal Physiol 285:F811, 2003. Madias NE, Adrogue HJ: Cross-talk between two organs: how the kidney responds to disruption of acid-base balance by the lung. Nephron Physiol 93:61, 2003. Wagner CA, Geibel JP: Acid-base transport in the collecting duct. J Nephrol 15(Suppl 5):S112, 2002. Wesson DE, Alpern RJ, Seldin DW: Clinical syndromes of metabolic alkalosis. In Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 2055-2072. White NH: Management of diabetic ketoacidosis. Rev Endocr Metab Disord 4:343, 2003. C H A P T E R 3 Kidney Diseases and Diuretics Diuretics and Their Mechanisms of Action A diuretic is a substance that increases the rate of urine volume output, as the name implies. Most diuretics also increase urinary excretion of solutes, especially sodium and chloride. In fact, most diuretics that are used clinically act by decreasing the rate of sodium reabsorption from the tubules, which causes natriuresis (increased sodium output), which in turn causes diuresis (increased water output). That is, in most cases, increased water output occurs secondary to inhibition of tubular sodium reabsorption, because sodium remaining in the tubules acts osmotically to decrease water reabsorption. Because the renal tubular reabsorption of many solutes, such as potassium, chloride, magnesium, and calcium, is also influenced secondarily by sodium reabsorption, many diuretics raise renal output of these solutes as well. The most common clinical use of diuretics is to reduce extracellular fluid volume, especially in diseases associated with edema and hypertension. As discussed in Chapter 25, loss of sodium from the body mainly decreases extracellular fluid volume; therefore, diuretics are most often administered in clinical conditions in which extracellular fluid volume is expanded. Some diuretics can increase urine output more than 20-fold within a few minutes after they are administered. However, the effect of most diuretics on renal output of salt and water subsides within a few days (Figure 31–1). This is due to activation of other compensatory mechanisms initiated by decreased extracellular fluid volume. For example, a decrease in extracellular fluid volume often reduces arterial pressure and glomerular filtration rate (GFR) and increases renin secretion and angiotensin II formation; all these responses, together, eventually override the chronic effects of the diuretic on urine output. Thus, in the steady state, urine output becomes equal to intake, but only after reductions in arterial pressure and extracellular fluid volume have occurred, relieving the hypertension or edema that prompted the use of diuretics in the first place. The many diuretics available for clinical use have different mechanisms of action and, therefore, inhibit tubular reabsorption at different sites along the renal nephron. The general classes of diuretics and their mechanisms of action are shown in Table 31–1. Osmotic Diuretics Decrease Water Reabsorption by Increasing Osmotic Pressure of Tubular Fluid Injection into the blood stream of substances that are not easily reabsorbed by the renal tubules, such as urea, mannitol, and sucrose, causes a marked increase in the concentration of osmotically active molecules in the tubules. The osmotic pressure of these solutes then greatly reduces water reabsorption, flushing large amounts of tubular fluid into the urine. Large volumes of urine are also formed in certain diseases associated with excess solutes that fail to be reabsorbed from the tubular fluid. For example, when the blood glucose concentration rises to high levels in diabetes mellitus, the increased filtered load of glucose into the tubules exceeds their capacity to reabsorb glucose (i.e., exceeds their transport maximum for glucose). Above a plasma glucose concentration of about 250 mg/dl, little of the extra glucose is reabsorbed by the tubules; instead, the excess glucose remains in the tubules, acts as an osmotic diuretic, and causes rapid loss of fluid into the urine. In patients with diabetes mellitus, the high 402 1 Chapter 31 403 Kidney Diseases and Diuretics urine output is balanced by a high level of fluid intake owing to activation of the thirst mechanism. Extracellular fluid volume (liters) Sodium excretion or sodium intake (mEq/day) Diuretic therapy 200 “Loop” Diuretics Decrease Active Sodium-Chloride-Potassium Reabsorption in the Thick Ascending Loop of Henle Excretion 100 Intake 15.0 14.0 13.0 -4 -2 0 2 4 Time (days) 6 8 Figure 31–1 Sodium excretion and extracellular fluid volume during diuretic administration. The immediate increase in sodium excretion is accompanied by a decrease in extracellular fluid volume. If sodium intake is held constant, compensatory mechanisms will eventually return sodium excretion to equal sodium intake, thus re-establishing sodium balance. Furosemide, ethacrynic acid, and bumetanide are powerful diuretics that decrease active reabsorption in the thick ascending limb of the loop of Henle by blocking the 1-sodium, 2-chloride, 1-potassium co-transporter located in the luminal membrane of the epithelial cells. These diuretics are among the most powerful of the clinically used diuretics. By blocking active sodium-chloride-potassium cotransport in the luminal membrane of the loop of Henle, the loop diuretics raise urine output of sodium, chloride, potassium, and other electrolytes, as well as water, for two reasons: (1) they greatly increase the quantities of solutes delivered to the distal parts of the nephrons, and these act as osmotic agents to prevent water reabsorption as well; and (2) they disrupt the countercurrent multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid. Because of this effect, loop diuretics impair the ability of the kidneys to either concentrate or dilute the urine. Urinary dilution is impaired because the inhibition of sodium and chloride reabsorption in the loop of Henle causes more of these ions to be excreted along with increased water excretion. Urinary concentration is impaired because the renal medullary interstitial fluid concentration of these ions, and therefore renal medullary osmolarity, is reduced. Consequently, reabsorption of fluid from the collecting ducts is decreased, so that the maximal concentrating ability of the kidneys is also greatly reduced. In addition, decreased renal medullary interstitial fluid osmolarity reduces absorption of water from the descending loop of Henle. Because of these multiple effects, 20 to 30 per cent of the glomerular filtrate may be delivered into the urine, causing, under acute conditions, urine output to be as great as 25 times normal for at least a few minutes. Table 31–1 Classes of Diuretics, Their Mechanisms of Action, and Tubular Sites of Action Class of Diuretic Mechanism of Action Tubular Site of Action Osmotic diuretics (mannitol) Inhibit water and solute reabsorption by increasing osmolarity of tubular fluid Inhibit Na+-K+-Cl- co-transport in luminal membrane Inhibit Na+-Cl- co-transport in luminal membrane Mainly proximal tubules Inhibit H+ secretion and HCO3– reabsorption, which reduces Na+ reabsorption Inhibit action of aldosterone on tubular receptor, decrease Na+ reabsorption, and decrease K+ secretion Block entry of Na+ into Na+ channels of luminal membrane, decrease Na+ reabsorption, and decrease K+ secretion Proximal tubules Loop diuretics (furosemide, bumetanide) Thiazide diuretics (hydrochlorothiazide, chlorthalidone) Carbonic anhydrase inhibitors (acetazolamide) Aldosterone antagonists (spironolactone, eplerenone) Sodium channel blockers (triamterene, amiloride) Thick ascending loop of Henle Early distal tubules Collecting tubules Collecting tubules 404 Unit V The Body Fluids and Kidneys Thiazide Diuretics Inhibit SodiumChloride Reabsorption in the Early Distal Tubule Diuretics That Block Sodium Channels in the Collecting Tubules Decrease Sodium Reabsorption The thiazide derivatives, such as chlorothiazide, act mainly on the early distal tubules to block the sodiumchloride co-transporter in the luminal membrane of the tubular cells. Under favorable conditions, these agents cause 5 to 10 per cent of the glomerular filtrate to pass into the urine. This is about the same amount of sodium normally reabsorbed by the distal tubules. Amiloride and triamterene also inhibit sodium reabsorption and potassium secretion in the collecting tubules, similar to the effects of spironolactone. However, at the cellular level, these drugs act directly to block the entry of sodium into the sodium channels of the luminal membrane of the collecting tubule epithelial cells. Because of this decreased sodium entry into the epithelial cells, there is also decreased sodium transport across the cells’ basolateral membranes and, therefore, decreased activity of the sodium-potassiumadenosine triphosphatase pump. This decreased activity reduces the transport of potassium into the cells and ultimately decreases the secretion of potassium into the tubular fluid. For this reason, the sodium channel blockers are also potassium-sparing diuretics and decrease the urinary excretion rate of potassium. Carbonic Anhydrase Inhibitors Block Sodium-Bicarbonate Reabsorption in the Proximal Tubules Acetazolamide inhibits the enzyme carbonic anhydrase, which is critical for the reabsorption of bicarbonate in the proximal tubule, as discussed in Chapter 30. Carbonic anhydrase is abundant in the proximal tubule, the primary site of action of carbonic anhydrase inhibitors. Some carbonic anhydrase is also present in other tubular cells, such as in the intercalated cells of the collecting tubule. Because hydrogen ion secretion and bicarbonate reabsorption in the proximal tubules are coupled to sodium reabsorption through the sodium-hydrogen ion counter-transport mechanism in the luminal membrane, decreasing bicarbonate reabsorption also reduces sodium reabsorption. The blockage of sodium and bicarbonate reabsorption from the tubular fluid causes these ions to remain in the tubules and act as an osmotic diuretic. Predictably, a disadvantage of the carbonic anhydrase inhibitors is that they cause some degree of acidosis because of the excessive loss of bicarbonate ions in the urine. Competitive Inhibitors of Aldosterone Decrease Sodium Reabsorption from and Potassium Secretion into the Cortical Collecting Tubule Spironolactone and eplerenone are aldosterone antagonists that compete with aldosterone for receptor sites in the cortical collecting tubule epithelial cells and, therefore, can decrease the reabsorption of sodium and secretion of potassium in this tubular segment.As a consequence, sodium remains in the tubules and acts as an osmotic diuretic, causing increased excretion of water as well as sodium. Because these drugs also block the effect of aldosterone to promote potassium secretion in the tubules, they decrease the excretion of potassium. Aldosterone antagonists also cause movement of potassium from the cells to the extracellular fluid. In some instances, this causes extracellular fluid potassium concentration to increase excessively. For this reason, spironolactone and other aldosterone inhibitors are referred to as potassium-sparing diuretics. Many of the other diuretics cause loss of potassium in the urine, in contrast to the aldosterone antagonists, which “spare” the loss of potassium. Kidney Diseases Diseases of the kidneys are among the most important causes of death and disability in many countries throughout the world. For example, in 2004, more than 20 million adults in the United States were estimated to have chronic kidney disease. Severe kidney diseases can be divided into two main categories: (1) acute renal failure, in which the kidneys abruptly stop working entirely or almost entirely but may eventually recover nearly normal function, and (2) chronic renal failure, in which there is progressive loss of function of more and more nephrons that gradually decreases overall kidney function. Within these two general categories, there are many specific kidney diseases that can affect the kidney blood vessels, glomeruli, tubules, renal interstitium, and parts of the urinary tract outside the kidney, including the ureters and bladder. In this chapter, we discuss specific physiologic abnormalities that occur in a few of the more important types of kidney diseases. Acute Renal Failure The causes of acute renal failure can be divided into three main categories: 1. Acute renal failure resulting from decreased blood supply to the kidneys; this condition is often referred to as prerenal acute renal failure to reflect the fact that the abnormality occurs in a system before the kidneys. This can be a consequence of heart failure with reduced cardiac output and low blood pressure or conditions associated with diminished blood volume and low blood pressure, such as severe hemorrhage. 2. Intrarenal acute renal failure resulting from abnormalities within the kidney itself, including those that affect the blood vessels, glomeruli, or tubules. 3. Postrenal acute renal failure, resulting from obstruction of the urinary collecting system Chapter 31 Kidney Diseases and Diuretics anywhere from the calyces to the outflow from the bladder. The most common causes of obstruction of the urinary tract outside the kidney are kidney stones, caused by precipitation of calcium, urate, or cystine. Prerenal Acute Renal Failure Caused by Decreased Blood Flow to the Kidney The kidneys normally receive an abundant blood supply of about 1100 ml/min, or about 20 to 25 per cent of the cardiac output.The main purpose of this high blood flow to the kidneys is to provide enough plasma for the high rates of glomerular filtration needed for effective regulation of body fluid volumes and solute concentrations. Therefore, decreased renal blood flow is usually accompanied by decreased GFR and decreased urine output of water and solutes. Consequently, conditions that acutely diminish blood flow to the kidneys usually cause oliguria, which refers to diminished urine output below the level of intake of water and solutes.This causes accumulation of water and solutes in the body fluids. If renal blood flow is markedly reduced, total cessation of urine output can occur, a condition referred to as anuria. As long as renal blood flow does not fall below about 20 to 25 per cent of normal, acute renal failure can usually be reversed if the cause of the ischemia is corrected before damage to the renal cells has occurred. Unlike some tissues, the kidney can endure a relatively large reduction in blood flow before actual damage to the renal cells occurs. The reason for this is that as renal blood flow is reduced, the GFR and the amount of sodium chloride filtered by the glomeruli (as well as the filtration rate of water and other electrolytes) are reduced. This decreases the amount of sodium chloride that must be reabsorbed by the tubules, which uses most of the energy and oxygen consumed by the normal kidney. Therefore, as renal blood flow and GFR fall, the requirement for renal oxygen consumption is also reduced. As the GFR approaches zero, oxygen consumption of the kidney approaches the rate that is required to keep the renal tubular cells alive even when they are not reabsorbing sodium. When blood flow is reduced below this basal requirement, which is usually less than 20 to 25 per cent of the normal renal blood flow, the renal cells start to become hypoxic, and further decreases in renal blood flow, if prolonged, will cause damage or even death of the renal cells, especially the tubular epithelial cells. If the cause of prerenal acute renal failure is not corrected and ischemia of the kidney persists longer than a few hours, this type of renal failure can evolve into intrarenal acute renal failure, as discussed later. Acute reduction of renal blood flow is a common cause of acute renal failure in hospitalized patients. Table 31–2 shows some of the common causes of decreased renal blood flow and prerenal acute renal failure. Intrarenal Acute Renal Failure Caused by Abnormalities Within the Kidney Abnormalities that originate within the kidney and that abruptly diminish urine output fall into the general category of intrarenal acute renal failure. This category of 405 Table 31–2 Some Causes of Prerenal Acute Renal Failure Intravascular volume depletion Hemorrhage (trauma, surgery, postpartum, gastrointestinal) Diarrhea or vomiting Burns Cardiac failure Myocardial infarction Valvular damage Peripheral vasodilation and resultant hypotension Anaphylactic shock Anesthesia Sepsis, severe infections Primary renal hemodynamic abnormalities Renal artery stenosis, embolism, or thrombosis of renal artery or vein Table 31–3 Some Causes of Intrarenal Acute Renal Failure Small vessel and/or glomerular injury Vasculitis (polyarteritis nodosa) Cholesterol emboli Malignant hypertension Acute glomerulonephritis Tubular epithelial injury (tubular necrosis) Acute tubular necrosis due to ischemia Acute tubular necrosis due to toxins (heavy metals, ethylene glycol, insecticides, poison mushrooms, carbon tetrachloride) Renal interstitial injury Acute pyelonephritis Acute allergic interstitial nephritis acute renal failure can be further divided into (1) conditions that injure the glomerular capillaries or other small renal vessels, (2) conditions that damage the renal tubular epithelium, and (3) conditions that cause damage to the renal interstitium. This type of classification refers to the primary site of injury, but because the renal vasculature and tubular system are functionally interdependent, damage to the renal blood vessels can lead to tubular damage, and primary tubular damage can lead to damage of the renal blood vessels. Causes of intrarenal acute renal failure are listed in Table 31–3. Acute Renal Failure Caused by Glomerulonephritis. Acute glomerulonephritis is a type of intrarenal acute renal failure usually caused by an abnormal immune reaction that damages the glomeruli. In about 95 per cent of the patients with this disease, damage to the glomeruli occurs 1 to 3 weeks after an infection elsewhere in the body, usually caused by certain types of group A beta streptococci. The infection may have been a streptococcal sore throat, streptococcal tonsillitis, or even streptococcal infection of the skin. It is not the infection itself that damages the kidneys. Instead, over a few weeks, as antibodies develop against the streptococcal antigen, the antibodies and antigen react with each other to form an insoluble immune complex that becomes entrapped in the glomeruli, especially in the basement membrane portion of the glomeruli. Once the immune complex has deposited in the glomeruli, many of the cells of the glomeruli begin to proliferate, but mainly the mesangial cells that lie 406 Unit V The Body Fluids and Kidneys between the endothelium and the epithelium. In addition, large numbers of white blood cells become entrapped in the glomeruli. Many of the glomeruli become blocked by this inflammatory reaction, and those that are not blocked usually become excessively permeable, allowing both protein and red blood cells to leak from the blood of the glomerular capillaries into the glomerular filtrate. In severe cases, either total or almost complete renal shutdown occurs. The acute inflammation of the glomeruli usually subsides in about 2 weeks, and in most patients, the kidneys return to almost normal function within the next few weeks to few months. Sometimes, however, many of the glomeruli are destroyed beyond repair, and in a small percentage of patients, progressive renal deterioration continues indefinitely, leading to chronic renal failure, as described in a subsequent section of this chapter. acute renal failure even when the kidneys’ blood supply and other functions are initially normal. If the urine output of only one kidney is diminished, no major change in body fluid composition will occur because the contralateral kidney can increase its urine output sufficiently to maintain relatively normal levels of extracellular electrolytes and solutes as well as normal extracellular fluid volume. With this type of renal failure, normal kidney function can be restored if the basic cause of the problem is corrected within a few hours. But chronic obstruction of the urinary tract, lasting for several days or weeks, can lead to irreversible kidney damage. Some of the causes of postrenal acute failure include (1) bilateral obstruction of the ureters or renal pelvises caused by large stones or blood clots, (2) bladder obstruction, and (3) obstruction of the urethra. Tubular Necrosis as a Cause of Acute Renal Failure. Another cause of intrarenal acute renal failure is tubular necrosis, which means destruction of epithelial cells in the tubules. Some common causes of tubular necrosis are (1) severe ischemia and inadequate supply of oxygen and nutrients to the tubular epithelial cells and (2) poisons, toxins, or medications that destroy the tubular epithelial cells. Acute Tubular Necrosis Caused by Severe Renal Ischemia. Severe ischemia of the kidney can result from circulatory shock or any other disturbance that severely impairs the blood supply to the kidney. If the ischemia is severe enough to seriously impair the delivery of nutrients and oxygen to the renal tubular epithelial cells, and if the insult is prolonged, damage or eventual destruction of the epithelial cells can occur. When this happens, tubular cells “slough off” and plug many of the nephrons, so that there is no urine output from the blocked nephrons; the affected nephrons often fail to excrete urine even when renal blood flow is restored to normal, as long as the tubules remain plugged. The most common causes of ischemic damage to the tubular epithelium are the prerenal causes of acute renal failure associated with circulatory shock, as discussed earlier in this chapter. Acute Tubular Necrosis Caused by Toxins or Medications. There is a long list of renal poisons and medications that can damage the tubular epithelium and cause acute renal failure. Some of these are carbon tetrachloride, heavy metals (such as mercury and lead), ethylene glycol (which is a major component in antifreeze), various insecticides, various medications (such as tetracyclines) used as antibiotics, and cis-platinum, which is used in treating certain cancers. Each of these substances has a specific toxic action on the renal tubular epithelial cells, causing death of many of them. As a result, the epithelial cells slough away from the basement membrane and plug the tubules. In some instances, the basement membrane also is destroyed. If the basement membrane remains intact, new tubular epithelial cells can grow along the surface of the membrane, so that the tubule repairs itself within 10 to 20 days. Postrenal Acute Renal Failure Caused by Abnormalities of the Lower Urinary Tract Multiple abnormalities in the lower urinary tract can block or partially block urine flow and therefore lead to Physiologic Effects of Acute Renal Failure A major physiologic effect of acute renal failure is retention in the blood and extracellular fluid of water, waste products of metabolism, and electrolytes. This can lead to water and salt overload, which in turn can lead to edema and hypertension. Excessive retention of potassium, however, is often a more serious threat to patients with acute renal failure, because increases in plasma potassium concentration (hyperkalemia) to more than about 8 mEq/L (only twice normal) can be fatal. Because the kidneys are also unable to excrete sufficient hydrogen ions, patients with acute renal failure develop metabolic acidosis, which in itself can be lethal or can aggravate the hyperkalemia. In the most severe cases of acute renal failure, complete anuria occurs. The patient will die in 8 to 14 days unless kidney function is restored or unless an artificial kidney is used to rid the body of the excessive retained water, electrolytes, and waste products of metabolism. Other effects of diminished urine output, as well as treatment with an artificial kidney, are discussed in the next section in relation to chronic renal failure. Chronic Renal Failure: An Irreversible Decrease in the Number of Functional Nephrons Chronic renal failure results from progressive and irreversible loss of large numbers of functioning nephrons. Serious clinical symptoms often do not occur until the number of functional nephrons falls to at least 70 to 75 per cent below normal. In fact, relatively normal blood concentrations of most electrolytes and normal body fluid volumes can still be maintained until the number of functioning nephrons decreases below 20 to 25 per cent of normal. Table 31–4 gives some of the most important causes of chronic renal failure. In general, chronic renal Chapter 31 407 Kidney Diseases and Diuretics Table 31–4 Primary kidney disease Some Causes of Chronic Renal Failure Metabolic disorders Diabetes mellitus Obesity Amyloidosis Hypertension Renal vascular disorders Atherosclerosis Nephrosclerosis-hypertension Immunologic disorders Glomerulonephritis Polyarteritis nodosa Lupus erythematosus Infections Pyelonephritis Tuberculosis Primary tubular disorders Nephrotoxins (analgesics, heavy metals) Urinary tract obstruction Renal calculi Hypertrophy of prostate Urethral constriction Congenital disorders Polycystic disease Congenital absence of kidney tissue (renal hypoplasia) failure, like acute renal failure, can occur because of disorders of the blood vessels, glomeruli, tubules, renal interstitium, and lower urinary tract. Despite the wide variety of diseases that can lead to chronic renal failure, the end result is essentially the same—a decrease in the number of functional nephrons. Vicious Circle of Chronic Renal Failure Leading to End-Stage Renal Disease In many cases, an initial insult to the kidney leads to progressive deterioration of kidney function and further loss of nephrons to the point where the person must be placed on dialysis treatment or transplanted with a functional kidney to survive. This condition is referred to as end-stage renal disease. Studies in laboratory animals have shown that surgical removal of large portions of the kidney initially causes adaptive changes in the remaining nephrons that lead to increased blood flow, increased GFR, and increased urine output in the surviving nephrons. The exact mechanisms responsible for these changes are not well understood but involve hypertrophy (growth of the various structures of the surviving nephrons) as well as functional changes that decrease vascular resistance and tubular reabsorption in the surviving nephrons. These adaptive changes permit a person to excrete normal amounts of water and solutes even when kidney mass is reduced to 20 to 25 per cent of normal. Over a period of several years, however, the renal functional changes may lead to further injury of the remaining nephrons, particularly to the glomeruli of these nephrons. + Nephron number Hypertrophy and vasodilation of surviving nephrons Glomerular sclerosis Arterial pressure Glomerular pressure and/or filtration Figure 31–2 Vicious circle that can occur with primary kidney disease. Loss of nephrons because of disease may increase pressure and flow in the surviving glomerular capillaries, which in turn may eventually injure these “normal” capillaries as well, thus causing progressive sclerosis and eventual loss of these glomeruli. The cause of this additional injury is not known, but some investigators believe that it may be related in part to increased pressure or stretch of the remaining glomeruli, which occurs as a result of functional vasodilation or increased blood pressure; the chronic increase in pressure and stretch of the small arterioles and glomeruli are believed to cause sclerosis of these vessels (replacement of normal tissue with connective tissue). These sclerotic lesions can eventually obliterate the glomerulus, leading to further reduction in kidney function, further adaptive changes in the remaining nephrons, and a slowly progressing vicious circle that eventually terminates in end-stage renal disease (Figure 31–2). The only proven method of slowing down this progressive loss of kidney function is to lower arterial pressure and glomerular hydrostatic pressure, especially by using drugs such as angiotensin-converting enzyme inhibitors or angiotensin II antagonists. Table 31–5 gives the most common causes of endstage renal disease. In the early 1980s, glomerulonephritis in all its various forms was believed to be the most common initiating cause of end-stage renal disease. In recent years, diabetes mellitus and hypertension have become recognized as the leading causes of end-stage renal disease, together accounting for approximately 70 per cent of all chronic renal failure. Excessive weight gain (obesity) appears to be the most important risk factor for the two main causes of end-stage renal disease—diabetes and hypertension. As discussed in Chapter 78, type II diabetes, which is 408 Unit V The Body Fluids and Kidneys Table 31–5 Most Common Causes of End-Stage Renal Disease (ESRD) 2.5 Diabetes mellitus Hypertension Glomerulonephritis Polycystic kidney disease Other/unknown Percentage of Total ESRD Patients 44 26 8 2 20 closely linked to obesity, accounts for approximately 90 per cent of all diabetes mellitus. Excess weight gain is also a major cause of essential hypertension, accounting for as much as 65 to 75 per cent of the risk for developing hypertension in adults. In addition to causing renal injury through diabetes and hypertension, obesity may have additive or synergistic effects to worsen renal function in patients with pre-existing kidney disease. Injury to the Renal Vasculature as a Cause of Chronic Renal Failure Many types of vascular lesions can lead to renal ischemia and death of kidney tissue. The most common of these are (1) atherosclerosis of the larger renal arteries, with progressive sclerotic constriction of the vessels; (2) fibromuscular hyperplasia of one or more of the large arteries, which also causes occlusion of the vessels; and (3) nephrosclerosis, caused by sclerotic lesions of the smaller arteries, arterioles, and glomeruli. Atherosclerotic or hyperplastic lesions of the large arteries frequently affect one kidney more than the other and, therefore, cause unilaterally diminished kidney function. As discussed in Chapter 19, hypertension often occurs when the artery of one kidney is constricted while the artery of the other kidney is still normal, a condition analogous to “two-kidney” Goldblatt hypertension. Benign nephrosclerosis, the most common form of kidney disease, is seen to at least some extent in about 70 per cent of postmortem examinations in people who die after the age of 60. This type of vascular lesion occurs in the smaller interlobular arteries and in the afferent arterioles of the kidney. It is believed to begin with leakage of plasma through the intimal membrane of these vessels. This causes fibrinoid deposits to develop in the medial layers of these vessels, followed by progressive thickening of the vessel wall that eventually constricts the vessels and, in some cases, occludes them. Because there is essentially no collateral circulation among the smaller renal arteries, occlusion of one or more of them causes destruction of a comparable number of nephrons. Therefore, much of the kidney tissue becomes replaced by small amounts of fibrous tissue. When sclerosis occurs in the glomeruli, the injury is referred to as glomerulosclerosis. Nephrosclerosis and glomerulosclerosis occur to some extent in most people after the fourth decade of life, causing about a 10 per cent decrease in the number of functional nephrons each 10 years after age 40 (Figure 31–3). This loss of glomeruli and overall nephron function is reflected by a progressive decrease Glomeruli (x 106) Cause 2.0 1.5 1.0 0.5 0.0 0 20 40 Age (years) 60 80 Figure 31–3 Effect of aging on the number of functional glomeruli. in both renal blood flow and GFR. Even in “normal” people, kidney plasma flow and GFR decrease by 40 to 50 per cent by age 80. The frequency and severity of nephrosclerosis and glomerulosclerosis are greatly increased by concurrent hypertension or diabetes mellitus. In fact, diabetes mellitus and hypertension are the two most important causes of end-stage renal disease, as discussed previously. Thus, benign nephrosclerosis in association with severe hypertension can lead to a rapidly progressing malignant nephrosclerosis. The characteristic histological features of malignant nephrosclerosis include large amounts of fibrinoid deposits in the arterioles and progressive thickening of the vessels, with severe ischemia occurring in the affected nephrons. For unknown reasons, the incidence of malignant nephrosclerosis and severe glomerulosclerosis is significantly higher in blacks than in whites of similar ages who have similar degrees of severity of hypertension or diabetes. Injury to the Glomeruli as a Cause of Chronic Renal Failure— Glomerulonephritis Chronic glomerulonephritis can be caused by several diseases that cause inflammation and damage to the capillary loops in the glomeruli of the kidneys. In contrast to the acute form of this disease, chronic glomerulonephritis is a slowly progressive disease that often leads to irreversible renal failure. It may be a primary kidney disease, following acute glomerulonephritis, or it may be secondary to systemic diseases, such as lupus erythematosus. In most cases, chronic glomerulonephritis begins with accumulation of precipitated antigen-antibody complexes in the glomerular membrane. In contrast to acute glomerulonephritis, streptococcal infections account for only a small percentage of patients with the chronic form of glomerulonephritis. The results of the accumulation of antigen-antibody complex in the glomerular membranes are inflammation, progressive thickening of the membranes, and eventual invasion of the glomeruli Chapter 31 Kidney Diseases and Diuretics by fibrous tissue. In the later stages of the disease, the glomerular capillary filtration coefficient becomes greatly reduced because of decreased numbers of filtering capillaries in the glomerular tufts and because of thickened glomerular membranes. In the final stages of the disease, many glomeruli are replaced by fibrous tissue and are, therefore, unable to filter fluid. Injury to the Renal Interstitium as a Cause of Chronic Renal Failure— Pyelonephritis Primary or secondary disease of the renal interstitium is referred to as interstitial nephritis. In general, this can result from vascular, glomerular, or tubular damage that destroys individual nephrons, or it can involve primary damage to the renal interstitium by poisons, drugs, and bacterial infections. Renal interstitial injury caused by bacterial infection is called pyelonephritis. The infection can result from different types of bacteria but especially from Escherichia coli that originate from fecal contamination of the urinary tract. These bacteria reach the kidneys either by way of the blood stream or, more commonly, by ascension from the lower urinary tract by way of the ureters to the kidneys. Although the normal bladder is able to clear bacteria readily, there are two general clinical conditions that may interfere with the normal flushing of bacteria from the bladder: (1) the inability of the bladder to empty completely, leaving residual urine in the bladder, and (2) the existence of obstruction of urine outflow. With impaired ability to flush bacteria from the bladder, the bacteria multiply and the bladder becomes inflamed, a condition termed cystitis. Once cystitis has occurred, it may remain localized without ascending to the kidney, or in some people, bacteria may reach the renal pelvis because of a pathological condition in which urine is propelled up one or both of the ureters during micturition. This condition is called vesicoureteral reflux and is due to the failure of the bladder wall to occlude the ureter during micturition; as a result, some of the urine is propelled upward toward the kidney, carrying with it bacteria that can reach the renal pelvis and renal medulla, where they can initiate the infection and inflammation associated with pyelonephritis. Pyelonephritis begins in the renal medulla and therefore usually affects the function of the medulla more than it affects the cortex, at least in the initial stages. Because one of the primary functions of the medulla is to provide the countercurrent mechanism for concentrating urine, patients with pyelonephritis frequently have markedly impaired ability to concentrate the urine. With long-standing pyelonephritis, invasion of the kidneys by bacteria not only causes damage to the renal medulla interstitium but also results in progressive damage of renal tubules, glomeruli, and other structures throughout the kidney. Consequently, large parts of functional renal tissue are lost, and chronic renal failure can develop. Nephrotic Syndrome—Excretion of Protein in the Urine Because of Increased Glomerular Permeability Many patients with kidney disease develop the nephrotic syndrome, which is characterized by loss of 409 large quantities of plasma proteins into the urine. In some instances, this occurs without evidence of other major abnormalities of kidney function, but more often it is associated with some degree of renal failure. The cause of the protein loss in the urine is increased permeability of the glomerular membrane. Therefore, any disease that increases the permeability of this membrane can cause the nephrotic syndrome. Such diseases include (1) chronic glomerulonephritis, which affects primarily the glomeruli and often causes greatly increased permeability of the glomerular membrane; (2) amyloidosis, which results from deposition of an abnormal proteinoid substance in the walls of the blood vessels and seriously damages the basement membrane of the glomeruli; and (3) minimal change nephrotic syndrome, which is associated with no major abnormality in the glomerular capillary membrane that can be detected with light microscopy. As discussed in Chapter 26, minimal change nephropathy has been found to be associated with loss of the negative charges that are normally present in the glomerular capillary basement membrane. Immunologic studies have also shown abnormal immune reactions in some cases, suggesting that the loss of the negative charges may have resulted from antibody attack on the membrane. Loss of normal negative charges in the basement membrane of the glomerular capillaries allows proteins, especially albumin, to pass through the glomerular membrane with ease because the negative charges in the basement membrane normally repel the negatively charged plasma proteins. Minimal change nephropathy can occur in adults, but more frequently it occurs in children between the ages of 2 and 6 years. Increased permeability of the glomerular capillary membrane occasionally allows as much as 40 grams of plasma protein loss into the urine each day, which is an extreme amount for a young child. Therefore, the child’s plasma protein concentration often falls below 2 g/dl, and the colloid osmotic pressure falls from a normal value of 28 to less than 10 mm Hg. As a consequence of this low colloid osmotic pressure in the plasma, large amounts of fluid leak from the capillaries all over the body into most of the tissues, causing severe edema, as discussed in Chapter 25. Nephron Function in Chronic Renal Failure Loss of Functional Nephrons Requires the Surviving Nephrons to Excrete More Water and Solutes. It would be reasonable to suspect that decreasing the number of functional nephrons, which reduces the GFR, would also cause major decreases in renal excretion of water and solutes. Yet patients who have lost as much as 75 per cent of their nephrons are able to excrete normal amounts of water and electrolytes without serious accumulation of any of these in the body fluids. Further reduction in the number of nephrons, however, leads to electrolyte and fluid retention, and death usually ensues when the number of nephrons falls below 5 to 10 per cent of normal. In contrast to the electrolytes, many of the waste products of metabolism, such as urea and creatinine, accumulate almost in proportion to the number of nephrons that have been destroyed.The reason for this 410 Unit V The Body Fluids and Kidneys 50 Plasma concentration GFR (ml/min) 100 Creatinine production and renal excretion (g/day) Serum creatinine concentration (mg/dl) 0 2 A B 1 C 0 0 Positive balance 25 50 75 Glomerular filtration rate (percentage of normal) 100 Production 2 Excretion GFR x PCreatinine 1 0 0 1 2 Days 3 4 Figure 31–4 Effect of reducing glomerular filtration rate (GFR) by 50 per cent on serum creatinine concentration and on creatinine excretion rate when the production rate of creatinine remains constant. is that substances such as creatinine and urea depend largely on glomerular filtration for their excretion, and they are not reabsorbed as avidly as the electrolytes. Creatinine, for example, is not reabsorbed at all, and the excretion rate is equal to the rate at which it is filtered. Creatinine filtration rate = GFR ¥ Plasma creatinine concentration = Creatinine excretion rate Therefore, if GFR decreases, the creatinine excretion rate also transiently decreases, causing accumulation of creatinine in the body fluids and raising plasma concentration until the excretion rate of creatinine returns to normal—the same rate at which creatinine is produced in the body (Figure 31–4). Thus, under steady-state conditions, the creatinine excretion rate equals the rate of creatinine production, despite reductions in GFR; however, this normal rate of creatinine excretion occurs at the expense of elevated plasma creatinine concentration, as shown in curve A of Figure 31–5. Figure 31–5 Representative patterns of adaptation for different types of solutes in chronic renal failure. Curve A shows the approximate changes in the plasma concentrations of solutes such as creatinine and urea that are filtered and poorly reabsorbed. Curve B shows the approximate concentrations for solutes such as phosphate and urate. Curve C shows the approximate concentrations for solutes such as sodium and chloride. Some solutes, such as phosphate, urate, and hydrogen ions, are often maintained near the normal range until GFR falls below 20 to 30 per cent of normal. Thereafter, the plasma concentrations of these substances rise, but not in proportion to the fall in GFR, as shown in curve B of Figure 31–5. Maintenance of relatively constant plasma concentrations of these solutes as GFR declines is accomplished by excreting progressively larger fractions of the amounts of these solutes that are filtered at the glomerular capillaries; this occurs by decreasing the rate of tubular reabsorption or, in some instances, by increasing tubular secretion rates. In the case of sodium and chloride ions, their plasma concentrations are maintained virtually constant even with severe decreases in GFR (see curve C of Figure 31–5). This is accomplished by greatly decreasing tubular reabsorption of these electrolytes. For example, with a 75 per cent loss of functional nephrons, each surviving nephron must excrete four times as much sodium and four times as much volume as under normal conditions (Table 31–6). Part of this adaptation occurs because of increased blood flow and increased GFR in each of the surviving nephrons, owing to hypertrophy of the blood vessels and glomeruli, as well as functional changes that cause the blood vessels to vasodilate. Even with large decreases in the total GFR, normal rates of renal Chapter 31 411 Kidney Diseases and Diuretics Table 31–6 Total Kidney Excretion and Excretion per Nephron in Renal Failure 3.0 GFR, glomerular filtration rate. excretion can still be maintained by decreasing the rate at which the tubules reabsorb water and solutes. Isosthenuria—Inability of the Kidney to Concentrate or Dilute the Urine. One important effect of the rapid rate of tubular flow that occurs in the remaining nephrons of diseased kidneys is that the renal tubules lose their ability to concentrate or dilute the urine. The concentrating ability of the kidney is impaired mainly because (1) the rapid flow of tubular fluid through the collecting ducts prevents adequate water reabsorption, and (2) the rapid flow through both the loop of Henle and the collecting ducts prevents the countercurrent mechanism from operating effectively to concentrate the medullary interstitial fluid solutes. Therefore, as progressively more nephrons are destroyed, the maximum concentrating ability of the kidney declines, and urine osmolarity and specific gravity (a measure of the total solute concentration) approach the osmolarity and specific gravity of the glomerular filtrate, as shown in Figure 31–6. The diluting mechanism in the kidney is also impaired when the number of nephrons decreases because the rapid flushing of fluid through the loops of Henle and the high load of solutes such as urea cause a relatively high solute concentration in the tubular fluid of this part of the nephron. As a consequence, the diluting capacity of the kidney is impaired, and the minimal urine osmolality and specific gravity approach those of the glomerular filtrate. Because the concentrating mechanism becomes impaired to a greater extent than does the diluting mechanism in chronic renal failure, an important clinical test of renal function is to determine how well the kidneys can concentrate urine when a person’s water intake is restricted for 12 or more hours. Effects of Renal Failure on the Body Fluids—Uremia The effect of complete renal failure on the body fluids depends on (1) water and food intake and (2) the degree of impairment of renal function. Assuming that a person with complete renal failure continues to ingest the same amounts of water and food, the concentrations Specific gravity of urine 0.75 500,000 40 80 1.5 1.030 Isosthenuria 1.020 1.010 Glomerular filtrate specific gravity 1.000 2,000,000 1,500,000 1,000,000 500,000 0 Number of nephrons in both kidneys Figure 31–6 Development of isosthenuria in a patient with decreased numbers of functional nephrons. Increase 2,000,000 125 62.5 1.5 1.040 ter Wa + Na H+ Phenols N NP K+ Normal HPO4= HCO Decrease 75% Loss of Nephrons Normal Number of nephrons Total GFR (ml/min) Single nephron GFR (nl/min) Volume excreted for all nephrons (ml/min) Volume excreted per nephron (nl/min) 1.050 3 SO4= - Kidney shutdown 0 3 6 Days 9 12 Figure 31–7 Effect of kidney failure on extracellular fluid constituents. NPN, nonprotein nitrogens. of different substances in the extracellular fluid are approximately those shown in Figure 31–7. Important effects include (1) generalized edema resulting from water and salt retention, (2) acidosis resulting from failure of the kidneys to rid the body of normal acidic products, (3) high concentration of the nonprotein nitrogens—especially urea, creatinine, and uric acid—resulting from failure of the body to excrete the metabolic end products of proteins, and (4) high concentrations of other substances excreted by the kidney, including phenols, sulfates, phosphates, potassium, and guanidine bases. This total condition is called uremia because of the high concentration of urea in the body fluids. 412 Unit V The Body Fluids and Kidneys Water Retention and Development of Edema in Renal Failure. If water intake is restricted immediately after acute renal failure begins, the total body fluid content may become only slightly increased. If fluid intake is not limited and the patient drinks in response to the normal thirst mechanisms, the body fluids begin to increase immediately and rapidly. With chronic partial kidney failure, accumulation of fluid may not be severe, as long as salt and fluid intake are not excessive, until kidney function falls to 25 per cent of normal or lower. The reason for this, as discussed previously, is that the surviving nephrons excrete larger amounts of salt and water. Even the small fluid retention that does occur, along with increased secretion of renin and angiotensin II that usually occurs in ischemic kidney disease, often causes severe hypertension in chronic renal failure. Almost all patients with kidney function so reduced as to require dialysis to preserve life develop hypertension. In most of these patients, severe reduction of salt intake or removal of extracellular fluid by dialysis can control the hypertension. The remaining patients continue to have hypertension even after excess sodium has been removed by dialysis. In this group, removal of the ischemic kidneys usually corrects the hypertension (as long as fluid retention is prevented by dialysis) because it removes the source of excessive renin secretion and subsequent increased angiotensin II formation. Uremia—Increase in Urea and Other Nonprotein Nitrogens (Azotemia). The nonprotein nitrogens include urea, uric acid, creatinine, and a few less important compounds. These, in general, are the end products of protein metabolism and must be removed from the body to ensure continued normal protein metabolism in the cells. The concentrations of these, particularly of urea, can rise to as high as 10 times normal during 1 to 2 weeks of total renal failure. With chronic renal failure, the concentrations rise approximately in proportion to the degree of reduction in functional nephrons. For this reason, measuring the concentrations of these substances, especially of urea and creatinine, provides an important means for assessing the degree of renal failure. Osteomalacia in Chronic Renal Failure Caused by Decreased Production of Active Vitamin D and by Phosphate Retention by the Kidneys. Prolonged renal failure also causes osteo- malacia, a condition in which the bones are partially absorbed and, therefore, become greatly weakened. An important cause of this condition is the following: Vitamin D must be converted by a two-stage process, first in the liver and then in the kidneys, into 1,25– dihydroxycholecalciferol before it is able to promote calcium absorption from the intestine. Therefore, serious damage to the kidney greatly reduces the blood concentration of active vitamin D, which in turn decreases intestinal absorption of calcium and the availability of calcium to the bones. Another important cause of demineralization of the skeleton in chronic renal failure is the rise in serum phosphate concentration that occurs as a result of decreased GFR. This rise in serum phosphate causes increased binding of phosphate with calcium in the plasma, thus decreasing the plasma serum ionized calcium concentration, which in turn stimulates parathyroid hormone secretion. This secondary hyperparathyroidism then stimulates the release of calcium from bones, causing further demineralization of the bones. Hypertension and Kidney Disease As discussed earlier in this chapter, hypertension can exacerbate injury to the glomeruli and blood vessels of the kidneys and is a major cause of end-stage renal disease. Conversely, abnormalities of kidney function can cause hypertension, as discussed in detail in Chapter 19. Thus, the relation between hypertension and kidney disease can, in some instances, propagate a vicious circle: primary kidney damage leads to increased blood pressure, which in turn causes further damage to the kidneys, further increases in blood pressure, and so forth, until end-stage renal disease develops. Not all types of kidney disease cause hypertension, because damage to certain portions of the kidney cause uremia without hypertension. Nevertheless, some types of renal damage are particularly prone to cause hypertension. A classification of kidney disease relative to hypertensive or nonhypertensive effects is the following. Acidosis in Renal Failure. Each day the body normally pro- duces about 50 to 80 millimoles more metabolic acid than metabolic alkali. Therefore, when the kidneys fail to function, acid accumulates in the body fluids. The buffers of the body fluids normally can buffer 500 to 1000 millimoles of acid without lethal increases in extracellular fluid hydrogen ion concentration, and the phosphate compounds in the bones can buffer an additional few thousand millimoles of hydrogen ion. However, when this buffering power is used up, the blood pH falls drastically, and the patient will become comatose and die if the pH falls below about 6.8. Anemia in Chronic Renal Failure Caused by Decreased Erythropoietin Secretion. Patients with severe chronic renal failure almost always develop anemia. The most important cause of this is decreased renal secretion of erythropoietin, which stimulates the bone marrow to produce red blood cells. If the kidneys are seriously damaged, they are unable to form adequate quantities of erythropoietin, which leads to diminished red blood cell production and consequent anemia. Renal Lesions That Reduce the Ability of the Kidneys to Excrete Sodium and Water Promote Hypertension. Renal lesions that decrease the ability of the kidneys to excrete sodium and water almost invariably cause hypertension. Therefore, lesions that either decrease GFR or increase tubular reabsorption usually lead to hypertension of varying degrees. Some specific types of renal abnormalities that can cause hypertension are as follows: 1. Increased renal vascular resistance, which reduces renal blood flow and GFR. An example is hypertension caused by renal artery stenosis. 2. Decreased glomerular capillary filtration coefficient, which reduces GFR. An example of this is chronic glomerulonephritis, which causes inflammation and thickening of the glomerular capillary membranes, thereby reducing the glomerular capillary filtration coefficient. 3. Excessive tubular sodium reabsorption. An example is hypertension caused by excessive aldosterone secretion, which increases sodium reabsorption mainly in the cortical collecting tubules. Chapter 31 Kidney Diseases and Diuretics Once hypertension has developed, renal excretion of sodium and water returns to normal because the high arterial pressure causes pressure natriuresis and pressure diuresis, so that intake and output of sodium and water become balanced once again. Even when there are large increases in renal vascular resistance or decreases in the glomerular capillary coefficient, the GFR may still return to nearly normal levels after the arterial blood pressure rises. Likewise, when tubular reabsorption is increased, as occurs with excessive aldosterone secretion, the urinary excretion rate is initially reduced but then returns to normal as arterial pressure rises. Thus, after hypertension develops, there may be no sign of impaired excretion of sodium and water other than the hypertension. As explained in Chapter 19, normal excretion of sodium and water at an elevated arterial pressure means that pressure natriuresis and pressure diuresis have been reset to a higher arterial pressure. Hypertension Caused by Patchy Renal Damage and Increased Renal Secretion of Renin. If one part of the kidney is ischemic and the remainder is not ischemic, such as occurs when one renal artery is severely constricted, the ischemic renal tissue secretes large quantities of renin. This secretion leads to the formation of angiotensin II, which can cause hypertension. The most likely sequence of events in causing this hypertension, as discussed in Chapter 19, is (1) the ischemic kidney tissue itself excretes less than normal amounts of water and salt; (2) the renin secreted by the ischemic kidney, and subsequent increased angiotensin II formation, affects the nonischemic kidney tissue, causing it also to retain salt and water; and (3) excess salt and water cause hypertension in the usual manner. A similar type of hypertension can result when patchy areas of one or both kidneys become ischemic as a result of arteriosclerosis or vascular injury in specific portions of the kidneys. When this occurs, the ischemic nephrons excrete less salt and water but secrete greater amounts of renin, which causes increased angiotensin II formation. The high levels of angiotensin II then impair the ability of the surrounding otherwise normal nephrons to excrete sodium and water. As a result, hypertension develops, which restores the overall excretion of sodium and water by the kidney, so that balance between intake and output of salt and water is maintained, but at the expense of high blood pressure. Kidney Diseases That Cause Loss of Entire Nephrons Lead to Renal Failure But May Not Cause Hypertension. Loss of large numbers of whole nephrons, such as occurs with the loss of one kidney and part of another kidney, almost always leads to renal failure if the amount of kidney tissue lost is great enough. If the remaining nephrons are normal and the salt intake is not excessive, this condition might not cause clinically significant hypertension, because even a slight rise in blood pressure will raise the GFR and decrease tubular sodium reabsorption sufficiently to promote enough water and salt excretion in the urine, even with the few nephrons that remain intact. However, a patient with this type of abnormality may become severely hypertensive if additional stresses are imposed, such as eating a large amount of salt. In this case, the kidneys simply cannot clear adequate quantities of salt with the small number of functioning nephrons that remain. 413 Specific Tubular Disorders In Chapter 27, we point out that several mechanisms are responsible for transporting different individual substances across the tubular epithelial membranes. In Chapter 3, we also point out that each cellular enzyme and each carrier protein is formed in response to a respective gene in the nucleus. If any required gene happens to be absent or abnormal, the tubules may be deficient in one of the appropriate carrier proteins or one of the enzymes needed for solute transport by the renal tubular epithelial cells. For this reason, many hereditary tubular disorders occur because of the transport of individual substances or groups of substances through the tubular membrane. In addition, damage to the tubular epithelial membrane by toxins or ischemia can cause important renal tubular disorders. Renal Glycosuria—Failure of the Kidneys to Reabsorb Glucose. In this condition, the blood glucose concentration may be normal, but the transport mechanism for tubular reabsorption of glucose is greatly limited or absent. Consequently, despite a normal blood glucose level, large amounts of glucose pass into the urine each day. Because diabetes mellitus is also associated with the presence of glucose in the urine, renal glycosuria, which is a relatively benign condition, must be ruled out before making a diagnosis of diabetes mellitus. Aminoaciduria—Failure of the Kidneys to Reabsorb Amino Acids. Some amino acids share mutual transport systems for reabsorption, whereas other amino acids have their own distinct transport systems. Rarely, a condition called generalized aminoaciduria results from deficient reabsorption of all amino acids; more frequently, deficiencies of specific carrier systems may result in (1) essential cystinuria, in which large amounts of cystine fail to be reabsorbed and often crystallize in the urine to form renal stones; (2) simple glycinuria, in which glycine fails to be reabsorbed; or (3) beta-aminoisobutyricaciduria, which occurs in about 5 per cent of all people but apparently has no major clinical significance. Renal Hypophosphatemia—Failure of the Kidneys to Reabsorb Phosphate. In renal hypophosphatemia, the renal tubules fail to reabsorb large enough quantities of phosphate ions when the phosphate concentration of the body fluids falls very low. This condition usually does not cause serious immediate abnormalities, because the phosphate concentration of the extracellular fluid can vary widely without causing major cellular dysfunction. Over a long period, a low phosphate level causes diminished calcification of the bones, causing the person to develop rickets. This type of rickets is refractory to vitamin D therapy, in contrast to the rapid response of the usual type of rickets, as discussed in Chapter 79. Renal Tubular Acidosis—Failure of the Tubules to Secrete Hydrogen Ions. In this condition, the renal tubules are unable to secrete adequate amounts of hydrogen ions. As a result, large amounts of sodium bicarbonate are continually lost in the urine. This causes a continued state of metabolic acidosis, as discussed in Chapter 30. This type of renal abnormality can be caused by hereditary disorders, or it can occur as a result of widespread injury to the renal tubules. 414 Unit V The Body Fluids and Kidneys Nephrogenic Diabetes Insipidus—Failure of the Kidneys to Respond to Antidiuretic Hormone. Occasionally, the renal tubules do not respond to antidiuretic hormone, causing large quantities of dilute urine to be excreted. As long as the person is supplied with plenty of water, this condition seldom causes severe difficulty. However, when adequate quantities of water are not available, the person rapidly becomes dehydrated. Semipermeable Flowing membrane blood Fanconi’s Syndrome—A Generalized Reabsorptive Defect of the Renal Tubules. Fanconi’s syndrome is usually associated with increased urinary excretion of virtually all amino acids, glucose, and phosphate. In severe cases, other manifestations are also observed, such as (1) failure to reabsorb sodium bicarbonate, which results in metabolic acidosis; (2) increased excretion of potassium and sometimes calcium; and (3) nephrogenic diabetes insipidus. There are multiple causes of Fanconi’s syndrome, which results from a generalized inability of the renal tubular cells to transport various substances. Some of these causes include (1) hereditary defects in cell transport mechanisms, (2) toxins or drugs that injure the renal tubular epithelial cells, and (3) injury to the renal tubular cells as a result of ischemia. The proximal tubular cells are especially affected in Fanconi’s syndrome caused by tubular injury, because these cells reabsorb and secrete many of the drugs and toxins that can cause damage. Treatment of Renal Failure by Dialysis with an Artificial Kidney Severe loss of kidney function, either acutely or chronically, is a threat to life and requires removal of toxic waste products and restoration of body fluid volume and composition toward normal. This can be accomplished by dialysis with an artificial kidney. In certain types of acute renal failure, an artificial kidney may be used to tide the patient over until the kidneys resume their function. If the loss of kidney function is irreversible, it is necessary to perform dialysis chronically to maintain life. In the United States alone, nearly 300,000 people with irreversible renal failure or even total kidney removal are being maintained by dialysis with artificial kidneys. Because dialysis cannot maintain completely normal body fluid composition and cannot replace all the multiple functions performed by the kidneys, the health of patients maintained on artificial kidneys usually remains significantly impaired. A better treatment for permanent loss of kidney function is to restore functional kidney tissue by means of a kidney transplant. Basic Principles of Dialysis. The basic principle of the arti- ficial kidney is to pass blood through minute blood channels bounded by a thin membrane. On the other side of the membrane is a dialyzing fluid into which unwanted substances in the blood pass by diffusion. Figure 31–8 shows the components of one type of artificial kidney in which blood flows continually between two thin membranes of cellophane; outside the membrane is a dialyzing fluid. The cellophane is porous enough to allow the constituents of the plasma, except the plasma proteins, to diffuse in both directions—from plasma into the dialyzing fluid or from the dialyzing Flowing dialysate Waste Water products Blood out Bubble trap Dialyzer Blood in Dialysate in Fresh dialyzing solution Constant temperature bath Dialysate out Used dialyzing solution Figure 31–8 Principles of dialysis with an artificial kidney. fluid back into the plasma. If the concentration of a substance is greater in the plasma than in the dialyzing fluid, there will be a net transfer of the substance from the plasma into the dialyzing fluid. The rate of movement of solute across the dialyzing membrane depends on (1) the concentration gradient of the solute between the two solutions, (2) the permeability of the membrane to the solute, (3) the surface area of the membrane, and (4) the length of time that the blood and fluid remain in contact with the membrane. Thus, the maximum rate of solute transfer occurs initially when the concentration gradient is greatest (when dialysis is begun) and slows down as the concentration gradient is dissipated. In a flowing system, as is the case with “hemodialysis,” in which blood and dialysate fluid flow through the artificial kidney, the dissipation of the concentration gradient can be reduced and diffusion of solute across the membrane can be optimized by increasing the flow rate of the blood, the dialyzing fluid, or both. In normal operation of the artificial kidney, blood flows continually or intermittently back into the vein. The total amount of blood in the artificial kidney at any one time is usually less than 500 milliliters, the rate of flow may be several hundred milliliters per minute, and Chapter 31 Kidney Diseases and Diuretics Table 31–7 Comparison of Dialyzing Fluid with Normal and Uremic Plasma Constituent Electrolytes (mEq/L) Na+ K+ Ca++ Mg++ Cl– HCO3– Lactate– HPO4= Urate– Sulfate= Nonelectrolytes Glucose Urea Creatinine Normal Plasma Dialyzing Fluid Uremic Plasma 142 5 3 1.5 107 24 1.2 3 0.3 0.5 133 1.0 3.0 1.5 105 35.7 1.2 0 0 0 142 7 2 1.5 107 14 1.2 9 2 3 100 26 1 125 0 0 100 200 6 the total diffusion surface area is between 0.6 and 2.5 square meters. To prevent coagulation of the blood in the artificial kidney, a small amount of heparin is infused into the blood as it enters the artificial kidney. In addition to diffusion of solutes, mass transfer of solutes and water can be produced by applying a hydrostatic pressure to force the fluid and solutes across the membranes of the dialyzer; such filtration is called bulk flow. Dialyzing Fluid. Table 31–7 compares the constituents in a typical dialyzing fluid with those in normal plasma and uremic plasma. Note that the concentrations of ions and other substances in dialyzing fluid are not the same as the concentrations in normal plasma or in uremic plasma. Instead, they are adjusted to levels that are needed to cause appropriate movement of water and solutes through the membrane during dialysis. Note that there is no phosphate, urea, urate, sulfate, or creatinine in the dialyzing fluid; however, these are present in high concentrations in the uremic blood. Therefore, when a uremic patient is dialyzed, these substances are lost in large quantities into the dialyzing fluid. The effectiveness of the artificial kidney can be expressed in terms of the amount of plasma that is cleared of different substances each minute, which, as discussed in Chapter 27, is the primary means for expressing the functional effectiveness of the kidneys themselves to rid the body of unwanted substances. Most artificial kidneys can clear urea from the plasma 415 at a rate of 100 to 225 ml/min, which shows that at least for the excretion of urea, the artificial kidney can function about twice as rapidly as two normal kidneys together, whose urea clearance is only 70 ml/min. Yet the artificial kidney is used for only 4 to 6 hours per day, three times a week. Therefore, the overall plasma clearance is still considerably limited when the artificial kidney replaces the normal kidneys. Also, it is important to keep in mind that the artificial kidney cannot replace some of the other functions of the kidneys, such as secretion of erythropoietin, which is necessary for red blood cell production. References Andreoli TE (ed): Cecil’s Essentials of Medicine, 6th ed. Philadelphia: WB Saunders, 2004. Fishbane SA, Scribner BH: Blood pressure control in dialysis patients. Semin Dial 15:144, 2002. Hall JE:The kidney, hypertension, and obesity. Hypertension 41:625, 2003. Hall JE, Henegar JR, Dwyer TM, et al: Is obesity a major cause of chronic renal disease? Adv Ren Replace Ther 11:41, 2004. Hostetter TH: Prevention of the development and progression of renal disease. J Am Soc Nephrol 14(Suppl 2):S144, 2003. Levey AS, Beto JA, Coronado BE, et al: Controlling the epidemic of cardiovascular disease in chronic renal disease. What do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 32:853, 1998. Luke RG: Chronic renal failure. In: Goldman F, Bennett JC (eds): Cecil Textbook of Medicine, 21st ed. Philadelphia: WB Saunders, 2000, pp 571-578. Mitch WE: Acute renal failure. In: Goldman F, Bennett JC (eds): Cecil Textbook of Medicine, 21st ed. Philadelphia: WB Saunders, 2000, pp 567-570. Molitoris BA: Transitioning to therapy in ischemic acute renal failure. J Am Soc Nephrol 14:265, 2003. Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney disease as a risk factor for development of cardiovascular disease. Hypertension 42:1050, 2003. Schrier RW: Atlas of Diseases of the Kidney. http:// www.kidneyatlas.org/. Shankar SS, Brater DC: Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol 284:F11, 2003. Singri N, Ahya SN, Levin ML: Acute renal failure. JAMA 289:747, 2003. United States Renal Data System. http://www.usrds.org/. Wilcox CS: New insights into diuretic use in patients with chronic renal disease. J Am Soc Nephrol 13:798, 2002. U N I Blood Cells, Immunity, and Blood Clotting 32. Red Blood Cells, Anemia, and Polycythemia 33. Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System, and Inflammation 34. Resistance of the Body to Infection: II. Immunity and Allergy 35. Blood Types; Transfusion; Tissue and Organ Transplantation 36. Hemostasis and Blood Coagulation T VI C H A P T E R 3 2 Red Blood Cells, Anemia, and Polycythemia With this chapter we begin discussing the blood cells and cells of the macrophage system and lymphatic system. We first present the functions of red blood cells, which are the most abundant cells of the blood and are necessary for the delivery of oxygen to the tissues. Red Blood Cells (Erythrocytes) The major function of red blood cells, also known as erythrocytes, is to transport hemoglobin, which in turn carries oxygen from the lungs to the tissues. In some lower animals, hemoglobin circulates as free protein in the plasma, not enclosed in red blood cells. When it is free in the plasma of the human being, about 3 per cent of it leaks through the capillary membrane into the tissue spaces or through the glomerular membrane of the kidney into the glomerular filtrate each time the blood passes through the capillaries. Therefore, for hemoglobin to remain in the human blood stream, it must exist inside red blood cells. The red blood cells have other functions besides transport of hemoglobin. For instance, they contain a large quantity of carbonic anhydrase, an enzyme that catalyzes the reversible reaction between carbon dioxide (CO2) and water to form carbonic acid (H2CO3), increasing the rate of this reaction several thousandfold. The rapidity of this reaction makes it possible for the water of the blood to transport enormous quantities of CO2 in the form of bicarbonate ion (HCO3–) from the tissues to the lungs, where it is reconverted to CO2 and expelled into the atmosphere as a body waste product. The hemoglobin in the cells is an excellent acid-base buffer (as is true of most proteins), so that the red blood cells are responsible for most of the acid-base buffering power of whole blood. Shape and Size of Red Blood Cells. Normal red blood cells, shown in Figure 32–3, are biconcave discs having a mean diameter of about 7.8 micrometers and a thickness of 2.5 micrometers at the thickest point and 1 micrometer or less in the center. The average volume of the red blood cell is 90 to 95 cubic micrometers. The shapes of red blood cells can change remarkably as the cells squeeze through capillaries. Actually, the red blood cell is a “bag” that can be deformed into almost any shape. Furthermore, because the normal cell has a great excess of cell membrane for the quantity of material inside, deformation does not stretch the membrane greatly and, consequently, does not rupture the cell, as would be the case with many other cells. Concentration of Red Blood Cells in the Blood. In normal men, the average number of red blood cells per cubic millimeter is 5,200,000 (±300,000); in normal women, it is 4,700,000 (±300,000). Persons living at high altitudes have greater numbers of red blood cells. This is discussed later. Quantity of Hemoglobin in the Cells. Red blood cells have the ability to concentrate hemoglobin in the cell fluid up to about 34 grams in each 100 milliliters of cells. 419 420 Unit VI Blood Cells, Immunity, and Blood Clotting The concentration does not rise above this value, because this is the metabolic limit of the cell’s hemoglobin-forming mechanism. Furthermore, in normal people, the percentage of hemoglobin is almost always near the maximum in each cell. However, when hemoglobin formation is deficient, the percentage of hemoglobin in the cells may fall considerably below this value, and the volume of the red cell may also decrease because of diminished hemoglobin to fill the cell. When the hematocrit (the percentage of blood that is cells—normally, 40 to 45 per cent) and the quantity of hemoglobin in each respective cell are normal, the whole blood of men contains an average of 15 grams of hemoglobin per 100 milliliters of cells; for women, it contains an average of 14 grams per 100 milliliters. As discussed in connection with blood transport of oxygen in Chapter 40, each gram of pure hemoglobin is capable of combining with 1.34 milliliters of oxygen. Therefore, in a normal man, a maximum of about 20 milliliters of oxygen can be carried in combination with hemoglobin in each 100 milliliters of blood, and in a normal woman, 19 milliliters of oxygen can be carried. Production of Red Blood Cells 100 Vertebra 50 Sternu m 0 sh ( ) aft (sh 25 r mu Fe 75 Tibia Cellularity (per cent) Areas of the Body That Produce Red Blood Cells. In the early weeks of embryonic life, primitive, nucleated red blood cells are produced in the yolk sac. During the middle trimester of gestation, the liver is the main organ for production of red blood cells, but reasonable numbers are also produced in the spleen and lymph nodes. Then, during the last month or so of gestation and after birth, red blood cells are produced exclusively in the bone marrow. As demonstrated in Figure 32–1, the bone marrow of essentially all bones produces red blood cells until a person is 5 years old. The marrow of the long bones, except for the proximal portions of the humeri and tibiae, becomes quite fatty and produces no more red blood cells after about age 20 years. Beyond this age, 0 5 10 15 20 Rib a ft ) 30 40 Age (years) 50 60 70 Figure 32–1 Relative rates of red blood cell production in the bone marrow of different bones at different ages. most red cells continue to be produced in the marrow of the membranous bones, such as the vertebrae, sternum, ribs, and ilia. Even in these bones, the marrow becomes less productive as age increases. Genesis of Blood Cells Pluripotential Hematopoietic Stem Cells, Growth Inducers, and Differentiation Inducers. The blood cells begin their lives in the bone marrow from a single type of cell called the pluripotential hematopoietic stem cell, from which all the cells of the circulating blood are eventually derived. Figure 32–2 shows the successive divisions of the pluripotential cells to form the different circulating blood cells. As these cells reproduce, a small portion of them remains exactly like the original pluripotential cells and is retained in the bone marrow to maintain a supply of these, although their numbers diminish with age. Most of the reproduced cells, however, differentiate to form the other cell types shown to the right in Figure 32–2. The intermediatestage cells are very much like the pluripotential stem cells, even though they have already become committed to a particular line of cells and are called committed stem cells. The different committed stem cells, when grown in culture, will produce colonies of specific types of blood cells. A committed stem cell that produces erythrocytes is called a colony-forming unit–erythrocyte, and the abbreviation CFU-E is used to designate this type of stem cell. Likewise, colony-forming units that form granulocytes and monocytes have the designation CFU-GM, and so forth. Growth and reproduction of the different stem cells are controlled by multiple proteins called growth inducers. Four major growth inducers have been described, each having different characteristics. One of these, interleukin-3, promotes growth and reproduction of virtually all the different types of committed stem cells, whereas the others induce growth of only specific types of cells. The growth inducers promote growth but not differentiation of the cells. This is the function of another set of proteins called differentiation inducers. Each of these causes one type of committed stem cell to differentiate one or more steps toward a final adult blood cell. Formation of the growth inducers and differentiation inducers is itself controlled by factors outside the bone marrow. For instance, in the case of erythrocytes (red blood cells), exposure of the blood to low oxygen for a long time results in growth induction, differentiation, and production of greatly increased numbers of erythrocytes, as discussed later in the chapter. In the case of some of the white blood cells, infectious diseases cause growth, differentiation, and eventual formation of specific types of white blood cells that are needed to combat each infection. Stages of Differentiation of Red Blood Cells The first cell that can be identified as belonging to the red blood cell series is the proerythroblast, shown at the starting point in Figure 32–3. Under appropriate Chapter 32 421 Red Blood Cells, Anemia, and Polycythemia Erythrocytes CFU-B (Colony-forming unit–blast) CFU-E (Colony-forming unit–erythrocytes) Granulocytes (Neutrophils) (Eosinophils) (Basophils) Monocytes PHSC (Pluripotent hematopoietic stem cell) CFU-S (Colony-forming unit–spleen) CFU-GM (Colony-forming unit– granulocytes, monocytes) Macrocytes Megakaryocytes CFU-M (Colony-forming unit– megakaryocytes) Platelets T lymphocytes Figure 32–2 Formation of the multiple different blood cells from the original pluripotent hematopoietic stem cell (PHSC) in the bone marrow. PHSC LSC (Lymphoid stem cell) B lymphocytes GENESIS OF RBC Proerythroblast Basophil erythroblast Microcytic, hypochromic anemia Sickle cell anemia Megaloblastic anemia Erythroblastosis fetalis Polychromatophil erythroblast Orthochromatic erythroblast Reticulocyte Erythrocytes Figure 32–3 Genesis of normal red blood cells (RBCs) and characteristics of RBCs in different types of anemias. 422 Unit VI Blood Cells, Immunity, and Blood Clotting stimulation, large numbers of these cells are formed from the CFU-E stem cells. Once the proerythroblast has been formed, it divides multiple times, eventually forming many mature red blood cells. The first-generation cells are called basophil erythroblasts because they stain with basic dyes; the cell at this time has accumulated very little hemoglobin. In the succeeding generations, as shown in Figure 32–3, the cells become filled with hemoglobin to a concentration of about 34 per cent, the nucleus condenses to a small size, and its final remnant is absorbed or extruded from the cell. At the same time, the endoplasmic reticulum is also reabsorbed. The cell at this stage is called a reticulocyte because it still contains a small amount of basophilic material, consisting of remnants of the Golgi apparatus, mitochondria, and a few other cytoplasmic organelles. During this reticulocyte stage, the cells pass from the bone marrow into the blood capillaries by diapedesis (squeezing through the pores of the capillary membrane). The remaining basophilic material in the reticulocyte normally disappears within 1 to 2 days, and the cell is then a mature erythrocyte. Because of the short life of the reticulocytes, their concentration among all the red cells of the blood is normally slightly less than 1 per cent. Regulation of Red Blood Cell Production—Role of Erythropoietin Hematopoietic Stem Cells Kidney Proerythroblasts Erythropoietin Red Blood Cells Decreases Tissue Oxygenation Decreases Factors that decrease oxygenation 1. Low blood volume 2. Anemia 3. Low hemoglobin 4. Poor blood flow 5. Pulmonary disease Figure 32–4 Function of the erythropoietin mechanism to increase production of red blood cells when tissue oxygenation decreases. The total mass of red blood cells in the circulatory system is regulated within narrow limits, so that (1) an adequate number of red cells is always available to provide sufficient transport of oxygen from the lungs to the tissues, yet (2) the cells do not become so numerous that they impede blood flow. What we know about this control mechanism is diagrammed in Figure 32–4 and is as follows. can also increase the rate of red cell production. This is especially apparent in prolonged cardiac failure and in many lung diseases, because the tissue hypoxia resulting from these conditions increases red cell production, with a resultant increase in hematocrit and usually total blood volume as well. Tissue Oxygenation Is the Most Essential Regulator of Red Blood Cell Production. Any condition that causes the Erythropoietin Stimulates Red Cell Production, and Its Formation Increases in Response to Hypoxia. The principal stim- quantity of oxygen transported to the tissues to decrease ordinarily increases the rate of red blood cell production. Thus, when a person becomes extremely anemic as a result of hemorrhage or any other condition, the bone marrow immediately begins to produce large quantities of red blood cells. Also, destruction of major portions of the bone marrow by any means, especially by x-ray therapy, causes hyperplasia of the remaining bone marrow, thereby attempting to supply the demand for red blood cells in the body. At very high altitudes, where the quantity of oxygen in the air is greatly decreased, insufficient oxygen is transported to the tissues, and red cell production is greatly increased. In this case, it is not the concentration of red blood cells in the blood that controls red cell production but the amount of oxygen transported to the tissues in relation to tissue demand for oxygen. Various diseases of the circulation that cause decreased blood flow through the peripheral vessels, and particularly those that cause failure of oxygen absorption by the blood as it passes through the lungs, ulus for red blood cell production in low oxygen states is a circulating hormone called erythropoietin, a glycoprotein with a molecular weight of about 34,000. In the absence of erythropoietin, hypoxia has little or no effect in stimulating red blood cell production. But when the erythropoietin system is functional, hypoxia causes a marked increase in erythropoietin production, and the erythropoietin in turn enhances red blood cell production until the hypoxia is relieved. Role of the Kidneys in Formation of Erythropoietin. In the normal person, about 90 per cent of all erythropoietin is formed in the kidneys; the remainder is formed mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is formed. One likely possibility is that the renal tubular epithelial cells secrete the erythropoietin, because anemic blood is unable to deliver enough oxygen from the peritubular capillaries to the highly oxygen-consuming tubular cells, thus stimulating erythropoietin production. Chapter 32 Red Blood Cells, Anemia, and Polycythemia At times, hypoxia in other parts of the body, but not in the kidneys, stimulates kidney erythropoietin secretion, which suggests that there might be some nonrenal sensor that sends an additional signal to the kidneys to produce this hormone. In particular, both norepinephrine and epinephrine and several of the prostaglandins stimulate erythropoietin production. When both kidneys are removed from a person or when the kidneys are destroyed by renal disease, the person invariably becomes very anemic because the 10 per cent of the normal erythropoietin formed in other tissues (mainly in the liver) is sufficient to cause only one third to one half the red blood cell formation needed by the body. 423 building blocks of DNA. Therefore, lack of either vitamin B12 or folic acid causes abnormal and diminished DNA and, consequently, failure of nuclear maturation and cell division. Furthermore, the erythroblastic cells of the bone marrow, in addition to failing to proliferate rapidly, produce mainly larger than normal red cells called macrocytes, and the cell itself has a flimsy membrane and is often irregular, large, and oval instead of the usual biconcave disc. These poorly formed cells, after entering the circulating blood, are capable of carrying oxygen normally, but their fragility causes them to have a short life, one half to one third normal. Therefore, it is said that deficiency of either vitamin B12 or folic acid causes maturation failure in the process of erythropoiesis. Effect of Erythropoietin in Erythrogenesis. When an animal or a person is placed in an atmosphere of low oxygen, erythropoietin begins to be formed within minutes to hours, and it reaches maximum production within 24 hours. Yet almost no new red blood cells appear in the circulating blood until about 5 days later. From this fact, as well as other studies, it has been determined that the important effect of erythropoietin is to stimulate the production of proerythroblasts from hematopoietic stem cells in the bone marrow. In addition, once the proerythroblasts are formed, the erythropoietin causes these cells to pass more rapidly through the different erythroblastic stages than they normally do, further speeding up the production of new red blood cells. The rapid production of cells continues as long as the person remains in a low oxygen state or until enough red blood cells have been produced to carry adequate amounts of oxygen to the tissues despite the low oxygen; at this time, the rate of erythropoietin production decreases to a level that will maintain the required number of red cells but not an excess. In the absence of erythropoietin, few red blood cells are formed by the bone marrow. At the other extreme, when large quantities of erythropoietin are formed available, and if there is plenty of iron and other required nutrients available, the rate of red blood cell production can rise to perhaps 10 or more times normal. Therefore, the erythropoietin mechanism for controlling red blood cell production is a powerful one. Maturation of Red Blood Cells—Requirement for Vitamin B12 (Cyanocobalamin) and Folic Acid Because of the continuing need to replenish red blood cells, the erythropoietic cells of the bone marrow are among the most rapidly growing and reproducing cells in the entire body. Therefore, as would be expected, their maturation and rate of production are affected greatly by a person’s nutritional status. Especially important for final maturation of the red blood cells are two vitamins, vitamin B12 and folic acid. Both of these are essential for the synthesis of DNA, because each in a different way is required for the formation of thymidine triphosphate, one of the essential Maturation Failure Caused by Poor Absorption of Vitamin B12 from the Gastrointestinal Tract—Pernicious Anemia. A common cause of red blood cell maturation failure is failure to absorb vitamin B12 from the gastrointestinal tract. This often occurs in the disease pernicious anemia, in which the basic abnormality is an atrophic gastric mucosa that fails to produce normal gastric secretions. The parietal cells of the gastric glands secrete a glycoprotein called intrinsic factor, which combines with vitamin B12 in food and makes the B12 available for absorption by the gut. It does this in the following way: (1) Intrinsic factor binds tightly with the vitamin B12. In this bound state, the B12 is protected from digestion by the gastrointestinal secretions. (2) Still in the bound state, intrinsic factor binds to specific receptor sites on the brush border membranes of the mucosal cells in the ileum. (3) Then, vitamin B12 is transported into the blood during the next few hours by the process of pinocytosis, carrying intrinsic factor and the vitamin together through the membrane. Lack of intrinsic factor, therefore, causes diminished availability of vitamin B12 because of faulty absorption of the vitamin. Once vitamin B12 has been absorbed from the gastrointestinal tract, it is first stored in large quantities in the liver, then released slowly as needed by the bone marrow. The minimum amount of vitamin B12 required each day to maintain normal red cell maturation is only 1 to 3 micrograms, and the normal storage in the liver and other body tissues is about 1000 times this amount.Therefore, 3 to 4 years of defective B12 absorption are usually required to cause maturation failure anemia. Failure of Maturation Caused by Deficiency of Folic Acid (Pteroylglutamic Acid). Folic acid is a normal constituent of green vegetables, some fruits, and meats (especially liver). However, it is easily destroyed during cooking. Also, people with gastrointestinal absorption abnormalities, such as the frequently occurring small intestinal disease called sprue, often have serious difficulty absorbing both folic acid and vitamin B12. Therefore, in many instances of maturation failure, the cause is deficiency of intestinal absorption of both folic acid and vitamin B12. 424 Unit VI I. 2 succinyl-CoA + 2 glycine II. III. IV. V. Blood Cells, Immunity, and Blood Clotting A P C C HC CH N H 4 pyrrole protoporphyrin IX (pyrrole) protoporphyrin IX + Fe++ heme heme + polypeptide hemoglobin chain (a or b) 2 a chains + 2 b chains hemoglobin A Figure 32–5 Formation of hemoglobin. Formation of Hemoglobin Synthesis of hemoglobin begins in the proerythroblasts and continues even into the reticulocyte stage of the red blood cells. Therefore, when reticulocytes leave the bone marrow and pass into the blood stream, they continue to form minute quantities of hemoglobin for another day or so until they become mature erythrocytes. Figure 32–5 shows the basic chemical steps in the formation of hemoglobin. First, succinyl-CoA, formed in the Krebs metabolic cycle (as explained in Chapter 67), binds with glycine to form a pyrrole molecule. In turn, four pyrroles combine to form protoporphyrin IX, which then combines with iron to form the heme molecule. Finally, each heme molecule combines with a long polypeptide chain, a globin synthesized by ribosomes, forming a subunit of hemoglobin called a hemoglobin chain (Figure 32–6). Each chain has a molecular weight of about 16,000; four of these in turn bind together loosely to form the whole hemoglobin molecule. There are several slight variations in the different subunit hemoglobin chains, depending on the amino acid composition of the polypeptide portion. The different types of chains are designated alpha chains, beta chains, gamma chains, and delta chains. The most common form of hemoglobin in the adult human being, hemoglobin A, is a combination of two alpha chains and two beta chains. Hemoglobin A has a molecular weight of 64,458. Because each hemoglobin chain has a heme prosthetic group containing an atom of iron, and because there are four hemoglobin chains in each hemoglobin molecule, one finds four iron atoms in each hemoglobin molecule; each of these can bind loosely with one molecule of oxygen, making a total of four molecules of oxygen (or eight oxygen atoms) that can be transported by each hemoglobin molecule. The types of hemoglobin chains in the hemoglobin molecule determine the binding affinity of the hemoglobin for oxygen. Abnormalities of the chains can alter the physical characteristics of the hemoglobin molecule as well. For instance, in sickle cell anemia, the amino acid valine is substituted for glutamic acid at CH2 H C CH H3C CH3 A B Fe HC CH2 (–)N N N(–) H3C CH O2 N C D CH2 CH C H CH3 CH2 CH2 CH2 COOH COOH Polypepitide (hemoglobin chain–a or b) Figure 32–6 Basic structure of the hemoglobin molecule, showing one of the four heme chains that bind together to form the hemoglobin molecule. one point in each of the two beta chains. When this type of hemoglobin is exposed to low oxygen, it forms elongated crystals inside the red blood cells that are sometimes 15 micrometers in length. These make it almost impossible for the cells to pass through many small capillaries, and the spiked ends of the crystals are likely to rupture the cell membranes, leading to sickle cell anemia. Combination of Hemoglobin with Oxygen. The most impor- tant feature of the hemoglobin molecule is its ability to combine loosely and reversibly with oxygen. This ability is discussed in detail in Chapter 40 in relation Chapter 32 425 Red Blood Cells, Anemia, and Polycythemia to respiration, because the primary function of hemoglobin in the body is to combine with oxygen in the lungs and then to release this oxygen readily in the peripheral tissue capillaries, where the gaseous tension of oxygen is much lower than in the lungs. Oxygen does not combine with the two positive bonds of the iron in the hemoglobin molecule. Instead, it binds loosely with one of the so-called coordination bonds of the iron atom. This is an extremely loose bond, so that the combination is easily reversible. Furthermore, the oxygen does not become ionic oxygen but is carried as molecular oxygen (composed of two oxygen atoms) to the tissues, where, because of the loose, readily reversible combination, it is released into the tissue fluids still in the form of molecular oxygen rather than ionic oxygen. Iron Metabolism Because iron is important for the formation not only of hemoglobin but also of other essential elements in the body (e.g., myoglobin, cytochromes, cytochrome oxidase, peroxidase, catalase), it is important to understand the means by which iron is utilized in the body. The total quantity of iron in the body averages 4 to 5 grams, about 65 per cent of which is in the form of hemoglobin. About 4 per cent is in the form of myoglobin, 1 per cent is in the form of the various heme compounds that promote intracellular oxidation, 0.1 per cent is combined with the protein transferrin in the blood plasma, and 15 to 30 per cent is stored for later use, mainly in the reticuloendothelial system and liver parenchymal cells, principally in the form of ferritin. Transport and Storage of Iron. Transport, storage, and metabolism of iron in the body are diagrammed in Figure 32–7 and can be explained as follows: When iron is absorbed from the small intestine, it immediately combines in the blood plasma with a beta globulin, apotransferrin, to form transferrin, which is then transported in the plasma. The iron is loosely bound in the transferrin and, consequently, can be released to any tissue cell at any point in the body. Excess iron in the blood is deposited especially in the liver hepatocytes and less in the reticuloendothelial cells of the bone marrow. In the cell cytoplasm, iron combines mainly with a protein, apoferritin, to form ferritin. Apoferritin has a molecular weight of about 460,000, and varying quantities of iron can combine in clusters of iron radicals with this large molecule; therefore, ferritin may contain only a small amount of iron or a large amount. This iron stored as ferritin is called storage iron. Smaller quantities of the iron in the storage pool are in an extremely insoluble form called hemosiderin. This is especially true when the total quantity of iron in the body is more than the apoferritin storage pool can accommodate. Hemosiderin collects in cells in the form of large clusters that can be observed microscopically as large particles. In contrast, ferritin particles are so small and dispersed that they usually can be seen in the cell cytoplasm only with the electron microscope. When the quantity of iron in the plasma falls low, some of the iron in the ferritin storage pool is removed easily and transported in the form of transferrin in the plasma to the areas of the body where it is needed. A unique characteristic of the transferrin molecule is that it binds strongly with receptors in the cell membranes of erythroblasts in the bone marrow. Then, along with its bound iron, it is ingested into the erythroblasts by endocytosis. There the transferrin delivers the iron directly to the mitochondria, where heme is synthesized. In people who do not have adequate quantities of transferrin in their blood, failure to transport iron to the erythroblasts in this manner can cause severe hypochromic anemia—that is, red cells that contain much less hemoglobin than normal. Bilirubin (excreted) Tissues Ferritin Hemosiderin Macrophages Degrading hemoglobin Hemoglobin Red Cells Heme Free iron Free iron Enzymes Transferrin–Fe Plasma Blood loss – 0.7 mg Fe Fe++ absorbed Fe excreted–0.6 mg daily (small intestine) daily in menses Figure 32–7 Iron transport and metabolism. 426 Unit VI Blood Cells, Immunity, and Blood Clotting When red blood cells have lived their life span and are destroyed, the hemoglobin released from the cells is ingested by monocyte-macrophage cells. There, iron is liberated and is stored mainly in the ferritin pool to be used as needed for the formation of new hemoglobin. Daily Loss of Iron. A man excretes about 0.6 milligram of iron each day, mainly into the feces. Additional quantities of iron are lost when bleeding occurs. For a woman, additional menstrual loss of blood brings longterm iron loss to an average of about 1.3 mg/day. Absorption of Iron from the Intestinal Tract Iron is absorbed from all parts of the small intestine, mostly by the following mechanism. The liver secretes moderate amounts of apotransferrin into the bile, which flows through the bile duct into the duodenum. Here, the apotransferrin binds with free iron and also with certain iron compounds, such as hemoglobin and myoglobin from meat, two of the most important sources of iron in the diet. This combination is called transferrin. It, in turn, is attracted to and binds with receptors in the membranes of the intestinal epithelial cells. Then, by pinocytosis, the transferrin molecule, carrying its iron store, is absorbed into the epithelial cells and later released into the blood capillaries beneath these cells in the form of plasma transferrin. Iron absorption from the intestines is extremely slow, at a maximum rate of only a few milligrams per day. This means that even when tremendous quantities of iron are present in the food, only small proportions can be absorbed. Regulation of Total Body Iron by Controlling Rate of Absorption. When the body has become saturated with iron so that essentially all apoferritin in the iron storage areas is already combined with iron, the rate of additional iron absorption from the intestinal tract becomes greatly decreased. Conversely, when the iron stores have become depleted, the rate of absorption can accelerate probably five or more times normal. Thus, total body iron is regulated mainly by altering the rate of absorption. Life Span and Destruction of Red Blood Cells When red blood cells are delivered from the bone marrow into the circulatory system, they normally circulate an average of 120 days before being destroyed. Even though mature red cells do not have a nucleus, mitochondria, or endoplasmic reticulum, they do have cytoplasmic enzymes that are capable of metabolizing glucose and forming small amounts of adenosine triphosphate. These enzymes also (1) maintain pliability of the cell membrane, (2) maintain membrane transport of ions, (3) keep the iron of the cells’ hemoglobin in the ferrous form rather than ferric form, and (4) prevent oxidation of the proteins in the red cells. Even so, the metabolic systems of old red cells become progressively less active, and the cells become more and more fragile, presumably because their life processes wear out. Once the red cell membrane becomes fragile, the cell ruptures during passage through some tight spot of the circulation. Many of the red cells self-destruct in the spleen, where they squeeze through the red pulp of the spleen. There, the spaces between the structural trabeculae of the red pulp, through which most of the cells must pass, are only 3 micrometers wide, in comparison with the 8-micrometer diameter of the red cell. When the spleen is removed, the number of old abnormal red cells circulating in the blood increases considerably. Destruction of Hemoglobin. When red blood cells burst and release their hemoglobin, the hemoglobin is phagocytized almost immediately by macrophages in many parts of the body, but especially by the Kupffer cells of the liver and macrophages of the spleen and bone marrow. During the next few hours to days, the macrophages release iron from the hemoglobin and pass it back into the blood, to be carried by transferrin either to the bone marrow for the production of new red blood cells or to the liver and other tissues for storage in the form of ferritin. The porphyrin portion of the hemoglobin molecule is converted by the macrophages, through a series of stages, into the bile pigment bilirubin, which is released into the blood and later removed from the body by secretion through the liver into the bile; this is discussed in relation to liver function in Chapter 70. Anemias Anemia means deficiency of hemoglobin in the blood, which can be caused by either too few red blood cells or too little hemoglobin in the cells. Some types of anemia and their physiologic causes are the following. Blood Loss Anemia. After rapid hemorrhage, the body replaces the fluid portion of the plasma in 1 to 3 days, but this leaves a low concentration of red blood cells. If a second hemorrhage does not occur, the red blood cell concentration usually returns to normal within 3 to 6 weeks. In chronic blood loss, a person frequently cannot absorb enough iron from the intestines to form hemoglobin as rapidly as it is lost. Red cells are then produced that are much smaller than normal and have too little hemoglobin inside them, giving rise to microcytic, hypochromic anemia, which is shown in Figure 32–3. Aplastic Anemia. Bone marrow aplasia means lack of functioning bone marrow. For instance, a person exposed to gamma ray radiation from a nuclear bomb blast can sustain complete destruction of bone marrow, followed in a few weeks by lethal anemia. Likewise, excessive x-ray treatment, certain industrial chemicals, and even drugs to which the person might be sensitive can cause the same effect. Chapter 32 Red Blood Cells, Anemia, and Polycythemia Megaloblastic Anemia. Based on the earlier discussions of vitamin B12, folic acid, and intrinsic factor from the stomach mucosa, one can readily understand that loss of any one of these can lead to slow reproduction of erythroblasts in the bone marrow. As a result, the red cells grow too large, with odd shapes, and are called megaloblasts. Thus, atrophy of the stomach mucosa, as occurs in pernicious anemia, or loss of the entire stomach after surgical total gastrectomy can lead to megaloblastic anemia. Also, patients who have intestinal sprue, in which folic acid, vitamin B12, and other vitamin B compounds are poorly absorbed, often develop megaloblastic anemia. Because in these states the erythroblasts cannot proliferate rapidly enough to form normal numbers of red blood cells, those red cells that are formed are mostly oversized, have bizarre shapes, and have fragile membranes. These cells rupture easily, leaving the person in dire need of an adequate number of red cells. Hemolytic Anemia. Different abnormalities of the red blood cells, many of which are hereditarily acquired, make the cells fragile, so that they rupture easily as they go through the capillaries, especially through the spleen. Even though the number of red blood cells formed may be normal, or even much greater than normal in some hemolytic diseases, the life span of the fragile red cell is so short that the cells are destroyed faster than they can be formed, and serious anemia results. Some of these types of anemia are the following. In hereditary spherocytosis, the red cells are very small and spherical rather than being biconcave discs. These cells cannot withstand compression forces because they do not have the normal loose, baglike cell membrane structure of the biconcave discs. On passing through the splenic pulp and some other tight vascular beds, they are easily ruptured by even slight compression. In sickle cell anemia, which is present in 0.3 to 1.0 per cent of West African and American blacks, the cells have an abnormal type of hemoglobin called hemoglobin S, containing faulty beta chains in the hemoglobin molecule, as explained earlier in the chapter. When this hemoglobin is exposed to low concentrations of oxygen, it precipitates into long crystals inside the red blood cell. These crystals elongate the cell and give it the appearance of a sickle rather than a biconcave disc. The precipitated hemoglobin also damages the cell membrane, so that the cells become highly fragile, leading to serious anemia. Such patients frequently experience a vicious circle of events called a sickle cell disease “crisis,” in which low oxygen tension in the tissues causes sickling, which leads to ruptured red cells, which causes a further decrease in oxygen tension and still more sickling and red cell destruction. Once the process starts, it progresses rapidly, eventuating in a serious decrease in red blood cells within a few hours and, often, death. In erythroblastosis fetalis, Rh-positive red blood cells in the fetus are attacked by antibodies from an Rh-negative mother. These antibodies make the 427 Rh-positive cells fragile, leading to rapid rupture and causing the child to be born with serious anemia. This is discussed in Chapter 35 in relation to the Rh factor of blood. The extremely rapid formation of new red cells to make up for the destroyed cells in erythroblastosis fetalis causes a large number of early blast forms of red cells to be released from the bone marrow into the blood. Effects of Anemia on Function of the Circulatory System The viscosity of the blood, which was discussed in Chapter 14, depends almost entirely on the blood concentration of red blood cells. In severe anemia, the blood viscosity may fall to as low as 1.5 times that of water rather than the normal value of about 3. This decreases the resistance to blood flow in the peripheral blood vessels, so that far greater than normal quantities of blood flow through the tissues and return to the heart, thereby greatly increasing cardiac output. Moreover, hypoxia resulting from diminished transport of oxygen by the blood causes the peripheral tissue blood vessels to dilate, allowing a further increase in the return of blood to the heart and increasing the cardiac output to a still higher level— sometimes three to four times normal. Thus, one of the major effects of anemia is greatly increased cardiac output, as well as increased pumping workload on the heart. The increased cardiac output in anemia partially offsets the reduced oxygen-carrying effect of the anemia, because even though each unit quantity of blood carries only small quantities of oxygen, the rate of blood flow may be increased enough so that almost normal quantities of oxygen are actually delivered to the tissues. However, when a person with anemia begins to exercise, the heart is not capable of pumping much greater quantities of blood than it is already pumping. Consequently, during exercise, which greatly increases tissue demand for oxygen, extreme tissue hypoxia results, and acute cardiac failure ensues. Polycythemia Secondary Polycythemia. Whenever the tissues become hypoxic because of too little oxygen in the breathed air, such as at high altitudes, or because of failure of oxygen delivery to the tissues, such as in cardiac failure, the blood-forming organs automatically produce large quantities of extra red blood cells. This condition is called secondary polycythemia, and the red cell count commonly rises to 6 to 7 million/mm3, about 30 per cent above normal. A common type of secondary polycythemia, called physiologic polycythemia, occurs in natives who live at altitudes of 14,000 to 17,000 feet, where the atmospheric oxygen is very low. The blood count is generally 6 to 7 million/mm3; this allows these people to perform 428 Unit VI Blood Cells, Immunity, and Blood Clotting reasonably high levels of continuous work even in a rarefied atmosphere. Polycythemia Vera (Erythremia). In addition to those people who have physiologic polycythemia, others have a pathological condition known as polycythemia vera, in which the red blood cell count may be 7 to 8 million/mm3 and the hematocrit may be 60 to 70 per cent instead of the normal 40 to 45 per cent. Polycythemia vera is caused by a genetic aberration in the hemocytoblastic cells that produce the blood cells. The blast cells no longer stop producing red cells when too many cells are already present. This causes excess production of red blood cells in the same manner that a breast tumor causes excess production of a specific type of breast cell. It usually causes excess production of white blood cells and platelets as well. In polycythemia vera, not only does the hematocrit increase, but the total blood volume also increases, on some occasions to almost twice normal. As a result, the entire vascular system becomes intensely engorged. In addition, many blood capillaries become plugged by the viscous blood; the viscosity of the blood in polycythemia vera sometimes increases from the normal of 3 times the viscosity of water to 10 times that of water. Effect of Polycythemia on Function of the Circulatory System Because of the greatly increased viscosity of the blood in polycythemia, blood flow through the peripheral blood vessels is often very sluggish. In accordance with the factors that regulate return of blood to the heart, as discussed in Chapter 20, increasing blood viscosity decreases the rate of venous return to the heart. Conversely, the blood volume is greatly increased in polycythemia, which tends to increase venous return. Actually, the cardiac output in polycythemia is not far from normal, because these two factors more or less neutralize each other. The arterial pressure is also normal in most people with polycythemia, although in about one third of them, the arterial pressure is elevated. This means that the blood pressure–regulating mechanisms can usually offset the tendency for increased blood viscosity to increase peripheral resistance and, thereby, increase arterial pressure. Beyond certain limits, however, these regulations fail, and hypertension develops. The color of the skin depends to a great extent on the quantity of blood in the skin subpapillary venous plexus. In polycythemia vera, the quantity of blood in this plexus is greatly increased. Further, because the blood passes sluggishly through the skin capillaries before entering the venous plexus, a larger than normal quantity of hemoglobin is deoxygenated. The blue color of all this deoxygenated hemoglobin masks the red color of the oxygenated hemoglobin. Therefore, a person with polycythemia vera ordinarily has a ruddy complexion with a bluish (cyanotic) tint to the skin. References Alayash AI: Oxygen therapeutics: can we tame haemoglobin? Nat Rev Drug Discov 3:152, 2004. Brissot P, Troadec MB, Loreal O: The clinical relevance of new insights in iron transport and metabolism. Curr Hematol Rep 3:107, 2004. Claster S, Vichinsky EP: Managing sickle cell disease. BMJ 327:1151, 2003. Fandrey J: Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am J Physiol Regul Integr Comp Physiol 286:R977, 2004. Hallberg L: Perspectives on nutritional iron deficiency. Annu Rev Nutr 21:1, 2001. Hentze MW, Muckenthaler MU, Andrews NC: Balancing acts: molecular control of mammalian iron metabolism. Cell 117:285, 2004. Lappin T: The cellular biology of erythropoietin receptors. Oncologist 8(Suppl 1):15, 2003. Maxwell P: HIF-1: an oxygen response system with special relevance to the kidney. J Am Soc Nephrol 14:2712, 2003. Persons DA: Update on gene therapy for hemoglobin disorders. Curr Opin Mol Ther 5:508, 2003. Pietrangelo A: Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 350:2383, 2004. Shah S, Vega R: Hereditary spherocytosis. Pediatr Rev 25:168, 2004. Tefferi A: A contemporary approach to the diagnosis and management of polycythemia vera. Curr Hematol Rep 2:237, 2003. Trigg ME: Hematopoietic stem cells. Pediatrics 113(4 Suppl):1051, 2004. C H A P T E R 3 3 Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System, and Inflammation Our bodies are exposed continually to bacteria, viruses, fungi, and parasites, all of which occur normally and to varying degrees in the skin, the mouth, the respiratory passageways, the intestinal tract, the lining membranes of the eyes, and even the urinary tract. Many of these infectious agents are capable of causing serious abnormal physiologic function or even death if they invade the deeper tissues. In addition, we are exposed intermittently to other highly infectious bacteria and viruses besides those that are normally present, and these can cause acute lethal diseases such as pneumonia, streptococcal infection, and typhoid fever. Our bodies have a special system for combating the different infectious and toxic agents. This is comprised of blood leukocytes (white blood cells) and tissue cells derived from leukocytes. These cells work together in two ways to prevent disease: (1) by actually destroying invading bacteria or viruses by phagocytosis, and (2) by forming antibodies and sensitized lymphocytes, one or both of which may destroy or inactivate the invader. This chapter is concerned with the first of these methods, and Chapter 34 with the second. Leukocytes (White Blood Cells) The leukocytes, also called white blood cells, are the mobile units of the body’s protective system. They are formed partially in the bone marrow (granulocytes and monocytes and a few lymphocytes) and partially in the lymph tissue (lymphocytes and plasma cells). After formation, they are transported in the blood to different parts of the body where they are needed. The real value of the white blood cells is that most of them are specifically transported to areas of serious infection and inflammation, thereby providing a rapid and potent defense against infectious agents. As we see later, the granulocytes and monocytes have a special ability to “seek out and destroy” a foreign invader. General Characteristics of Leukocytes Types of White Blood Cells. Six types of white blood cells are normally present in the blood. They are polymorphonuclear neutrophils, polymorphonuclear eosinophils, polymorphonuclear basophils, monocytes, lymphocytes, and, occasionally, plasma cells. In addition, there are large numbers of platelets, which are fragments of another type of cell similar to the white blood cells found in the bone marrow, the megakaryocyte. The first three types of cells, the polymorphonuclear cells, all have a granular appearance, as shown in cell numbers 7, 429 430 Unit VI Blood Cells, Immunity, and Blood Clotting Genesis of Myelocytes Genesis of Lymphocytes 1 3 2 13 4 8 11 Figure 33–1 14 Genesis of white blood cells. The different cells of the myelocyte series are 1, myeloblast; 2, promyelocyte; 3, megakaryocyte; 4, neutrophil myelocyte; 5, young neutrophil metamyelocyte; 6, “band” neutrophil metamyelocyte; 7, polymorphonuclear neutrophil; 8, eosinophil myelocyte; 9, eosinophil metamyelocyte; 10, polymorphonuclear eosinophil; 11, basophil myelocyte; 12, polymorphonuclear basophil; 13–16, stages of monocyte formation. 5 9 15 6 7 10 12 16 10, and 12 in Figure 33–1, for which reason they are called granulocytes, or, in clinical terminology, “polys,” because of the multiple nuclei. The granulocytes and monocytes protect the body against invading organisms mainly by ingesting them—that is, by phagocytosis. The lymphocytes and plasma cells function mainly in connection with the immune system; this is discussed in Chapter 34. Finally, the function of platelets is specifically to activate the blood clotting mechanism, which is discussed in Chapter 36. Diapedesis Chemotaxis source Concentrations of the Different White Blood Cells in the Blood. The adult human being has about 7000 white blood cells per microliter of blood (in comparison with 5 million red blood cells). Of the total white blood cells, the normal percentages of the different types are approximately the following: Polymorphonuclear neutrophils Polymorphonuclear eosinophils Polymorphonuclear basophils Monocytes Lymphocytes 62.0% 2.3% 0.4% 5.3% 30.0% The number of platelets, which are only cell fragments, in each microliter of blood is normally about 300,000. Genesis of the White Blood Cells Early differentiation of the pluripotential hematopoietic stem cell into the different types of committed stem cells is shown in Figure 32–2 in the previous Increased permeability Margination Chemotactic substance Figure 33–2 Movement of neutrophils by diapedesis through capillary pores and by chemotaxis toward an area of tissue damage. chapter. Aside from those cells committed to form red blood cells, two major lineages of white blood cells are formed, the myelocytic and the lymphocytic lineages. The left side of Figure 33–1 shows the myelocytic lineage, beginning with the myeloblast; the right shows the lymphocytic lineage, beginning with the lymphoblast. The granulocytes and monocytes are formed only in the bone marrow. Lymphocytes and plasma cells are produced mainly in the various lymphogenous tissues—especially the lymph glands, spleen, thymus, tonsils, and various pockets of lymphoid tissue Chapter 33 Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System elsewhere in the body, such as in the bone marrow and in so-called Peyer’s patches underneath the epithelium in the gut wall. The white blood cells formed in the bone marrow are stored within the marrow until they are needed in the circulatory system. Then, when the need arises, various factors cause them to be released (these factors are discussed later). Normally, about three times as many white blood cells are stored in the marrow as circulate in the entire blood.This represents about a 6-day supply of these cells. The lymphocytes are mostly stored in the various lymphoid tissues, except for a small number that are temporarily being transported in the blood. As shown in Figure 33–1, megakaryocytes (cell 3) are also formed in the bone marrow. These megakaryocytes fragment in the bone marrow; the small fragments, known as platelets (or thrombocytes), then pass into the blood. They are very important in the initiation of blood clotting. Life Span of the White Blood Cells The life of the granulocytes after being released from the bone marrow is normally 4 to 8 hours circulating in the blood and another 4 to 5 days in tissues where they are needed. In times of serious tissue infection, this total life span is often shortened to only a few hours because the granulocytes proceed even more rapidly to the infected area, perform their functions, and, in the process, are themselves destroyed. The monocytes also have a short transit time, 10 to 20 hours in the blood, before wandering through the capillary membranes into the tissues. Once in the tissues, they swell to much larger sizes to become tissue macrophages, and, in this form, can live for months unless destroyed while performing phagocytic functions. These tissue macrophages are the basis of the tissue macrophage system, discussed in greater detail later, which provides continuing defense against infection. Lymphocytes enter the circulatory system continually, along with drainage of lymph from the lymph nodes and other lymphoid tissue. After a few hours, they pass out of the blood back into the tissues by diapedesis. Then, still later, they re-enter the lymph and return to the blood again and again; thus, there is continual circulation of lymphocytes through the body. The lymphocytes have life spans of weeks or months; this life span depends on the body’s need for these cells. The platelets in the blood are replaced about once every 10 days; in other words, about 30,000 platelets are formed each day for each microliter of blood. 431 other injurious agents. The neutrophils are mature cells that can attack and destroy bacteria even in the circulating blood. Conversely, the tissue macrophages begin life as blood monocytes, which are immature cells while still in the blood and have little ability to fight infectious agents at that time. However, once they enter the tissues, they begin to swell—sometimes increasing their diameters as much as fivefold—to as great as 60 to 80 micrometers, a size that can barely be seen with the naked eye. These cells are now called macrophages, and they are extremely capable of combating intratissue disease agents. White Blood Cells Enter the Tissue Spaces by Diapedesis. Neutrophils and monocytes can squeeze through the pores of the blood capillaries by diapedesis. That is, even though a pore is much smaller than a cell, a small portion of the cell slides through the pore at a time; the portion sliding through is momentarily constricted to the size of the pore, as shown in Figure 33–2. White Blood Cells Move Through Tissue Spaces by Ameboid Motion. Both neutrophils and macrophages can move through the tissues by ameboid motion, described in Chapter 2. Some cells move at velocities as great as 40 mm/min, a distance as great as their own length each minute. White Blood Cells Are Attracted to Inflamed Tissue Areas by Chemotaxis. Many different chemical substances in the tissues cause both neutrophils and macrophages to move toward the source of the chemical. This phenomenon, shown in Figure 33–2, is known as chemotaxis. When a tissue becomes inflamed, at least a dozen different products are formed that can cause chemotaxis toward the inflamed area. They include (1) some of the bacterial or viral toxins, (2) degenerative products of the inflamed tissues themselves, (3) several reaction products of the “complement complex” (discussed in Chapter 34) activated in inflamed tissues, and (4) several reaction products caused by plasma clotting in the inflamed area, as well as other substances. As shown in Figure 33–2, chemotaxis depends on the concentration gradient of the chemotactic substance. The concentration is greatest near the source, which directs the unidirectional movement of the white cells. Chemotaxis is effective up to 100 micrometers away from an inflamed tissue. Therefore, because almost no tissue area is more than 50 micrometers away from a capillary, the chemotactic signal can easily move hordes of white cells from the capillaries into the inflamed area. Phagocytosis Neutrophils and Macrophages Defend Against Infections It is mainly the neutrophils and tissue macrophages that attack and destroy invading bacteria, viruses, and The most important function of the neutrophils and macrophages is phagocytosis, which means cellular ingestion of the offending agent. Phagocytes must be selective of the material that is phagocytized; otherwise, normal cells and structures of the body might be 432 Unit VI Blood Cells, Immunity, and Blood Clotting ingested. Whether phagocytosis will occur depends especially on three selective procedures. First, most natural structures in the tissues have smooth surfaces, which resist phagocytosis. But if the surface is rough, the likelihood of phagocytosis is increased. Second, most natural substances of the body have protective protein coats that repel the phagocytes. Conversely, most dead tissues and foreign particles have no protective coats, which makes them subject to phagocytosis. Third, the immune system of the body (described in detail in Chapter 34) develops antibodies against infectious agents such as bacteria. The antibodies then adhere to the bacterial membranes and thereby make the bacteria especially susceptible to phagocytosis. To do this, the antibody molecule also combines with the C3 product of the complement cascade, which is an additional part of the immune system discussed in the next chapter. The C3 molecules, in turn, attach to receptors on the phagocyte membrane, thus initiating phagocytosis. This selection and phagocytosis process is called opsonization. Phagocytosis by Neutrophils. The neutrophils entering the tissues are already mature cells that can immediately begin phagocytosis. On approaching a particle to be phagocytized, the neutrophil first attaches itself to the particle and then projects pseudopodia in all directions around the particle. The pseudopodia meet one another on the opposite side and fuse. This creates an enclosed chamber that contains the phagocytized particle. Then the chamber invaginates to the inside of the cytoplasmic cavity and breaks away from the outer cell membrane to form a free-floating phagocytic vesicle (also called a phagosome) inside the cytoplasm. A single neutrophil can usually phagocytize 3 to 20 bacteria before the neutrophil itself becomes inactivated and dies. Phagocytosis by Macrophages. Macrophages are the end- stage product of monocytes that enter the tissues from the blood. When activated by the immune system as described in Chapter 34, they are much more powerful phagocytes than neutrophils, often capable of phagocytizing as many as 100 bacteria. They also have the ability to engulf much larger particles, even whole red blood cells or, occasionally, malarial parasites, whereas neutrophils are not capable of phagocytizing particles much larger than bacteria. Also, after digesting particles, macrophages can extrude the residual products and often survive and function for many more months. Once Phagocytized, Most Particles Are Digested by Intracellular Enzymes. Once a foreign particle has been phagocy- tized, lysosomes and other cytoplasmic granules in the neutrophil or macrophage immediately come in contact with the phagocytic vesicle, and their membranes fuse, thereby dumping many digestive enzymes and bactericidal agents into the vesicle. Thus, the phagocytic vesicle now becomes a digestive vesicle, and digestion of the phagocytized particle begins immediately. Both neutrophils and macrophages contain an abundance of lysosomes filled with proteolytic enzymes especially geared for digesting bacteria and other foreign protein matter. The lysosomes of macrophages (but not of neutrophils) also contain large amounts of lipases, which digest the thick lipid membranes possessed by some bacteria such as the tuberculosis bacillus. Both Neutrophils and Macrophages Can Kill Bacteria. In addition to the digestion of ingested bacteria in phagosomes, neutrophils and macrophages contain bactericidal agents that kill most bacteria even when the lysosomal enzymes fail to digest them. This is especially important, because some bacteria have protective coats or other factors that prevent their destruction by digestive enzymes. Much of the killing effect results from several powerful oxidizing agents formed by enzymes in the membrane of the phagosome or by a special organelle called the peroxisome. These oxidizing agents include large quantities of superoxide (O2–), hydrogen peroxide (H2O2), and hydroxyl ions (–OH–), all of which are lethal to most bacteria, even in small quantities. Also, one of the lysosomal enzymes, myeloperoxidase, catalyzes the reaction between H2O2 and chloride ions to form hypochlorite, which is exceedingly bactericidal. Some bacteria, however, notably the tuberculosis bacillus, have coats that are resistant to lysosomal digestion and also secrete substances that partially resist the killing effects of the neutrophils and macrophages. These bacteria are responsible for many of the chronic diseases, an example of which is tuberculosis. Monocyte-Macrophage Cell System (Reticuloendothelial System) In the preceding paragraphs, we described the macrophages mainly as mobile cells that are capable of wandering through the tissues. However, after entering the tissues and becoming macrophages, another large portion of monocytes becomes attached to the tissues and remains attached for months or even years until they are called on to perform specific local protective functions. They have the same capabilities as the mobile macrophages to phagocytize large quantities of bacteria, viruses, necrotic tissue, or other foreign particles in the tissue. And, when appropriately stimulated, they can break away from their attachments and once again become mobile macrophages that respond to chemotaxis and all the other stimuli related to the inflammatory process.Thus, the body has a widespread “monocyte-macrophage system” in virtually all tissue areas. The total combination of monocytes, mobile macrophages, fixed tissue macrophages, and a few Chapter 33 Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System specialized endothelial cells in the bone marrow, spleen, and lymph nodes is called the reticuloendothelial system. However, all or almost all these cells originate from monocytic stem cells; therefore, the reticuloendothelial system is almost synonymous with the monocyte-macrophage system. Because the term reticuloendothelial system is much better known in medical literature than the term monocytemacrophage system, it should be remembered as a generalized phagocytic system located in all tissues, especially in those tissue areas where large quantities of particles, toxins, and other unwanted substances must be destroyed. Tissue Macrophages in the Skin and Subcutaneous Tissues (Histiocytes). Although the skin is mainly impregnable to infectious agents, this is no longer true when the skin is broken. When infection begins in a subcutaneous tissue and local inflammation ensues, local tissue macrophages can divide in situ and form still more macrophages. Then they perform the usual functions of attacking and destroying the infectious agents, as described earlier. Macrophages in the Lymph Nodes. Essentially no particulate matter that enters the tissues, such as bacteria, can be absorbed directly through the capillary membranes into the blood. Instead, if the particles are not destroyed locally in the tissues, they enter the lymph and flow to the lymph nodes located intermittently along the course of the lymph flow. The foreign particles are then trapped in these nodes in a meshwork of sinuses lined by tissue macrophages. Figure 33–3 illustrates the general organization of the lymph node, showing lymph entering through the lymph node capsule by way of afferent lymphatics, then flowing through the nodal medullary sinuses, and finally passing out the hilus into efferent lymphatics that eventually empty into the venous blood. 433 Large numbers of macrophages line the lymph sinuses, and if any particles enter the sinuses by way of the lymph, the macrophages phagocytize them and prevent general dissemination throughout the body. Alveolar Macrophages in the Lungs. Another route by which invading organisms frequently enter the body is through the lungs. Large numbers of tissue macrophages are present as integral components of the alveolar walls. They can phagocytize particles that become entrapped in the alveoli. If the particles are digestible, the macrophages can also digest them and release the digestive products into the lymph. If the particle is not digestible, the macrophages often form a “giant cell” capsule around the particle until such time—if ever—that it can be slowly dissolved. Such capsules are frequently formed around tuberculosis bacilli, silica dust particles, and even carbon particles. Macrophages (Kupffer Cells) in the Liver Sinusoids. Still another favorite route by which bacteria invade the body is through the gastrointestinal tract. Large numbers of bacteria from ingested food constantly pass through the gastrointestinal mucosa into the portal blood. Before this blood enters the general circulation, it passes through the sinusoids of the liver; these sinusoids are lined with tissue macrophages called Kupffer cells, shown in Figure 33–4. These cells form such an effective particulate filtration system that almost none of the bacteria from the gastrointestinal tract succeeds in passing from the portal blood into the general systemic circulation. Indeed, motion pictures of phagocytosis by Kupffer cells have demonstrated phagocytosis of a single bacterium in less than 1/100 of a second. Afferent lymphatics Primary nodule Capsule Valve Subcapsular sinus Lymph in medullary sinuses Hilus Medullary cord Germinal center Kupffer cells Efferent lymphatics Figure 33–3 Functional diagram of a lymph node. (Redrawn from Ham AW: Histology, 6th ed. Philadelphia: JB Lippincott, 1969.) (Modified from Gartner LP, Hiatt JL: Color Textbook of Histology, 2nd ed. Philadelphia, WB Saunders, 2001.) Figure 33–4 Kupffer cells lining the liver sinusoids, showing phagocytosis of India ink particles into the cytoplasm of the Kupffer cells. (Redrawn from Copenhaver WM, et al: Bailey’s Textbook of Histology, 10th ed. Baltimore: Williams & Wilkins, 1971.) 434 Unit VI Blood Cells, Immunity, and Blood Clotting Macrophages of the Spleen and Bone Marrow. If an invad- ing organism succeeds in entering the general circulation, there are other lines of defense by the tissue macrophage system, especially by macrophages of the spleen and bone marrow. In both these tissues, macrophages have become entrapped by the reticular meshwork of the two organs, and when foreign particles come in contact with these macrophages, they are phagocytized. The spleen is similar to the lymph nodes, except that blood, instead of lymph, flows through the tissue spaces of the spleen. Figure 33–5 shows a small peripheral segment of spleen tissue. Note that a small artery penetrates from the splenic capsule into the splenic pulp and terminates in small capillaries. The capillaries are highly porous, allowing whole blood to pass out of the capillaries into cords of red pulp. The blood then gradually squeezes through the trabecular meshwork of these cords and eventually returns to the circulation through the endothelial walls of the venous sinuses. The trabeculae of the red pulp are lined with vast numbers of macrophages, and the venous sinuses are also lined with macrophages. This peculiar passage of blood through the cords of the red pulp provides an exceptional means of phagocytizing unwanted debris in the blood, including especially old and abnormal red blood cells. Inflammation: Role of Neutrophils and Macrophages Inflammation When tissue injury occurs, whether caused by bacteria, trauma, chemicals, heat, or any other phenomenon, multiple substances are released by the injured tissues Pulp Capillaries Venous sinuses Vein Artery and cause dramatic secondary changes in the surrounding uninjured tissues. This entire complex of tissue changes is called inflammation. Inflammation is characterized by (1) vasodilation of the local blood vessels, with consequent excess local blood flow; (2) increased permeability of the capillaries, allowing leakage of large quantities of fluid into the interstitial spaces; (3) often clotting of the fluid in the interstitial spaces because of excessive amounts of fibrinogen and other proteins leaking from the capillaries; (4) migration of large numbers of granulocytes and monocytes into the tissue; and (5) swelling of the tissue cells. Some of the many tissue products that cause these reactions are histamine, bradykinin, serotonin, prostaglandins, several different reaction products of the complement system (described in Chapter 34), reaction products of the blood clotting system, and multiple substances called lymphokines that are released by sensitized T cells (part of the immune system; also discussed in Chapter 34). Several of these substances strongly activate the macrophage system, and within a few hours, the macrophages begin to devour the destroyed tissues. But at times, the macrophages also further injure the still-living tissue cells. “Walling-Off” Effect of Inflammation. One of the first results of inflammation is to “wall off ” the area of injury from the remaining tissues. The tissue spaces and the lymphatics in the inflamed area are blocked by fibrinogen clots so that after a while, fluid barely flows through the spaces. This walling-off process delays the spread of bacteria or toxic products. The intensity of the inflammatory process is usually proportional to the degree of tissue injury. For instance, when staphylococci invade tissues, they release extremely lethal cellular toxins. As a result, inflammation develops rapidly—indeed, much more rapidly than the staphylococci themselves can multiply and spread. Therefore, local staphylococcal infection is characteristically walled off rapidly and prevented from spreading through the body. Streptococci, in contrast, do not cause such intense local tissue destruction. Therefore, the walling-off process develops slowly over many hours, while many streptococci reproduce and migrate. As a result, streptococci often have a far greater tendency to spread through the body and cause death than do staphylococci, even though staphylococci are far more destructive to the tissues. Macrophage and Neutrophil Responses During Inflammation Tissue Macrophage Is a First Line of Defense Against Infection. Figure 33–5 Functional structures of the spleen. (Modified from Bloom W, Fawcett DW: A Textbook of Histology, 10th ed. Philadelphia: WB Saunders, 1975.) Within minutes after inflammation begins, the macrophages already present in the tissues, whether histiocytes in the subcutaneous tissues, alveolar macrophages in the lungs, microglia in the brain, or others, immediately begin their phagocytic actions. Chapter 33 Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System When activated by the products of infection and inflammation, the first effect is rapid enlargement of each of these cells. Next, many of the previously sessile macrophages break loose from their attachments and become mobile, forming the first line of defense against infection during the first hour or so. The numbers of these early mobilized macrophages often are not great, but they are lifesaving. Neutrophil Invasion of the Inflamed Area Is a Second Line of Defense. Within the first hour or so after inflammation begins, large numbers of neutrophils begin to invade the inflamed area from the blood. This is caused by products from the inflamed tissues that initiate the following reactions: (1) They alter the inside surface of the capillary endothelium, causing neutrophils to stick to the capillary walls in the inflamed area. This effect is called margination and is shown in Figure 33–2. (2) They cause the intercellular attachments between the endothelial cells of the capillaries and small venules to loosen, allowing openings large enough for neutrophils to pass by diapedesis directly from the blood into the tissue spaces. (3) Other products of inflammation then cause chemotaxis of the neutrophils toward the injured tissues, as explained earlier. Thus, within several hours after tissue damage begins, the area becomes well supplied with neutrophils. Because the blood neutrophils are already mature cells, they are ready to immediately begin their scavenger functions for killing bacteria and removing foreign matter. Acute Increase in Number of Neutrophils in the Blood—“Neutrophilia.” Also within a few hours after the onset of acute, severe inflammation, the number of neutrophils in the blood sometimes increases fourfold to fivefold—from a normal of 4000 to 5000 to 15,000 to 25,000 neutrophils per microliter. This is called neutrophilia, which means an increase in the number of neutrophils in the blood. Neutrophilia is caused by products of inflammation that enter the blood stream, are transported to the bone marrow, and there act on the stored neutrophils of the marrow to mobilize these into the circulating blood. This makes even more neutrophils available to the inflamed tissue area. Second Macrophage Invasion into the Inflamed Tissue Is a Third Line of Defense. Along with the invasion of neutrophils, monocytes from the blood enter the inflamed tissue and enlarge to become macrophages. However, the number of monocytes in the circulating blood is low: also, the storage pool of monocytes in the bone marrow is much less than that of neutrophils. Therefore, the buildup of macrophages in the inflamed tissue area is much slower than that of neutrophils, requiring several days to become effective. Furthermore, even after invading the inflamed tissue, monocytes are still immature cells, requiring 8 hours or more to swell to much larger sizes and develop tremendous quantities of lysosomes; only then do they acquire the full capacity of tissue macrophages for phagocytosis. Yet, after several days to several weeks, the macrophages finally 435 come to dominate the phagocytic cells of the inflamed area because of greatly increased bone marrow production of new monocytes, as explained later. As already pointed out, macrophages can phagocytize far more bacteria (about five times as many) and far larger particles, including even neutrophils themselves and large quantities of necrotic tissue, than can neutrophils. Also, the macrophages play an important role in initiating the development of antibodies, as we discuss in Chapter 34. Increased Production of Granulocytes and Monocytes by the Bone Marrow Is a Fourth Line of Defense. The fourth line of defense is greatly increased production of both granulocytes and monocytes by the bone marrow. This results from stimulation of the granulocytic and monocytic progenitor cells of the marrow. However, it takes 3 to 4 days before newly formed granulocytes and monocytes reach the stage of leaving the bone marrow. If the stimulus from the inflamed tissue continues, the bone marrow can continue to produce these cells in tremendous quantities for months and even years, sometimes at a rate 20 to 50 times normal. Feedback Control of the Macrophage and Neutrophil Responses Although more than two dozen factors have been implicated in control of the macrophage response to inflammation, five of these are believed to play dominant roles. They are shown in Figure 33–6 and consist of (1) tumor necrosis factor (TNF), (2) interleukin-1 (IL-1), (3) granulocyte-monocyte colony-stimulating factor (GM-CSF), (4) granulocyte colony-stimulating factor (G-CSF), and (5) monocyte colony-stimulating factor (M-CSF). These factors are formed by activated macrophage cells in the inflamed tissues and in smaller quantities by other inflamed tissue cells. The cause of the increased production of granulocytes and monocytes by the bone marrow is mainly the three colony-stimulating factors, one of which, GM-CSF, stimulates both granulocyte and monocyte production; the other two, G-CSF and M-CSF, stimulate granulocyte and monocyte production, respectively. This combination of TNF, IL-1, and colony-stimulating factors provides a powerful feedback mechanism that begins with tissue inflammation and proceeds to formation of large numbers of defensive white blood cells that help remove the cause of the inflammation. Formation of Pus When neutrophils and macrophages engulf large numbers of bacteria and necrotic tissue, essentially all the neutrophils and many, if not most, of the macrophages eventually die. After several days, a cavity is often excavated in the inflamed tissues that contains varying portions of necrotic tissue, dead neutrophils, dead macrophages, and tissue fluid. This mixture is commonly known as pus. After the infection has been suppressed, the dead cells and necrotic tissue in the pus gradually autolyze over a period of days, and the end products are eventually absorbed 436 Unit VI Blood Cells, Immunity, and Blood Clotting INFLAMMATION Activated macrophage TNF IL-1 Endothelial cells, fibroblasts, lymphocytes TNF IL-1 GM-CSF G-CSF M-CSF GM-CSF G-CSF M-CSF Bone marrow Granulocytes Monocytes/macrophages Figure 33–6 Control of bone marrow production of granulocytes and monocyte-macrophages in response to multiple growth factors released from activated macrophages in an inflamed tissue. G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; IL-1, interleukin-1; M-CSF, monocyte colony-stimulating factor; TNF, tumor necrosis factor. into the surrounding tissues and lymph until most of the evidence of tissue damage is gone. Eosinophils The eosinophils normally constitute about 2 per cent of all the blood leukocytes. Eosinophils are weak phagocytes, and they exhibit chemotaxis, but in comparison with the neutrophils, it is doubtful that the eosinophils are significant in protecting against the usual types of infection. Eosinophils, however, are often produced in large numbers in people with parasitic infections, and they migrate in large numbers into tissues diseased by parasites. Although most parasites are too large to be phagocytized by eosinophils or any other phagocytic cells, eosinophils attach themselves to the parasites by way of special surface molecules and release substances that kill many of the parasites. For instance, one of the most widespread infections is schistosomiasis, a parasitic infection found in as many as one third of the population of some Third World countries; the parasite can invade any part of the body. Eosinophils attach themselves to the juvenile forms of the parasite and kill many of them. They do so in several ways: (1) by releasing hydrolytic enzymes from their granules, which are modified lysosomes; (2) probably by also releasing highly reactive forms of oxygen that are especially lethal to parasites; and (3) by releasing from the granules a highly larvacidal polypeptide called major basic protein. In a few areas of the world, another parasitic disease that causes eosinophilia is trichinosis. This results from invasion of the body’s muscles by the Trichinella parasite (“pork worm”) after a person eats undercooked infested pork. Eosinophils also have a special propensity to collect in tissues in which allergic reactions occur, such as in the peribronchial tissues of the lungs in people with asthma and in the skin after allergic skin reactions. This is caused at least partly by the fact that many mast cells and basophils participate in allergic reactions, as we discuss in the next paragraph. The mast cells and basophils release an eosinophil chemotactic factor that causes eosinophils to migrate toward the inflamed allergic tissue. The eosinophils are believed to detoxify some of the inflammation-inducing substances released by the mast cells and basophils and probably also to phagocytize and destroy allergen-antibody complexes, thus preventing excess spread of the local inflammatory process. Basophils The basophils in the circulating blood are similar to the large tissue mast cells located immediately outside many of the capillaries in the body. Both mast cells and basophils liberate heparin into the blood, a substance that can prevent blood coagulation. The mast cells and basophils also release histamine, as well as smaller quantities of bradykinin and serotonin. Indeed, it is mainly the mast cells in inflamed tissues that release these substances during inflammation. The mast cells and basophils play an exceedingly important role in some types of allergic reactions because the type of antibody that causes allergic reactions, the immunoglobulin E (IgE) type (see Chapter 34), has a special propensity to become attached to mast cells and basophils. Then, when the specific antigen for the specific IgE antibody subsequently reacts with the antibody, the resulting attachment of antigen to antibody causes the mast cell or basophil to rupture and release exceedingly large quantities of histamine, bradykinin, serotonin, heparin, slow-reacting substance of anaphylaxis, and a number of lysosomal enzymes. These cause local vascular and tissue reactions that cause many, if not most, of the allergic manifestations. These reactions are discussed in greater detail in Chapter 34. Leukopenia A clinical condition known as leukopenia occasionally occurs in which the bone marrow produces very few Chapter 33 Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System white blood cells, leaving the body unprotected against many bacteria and other agents that might invade the tissues. Normally, the human body lives in symbiosis with many bacteria, because all the mucous membranes of the body are constantly exposed to large numbers of bacteria. The mouth almost always contains various spirochetal, pneumococcal, and streptococcal bacteria, and these same bacteria are present to a lesser extent in the entire respiratory tract. The distal gastrointestinal tract is especially loaded with colon bacilli. Furthermore, one can always find bacteria on the surfaces of the eyes, urethra, and vagina. Any decrease in the number of white blood cells immediately allows invasion of adjacent tissues by bacteria that are already present. Within 2 days after the bone marrow stops producing white blood cells, ulcers may appear in the mouth and colon, or the person might develop some form of severe respiratory infection. Bacteria from the ulcers rapidly invade surrounding tissues and the blood. Without treatment, death often ensues in less than a week after acute total leukopenia begins. Irradiation of the body by x-rays or gamma rays, or exposure to drugs and chemicals that contain benzene or anthracene nuclei, is likely to cause aplasia of the bone marrow. Indeed, some common drugs, such as chloramphenicol (an antibiotic), thiouracil (used to treat thyrotoxicosis), and even various barbiturate hypnotics, on very rare occasions cause leukopenia, thus setting off the entire infectious sequence of this malady. After moderate irradiation injury to the bone marrow, some stem cells, myeloblasts, and hemocytoblasts may remain undestroyed in the marrow and are capable of regenerating the bone marrow, provided sufficient time is available. A patient properly treated with transfusions, plus antibiotics and other drugs to ward off infection, usually develops enough new bone marrow within weeks to months for blood cell concentrations to return to normal. The Leukemias Uncontrolled production of white blood cells can be caused by cancerous mutation of a myelogenous or lymphogenous cell. This causes leukemia, which is usually characterized by greatly increased numbers of abnormal white blood cells in the circulating blood. 437 extramedullary tissues—especially in the lymph nodes, spleen, and liver. In myelogenous leukemia, the cancerous process occasionally produces partially differentiated cells, resulting in what might be called neutrophilic leukemia, eosinophilic leukemia, basophilic leukemia, or monocytic leukemia. More frequently, however, the leukemia cells are bizarre and undifferentiated and not identical to any of the normal white blood cells. Usually, the more undifferentiated the cell, the more acute is the leukemia, often leading to death within a few months if untreated. With some of the more differentiated cells, the process can be chronic, sometimes developing slowly over 10 to 20 years. Leukemic cells, especially the very undifferentiated cells, are usually nonfunctional for providing the normal protection against infection. Effects of Leukemia on the Body The first effect of leukemia is metastatic growth of leukemic cells in abnormal areas of the body. Leukemic cells from the bone marrow may reproduce so greatly that they invade the surrounding bone, causing pain and, eventually, a tendency for bones to fracture easily. Almost all leukemias eventually spread to the spleen, lymph nodes, liver, and other vascular regions, regardless of whether the origin of the leukemia is in the bone marrow or the lymph nodes. Common effects in leukemia are the development of infection, severe anemia, and a bleeding tendency caused by thrombocytopenia (lack of platelets). These effects result mainly from displacement of the normal bone marrow and lymphoid cells by the nonfunctional leukemic cells. Finally, perhaps the most important effect of leukemia on the body is excessive use of metabolic substrates by the growing cancerous cells. The leukemic tissues reproduce new cells so rapidly that tremendous demands are made on the body reserves for foodstuffs, specific amino acids, and vitamins. Consequently, the energy of the patient is greatly depleted, and excessive utilization of amino acids by the leukemic cells causes especially rapid deterioration of the normal protein tissues of the body. Thus, while the leukemic tissues grow, other tissues become debilitated. After metabolic starvation has continued long enough, this alone is sufficient to cause death. Types of Leukemia. Leukemias are divided into two References general types: lymphocytic leukemias and myelogenous leukemias. The lymphocytic leukemias are caused by cancerous production of lymphoid cells, usually beginning in a lymph node or other lymphocytic tissue and spreading to other areas of the body. The second type of leukemia, myelogenous leukemia, begins by cancerous production of young myelogenous cells in the bone marrow and then spreads throughout the body so that white blood cells are produced in many Alexander JS, Granger DN: Lymphocyte trafficking mediated by vascular adhesion protein-1: implications for immune targeting and cardiovascular disease. Circ Res 86:1190, 2000. Blander JM, Medzhitov R: Regulation of phagosome maturation by signals from toll-like receptors. Science 304:1014, 2004. Bleakley M, Riddell SR: Molecules and mechanisms of the graft-versus-leukaemia effect. Nat Rev Cancer 4:371, 2004. 438 Unit VI Blood Cells, Immunity, and Blood Clotting Ferrajoli A, O’Brien SM: Treatment of chronic lymphocytic leukemia. Semin Oncol 31(Suppl 4):60, 2004. Heasman SJ, Giles KM, Ward C, et al: Glucocorticoidmediated regulation of granulocyte apoptosis and macrophage phagocytosis of apoptotic cells: implications for the resolution of inflammation. J Endocrinol 178:29, 2003. Kunkel EJ, Butcher EC: Plasma-cell homing. Nat Rev Immunol 3:822, 2003. Kvietys PR, Sandig M: Neutrophil diapedesis: paracellular or transcellular? News Physiol Sci 16:15, 2001. Ley K, Kansas GS: Selectins in T-cell recruitment to nonlymphoid tissues and sites of inflammation. Nat Rev Immunol 4:325, 2004. Moser B, Wolf M, Walz A, Loetscher P: Chemokines: multiple levels of leukocyte migration control. Trends Immunol 25:75, 2004. Muller WA: Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 24:327, 2003. Ossovskaya VS, Bunnett NW: Protease-activated receptors: contribution to physiology and disease. Physiol Rev 84:579, 2004. Park JE, Barbul A: Understanding the role of immune regulation in wound healing. Am J Surg 187:11S, 2004. Pui CH, Relling MV, Downing JR: Acute lymphoblastic leukemia. N Engl J Med 350:1535, 2004. Roufosse F, Cogan E, Goldman M: The hypereosinophilic syndrome revisited. Annu Rev Med 54:169, 2003. von Herrath MG, Harrison LC: Regulatory lymphocytes: antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 3:223, 2003. Werner S, Grose R: Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835, 2003. Zullig S, Hengartner MO: Cell biology: tickling macrophages, a serious business. Science 304:1123, 2004. C H A P T E R 3 4 Resistance of the Body to Infection: II. Immunity and Allergy Innate Immunity The human body has the ability to resist almost all types of organisms or toxins that tend to damage the tissues and organs. This capability is called immunity. Much of immunity is acquired immunity that does not develop until after the body is first attacked by a bacterium, virus, or toxin, often requiring weeks or months to develop the immunity. An additional portion of immunity results from general processes, rather than from processes directed at specific disease organisms. This is called innate immunity. It includes the following: 1. Phagocytosis of bacteria and other invaders by white blood cells and cells of the tissue macrophage system, as described in Chapter 33. 2. Destruction of swallowed organisms by the acid secretions of the stomach and the digestive enzymes. 3. Resistance of the skin to invasion by organisms. 4. Presence in the blood of certain chemical compounds that attach to foreign organisms or toxins and destroy them. Some of these compounds are (1) lysozyme, a mucolytic polysaccharide that attacks bacteria and causes them to dissolute; (2) basic polypeptides, which react with and inactivate certain types of gram-positive bacteria; (3) the complement complex that is described later, a system of about 20 proteins that can be activated in various ways to destroy bacteria; and (4) natural killer lymphocytes that can recognize and destroy foreign cells, tumor cells, and even some infected cells. This innate immunity makes the human body resistant to such diseases as some paralytic viral infections of animals, hog cholera, cattle plague, and distemper—a viral disease that kills a large percentage of dogs that become afflicted with it. Conversely, many lower animals are resistant or even immune to many human diseases, such as poliomyelitis, mumps, human cholera, measles, and syphilis, which are very damaging or even lethal to human beings. Acquired (Adaptive) Immunity In addition to its generalized innate immunity, the human body has the ability to develop extremely powerful specific immunity against individual invading agents such as lethal bacteria, viruses, toxins, and even foreign tissues from other animals. This is called acquired or adaptive immunity. Acquired immunity is caused by a special immune system that forms antibodies and/or activated lymphocytes that attack and destroy the specific invading organism or toxin. It is with this acquired immunity mechanism and some of its associated reactions— especially the allergies—that this chapter is concerned. Acquired immunity can often bestow extreme protection. For instance, certain toxins, such as the paralytic botulinum toxin or the tetanizing toxin of tetanus, can be protected against in doses as high as 100,000 times the amount that would be lethal without immunity. This is the reason the treatment process known as immunization is so important in protecting human beings against 439 440 Unit VI Blood Cells, Immunity, and Blood Clotting disease and against toxins, as explained in the course of this chapter. Basic Types of Acquired Immunity Two basic but closely allied types of acquired immunity occur in the body. In one of these the body develops circulating antibodies, which are globulin molecules in the blood plasma that are capable of attacking the invading agent. This type of immunity is called humoral immunity or B-cell immunity (because B lymphocytes produce the antibodies). The second type of acquired immunity is achieved through the formation of large numbers of activated T lymphocytes that are specifically crafted in the lymph nodes to destroy the foreign agent. This type of immunity is called cell-mediated immunity or T-cell immunity (because the activated lymphocytes are T lymphocytes). We shall see shortly that both the antibodies and the activated lymphocytes are formed in the lymphoid tissues of the body. Let us discuss the initiation of the immune process by antigens. Both Types of Acquired Immunity Are Initiated by Antigens Because acquired immunity does not develop until after invasion by a foreign organism or toxin, it is clear that the body must have some mechanism for recognizing this invasion. Each toxin or each type of organism almost always contains one or more specific chemical compounds in its makeup that are different from all other compounds. In general, these are proteins or large polysaccharides, and it is they that initiate the acquired immunity. These substances are called antigens (antibody generations). For a substance to be antigenic, it usually must have a high molecular weight, 8000 or greater. Furthermore, the process of antigenicity usually depends on regularly recurring molecular groups, called epitopes, on the surface of the large molecule. This also explains why proteins and large polysaccharides are almost always antigenic, because both of these have this stereochemical characteristic. Lymphocytes Are Responsible for Acquired Immunity Acquired immunity is the product of the body’s lymphocytes. In people who have a genetic lack of lymphocytes or whose lymphocytes have been destroyed by radiation or chemicals, no acquired immunity can develop. And within days after birth, such a person dies of fulminating bacterial infection unless treated by heroic measures. Therefore, it is clear that the lymphocytes are essential to survival of the human being. The lymphocytes are located most extensively in the lymph nodes, but they are also found in special lymphoid tissues such as the spleen, submucosal areas of the gastrointestinal tract, thymus, and bone marrow. The lymphoid tissue is distributed advantageously in the body to intercept invading organisms or toxins before they can spread too widely. In most instances, the invading agent first enters the tissue fluids and then is carried by way of lymph vessels to the lymph node or other lymphoid tissue. For instance, the lymphoid tissue of the gastrointestinal walls is exposed immediately to antigens invading from the gut. The lymphoid tissue of the throat and pharynx (the tonsils and adenoids) is well located to intercept antigens that enter by way of the upper respiratory tract. The lymphoid tissue in the lymph nodes is exposed to antigens that invade the peripheral tissues of the body. And, finally, the lymphoid tissue of the spleen, thymus, and bone marrow plays the specific role of intercepting antigenic agents that have succeeded in reaching the circulating blood. Two Types of Lymphocytes Promote “Cell-Mediated” Immunity or “Humoral” Immunity—the T and the B Lymphocytes. Although most lymphocytes in normal lymphoid tissue look alike when studied under the microscope, these cells are distinctly divided into two major populations. One of the populations, the T lymphocytes, is responsible for forming the activated lymphocytes that provide “cell-mediated” immunity, and the other population, the B lymphocytes, is responsible for forming antibodies that provide “humoral” immunity. Both types of lymphocytes are derived originally in the embryo from pluripotent hematopoietic stem cells that form lymphocytes as one of their most important offspring as they differentiate. Almost all of the lymphocytes that are formed eventually end up in the lymphoid tissue, but before doing so, they are further differentiated or “preprocessed” in the following ways. The lymphocytes that are destined to eventually form activated T lymphocytes first migrate to and are preprocessed in the thymus gland, and thus they are called “T” lymphocytes to designate the role of the thymus. They are responsible for cell-mediated immunity. The other population of lymphocytes—the B lymphocytes that are destined to form antibodies—are preprocessed in the liver during midfetal life and in the bone marrow in late fetal life and after birth. This population of cells was first discovered in birds, which have a special preprocessing organ called the bursa of Fabricius. For this reason, these lymphocytes are called “B” lymphocytes to designate the role of the bursa, and they are responsible for humoral immunity. Figure 34–1 shows the two lymphocyte systems for the formation, respectively, of (1) the activated T lymphocytes and (2) the antibodies. Preprocessing of the T and B Lymphocytes Although all lymphocytes in the body originate from lymphocyte-committed stem cells of the embryo, these Chapter 34 441 Resistance of the Body to Infection: II. Immunity and Allergy Cell-Mediated Immunity Thymus Activated T lymphocytes Antigen T lymphocytes Lymph node Figure 34–1 Formation of antibodies and sensitized lymphocytes by a lymph node in response to antigens. This figure also shows the origin of thymic (T) and bursal (B) lymphocytes that respectively are responsible for the cell-mediated and humoral immune processes. B lymphocytes Stem cell Antigen Plasma cells Antibodies Fetal liver, bone marrow stem cells themselves are incapable of forming directly either activated T lymphocytes or antibodies. Before they can do so, they must be further differentiated in appropriate processing areas as follows. Thymus Gland Preprocesses the T Lymphocytes. The T lym- phocytes, after origination in the bone marrow, first migrate to the thymus gland. Here they divide rapidly and at the same time develop extreme diversity for reacting against different specific antigens. That is, one thymic lymphocyte develops specific reactivity against one antigen. Then the next lymphocyte develops specificity against another antigen. This continues until there are thousands of different types of thymic lymphocytes with specific reactivities against many thousands of different antigens. These different types of preprocessed T lymphocytes now leave the thymus and spread by way of the blood throughout the body to lodge in lymphoid tissue everywhere. The thymus also makes certain that any T lymphocytes leaving the thymus will not react against proteins or other antigens that are present in the body’s own tissues; otherwise, the T lymphocytes would be lethal to the person’s own body in only a few days. The thymus selects which T lymphocytes will be released by first mixing them with virtually all the specific “self-antigens” from the body’s own tissues. If a T lymphocyte reacts, it is destroyed and phagocytized instead of being released. This happens to as many as 90 per cent of the cells. Thus, the only cells that are finally released are those that are nonreactive against the body’s own antigens—they react only against antigens from an outside source, such as from a bacterium, a toxin, or even transplanted tissue from another person. Humoral Immunity Most of the preprocessing of T lymphocytes in the thymus occurs shortly before birth of a baby and for a few months after birth. Beyond this period, removal of the thymus gland diminishes (but does not eliminate) the T-lymphocytic immune system. However, removal of the thymus several months before birth can prevent development of all cell-mediated immunity. Because this cellular type of immunity is mainly responsible for rejection of transplanted organs, such as hearts and kidneys, one can transplant organs with much less likelihood of rejection if the thymus is removed from an animal a reasonable time before its birth. Liver and Bone Marrow Preprocess the B Lymphocytes. Much less is known about the details for preprocessing B lymphocytes than for preprocessing T lymphocytes. In the human being, B lymphocytes are known to be preprocessed in the liver during midfetal life and in the bone marrow during late fetal life and after birth. B lymphocytes are different from T lymphocytes in two ways: First, instead of the whole cell developing reactivity against the antigen, as occurs for the T lymphocytes, the B lymphocytes actively secrete antibodies that are the reactive agents. These agents are large protein molecules that are capable of combining with and destroying the antigenic substance, which is explained elsewhere in this chapter and in Chapter 33. Second, the B lymphocytes have even greater diversity than the T lymphocytes, thus forming many millions of types of B-lymphocyte antibodies with different specific reactivities. After preprocessing, the B lymphocytes, like the T lymphocytes, migrate to lymphoid tissue throughout the body, where they lodge near but slightly removed from the T-lymphocyte areas. 442 Unit VI Blood Cells, Immunity, and Blood Clotting T Lymphocytes and B-Lymphocyte Antibodies React Highly Specifically Against Specific Antigens—Role of Lymphocyte Clones When specific antigens come in contact with T and B lymphocytes in the lymphoid tissue, certain of the T lymphocytes become activated to form activated T cells, and certain of the B lymphocytes become activated to form antibodies. The activated T cells and antibodies in turn react highly specifically against the particular types of antigens that initiated their development. The mechanism of this specificity is the following. Millions of Specific Types of Lymphocytes Are Stored in the Lymphoid Tissue. Millions of different types of pre- formed B lymphocytes and preformed T lymphocytes that are capable of forming highly specific types of antibodies or T cells have been stored in the lymph tissue, as explained earlier. Each of these preformed lymphocytes is capable of forming only one type of antibody or one type of T cell with a single type of specificity. And only the specific type of antigen with which it can react can activate it. Once the specific lymphocyte is activated by its antigen, it reproduces wildly, forming tremendous numbers of duplicate lymphocytes. If it is a B lymphocyte, its progeny will eventually secrete the specific type of antibody that then circulates throughout the body. If it is a T lymphocyte, its progeny are specific sensitized T cells that are released into the lymph and then carried to the blood and circulated through all the tissue fluids and back into the lymph, sometimes circulating around and around in this circuit for months or years. All the different lymphocytes that are capable of forming one specificity of antibody or T cell are called a clone of lymphocytes. That is, the lymphocytes in each clone are alike and are derived originally from one or a few early lymphocytes of its specific type. Origin of the Many Clones of Lymphocytes Only several hundred to a few thousand genes code for the millions of different types of antibodies and T lymphocytes. At first, it was a mystery how it was possible for so few genes to code for the millions of different specificities of antibody molecules or T cells that can be produced by the lymphoid tissue, especially when one considers that a single gene is usually necessary for the formation of each different type of protein. This mystery has now been solved. The whole gene for forming each type of T cell or B cell is never present in the original stem cells from which the functional immune cells are formed. Instead, there are only “gene segments”—actually, hundreds of such segments—but not whole genes. During preprocessing of the respective T- and B-cell lymphocytes, these gene segments become mixed with one another in random combinations, in this way finally forming whole genes. Because there are several hundred types of gene segments, as well as millions of different combinations in which the segments can be arranged in single cells, one can understand the millions of different cell gene types that can occur. For each functional T or B lymphocyte that is finally formed, the gene structure codes for only a single antigen specificity. These mature cells then become the highly specific T and B cells that spread to and populate the lymphoid tissue. Mechanism for Activating a Clone of Lymphocytes Each clone of lymphocytes is responsive to only a single type of antigen (or to several similar antigens that have almost exactly the same stereochemical characteristics). The reason for this is the following: In the case of the B lymphocytes, each of these has on the surface of its cell membrane about 100,000 antibody molecules that will react highly specifically with only one specific type of antigen. Therefore, when the appropriate antigen comes along, it immediately attaches to the antibody in the cell membrane; this leads to the activation process, which we describe in more detail subsequently. In the case of the T lymphocytes, molecules similar to antibodies, called surface receptor proteins (or T-cell markers), are on the surface of the T-cell membrane, and these, too, are highly specific for one specified activating antigen. Role of Macrophages in the Activation Process. Aside from the lymphocytes in lymphoid tissue, literally millions of macrophages are also present in the same tissue. These line the sinusoids of the lymph nodes, spleen, and other lymphoid tissue, and they lie in apposition to many of the lymph node lymphocytes. Most invading organisms are first phagocytized and partially digested by the macrophages, and the antigenic products are liberated into the macrophage cytosol. The macrophages then pass these antigens by cell-to-cell contact directly to the lymphocytes, thus leading to activation of the specified lymphocytic clones. The macrophages, in addition, secrete a special activating substance that promotes still further growth and reproduction of the specific lymphocytes. This substance is called interleukin-1. Role of the T Cells in Activation of the B Lymphocytes. Most antigens activate both T lymphocytes and B lymphocytes at the same time. Some of the T cells that are formed, called helper cells, secrete specific substances (collectively called lymphokines) that activate the specific B lymphocytes. Indeed, without the aid of these helper T cells, the quantity of antibodies formed by the B lymphocytes is usually slight. We will discuss this cooperative relationship between helper T cells and B cells again after we have an opportunity to describe the mechanisms of the T-cell system of immunity. 443 Resistance of the Body to Infection: II. Immunity and Allergy Specific Attributes of the B-Lymphocyte System—Humoral Immunity and the Antibodies Formation of Antibodies by Plasma Cells. Before exposure to a specific antigen, the clones of B lymphocytes remain dormant in the lymphoid tissue. On entry of a foreign antigen, macrophages in the lymphoid tissue phagocytize the antigen and then present it to adjacent B lymphocytes. In addition, the antigen is presented to T cells at the same time, and activated helper T cells are formed. These helper cells also contribute to extreme activation of the B lymphocytes, as we discuss more fully later. Those B lymphocytes specific for the antigen immediately enlarge and take on the appearance of lymphoblasts. Some of the lymphoblasts further differentiate to form plasmablasts, which are precursors of plasma cells. In the plasmablasts, the cytoplasm expands and the rough endoplasmic reticulum vastly proliferates. The plasmablasts then begin to divide at a rate of about once every 10 hours for about nine divisions, giving in 4 days a total population of about 500 cells for each original plasmablast. The mature plasma cell then produces gamma globulin antibodies at an extremely rapid rate—about 2000 molecules per second for each plasma cell. In turn, the antibodies are secreted into the lymph and carried to the circulating blood.This process continues for several days or weeks until finally exhaustion and death of the plasma cells occur. Formation of “Memory” Cells—Difference Between Primary Response and Secondary Response. A few of the lym- phoblasts formed by activation of a clone of B lymphocytes do not go on to form plasma cells but instead form moderate numbers of new B lymphocytes similar to those of the original clone. In other words, the Bcell population of the specifically activated clone becomes greatly enhanced, and the new B lymphocytes are added to the original lymphocytes of the same clone. They also circulate throughout the body to populate all the lymphoid tissue; immunologically, however, they remain dormant until activated once again by a new quantity of the same antigen. These lymphocytes are called memory cells. Subsequent exposure to the same antigen will cause a much more rapid and much more potent antibody response this second time around, because there are many more memory cells than there were original B lymphocytes of the specific clone. Figure 34–2 shows the differences between the primary response for forming antibodies that occurs on first exposure to a specific antigen and the secondary response that occurs after second exposure to the same antigen. Note the 1-week delay in the appearance of the primary response, its weak potency, and its short life. The secondary response, by contrast, begins rapidly after exposure to the antigen (often within hours), is far more potent, and forms antibodies for many months rather than for only a few weeks. The 128 Concentration of antibody Chapter 34 Secondary Primary 64 32 16 8 0 0 2 4 Weeks 6 8 Figure 34–2 Time course of the antibody response in the circulating blood to a primary injection of antigen and to a secondary injection several months later. increased potency and duration of the secondary response explain why immunization is usually accomplished by injecting antigen in multiple doses with periods of several weeks or several months between injections. Nature of the Antibodies The antibodies are gamma globulins called immunoglobulins (abbreviated as Ig), and they have molecular weights between 160,000 and 970,000. They usually constitute about 20 per cent of all the plasma proteins. All the immunoglobulins are composed of combinations of light and heavy polypeptide chains. Most are a combination of two light and two heavy chains, as shown in Figure 34–3. However, some of the immunoglobulins have combinations of as many as 10 heavy and 10 light chains, which gives rise to high-molecular-weight immunoglobulins. Yet, in all immunoglobulins, each heavy chain is paralleled by a light chain at one of its ends, thus forming a heavy-light pair, and there are always at least 2 and as many as 10 such pairs in each immunoglobulin molecule. Figure 34–3 shows by the circled area a designated end of each light and heavy chain, called the variable portion; the remainder of each chain is called the constant portion. The variable portion is different for each specificity of antibody, and it is this portion that attaches specifically to a particular type of antigen. The constant portion of the antibody determines other properties of the antibody, establishing such factors as diffusivity of the antibody in the tissues, adherence of the antibody to specific structures within the tissues, attachment to the complement complex, the ease with which the antibodies pass through membranes, and other biological properties of the antibody. 444 Unit VI Blood Cells, Immunity, and Blood Clotting Antigen-binding sites Antigen Variable portion Antigen S Light chain •S S S•S S•S Antibodies •S Constant portion Heavy chain Figure 34–3 Structure of the typical IgG antibody, showing it to be composed of two heavy polypeptide chains and two light polypeptide chains. The antigen binds at two different sites on the variable portions of the chains. Specificity of Antibodies. Each antibody is specific for a particular antigen; this is caused by its unique structural organization of amino acids in the variable portions of both the light and heavy chains. The amino acid organization has a different steric shape for each antigen specificity, so that when an antigen comes in contact with it, multiple prosthetic groups of the antigen fit as a mirror image with those of the antibody, thus allowing rapid and tight bonding between the antibody and the antigen. When the antibody is highly specific, there are so many bonding sites that the antibody-antigen coupling is exceedingly strong, held together by (1) hydrophobic bonding, (2) hydrogen bonding, (3) ionic attractions, and (4) van der Waals forces. It also obeys the thermodynamic mass action law. Concentration of bound antibody-antigen Ka = Concentration of antibody ¥ Concentration of antigen Ka is called the affinity constant and is a measure of how tightly the antibody binds with the antigen. Note, especially, in Figure 34–3 that there are two variable sites on the illustrated antibody for attachment of antigens, making this type of antibody bivalent. A small proportion of the antibodies, which consist of combinations of up to 10 light and 10 heavy chains, have as many as 10 binding sites. Classes of Antibodies. There are five general classes of antibodies, respectively named IgM, IgG, IgA, IgD, and IgE. Ig stands for immunoglobulin, and the other five respective letters designate the respective classes. For the purpose of our present limited discussion, two of these classes of antibodies are of particular importance: IgG, which is a bivalent antibody and constitutes about 75 per cent of the antibodies of the normal person, and IgE, which constitutes only a small percentage of the antibodies but is especially involved Figure 34–4 Binding of antigen molecules to one another by bivalent antibodies. in allergy. The IgM class is also interesting because a large share of the antibodies formed during the primary response are of this type. These antibodies have 10 binding sites that make them exceedingly effective in protecting the body against invaders, even though there are not many IgM antibodies. Mechanisms of Action of Antibodies Antibodies act mainly in two ways to protect the body against invading agents: (1) by direct attack on the invader and (2) by activation of the “complement system” that then has multiple means of its own for destroying the invader. Direct Action of Antibodies on Invading Agents. Figure 34–4 shows antibodies (designated by the red Y-shaped bars) reacting with antigens (designated by the shaded objects). Because of the bivalent nature of the antibodies and the multiple antigen sites on most invading agents, the antibodies can inactivate the invading agent in one of several ways, as follows: 1. Agglutination, in which multiple large particles with antigens on their surfaces, such as bacteria or red cells, are bound together into a clump 2. Precipitation, in which the molecular complex of soluble antigen (such as tetanus toxin) and antibody becomes so large that it is rendered insoluble and precipitates 3. Neutralization, in which the antibodies cover the toxic sites of the antigenic agent 4. Lysis, in which some potent antibodies are occasionally capable of directly attacking membranes of cellular agents and thereby cause rupture of the agent These direct actions of antibodies attacking the antigenic invaders often are not strong enough to play a major role in protecting the body against the invader. Most of the protection comes through the amplifying effects of the complement system described next. Chapter 34 445 Resistance of the Body to Infection: II. Immunity and Allergy Antigen–antibody complex Opsonization of bacteria C1 C1 Activate mast cells and basophils C4 + C2 C42 + C4a Chemotaxis of white blood cells C3b + C3a C3 C5b + C5a C5 Micro-organism + B and D C6 + C7 C5b67 Figure 34–5 Cascade of reactions during activation of the classic pathway of complement. (Modified from Alexander JW, Good RA: Fundamentals of Clinical Immunology. Philadelphia: WB Saunders, 1977.) C8 + C9 Lysis of cells Complement System for Antibody Action “Complement” is a collective term that describes a system of about 20 proteins, many of which are enzyme precursors. The principal actors in this system are 11 proteins designated C1 through C9, B, and D, shown in Figure 34–5. All these are present normally among the plasma proteins in the blood as well as among the proteins that leak out of the capillaries into the tissue spaces. The enzyme precursors are normally inactive, but they can be activated mainly by the so-called classic pathway. Classic Pathway. The classic pathway is initiated by an antigen-antibody reaction. That is, when an antibody binds with an antigen, a specific reactive site on the “constant” portion of the antibody becomes uncovered, or “activated,” and this in turn binds directly with the C1 molecule of the complement system, setting into motion a “cascade” of sequential reactions, shown in Figure 34–5, beginning with activation of the proenzyme C1 itself. The C1 enzymes that are formed then activate successively increasing quantities of enzymes in the later stages of the system, so that from a small beginning, an extremely large “amplified” reaction occurs. Multiple end products are formed, as shown to the right in the figure, and several of these cause important effects that help to prevent damage to the body’s tissues caused by the invading organism or toxin. Among the more important effects are the following: 1. Opsonization and phagocytosis. One of the products of the complement cascade, C3b, strongly activates phagocytosis by both neutrophils and macrophages, causing these cells C5b6789 2. 3. 4. 5. 6. to engulf the bacteria to which the antigenantibody complexes are attached. This process is called opsonization. It often enhances the number of bacteria that can be destroyed by many hundredfold. Lysis. One of the most important of all the products of the complement cascade is the lytic complex, which is a combination of multiple complement factors and designated C5b6789. This has a direct effect of rupturing the cell membranes of bacteria or other invading organisms. Agglutination. The complement products also change the surfaces of the invading organisms, causing them to adhere to one another, thus promoting agglutination. Neutralization of viruses. The complement enzymes and other complement products can attack the structures of some viruses and thereby render them nonvirulent. Chemotaxis. Fragment C5a initiates chemotaxis of neutrophils and macrophages, thus causing large numbers of these phagocytes to migrate into the tissue area adjacent to the antigenic agent. Activation of mast cells and basophils. Fragments C3a, C4a, and C5a activate mast cells and basophils, causing them to release histamine, heparin, and several other substances into the local fluids. These substances in turn cause increased local blood flow, increased leakage of fluid and plasma protein into the tissue, and other local tissue reactions that help inactivate or immobilize the antigenic agent. The same factors play a major role in inflammation (which was 446 Unit VI Blood Cells, Immunity, and Blood Clotting discussed in Chapter 33) and in allergy, as we discuss later. 7. Inflammatory effects. In addition to inflammatory effects caused by activation of the mast cells and basophils, several other complement products contribute to local inflammation. These products cause (1) the already increased blood flow to increase still further, (2) the capillary leakage of proteins to be increased, and (3) the interstitial fluid proteins to coagulate in the tissue spaces, thus preventing movement of the invading organism through the tissues. T cell Cell-cell adhesion proteins T-cell receptor Foreign protein MHC protein Antigenpresenting cell Special Attributes of the T-Lymphocyte System–Activated T Cells and Cell-Mediated Immunity Figure 34–6 Release of Activated T Cells from Lymphoid Tissue and Formation of Memory Cells. On exposure to the proper antigen, as presented by adjacent macrophages, the T lymphocytes of a specific lymphocyte clone proliferate and release large numbers of activated, specifically reacting T cells in ways that parallel antibody release by activated B cells. The principal difference is that instead of releasing antibodies, whole activated T cells are formed and released into the lymph. These then pass into the circulation and are distributed throughout the body, passing through the capillary walls into the tissue spaces, back into the lymph and blood once again, and circulating again and again throughout the body, sometimes lasting for months or even years. Also, T-lymphocyte memory cells are formed in the same way that B memory cells are formed in the antibody system. That is, when a clone of T lymphocytes is activated by an antigen, many of the newly formed lymphocytes are preserved in the lymphoid tissue to become additional T lymphocytes of that specific clone; in fact, these memory cells even spread throughout the lymphoid tissue of the entire body. Therefore, on subsequent exposure to the same antigen anywhere in the body, release of activated T cells occurs far more rapidly and much more powerfully than had occurred during first exposure. Antigen-Presenting Cells, MHC Proteins, and Antigen Receptors on the T Lymphocytes. T-cell responses are extremely antigen specific, like the antibody responses of B cells, and are at least as important as antibodies in defending against infection. In fact, acquired immune responses usually require assistance from T cells to begin the process, and T cells play a major role in actually helping to eliminate invading pathogens. Although B lymphocytes recognize intact antigens, T lymphocytes respond to antigens only when they are bound to specific molecules called MHC proteins on the surface of antigen-presenting cells in the lymphoid tissues (Figure 34–6). The three major types of antigen-presenting cells are macrophages, B lymphocytes, and dendritic cells. The dendritic cells, the most potent of the antigen-presenting cells, are located throughout the body, and their only known function is Activation of T cells requires interaction of T-cell receptors with an antigen (foreign protein) that is transported to the surface of the antigen-presenting cell by a major histocompatibility complex (MHC) protein. Cell-to-cell adhesion proteins enable the T cell to bind to the antigen-presenting cell long enough to become activated. to present antigens to T cells. Interaction of cell adhesion proteins is critical in permitting the T cells to bind to antigen-presenting cells long enough to become activated. The MHC proteins are encoded by a large group of genes called the major histocompatibility complex (MHC). The MHC proteins bind peptide fragments of antigen proteins that are degraded inside antigenpresenting cells and then transport them to the cell surface. There are two types of MHC proteins: (1) MHC I proteins, which present antigens to cytotoxic T cells, and (2) MHC II proteins, which present antigens to T helper cells. The specific functions of cytotoxic and helper T cells are discussed later. The antigens on the surface of antigen-presenting cells bind with receptor molecules on the surfaces of T cells in the same way that they bind with plasma protein antibodies. These receptor molecules are composed of a variable unit similar to the variable portion of the humoral antibody, but its stem section is firmly bound to the cell membrane of the T lymphocyte. There are as many as 100,000 receptor sites on a single T cell. Several Types of T Cells and Their Different Functions It has become clear that there are multiple types of T cells. They are classified into three major groups: (1) helper T cells, (2) cytotoxic T cells, and (3) suppressor T cells. The functions of each of these are distinct. Helper T Cells—Their Role in Overall Regulation of Immunity The helper T cells are by far the most numerous of the T cells, usually constituting more than three quarters Chapter 34 Resistance of the Body to Infection: II. Immunity and Allergy lethal effects of AIDS. Some of the specific regulatory functions are the following. Preprocessor Preprocessor areas areas Processed antigen Antigen Stimulation of Growth and Proliferation of Cytotoxic T Cells and Suppressor T Cells. In the absence of helper MHC Interleukin-1 Antigen-specific receptor Cytotoxic T cells Helper T cells Suppressor T cells Differentiation Plasma cells IgM IgG Antigen IgA B cell T cells, the clones for producing cytotoxic T cells and suppressor T cells are activated only slightly by most antigens. The lymphokine interleukin-2 has an especially strong stimulatory effect in causing growth and proliferation of both cytotoxic and suppressor T cells. In addition, several of the other lymphokines have less potent effects. Stimulation of B-Cell Growth and Differentiation to Form Plasma Cells and Antibodies. The direct actions Lymphokines!! Proliferation 447 IgE Figure 34–7 Regulation of the immune system, emphasizing a pivotal role of the helper T cells. MHC, major histocompatibility complex. of antigen to cause B-cell growth, proliferation, formation of plasma cells, and secretion of antibodies are also slight without the “help” of the helper T cells. Almost all the interleukins participate in the B-cell response, but especially interleukins 4, 5, and 6. In fact, these three interleukins have such potent effects on the B cells that they have been called B-cell stimulating factors or B-cell growth factors. Activation of the Macrophage System. The lymphokines also affect the macrophages. First, they slow or stop the migration of the macrophages after they have been chemotactically attracted into the inflamed tissue area, thus causing great accumulation of macrophages. Second, they activate the macrophages to cause far more efficient phagocytosis, allowing them to attack and destroy increasing numbers of invading bacteria or other tissue-destroying agents. Feedback Stimulatory Effect on the Helper Cells Themselves. Some of the lymphokines, especially inter- of all of them. As their name implies, they help in the functions of the immune system, and they do so in many ways. In fact, they serve as the major regulator of virtually all immune functions, as shown in Figure 34–7. They do this by forming a series of protein mediators, called lymphokines, that act on other cells of the immune system as well as on bone marrow cells. Among the important lymphokines secreted by the helper T cells are the following: Interleukin-2 Interleukin-3 Interleukin-4 Interleukin-5 Interleukin-6 Granulocyte-monocyte colony-stimulating factor Interferon-g Specific Regulatory Functions of the Lymphokines. In the absence of the lymphokines from the helper T cells, the remainder of the immune system is almost paralyzed. In fact, it is the helper T cells that are inactivated or destroyed by the acquired immunodeficiency syndrome (AIDS) virus, which leaves the body almost totally unprotected against infectious disease, therefore leading to the now well-known debilitating and leukin-2, have a direct positive feedback effect in stimulating activation of the helper T cells themselves. This acts as an amplifier by further enhancing the helper cell response as well as the entire immune response to an invading antigen. Cytotoxic T Cells The cytotoxic T cell is a direct-attack cell that is capable of killing micro-organisms and, at times, even some of the body’s own cells. For this reason, these cells are called killer cells. The receptor proteins on the surfaces of the cytotoxic cells cause them to bind tightly to those organisms or cells that contain the appropriate binding-specific antigen. Then, they kill the attacked cell in the manner shown in Figure 34–8. After binding, the cytotoxic T cell secretes holeforming proteins, called perforins, that literally punch round holes in the membrane of the attacked cell. Then fluid flows rapidly into the cell from the interstitial space. In addition, the cytotoxic T cell releases cytotoxic substances directly into the attacked cell. Almost immediately, the attacked cell becomes greatly swollen, and it usually dissolves shortly thereafter. Especially important, these cytotoxic killer cells can pull away from the victim cells after they have punched holes and delivered cytotoxic substances and 448 Unit VI Blood Cells, Immunity, and Blood Clotting Cytotoxic T cells (killer cells) Cytotoxic and digestive enzymes Antigen receptors as being distinctive from bacteria or viruses, and the person’s immunity system forms few antibodies or activated T cells against his or her own antigens. Most Tolerance Results from Clone Selection During Preprocessing. It is believed that most tolerance develops Attacked cell Specific binding Antigen Figure 34–8 Direct destruction of an invading cell by sensitized lymphocytes (cytotoxic T cells). then move on to kill more cells. Indeed, some of these cells persist for months in the tissues. Some of the cytotoxic T cells are especially lethal to tissue cells that have been invaded by viruses because many virus particles become entrapped in the membranes of the tissue cells and attract T cells in response to the viral antigenicity. The cytotoxic cells also play an important role in destroying cancer cells, heart transplant cells, or other types of cells that are foreign to the person’s own body. Suppressor T Cells Much less is known about the suppressor T cells than about the others, but they are capable of suppressing the functions of both cytotoxic and helper T cells. It is believed that these suppressor functions serve the purpose of preventing the cytotoxic cells from causing excessive immune reactions that might be damaging to the body’s own tissues. For this reason, the suppressor cells are classified, along with the helper T cells, as regulatory T cells. It is probable that the suppressor T-cell system plays an important role in limiting the ability of the immune system to attack a person’s own body tissues, called immune tolerance, as we discuss in the next section. Tolerance of the Acquired Immunity System to One’s Own Tissues—Role of Preprocessing in the Thymus and Bone Marrow If a person should become immune to his or her own tissues, the process of acquired immunity would destroy the individual’s own body. The immune mechanism normally “recognizes” a person’s own tissues during preprocessing of T lymphocytes in the thymus and of B lymphocytes in the bone marrow. The reason for this belief is that injecting a strong antigen into a fetus while the lymphocytes are being preprocessed in these two areas prevents development of clones of lymphocytes in the lymphoid tissue that are specific for the injected antigen. Experiments have shown that specific immature lymphocytes in the thymus, when exposed to a strong antigen, become lymphoblastic, proliferate considerably, and then combine with the stimulating antigen—an effect that is believed to cause the cells themselves to be destroyed by the thymic epithelial cells before they can migrate to and colonize the total body lymphoid tissue. It is believed that during the preprocessing of lymphocytes in the thymus and bone marrow, all or most of those clones of lymphocytes that are specific to damage the body’s own tissues are self-destroyed because of their continual exposure to the body’s antigens. Failure of the Tolerance Mechanism Causes Autoimmune Diseases. Sometimes people lose their immune tolerance of their own tissues. This occurs to a greater extent the older a person becomes. It usually occurs after destruction of some of the body’s own tissues, which releases considerable quantities of “self-antigens” that circulate in the body and presumably cause acquired immunity in the form of either activated T cells or antibodies. Several specific diseases that result from autoimmunity include (1) rheumatic fever, in which the body becomes immunized against tissues in the joints and heart, especially the heart valves, after exposure to a specific type of streptococcal toxin that has an epitope in its molecular structure similar to the structure of some of the body’s own self-antigens; (2) one type of glomerulonephritis, in which the person becomes immunized against the basement membranes of glomeruli; (3) myasthenia gravis, in which immunity develops against the acetylcholine receptor proteins of the neuromuscular junction, causing paralysis; and (4) lupus erythematosus, in which the person becomes immunized against many different body tissues at the same time, a disease that causes extensive damage and often rapid death. Immunization by Injection of Antigens Immunization has been used for many years to produce acquired immunity against specific diseases.A person can be immunized by injecting dead organisms that are no longer capable of causing disease but that still have some of their chemical antigens. This type of immunization is used to protect against typhoid fever, Chapter 34 Resistance of the Body to Infection: II. Immunity and Allergy 449 whooping cough, diphtheria, and many other types of bacterial diseases. Immunity can be achieved against toxins that have been treated with chemicals so that their toxic nature has been destroyed even though their antigens for causing immunity are still intact. This procedure is used in immunizing against tetanus, botulism, and other similar toxic diseases. And, finally, a person can be immunized by being infected with live organisms that have been “attenuated.” That is, these organisms either have been grown in special culture media or have been passed through a series of animals until they have mutated enough that they will not cause disease but do still carry specific antigens required for immunization. This procedure is used to protect against poliomyelitis, yellow fever, measles, smallpox, and many other viral diseases. diffuse from the circulating blood in large numbers into the skin to respond to the poison ivy toxin. And, at the same time, these T cells elicit a cell-mediated type of immune reaction. Remembering that this type of immunity can cause release of many toxic substances from the activated T cells as well as extensive invasion of the tissues by macrophages along with their subsequent effects, one can well understand that the eventual result of some delayed-reaction allergies can be serious tissue damage. The damage normally occurs in the tissue area where the instigating antigen is present, such as in the skin in the case of poison ivy, or in the lungs to cause lung edema or asthmatic attacks in the case of some airborne antigens. Passive Immunity Some people have an “allergic” tendency. Their allergies are called atopic allergies because they are caused by a nonordinary response of the immune system. The allergic tendency is genetically passed from parent to child and is characterized by the presence of large quantities of IgE antibodies in the blood. These antibodies are called reagins or sensitizing antibodies to distinguish them from the more common IgG antibodies. When an allergen (defined as an antigen that reacts specifically with a specific type of IgE reagin antibody) enters the body, an allergen-reagin reaction lakes place, and a subsequent allergic reaction occurs. A special characteristic of the IgE antibodies (the reagins) is a strong propensity to attach to mast cells and basophils. Indeed, a single mast cell or basophil can bind as many as half a million molecules of IgE antibodies. Then, when an antigen (an allergen) that has multiple binding sites binds with several IgE antibodies that are already attached to a mast cell or basophil, this causes immediate change in the membrane of the mast cell or basophil, perhaps resulting from a physical effect of the antibody molecules to contort the cell membrane. At any rate, many of the mast cells and basophils rupture; others release special agents immediately or shortly thereafter, including histamine, protease, slow-reacting substance of anaphylaxis (which is a mixture of toxic leukotrienes), eosinophil chemotactic substance, neutrophil chemotactic substance, heparin, and platelet activating factors. These substances cause such effects as dilation of the local blood vessels; attraction of eosinophils and neutrophils to the reactive site; increased permeability of the capillaries with loss of fluid into the tissues; and contraction of local smooth muscle cells. Therefore, several different tissue responses can occur, depending on the type of tissue in which the allergen-reagin reaction occurs. Among the different types of allergic reactions caused in this manner are the following. Thus far, all the acquired immunity we have discussed has been active immunity. That is, the person’s own body develops either antibodies or activated T cells in response to invasion of the body by a foreign antigen. However, temporary immunity can be achieved in a person without injecting any antigen. This is done by infusing antibodies, activated T cells, or both obtained from the blood of someone else or from some other animal that has been actively immunized against the antigen. Antibodies last in the body of the recipient for 2 to 3 weeks, and during that time, the person is protected against the invading disease. Activated T cells last for a few weeks if transfused from another person but only for a few hours to a few days if transfused from an animal. Such transfusion of antibodies or T lymphocytes to confer immunity is called passive immunity. ALLERGY AND HYPERSENSITIVITY An important undesirable side effect of immunity is the development, under some conditions, of allergy or other types of immune hypersensitivity. There are several types of allergy and other hypersensitivities, some of which occur only in people who have a specific allergic tendency. Allergy Caused by Activated T Cells: Delayed-Reaction Allergy Delayed-reaction allergy is caused by activated T cells and not by antibodies. In the case of poison ivy, the toxin of poison ivy in itself does not cause much harm to the tissues. However, on repeated exposure, it does cause the formation of activated helper and cytotoxic T cells. Then, after subsequent exposure to the poison ivy toxin, within a day or so, the activated T cells Allergies in the “Allergic” Person, Who Has Excess IgE Antibodies Anaphylaxis. When a specific allergen is injected directly into the circulation, the allergen can react with basophils of the blood and mast cells in the tissues 450 Unit VI Blood Cells, Immunity, and Blood Clotting located immediately outside the small blood vessels if the basophils and mast cells have been sensitized by attachment of IgE reagins. Therefore, a widespread allergic reaction occurs throughout the vascular system and closely associated tissues. This is called anaphylaxis. Histamine is released into the circulation and causes body-wide vasodilation as well as increased permeability of the capillaries with resultant marked loss of plasma from the circulation. An occasional person who experiences this reaction dies of circulatory shock within a few minutes unless treated with epinephrine to oppose the effects of the histamine. Also released from the activated basophils and mast cells is a mixture of leukotrienes called slow-reacting substance of anaphylaxis. These leukotrienes can cause spasm of the smooth muscle of the bronchioles, eliciting an asthma-like attack, sometimes causing death by suffocation. Urticaria. Urticaria results from antigen entering specific skin areas and causing localized anaphylactoid reactions. Histamine released locally causes (1) vasodilation that induces an immediate red flare and (2) increased local permeability of the capillaries that leads to local circumscribed areas of swelling of the skin within another few minutes. The swellings are commonly called hives. Administration of antihistamine drugs to a person before exposure will prevent the hives. Hay Fever. In hay fever, the allergen-reagin reaction occurs in the nose. Histamine released in response to the reaction causes local intranasal vascular dilation, with resultant increased capillary pressure as well as increased capillary permeability. Both these effects cause rapid fluid leakage into the nasal cavities and into associated deeper tissues of the nose; and the nasal linings become swollen and secretory. Here again, use of antihistamine drugs can prevent this swelling reaction. But other products of the allergenreagin reaction can still cause irritation of the nose, eliciting the typical sneezing syndrome. Asthma. Asthma often occurs in the “allergic” type of person. In such a person, the allergen-reagin reaction occurs in the bronchioles of the lungs. Here, an important product released from the mast cells is believed to be the slow-reacting substance of anaphylaxis, which causes spasm of the bronchiolar smooth muscle. Consequently, the person has difficulty breathing until the reactive products of the allergic reaction have been removed. Administration of antihistaminics has less effect on the course of asthma because histamine does not appear to be the major factor eliciting the asthmatic reaction. References Abreu MT, Arditi M: Innate immunity and toll-like receptors: clinical implications of basic science research. J Pediatr 144(4):421, 2004. Albert ML: Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev Immunol 4:223, 2004. Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell. New York: Garland Science, 2002. Cheroutre H, Madakamutil L: Acquired and natural memory T cells join forces at the mucosal front line. Nat Rev Immunol 4:290, 2004. Cooper MA, Pommering TL, Koranyi K: Primary immunodeficiencies. Am Fam Physician 68:2001, 2003. Cossart P, Sansonetti PJ: Bacterial invasion: the paradigms of enteroinvasive pathogens. Science 304:242, 2004. Eisenbarth GS, Gottlieb PA: Autoimmune polyendocrine syndromes. N Engl J Med. 350:2068, 2004. Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ: Dendritic cell immunotherapy: mapping the way. Nat Med 10:475, 2004. Frossi B, De Carli M, Pucillo C: The mast cell: an antenna of the microenvironment that directs the immune response. J Leukoc Biol 75:579, 2004. Grossman Z, Min B, Meier-Schellersheim M, Paul WE: Concomitant regulation of T-cell activation and homeostasis. Nat Rev Immunol 4:387, 2004. Kupper TS, Fuhlbrigge RC: Immune surveillance in the skin: mechanisms and clinical consequences. Nat Rev Immunol 4:211, 2004. La Cava A, Matarese G: The weight of leptin in immunity. Nat Rev Immunol 4:371, 2004. Linton PJ, Dorshkind K: Age-related changes in lymphocyte development and function. Nat Immunol 5:133, 2004. MacGlashan D Jr: Histamine: a mediator of inflammation. J Allergy Clin Immunol 112(4 Suppl):S53, 2003. McGeady SJ: Immunocompetence and allergy. Pediatrics 113(4 Suppl):1107, 2004. Nikolich-Zugich J, Slifka MK, Messaoudi I: The many important facets of T-cell repertoire diversity. Nat Rev Immunol 4:123, 2004 . Petrie HT: Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nat Rev Immunol 3:859, 2003. Scott CC, Botelho RJ, Grinstein S: Phagosome maturation: a few bugs in the system. J Membr Biol 193:137, 2003. Theoharides TC, Cochrane DE: Critical role of mast cells in inflammatory diseases and the effect of acute stress. J Neuroimmunol 146:1, 2004. Vivier E, Anfossi N: Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future. Nat Rev Immunol 4:190, 2004. C H A P T E R 3 5 Blood Types; Transfusion; Tissue and Organ Transplantation Antigenicity Causes Immune Reactions of Blood When blood transfusions from one person to another were first attempted, immediate or delayed agglutination and hemolysis of the red blood cells often occurred, resulting in typical transfusion reactions that frequently led to death. Soon it was discovered that the bloods of different people have different antigenic and immune properties, so that antibodies in the plasma of one blood will react with antigens on the surfaces of the red cells of another blood type. If proper precautions are taken, one can determine ahead of time whether the antibodies and antigens present in the donor and recipient bloods will cause a transfusion reaction. Multiplicity of Antigens in the Blood Cells. At least 30 commonly occurring antigens and hundreds of other rare antigens, each of which can at times cause antigenantibody reactions, have been found in human blood cells, especially on the surfaces of the cell membranes. Most of the antigens are weak and therefore are of importance principally for studying the inheritance of genes to establish parentage. Two particular types of antigens are much more likely than the others to cause blood transfusion reactions. They are the O-A-B system of antigens and the Rh system. O-A-B Blood Types A and B Antigens—Agglutinogens Two antigens—type A and type B—occur on the surfaces of the red blood cells in a large proportion of human beings. It is these antigens (also called agglutinogens because they often cause blood cell agglutination) that cause most blood transfusion reactions. Because of the way these agglutinogens are inherited, people may have neither of them on their cells, they may have one, or they may have both simultaneously. Major O-A-B Blood Types. In transfusing blood from one person to another, the bloods of donors and recipients are normally classified into four major O-A-B blood types, as shown in Table 35–1, depending on the presence or absence of the two agglutinogens, the A and B agglutinogens. When neither A nor B agglutinogen is present, the blood is type O. When only type A agglutinogen is present, the blood is type A.When only type B agglutinogen is present, the blood is type B. When both A and B agglutinogens are present, the blood is type AB. Genetic Determination of the Agglutinogens. Two genes, one on each of two paired chromosomes, determine the O-A-B blood type. These genes can be any one of three types but only one type on each of the two chromosomes: type O, type A, 451 452 Unit VI Blood Cells, Immunity, and Blood Clotting Table 35–1 Blood Types with Their Genotypes and Their Constituent Agglutinogens and Agglutinins Blood Types Agglutinogens Agglutinins OO O — OA or AA OB or BB AB A B AB A B A and B Anti-A and Anti-B Anti-B Anti-A — or type B. The type O gene is either functionless or almost functionless, so that it causes no significant type O agglutinogen on the cells. Conversely, the type A and type B genes do cause strong agglutinogens on the cells. The six possible combinations of genes, as shown in Table 35–1, are OO, OA, OB, AA, BB, and AB. These combinations of genes are known as the genotypes, and each person is one of the six genotypes. One can also observe from Table 35–1 that a person with genotype OO produces no agglutinogens, and therefore the blood type is O. A person with genotype OA or AA produces type A agglutinogens and therefore has blood type A. Genotypes OB and BB give type B blood, and genotype AB gives type AB blood. Relative Frequencies of the Different Blood Types. The prevalence of the different blood types among one group of persons studied was approximately: O A B AB 47% 41% 9% 3% It is obvious from these percentages that the O and A genes occur frequently, whereas the B gene is infrequent. Agglutinins When type A agglutinogen is not present in a person’s red blood cells, antibodies known as anti-A agglutinins develop in the plasma. Also, when type B agglutinogen is not present in the red blood cells, antibodies known as anti-B agglutinins develop in the plasma. Thus, referring once again to Table 35–1, note that type O blood, although containing no agglutinogens, does contain both anti-A and anti-B agglutinins; type A blood contains type A agglutinogens and anti-B agglutinins; type B blood contains type B agglutinogens and anti-A agglutinins. Finally, type AB blood contains both A and B agglutinogens but no agglutinins. Titer of the Agglutinins at Different Ages. Immediately after birth, the quantity of agglutinins in the plasma is almost zero. Two to 8 months after birth, an infant begins to produce agglutinins—anti-A agglutinins Average titer of agglutinins Genotypes Anti-A agglutinins in groups B and O blood 400 Anti-B agglutinins in groups A and O blood 300 200 100 0 0 10 20 30 40 50 60 70 80 90 100 Age of person (years) Figure 35–1 Average titers of anti-A and anti-B agglutinins in the plasmas of people with different blood types. when type A agglutinogens are not present in the cells, and anti-B agglutinins when type B agglutinogens are not in the cells. Figure 35–1 shows the changing titers of the anti-A and anti-B agglutinins at different ages. A maximum titer is usually reached at 8 to 10 years of age, and this gradually declines throughout the remaining years of life. Origin of Agglutinins in the Plasma. The agglutinins are gamma globulins, as are almost all antibodies, and they are produced by the same bone marrow and lymph gland cells that produce antibodies to any other antigens. Most of them are IgM and IgG immunoglobulin molecules. But why are these agglutinins produced in people who do not have the respective agglutinogens in their red blood cells? The answer to this is that small amounts of type A and B antigens enter the body in food, in bacteria, and in other ways, and these substances initiate the development of the anti-A and anti-B agglutinins. For instance, infusion of group A antigen into a recipient having a non-A blood type causes a typical immune response with formation of greater quantities of anti-A agglutinins than ever. Also, the neonate has few, if any, agglutinins, showing that agglutinin formation occurs almost entirely after birth. Agglutination Process In Transfusion Reactions When bloods are mismatched so that anti-A or anti-B plasma agglutinins are mixed with red blood cells that contain A or B agglutinogens, respectively, the red Chapter 35 Blood Types; Transfusion; Tissue and Organ Transplantation cells agglutinate as a result of the agglutinins’ attaching themselves to the red blood cells. Because the agglutinins have two binding sites (IgG type) or 10 binding sites (IgM type), a single agglutinin can attach to two or more red blood cells at the same time, thereby causing the cells to be bound together by the agglutinin. This causes the cells to clump, which is the process of “agglutination.” Then these clumps plug small blood vessels throughout the circulatory system. During ensuing hours to days, either physical distortion of the cells or attack by phagocytic white blood cells destroys the membranes of the agglutinated cells, releasing hemoglobin into the plasma, which is called “hemolysis” of the red blood cells. Acute Hemolysis Occurs in Some Transfusion Reactions. Sometimes, when recipient and donor bloods are mismatched, immediate hemolysis of red cells occurs in the circulating blood. In this case, the antibodies cause lysis of the red blood cells by activating the complement system, which releases proteolytic enzymes (the lytic complex) that rupture the cell membranes, as described in Chapter 34. Immediate intravascular hemolysis is far less common than agglutination followed by delayed hemolysis, because not only does there have to be a high titer of antibodies for lysis to occur, but also a different type of antibody seems to be required, mainly the IgM antibodies; these antibodies are called hemolysins. Blood Typing Before giving a transfusion to a person, it is necessary to determine the blood type of the recipient’s blood and the blood type of the donor blood so that the bloods can be appropriately matched. This is called blood typing and blood matching, and these are performed in the following way: The red blood cells are first separated from the plasma and diluted with saline. One portion is then mixed with anti-A agglutinin and another portion with anti-B agglutinin. After several minutes, the mixtures are observed under a microscope. If the red blood cells have become clumped— that is, “agglutinated”—one knows that an antibodyantigen reaction has resulted. Table 35–2 lists the presence (+) or absence (-) of agglutination of the four types of red blood cells. Type Table 35–2 O red blood cells have no agglutinogens and therefore do not react with either the anti-A or the anti-B agglutinins. Type A blood has A agglutinogens and therefore agglutinates with anti-A agglutinins. Type B blood has B agglutinogens and agglutinates with anti-B agglutinins. Type AB blood has both A and B agglutinogens and agglutinates with both types of agglutinins. Rh Blood Types Along with the O-A-B blood type system, the Rh blood type system is also important when transfusing blood. The major difference between the O-A-B system and the Rh system is the following: In the O-A-B system, the plasma agglutinins responsible for causing transfusion reactions develop spontaneously, whereas in the Rh system, spontaneous agglutinins almost never occur. Instead, the person must first be massively exposed to an Rh antigen, such as by transfusion of blood containing the Rh antigen, before enough agglutinins to cause a significant transfusion reaction will develop. Rh Antigens—“Rh-Positive” and “Rh-Negative” People. There are six common types of Rh antigens, each of which is called an Rh factor. These types are designated C, D, E, c, d, and e. A person who has a C antigen does not have the c antigen, but the person missing the C antigen always has the c antigen. The same is true for the D-d and E-e antigens. Also, because of the manner of inheritance of these factors, each person has one of each of the three pairs of antigens. The type D antigen is widely prevalent in the population and considerably more antigenic than the other Rh antigens. Anyone who has this type of antigen is said to be Rh positive, whereas a person who does not have type D antigen is said to be Rh negative. However, it must be noted that even in Rh-negative people, some of the other Rh antigens can still cause transfusion reactions, although the reactions are usually much milder. About 85 per cent of all white people are Rh positive and 15 per cent, Rh negative. In American blacks, the percentage of Rh-positives is about 95, whereas in African blacks, it is virtually 100 per cent. Rh Immune Response Blood Typing, Showing Agglutination of Cells of the Different Blood Types with Anti-A or Anti-B Agglutinins in the Sera Red Blood Cell Types O A B AB 453 Formation of Anti-Rh Agglutinins. When red blood cells Sera Anti-A Anti-B + + + + containing Rh factor are injected into a person whose blood does not contain the Rh factor—that is, into an Rh-negative person—anti-Rh agglutinins develop slowly, reaching maximum concentration of agglutinins about 2 to 4 months later. This immune response occurs to a much greater extent in some people than in others. With multiple exposures to the Rh factor, an Rh-negative person eventually becomes strongly “sensitized” to Rh factor. 454 Unit VI Blood Cells, Immunity, and Blood Clotting Characteristics of Rh Transfusion Reactions. If an Rhnegative person has never before been exposed to Rhpositive blood, transfusion of Rh-positive blood into that person will likely cause no immediate reaction. However, anti-Rh antibodies can develop in sufficient quantities during the next 2 to 4 weeks to cause agglutination of those transfused cells that are still circulating in the blood. These cells are then hemolyzed by the tissue macrophage system. Thus, a delayed transfusion reaction occurs, although it is usually mild. On subsequent transfusion of Rh-positive blood into the same person, who is now already immunized against the Rh factor, the transfusion reaction is greatly enhanced and can be immediate and as severe as a transfusion reaction caused by mismatched type A or B blood. Erythroblastosis Fetalis (“Hemolytic Disease of the Newborn”) Erythroblastosis fetalis is a disease of the fetus and newborn child characterized by agglutination and phagocytosis of the fetus’s red blood cells. In most instances of erythroblastosis fetalis, the mother is Rh negative and the father Rh positive. The baby has inherited the Rh-positive antigen from the father, and the mother develops anti-Rh agglutinins from exposure to the fetus’s Rh antigen. In turn, the mother’s agglutinins diffuse through the placenta into the fetus and cause red blood cell agglutination. Incidence of the Disease. An Rh-negative mother having her first Rh-positive child usually does not develop sufficient anti-Rh agglutinins to cause any harm. However, about 3 per cent of second Rh-positive babies exhibit some signs of erythroblastosis fetalis; about 10 per cent of third babies exhibit the disease; and the incidence rises progressively with subsequent pregnancies. Effect of the Mother’s Antibodies on the Fetus. After antiRh antibodies have formed in the mother, they diffuse slowly through the placental membrane into the fetus’s blood. There they cause agglutination of the fetus’s blood. The agglutinated red blood cells subsequently hemolyze, releasing hemoglobin into the blood. The fetus’s macrophages then convert the hemoglobin into bilirubin, which causes the baby’s skin to become yellow (jaundiced). The antibodies can also attack and damage other cells of the body. passed from the baby’s bone marrow into the circulatory system, and it is because of the presence of these nucleated blastic red blood cells that the disease is called erythroblastosis fetalis. Although the severe anemia of erythroblastosis fetalis is usually the cause of death, many children who barely survive the anemia exhibit permanent mental impairment or damage to motor areas of the brain because of precipitation of bilirubin in the neuronal cells, causing destruction of many, a condition called kernicterus. Treatment of the Erythroblastotic Neonate. One treatment for erythroblastosis fetalis is to replace the neonate’s blood with Rh-negative blood. About 400 milliliters of Rh-negative blood is infused over a period of 1.5 or more hours while the neonate’s own Rh-positive blood is being removed. This procedure may be repeated several times during the first few weeks of life, mainly to keep the bilirubin level low and thereby prevent kernicterus. By the time these transfused Rh-negative cells are replaced with the infant’s own Rh-positive cells, a process that requires 6 or more weeks, the antiRh agglutinins that had come from the mother will have been destroyed. Prevention of Erythroblastosis Fetalis. The D antigen of the Rh blood group system is the primary culprit in causing immunization of an Rh-negative mother to an Rh-positive fetus. In the 1970’s, a dramatic reduction in the incidence of erythroblastosis fetalis was achieved with the development of Rh immunoglobulin globin, an anti-D antibody that is administered to the expectant mother starting at 28 to 30 weeks of gestation. The anti-D antibody is also administered to Rh-negative women who deliver Rh-positive babies to prevent sensitization of the mothers to the D antigen. This greatly reduces the risk of developing large amounts of D antibodies during the second pregnancy. The mechanism by which Rh immunoglobulin globin prevents sensitization of the D antigen is not completely understood, but one effect of the anti-D antibody is to inhibit antigen-induced B lymphocyte antibody production in the expectant mother. The administered anti-D antibody also attaches to Dantigen sites on Rh-positive fetal red blood cells that may cross the placenta and enter the circulation of the expectant mother, thereby interfering with the immune response to the D antigen. Clinical Picture of Erythroblastosis. The jaundiced, ery- throblastotic newborn baby is usually anemic at birth, and the anti-Rh agglutinins from the mother usually circulate in the infant’s blood for another 1 to 2 months after birth, destroying more and more red blood cells. The hematopoietic tissues of the infant attempt to replace the hemolyzed red blood cells. The liver and spleen become greatly enlarged and produce red blood cells in the same manner that they normally do during the middle of gestation. Because of the rapid production of red cells, many early forms of red blood cells, including many nucleated blastic forms, are Transfusion Reactions Resulting from Mismatched Blood Types If donor blood of one blood type is transfused into a recipient who has another blood type, a transfusion reaction is likely to occur in which the red blood cells of the donor blood are agglutinated. It is rare that the transfused blood causes agglutination of the recipient’s cells, for the following reason: The plasma portion of the donor blood immediately becomes diluted by all the plasma of the recipient, thereby decreasing the Chapter 35 Blood Types; Transfusion; Tissue and Organ Transplantation titer of the infused agglutinins to a level usually too low to cause agglutination. Conversely, the small amount of infused blood does not significantly dilute the agglutinins in the recipient’s plasma. Therefore, the recipient’s agglutinins can still agglutinate the mismatched donor cells. As explained earlier, all transfusion reactions eventually cause either immediate hemolysis resulting from hemolysins or later hemolysis resulting from phagocytosis of agglutinated cells. The hemoglobin released from the red cells is then converted by the phagocytes into bilirubin and later excreted in the bile by the liver, as discussed in Chapter 70. The concentration of bilirubin in the body fluids often rises high enough to cause jaundice—that is, the person’s internal tissues and skin become colored with yellow bile pigment. But if liver function is normal, the bile pigment will be excreted into the intestines by way of the liver bile, so that jaundice usually does not appear in an adult person unless more than 400 milliliters of blood is hemolyzed in less than a day. Acute Kidney Shutdown After Transfusion Reactions. One of the most lethal effects of transfusion reactions is kidney failure, which can begin within a few minutes to few hours and continue until the person dies of renal failure. The kidney shutdown seems to result from three causes: First, the antigen-antibody reaction of the transfusion reaction releases toxic substances from the hemolyzing blood that cause powerful renal vasoconstriction. Second, loss of circulating red cells in the recipient, along with production of toxic substances from the hemolyzed cells and from the immune reaction, often causes circulatory shock. The arterial blood pressure falls very low, and renal blood flow and urine output decrease. Third, if the total amount of free hemoglobin released into the circulating blood is greater than the quantity that can bind with “haptoglobin” (a plasma protein that binds small amounts of hemoglobin), much of the excess leaks through the glomerular membranes into the kidney tubules. If this amount is still slight, it can be reabsorbed through the tubular epithelium into the blood and will cause no harm; if it is great, then only a small percentage is reabsorbed. Yet water continues to be reabsorbed, causing the tubular hemoglobin concentration to rise so high that the hemoglobin precipitates and blocks many of the kidney tubules. Thus, renal vasoconstriction, circulatory shock, and renal tubular blockage together cause acute renal shutdown. If the shutdown is complete and fails to resolve, the patient dies within a week to 12 days, as explained in Chapter 31, unless treated with an artificial kidney. Transplantation of Tissues and Organs Most of the different antigens of red blood cells that cause transfusion reactions are also widely present in other cells of the body, and each bodily tissue has 455 its own additional complement of antigens. Consequently, foreign cells transplanted anywhere into the body of a recipient can produce immune reactions. In other words, most recipients are just as able to resist invasion by foreign tissue cells as to resist invasion by foreign bacteria or red cells. Autografts, Isografts, Allografts, and Xenografts. A trans- plant of a tissue or whole organ from one part of the same animal to another part is called an autograft; from one identical twin to another, an isograft; from one human being to another or from any animal to another animal of the same species, an allograft; and from a lower animal to a human being or from an animal of one species to one of another species, a xenograft. Transplantation of Cellular Tissues. In the case of auto- grafts and isografts, cells in the transplant contain virtually the same types of antigens as in the tissues of the recipient and will almost always continue to live normally and indefinitely if an adequate blood supply is provided. At the other extreme, in the case of xenografts, immune reactions almost always occur, causing death of the cells in the graft within 1 day to 5 weeks after transplantation unless some specific therapy is used to prevent the immune reactions. Some of the different cellular tissues and organs that have been transplanted as allografts, either experimentally or for therapeutic purposes, from one person to another are skin, kidney, heart, liver, glandular tissue, bone marrow, and lung. With proper “matching” of tissues between persons, many kidney allografts have been successful for at least 5 to 15 years, and allograft liver and heart transplants for 1 to 15 years. Attempts to Overcome Immune Reactions in Transplanted Tissue Because of the extreme potential importance of transplanting certain tissues and organs, serious attempts have been made to prevent antigen-antibody reactions associated with transplantation. The following specific procedures have met with some degrees of clinical or experimental success. Tissue Typing—The HLA Complex of Antigens The most important antigens for causing graft rejection are a complex called the HLA antigens. Six of these antigens are present on the tissue cell membranes of each person, but there are about 150 different HLA antigens to choose from. Therefore, this represents more than a trillion possible combinations. Consequently, it is virtually impossible for two persons, except in the case of identical twins, to have the same six HLA antigens. Development of significant immunity against any one of these antigens can cause graft rejection. The HLA antigens occur on the white blood cells as well as on the tissue cells. Therefore, tissue typing for 456 Unit VI Blood Cells, Immunity, and Blood Clotting these antigens is done on the membranes of lymphocytes that have been separated from the person’s blood. The lymphocytes are mixed with appropriate antisera and complement; after incubation, the cells are tested for membrane damage, usually by testing the rate of trans-membrane uptake by the lymphocytic cells of a special dye. Some of the HLA antigens are not severely antigenic, for which reason a precise match of some antigens between donor and recipient is not always essential to allow allograft acceptance. Therefore, by obtaining the best possible match between donor and recipient, the grafting procedure has become far less hazardous. The best success has been with tissue-type matches between siblings and between parent and child. The match in identical twins is exact, so that transplants between identical twins are almost never rejected because of immune reactions. Prevention of Graft Rejection by Suppressing the Immune System If the immune system were completely suppressed, graft rejection would not occur. In fact, in an occasional person who has serious depression of the immune system, grafts can be successful without the use of significant therapy to prevent rejection. But in the normal person, even with the best possible tissue typing, allografts seldom resist rejection for more than a few days or weeks without use of specific therapy to suppress the immune system. Furthermore, because the T cells are mainly the portion of the immune system important for killing grafted cells, their suppression is much more important than suppression of plasma antibodies. Some of the therapeutic agents that have been used for this purpose include the following: 1. Glucocorticoid hormones isolated from adrenal cortex glands (or drugs with glucocorticoid-like activity), which suppress the growth of all lymphoid tissue and, therefore, decrease formation of antibodies and T cells. 2. Various drugs that have a toxic effect on the lymphoid system and, therefore, block formation of antibodies and T cells, especially the drug azathioprine. 3. Cyclosporine, which has a specific inhibitory effect on the formation of helper T cells and, therefore, is especially efficacious in blocking the T-cell rejection reaction. This has proved to be one of the most valuable of all the drugs because it does not depress some other portions of the immune system. Use of these agents often leaves the person unprotected from infectious disease; therefore, sometimes bacterial and viral infections become rampant. In addition, the incidence of cancer is several times as great in an immunosuppressed person, presumably because the immune system is important in destroying many early cancer cells before they can begin to proliferate. To summarize, transplantation of living tissues in human beings has had very limited but important success. When someone does finally succeed in blocking the immune response of the recipient without at the same time destroying the recipient’s specific immunity for disease, the story will change overnight. References Alayash AI: Oxygen therapeutics: can we tame haemoglobin? Nat Rev Drug Discov 3:152, 2004. Altomonte M, Fonsatti E, Visintin A, Maio M: Targeted therapy of solid malignancies via HLA class II antigens: a new biotherapeutic approach? Oncogene 22:6564, 2003. Avent ND, Reid ME: The Rh blood group system: a review. Blood 95:375, 2000. Bowman J: Thirty-five years of Rh prophylaxis. Transfusion 43:1661, 2003. Goodnough LT, Shander A: Evolution in alternatives to blood transfusion. Hematol J 4:87, 2003. Gottstein R, Cooke RW: Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 88:F6, 2003. Heeger PS: T-cell allorecognition and transplant rejection: a summary and update. Am J Transplant 3:525, 2003. Horn KD: The classification, recognition and significance of polyagglutination in transfusion medicine. Blood Rev 13:36, 1999. Miller J, Mathew JM, Esquenazi V: Toward tolerance to human organ transplants: a few additional corollaries and questions. Transplantation 77:940, 2004. Ricordi C, Strom TB: Clinical islet transplantation: advances and immunological challenges. Nat Rev Immunol 4:259, 2004. Schroeder RA, Marroquin CE, Kuo PC: Tolerance and the “Holy Grail” of transplantation. J Surg Res 111:109, 2003. Schulak JA: Steroid immunosuppression in kidney transplantation: a passing era. J Surg Res 117:154, 2004. Spahn DR, Pasch T: Physiological properties of blood substitutes. News Physiol Sci 16:38, 2001. Strober S, Lowsky RJ, Shizuru JA, et al: Approaches to transplantation tolerance in humans. Transplantation 77:932, 2004. Sumpter TL, Wilkes DS: Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection. Am J Physiol Lung Cell Mol Physiol 286:L1129, 2004. Telen MJ: Red blood cell surface adhesion molecules: their possible roles in normal human physiology and disease. Semin Hematol 37:130, 2000. Trigg ME: Hematopoietic stem cells. Pediatrics 113(4 Suppl):1051, 2004. Triulzi DJ: Specialized transfusion support for solid organ transplantation. Curr Opin Hematol 9:527, 2002. C H A P T E R 3 6 Hemostasis and Blood Coagulation Events in Hemostasis The term hemostasis means prevention of blood loss. Whenever a vessel is severed or ruptured, hemostasis is achieved by several mechanisms: (1) vascular constriction, (2) formation of a platelet plug, (3) formation of a blood clot as a result of blood coagulation, and (4) eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently. Vascular Constriction Immediately after a blood vessel has been cut or ruptured, the trauma to the vessel wall itself causes the smooth muscle in the wall to contract; this instantaneously reduces the flow of blood from the ruptured vessel. The contraction results from (1) local myogenic spasm, (2) local autacoid factors from the traumatized tissues and blood platelets, and (3) nervous reflexes. The nervous reflexes are initiated by pain nerve impulses or other sensory impulses that originate from the traumatized vessel or nearby tissues. However, even more vasoconstriction probably results from local myogenic contraction of the blood vessels initiated by direct damage to the vascular wall. And, for the smaller vessels, the platelets are responsible for much of the vasoconstriction by releasing a vasoconstrictor substance, thromboxane A2. The more severely a vessel is traumatized, the greater the degree of vascular spasm. The spasm can last for many minutes or even hours, during which time the processes of platelet plugging and blood coagulation can take place. Formation of the Platelet Plug If the cut in the blood vessel is very small—indeed, many very small vascular holes do develop throughout the body each day—the cut is often sealed by a platelet plug, rather than by a blood clot. To understand this, it is important that we first discuss the nature of platelets themselves. Physical and Chemical Characteristics of Platelets Platelets (also called thrombocytes) are minute discs 1 to 4 micrometers in diameter. They are formed in the bone marrow from megakaryocytes, which are extremely large cells of the hematopoietic series in the marrow; the megakaryocytes fragment into the minute platelets either in the bone marrow or soon after entering the blood, especially as they squeeze through capillaries. The normal concentration of platelets in the blood is between 150,000 and 300,000 per microliter. Platelets have many functional characteristics of whole cells, even though they do not have nuclei and cannot reproduce. In their cytoplasm are such active factors as (1) actin and myosin molecules, which are contractile proteins similar to those found in muscle cells, and still another contractile protein, thrombosthenin, that can cause the platelets to contract; (2) residuals of both the endoplasmic reticulum and the Golgi apparatus that synthesize various enzymes and especially store large quantities of calcium ions; (3) mitochondria and 457 458 Unit VI Blood Cells, Immunity, and Blood Clotting enzyme systems that are capable of forming adenosine triphosphate (ATP) and adenosine diphosphate (ADP); (4) enzyme systems that synthesize prostaglandins, which are local hormones that cause many vascular and other local tissue reactions; (5) an important protein called fibrin-stabilizing factor, which we discuss later in relation to blood coagulation; and (6) a growth factor that causes vascular endothelial cells, vascular smooth muscle cells, and fibroblasts to multiply and grow, thus causing cellular growth that eventually helps repair damaged vascular walls. The cell membrane of the platelets is also important. On its surface is a coat of glycoproteins that repulses adherence to normal endothelium and yet causes adherence to injured areas of the vessel wall, especially to injured endothelial cells and even more so to any exposed collagen from deep within the vessel wall. In addition, the platelet membrane contains large amounts of phospholipids that activate multiple stages in the blood-clotting process, as we discuss later. Thus, the platelet is an active structure. It has a halflife in the blood of 8 to 12 days, so that over several weeks its functional processes run out. Then it is eliminated from the circulation mainly by the tissue macrophage system. More than one half of the platelets are removed by macrophages in the spleen, where the blood passes through a latticework of tight trabeculae. Mechanism of the Platelet Plug Platelet repair of vascular openings is based on several important functions of the platelet itself. When platelets come in contact with a damaged vascular surface, especially with collagen fibers in the vascular wall, the platelets themselves immediately change their own characteristics drastically. They begin to swell; they assume irregular forms with numerous irradiating pseudopods protruding from their surfaces; their contractile proteins contract forcefully and cause the release of granules that contain multiple active factors; they become sticky so that they adhere to collagen in the tissues and to a protein called von Willebrand factor that leaks into the traumatized tissue from the plasma; they secrete large quantities of ADP; and their enzymes form thromboxane A2. The ADP and thromboxane in turn act on nearby platelets to activate them as well, and the stickiness of these additional platelets causes them to adhere to the original activated platelets. Therefore, at the site of any opening in a blood vessel wall, the damaged vascular wall activates successively increasing numbers of platelets that themselves attract more and more additional platelets, thus forming a platelet plug. This is at first a loose plug, but it is usually successful in blocking blood loss if the vascular opening is small. Then, during the subsequent process of blood coagulation, fibrin threads form. These attach tightly to the platelets, thus constructing an unyielding plug. Importance of the Platelet Mechanism for Closing Vascular Holes. The platelet-plugging mechanism is extremely important for closing minute ruptures in very small blood vessels that occur many thousands of times daily. Indeed, multiple small holes through the endothelial cells themselves are often closed by platelets actually fusing with the endothelial cells to form additional endothelial cell membrane. A person who has few blood platelets develops each day literally thousands of small hemorrhagic areas under the skin and throughout the internal tissues, but this does not occur in the normal person. Blood Coagulation in the Ruptured Vessel The third mechanism for hemostasis is formation of the blood clot. The clot begins to develop in 15 to 20 seconds if the trauma to the vascular wall has been severe, and in 1 to 2 minutes if the trauma has been minor. Activator substances from the traumatized vascular wall, from platelets, and from blood proteins adhering to the traumatized vascular wall initiate the clotting process. The physical events of this process are shown in Figure 36–1, and Table 36–1 lists the most important of the clotting factors. Within 3 to 6 minutes after rupture of a vessel, if the vessel opening is not too large, the entire opening or broken end of the vessel is filled with clot. After 20 minutes to an hour, the clot retracts; this closes the vessel still further. Platelets also play an important role in this clot retraction, as is discussed later. Fibrous Organization or Dissolution of the Blood Clot Once a blood clot has formed, it can follow one of two courses: (1) It can become invaded by fibroblasts, 1. Severed vessel 2. Platelets agglutinate 3. Fibrin appears 4. Fibrin clot forms 5. Clot retraction occurs Figure 36–1 Clotting process in a traumatized blood vessel. (Modified from Seegers WH: Hemostatic Agents, 1948. Courtesy of Charles C Thomas, Publisher, Ltd., Springfield, IL.) Chapter 36 459 Hemostasis and Blood Coagulation Table 36–1 Prothrombin Clotting Factors in Blood and Their Synonyms Clotting Factor Synonyms Fibrinogen Prothrombin Tissue factor Calcium Factor V Factor I Factor II Factor III; tissue thromboplastin Factor IV Proaccelerin; labile factor; Ac-globulin (Ac-G) Serum prothrombin conversion accelerator (SPCA); proconvertin; stable factor Antihemophilic factor (AHF); antihemophilic globulin (AHG); antihemophilic factor A Plasma thromboplastin component (PTC); Christmas factor; antihemophilic factor B Stuart factor; Stuart-Prower factor Plasma thromboplastin antecedent (PTA); antihemophilic factor C Hageman factor Fibrin-stabilizing factor Fletcher factor Fitzgerald factor; HMWK (high-molecular-weight) kininogen Factor VII Factor VIII Factor IX Factor X Factor XI Factor XII Factor XIII Prekallikrein High-molecular-weight kininogen Platelets Prothrombin activator Ca++ Thrombin Fibrinogen Fibrinogen monomer Ca++ Fibrin fibers Thrombin activated fibrin-stabilizing factor Cross-linked fibrin fibers Figure 36–2 Schema for conversion of prothrombin to thrombin and polymerization of fibrinogen to form fibrin fibers. which subsequently form connective tissue all through the clot, or (2) it can dissolve. The usual course for a clot that forms in a small hole of a vessel wall is invasion by fibroblasts, beginning within a few hours after the clot is formed (which is promoted at least partially by growth factor secreted by platelets). This continues to complete organization of the clot into fibrous tissue within about 1 to 2 weeks. Conversely, when excess blood has leaked into the tissues and tissue clots have occurred where they are not needed, special substances within the clot itself usually become activated. These function as enzymes to dissolve the clot, as discussed later in the chapter. three essential steps: (1) In response to rupture of the vessel or damage to the blood itself, a complex cascade of chemical reactions occurs in the blood involving more than a dozen blood coagulation factors. The net result is formation of a complex of activated substances collectively called prothrombin activator. (2) The prothrombin activator catalyzes conversion of prothrombin into thrombin. (3) The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot. Let us discuss first the mechanism by which the blood clot itself is formed, beginning with conversion of prothrombin to thrombin; then we will come back to the initiating stages in the clotting process by which prothrombin activator is formed. Mechanism of Blood Coagulation Conversion of Prothrombin to Thrombin Basic Theory. More than 50 important substances that cause or affect blood coagulation have been found in the blood and in the tissues—some that promote coagulation, called procoagulants, and others that inhibit coagulation, called anticoagulants. Whether blood will coagulate depends on the balance between these two groups of substances. In the blood stream, the anticoagulants normally predominate, so that the blood does not coagulate while it is circulating in the blood vessels. But when a vessel is ruptured, procoagulants from the area of tissue damage become “activated” and override the anticoagulants, and then a clot does develop. First, prothrombin activator is formed as a result of rupture of a blood vessel or as a result of damage to special substances in the blood. Second, the prothrombin activator, in the presence of sufficient amounts of ionic Ca++, causes conversion of prothrombin to thrombin (Figure 36–2). Third, the thrombin causes polymerization of fibrinogen molecules into fibrin fibers within another 10 to 15 seconds. Thus, the rate-limiting factor in causing blood coagulation is usually the formation of prothrombin activator and not the subsequent reactions beyond that point, because these terminal steps normally occur rapidly to form the clot itself. Platelets also play an important role in the conversion of prothrombin to thrombin because much of the prothrombin first attaches to prothrombin General Mechanism. All research workers in the field of blood coagulation agree that clotting takes place in 460 Unit VI Blood Cells, Immunity, and Blood Clotting receptors on the platelets already bound to the damaged tissue. Prothrombin and Thrombin. Prothrombin is a plasma protein, an alpha2-globulin, having a molecular weight of 68,700. It is present in normal plasma in a concentration of about 15 mg/dl. It is an unstable protein that can split easily into smaller compounds, one of which is thrombin, which has a molecular weight of 33,700, almost exactly one half that of prothrombin. Prothrombin is formed continually by the liver, and it is continually being used throughout the body for blood clotting. If the liver fails to produce prothrombin, in a day or so prothrombin concentration in the plasma falls too low to provide normal blood coagulation. Vitamin K is required by the liver for normal formation of prothrombin as well as for formation of a few other clotting factors. Therefore, either lack of vitamin K or the presence of liver disease that prevents normal prothrombin formation can decrease the prothrombin level so low that a bleeding tendency results. Conversion of Fibrinogen to Fibrin— Formation of the Clot Fibrinogen. Fibrinogen is a high-molecular-weight protein (MW = 340,000) that occurs in the plasma in quantities of 100 to 700 mg/dl. Fibrinogen is formed in the liver, and liver disease can decrease the concentration of circulating fibrinogen, as it does the concentration of prothrombin, pointed out above. Because of its large molecular size, little fibrinogen normally leaks from the blood vessels into the interstitial fluids, and because fibrinogen is one of the essential factors in the coagulation process, interstitial fluids ordinarily do not coagulate. Yet, when the permeability of the capillaries becomes pathologically increased, fibrinogen does then leak into the tissue fluids in sufficient quantities to allow clotting of these fluids in much the same way that plasma and whole blood can clot. Action of Thrombin on Fibrinogen to Form Fibrin. Thrombin is a protein enzyme with weak proteolytic capabilities. It acts on fibrinogen to remove four low-molecularweight peptides from each molecule of fibrinogen, forming one molecule of fibrin monomer that has the automatic capability to polymerize with other fibrin monomer molecules to form fibrin fibers. Therefore, many fibrin monomer molecules polymerize within seconds into long fibrin fibers that constitute the reticulum of the blood clot. In the early stages of polymerization, the fibrin monomer molecules are held together by weak noncovalent hydrogen bonding, and the newly forming fibers are not cross-linked with one another; therefore, the resultant clot is weak and can be broken apart with ease. But another process occurs during the next few minutes that greatly strengthens the fibrin reticulum. This involves a substance called fibrin-stabilizing factor that is present in small amounts in normal plasma globulins but is also released from platelets entrapped in the clot. Before fibrin-stabilizing factor can have an effect on the fibrin fibers, it must itself be activated. The same thrombin that causes fibrin formation also activates the fibrin-stabilizing factor. Then this activated substance operates as an enzyme to cause covalent bonds between more and more of the fibrin monomer molecules, as well as multiple crosslinkages between adjacent fibrin fibers, thus adding tremendously to the three-dimensional strength of the fibrin meshwork. Blood Clot. The clot is composed of a meshwork of fibrin fibers running in all directions and entrapping blood cells, platelets, and plasma. The fibrin fibers also adhere to damaged surfaces of blood vessels; therefore, the blood clot becomes adherent to any vascular opening and thereby prevents further blood loss. Clot Retraction—Serum. Within a few minutes after a clot is formed, it begins to contract and usually expresses most of the fluid from the clot within 20 to 60 minutes. The fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed; in this way, serum differs from plasma. Serum cannot clot because it lacks these factors. Platelets are necessary for clot retraction to occur. Therefore, failure of clot retraction is an indication that the number of platelets in the circulating blood might be low. Electron micrographs of platelets in blood clots show that they become attached to the fibrin fibers in such a way that they actually bond different fibers together. Furthermore, platelets entrapped in the clot continue to release procoagulant substances, one of the most important of which is fibrin-stabilizing factor, which causes more and more cross-linking bonds between adjacent fibrin fibers. In addition, the platelets themselves contribute directly to clot contraction by activating platelet thrombosthenin, actin, and myosin molecules, which are all contractile proteins in the platelets and cause strong contraction of the platelet spicules attached to the fibrin. This also helps compress the fibrin meshwork into a smaller mass. The contraction is activated and accelerated by thrombin as well as by calcium ions released from calcium stores in the mitochondria, endoplasmic reticulum, and Golgi apparatus of the platelets. As the clot retracts, the edges of the broken blood vessel are pulled together, thus contributing still further to the ultimate state of hemostasis. Vicious Circle of Clot Formation Once a blood clot has started to develop, it normally extends within minutes into the surrounding blood. That is, the clot itself initiates a vicious circle (positive feedback) to promote more clotting. One of the most Chapter 36 461 Hemostasis and Blood Coagulation Prothrombin activator is generally considered to be formed in two ways, although, in reality, the two ways interact constantly with each other: (1) by the extrinsic pathway that begins with trauma to the vascular wall and surrounding tissues and (2) by the intrinsic pathway that begins in the blood itself. In both the extrinsic and the intrinsic pathways, a series of different plasma proteins called bloodclotting factors play major roles. Most of these are inactive forms of proteolytic enzymes. When converted to the active forms, their enzymatic actions cause the successive, cascading reactions of the clotting process. Most of the clotting factors, which are listed in Table 36–1, are designated by Roman numerals. To indicate the activated form of the factor, a small letter “a” is added after the Roman numeral, such as Factor VIIIa to indicate the activated state of Factor VIII. important causes of this is the fact that the proteolytic action of thrombin allows it to act on many of the other blood-clotting factors in addition to fibrinogen. For instance, thrombin has a direct proteolytic effect on prothrombin itself, tending to convert this into still more thrombin, and it acts on some of the blood-clotting factors responsible for formation of prothrombin activator. (These effects, discussed in subsequent paragraphs, include acceleration of the actions of Factors VIII, IX, X, XI, and XII and aggregation of platelets.) Once a critical amount of thrombin is formed, a vicious circle develops that causes still more blood clotting and more and more thrombin to be formed; thus, the blood clot continues to grow until blood leakage ceases. Initiation of Coagulation: Formation of Prothrombin Activator Extrinsic Pathway for Initiating Clotting The extrinsic pathway for initiating the formation of prothrombin activator begins with a traumatized vascular wall or traumatized extravascular tissues that come in contact with the blood. This leads to the following steps, as shown in Figure 36–3: 1. Release of tissue factor. Traumatized tissue releases a complex of several factors called tissue factor or tissue thromboplastin. This factor is composed especially of phospholipids from the membranes of the tissue plus a lipoprotein complex that functions mainly as a proteolytic enzyme. Now that we have discussed the clotting process itself, we must turn to the more complex mechanisms that initiate clotting in the first place. These mechanisms are set into play by (1) trauma to the vascular wall and adjacent tissues, (2) trauma to the blood, or (3) contact of the blood with damaged endothelial cells or with collagen and other tissue elements outside the blood vessel. In each instance, this leads to the formation of prothrombin activator, which then causes prothrombin conversion to thrombin and all the subsequent clotting steps. (1) Tissue trauma Tissue factor Vll (2) VIIa Activated X (Xa) X Ca++ V (3) Platelet phospholipids Prothrombin Activator Prothrombin Figure 36–3 Extrinsic pathway for initiating blood clotting. Ca++ Thrombin Ca++ 462 Unit VI Blood Cells, Immunity, and Blood Clotting 2. Activation of Factor X—role of Factor VII and tissue factor. The lipoprotein complex of tissue factor further complexes with blood coagulation Factor VII and, in the presence of calcium ions, acts enzymatically on Factor X to form activated Factor X (Xa). 3. Effect of activated Factor X (Xa) to form prothrombin activator—role of Factor V. The activated Factor X combines immediately with tissue phospholipids that are part of tissue factor or with additional phospholipids released from platelets as well as with Factor V to form the complex called prothrombin activator. Within a few seconds, in the presence of calcium ions (Ca++), this splits prothrombin to form thrombin, and the clotting process proceeds as already explained. At first, the Factor V in the prothrombin activator complex is inactive, but once clotting begins and thrombin begins to form, the proteolytic action of thrombin activates Factor V. This then becomes an additional strong accelerator of prothrombin activation. Thus, in the final prothrombin activator complex, activated Factor X is the actual protease that causes splitting of prothrombin to form thrombin; activated Factor V greatly accelerates this protease activity, and platelet phospholipids act as a vehicle that further accelerates the process. Note especially the positive feedback effect of thrombin, acting through Factor V, to accelerate the entire process once it begins. Intrinsic Pathway for Initiating Clotting The second mechanism for initiating formation of prothrombin activator, and therefore for initiating clotting, begins with trauma to the blood itself or exposure of the blood to collagen from a traumatized blood vessel wall. Then the process continues through the series of cascading reactions shown in Figure 36–4. 1. Blood trauma causes (1) activation of Factor XII and (2) release of platelet phospholipids. Trauma to the blood or exposure of the blood to vascular Blood trauma or contact with collagen (1) XII Activated XII (XIIa) (HMW kininogen, prekallikrein) (2) (3) XI Activated XI (XIa) Ca++ IX Activated IX (IXa) VIII Thrombin VIIIa (4) (5) X Ca++ Activated X (Xa) Platelet phospholipids Thrombin Ca++ V Prothrombin Activator Platelet phospholipids Prothrombin Thrombin Ca++ Figure 36–4 Intrinsic pathway for initiating blood clotting. Chapter 36 2. 3. 4. 5. Hemostasis and Blood Coagulation wall collagen alters two important clotting factors in the blood: Factor XII and the platelets. When Factor XII is disturbed, such as by coming into contact with collagen or with a wettable surface such as glass, it takes on a new molecular configuration that converts it into a proteolytic enzyme called “activated Factor XII.” Simultaneously, the blood trauma also damages the platelets because of adherence to either collagen or a wettable surface (or by damage in other ways), and this releases platelet phospholipids that contain the lipoprotein called platelet factor 3, which also plays a role in subsequent clotting reactions. Activation of Factor XI. The activated Factor XII acts enzymatically on Factor XI to activate this factor as well, which is the second step in the intrinsic pathway. This reaction also requires HMW (high-molecular-weight) kininogen and is accelerated by prekallikrein. Activation of Factor IX by activated Factor XI. The activated Factor XI then acts enzymatically on Factor IX to activate this factor also. Activation of Factor X—role of Factor VIII. The activated Factor IX, acting in concert with activated Factor VIII and with the platelet phospholipids and factor 3 from the traumatized platelets, activates Factor X. It is clear that when either Factor VIII or platelets are in short supply, this step is deficient. Factor VIII is the factor that is missing in a person who has classic hemophilia, for which reason it is called antihemophilic factor. Platelets are the clotting factor that is lacking in the bleeding disease called thrombocytopenia. Action of activated Factor X to form prothrombin activator—role of Factor V. This step in the intrinsic pathway is the same as the last step in the extrinsic pathway. That is, activated Factor X combines with Factor V and platelet or tissue phospholipids to form the complex called prothrombin activator. The prothrombin activator in turn initiates within seconds the cleavage of prothrombin to form thrombin, thereby setting into motion the final clotting process, as described earlier. Role of Calcium Ions in the Intrinsic and Extrinsic Pathways Except for the first two steps in the intrinsic pathway, calcium ions are required for promotion or acceleration of all the blood-clotting reactions. Therefore, in the absence of calcium ions, blood clotting by either pathway does not occur. In the living body, the calcium ion concentration seldom falls low enough to significantly affect the kinetics of blood clotting. But, when blood is removed from a person, it can be prevented from clotting by reducing the calcium ion concentration below the threshold level for clotting, either by deionizing the calcium by causing it to react with substances such as citrate ion or by precipitating the calcium with substances such as oxalate ion. 463 Interaction Between the Extrinsic and Intrinsic Pathways—Summary of Blood-Clotting Initiation It is clear from the schemas of the intrinsic and extrinsic systems that after blood vessels rupture, clotting occurs by both pathways simultaneously. Tissue factor initiates the extrinsic pathway, whereas contact of Factor XII and platelets with collagen in the vascular wall initiates the intrinsic pathway. An especially important difference between the extrinsic and intrinsic pathways is that the extrinsic pathway can be explosive; once initiated, its speed of completion to the final clot is limited only by the amount of tissue factor released from the traumatized tissues and by the quantities of Factors X, VII, and V in the blood. With severe tissue trauma, clotting can occur in as little as 15 seconds. The intrinsic pathway is much slower to proceed, usually requiring 1 to 6 minutes to cause clotting. Prevention of Blood Clotting in the Normal Vascular System— Intravascular Anticoagulants Endothelial Surface Factors. Probably the most important factors for preventing clotting in the normal vascular system are (1) the smoothness of the endothelial cell surface, which prevents contact activation of the intrinsic clotting system; (2) a layer of glycocalyx on the endothelium (glycocalyx is a mucopolysaccharide adsorbed to the surfaces of the endothelial cells), which repels clotting factors and platelets, thereby preventing activation of clotting; and (3) a protein bound with the endothelial membrane, thrombomodulin, which binds thrombin. Not only does the binding of thrombin with thrombomodulin slow the clotting process by removing thrombin, but the thrombomodulin-thrombin complex also activates a plasma protein, protein C, that acts as an anticoagulant by inactivating activated Factors V and VIII. When the endothelial wall is damaged, its smoothness and its glycocalyx-thrombomodulin layer are lost, which activates both Factor XII and the platelets, thus setting off the intrinsic pathway of clotting. If Factor XII and platelets come in contact with the subendothelial collagen, the activation is even more powerful. Antithrombin Action of Fibrin and Antithrombin III. Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood. The most powerful of these are (1) the fibrin fibers that themselves are formed during the process of clotting and (2) an alpha-globulin called antithrombin III or antithrombin-heparin cofactor. While a clot is forming, about 85 to 90 per cent of the thrombin formed from the prothrombin becomes adsorbed to the fibrin fibers as they develop. This helps prevent the spread of thrombin into the remaining blood and, therefore, prevents excessive spread of the clot. 464 Unit VI Blood Cells, Immunity, and Blood Clotting The thrombin that does not adsorb to the fibrin fibers soon combines with antithrombin III, which further blocks the effect of the thrombin on the fibrinogen and then also inactivates the thrombin itself during the next 12 to 20 minutes. Heparin. Heparin is another powerful anticoagulant, but its concentration in the blood is normally low, so that only under special physiologic conditions does it have significant anticoagulant effects. However, heparin is used widely as a pharmacological agent in medical practice in much higher concentrations to prevent intravascular clotting. The heparin molecule is a highly negatively charged conjugated polysaccharide. By itself, it has little or no anticoagulant properties, but when it combines with antithrombin III, the effectiveness of antithrombin III for removing thrombin increases by a hundredfold to a thousandfold, and thus it acts as an anticoagulant. Therefore, in the presence of excess heparin, removal of free thrombin from the circulating blood by antithrombin III is almost instantaneous. The complex of heparin and antithrombin III removes several other activated coagulation factors in addition to thrombin, further enhancing the effectiveness of anticoagulation. The others include activated Factors XII, XI, X, and IX. Heparin is produced by many different cells of the body, but especially large quantities are formed by the basophilic mast cells located in the pericapillary connective tissue throughout the body. These cells continually secrete small quantities of heparin that diffuse into the circulatory system. The basophil cells of the blood, which are functionally almost identical to the mast cells, release small quantities of heparin into the plasma. Mast cells are abundant in tissue surrounding the capillaries of the lungs and to a lesser extent capillaries of the liver. It is easy to understand why large quantities of heparin might be needed in these areas because the capillaries of the lungs and liver receive many embolic clots formed in slowly flowing venous blood; sufficient formation of heparin prevents further growth of the clots. Lysis of Blood Clots—Plasmin The plasma proteins contain a euglobulin called plasminogen (or profibrinolysin) that, when activated, becomes a substance called plasmin (or fibrinolysin). Plasmin is a proteolytic enzyme that resembles trypsin, the most important proteolytic digestive enzyme of pancreatic secretion. Plasmin digests fibrin fibers and some other protein coagulants such as fibrinogen, Factor V, Factor VIII, prothrombin, and Factor XII. Therefore, whenever plasmin is formed, it can cause lysis of a clot by destroying many of the clotting factors, thereby sometimes even causing hypocoagulability of the blood. Activation of Plasminogen to Form Plasmin: Then Lysis of Clots. When a clot is formed, a large amount of plasminogen is trapped in the clot along with other plasma proteins. This will not become plasmin or cause lysis of the clot until it is activated. The injured tissues and vascular endothelium very slowly release a powerful activator called tissue plasminogen activator (t-PA) that a few days later, after the clot has stopped the bleeding, eventually converts plasminogen to plasmin, which in turn removes the remaining unnecessary blood clot. In fact, many small blood vessels in which blood flow has been blocked by clots are reopened by this mechanism. Thus, an especially important function of the plasmin system is to remove minute clots from millions of tiny peripheral vessels that eventually would become occluded were there no way to clear them. Conditions That Cause Excessive Bleeding in Human Beings Excessive bleeding can result from deficiency of any one of the many blood-clotting factors. Three particular types of bleeding tendencies that have been studied to the greatest extent are discussed here: bleeding caused by (1) vitamin K deficiency, (2) hemophilia, and (3) thrombocytopenia (platelet deficiency). Decreased Prothrombin, Factor VII, Factor IX, and Factor X Caused by Vitamin K Deficiency With few exceptions, almost all the blood-clotting factors are formed by the liver. Therefore, diseases of the liver such as hepatitis, cirrhosis, and acute yellow atrophy can sometimes depress the clotting system so greatly that the patient develops a severe tendency to bleed. Another cause of depressed formation of clotting factors by the liver is vitamin K deficiency. Vitamin K is necessary for liver formation of five of the important clotting factors: prothrombin, Factor VII, Factor IX, Factor X, and protein C. In the absence of vitamin K, subsequent insufficiency of these coagulation factors in the blood can lead to serious bleeding tendencies. Vitamin K is continually synthesized in the intestinal tract by bacteria, so that vitamin K deficiency seldom occurs in the normal person as a result of vitamin K absence from the diet (except in neonates before they establish their intestinal bacterial flora). However, in gastrointestinal disease, vitamin K deficiency often occurs as a result of poor absorption of fats from the gastrointestinal tract. The reason is that vitamin K is fat-soluble and ordinarily is absorbed into the blood along with the fats. One of the most prevalent causes of vitamin K deficiency is failure of the liver to secrete bile into the gastrointestinal tract (which occurs either as a result of obstruction of the bile ducts or as a result of liver disease). Lack of bile prevents adequate fat digestion Chapter 36 Hemostasis and Blood Coagulation and absorption and, therefore, depresses vitamin K absorption as well. Thus, liver disease often causes decreased production of prothrombin and some other clotting factors both because of poor vitamin K absorption and because of the diseased liver cells. Because of this, vitamin K is injected into all surgical patients with liver disease or with obstructed bile ducts before performing the surgical procedure. Ordinarily, if vitamin K is given to a deficient patient 4 to 8 hours before the operation and the liver parenchymal cells are at least one-half normal in function, sufficient clotting factors will be produced to prevent excessive bleeding during the operation. Hemophilia Hemophilia is a bleeding disease that occurs almost exclusively in males. In 85 per cent of cases, it is caused by an abnormality or deficiency of Factor VIII; this type of hemophilia is called hemophilia A or classic hemophilia. About 1 of every 10,000 males in the United States has classic hemophilia. In the other 15 per cent of hemophilia patients, the bleeding tendency is caused by deficiency of Factor IX. Both of these factors are transmitted genetically by way of the female chromosome. Therefore, almost never will a woman have hemophilia because at least one of her two X chromosomes will have the appropriate genes. If one of her X chromosomes is deficient, she will be a hemophilia carrier, transmitting the disease to half of her male offspring and transmitting the carrier state to half of her female offspring. The bleeding trait in hemophilia can have various degrees of severity, depending on the character of the genetic deficiency. Bleeding usually does not occur except after trauma, but in some patients, the degree of trauma required to cause severe and prolonged bleeding may be so mild that it is hardly noticeable. For instance, bleeding can often last for days after extraction of a tooth. Factor VIII has two active components, a large component with a molecular weight in the millions and a smaller component with a molecular weight of about 230,000. The smaller component is most important in the intrinsic pathway for clotting, and it is deficiency of this part of Factor VIII that causes classic hemophilia. Another bleeding disease with somewhat different characteristics, called von Willebrand’s disease, results from loss of the large component. When a person with classic hemophilia experiences severe prolonged bleeding, almost the only therapy that is truly effective is injection of purified Factor VIII. The cost of Factor VIII is high, and its availability is limited because it can be gathered only from human blood and only in extremely small quantities. Thrombocytopenia Thrombocytopenia means the presence of very low numbers of platelets in the circulating blood. People 465 with thrombocytopenia have a tendency to bleed, as do hemophiliacs, except that the bleeding is usually from many small venules or capillaries, rather than from larger vessels as in hemophilia. As a result, small punctate hemorrhages occur throughout all the body tissues. The skin of such a person displays many small, purplish blotches, giving the disease the name thrombocytopenic purpura. As stated earlier, platelets are especially important for repair of minute breaks in capillaries and other small vessels. Ordinarily, bleeding will not occur until the number of platelets in the blood falls below 50,000/ml, rather than the normal 150,000 to 300,000. Levels as low as 10,000/ml are frequently lethal. Even without making specific platelet counts in the blood, sometimes one can suspect the existence of thrombocytopenia if the person’s blood fails to retract, because, as pointed out earlier, clot retraction is normally dependent on release of multiple coagulation factors from the large numbers of platelets entrapped in the fibrin mesh of the clot. Most people with thrombocytopenia have the disease known as idiopathic thrombocytopenia, which means thrombocytopenia of unknown cause. In most of these people, it has been discovered that for unknown reasons, specific antibodies have formed and react against the platelets themselves to destroy them. Relief from bleeding for 1 to 4 days can often be effected in a patient with thrombocytopenia by giving fresh whole blood transfusions that contain large numbers of platelets. Also, splenectomy is often helpful, sometimes effecting almost complete cure because the spleen normally removes large numbers of platelets from the blood. Thromboembolic Conditions in the Human Being Thrombi and Emboli. An abnormal clot that develops in a blood vessel is called a thrombus. Once a clot has developed, continued flow of blood past the clot is likely to break it away from its attachment and cause the clot to flow with the blood; such freely flowing clots are known as emboli. Also, emboli that originate in large arteries or in the left side of the heart can flow peripherally and plug arteries or arterioles in the brain, kidneys, or elsewhere. Emboli that originate in the venous system or in the right side of the heart generally flow into the lungs to cause pulmonary arterial embolism. Cause of Thromboembolic Conditions. The causes of throm- boembolic conditions in the human being are usually twofold: (1) Any roughened endothelial surface of a vessel—as may be caused by arteriosclerosis, infection, or trauma—is likely to initiate the clotting process. (2) Blood often clots when it flows very slowly through blood vessels, where small quantities of thrombin and other procoagulants are always being formed. 466 Unit VI Blood Cells, Immunity, and Blood Clotting Use of t-PA in Treating Intravascular Clots. Genetically engineered t-PA (tissue plasminogen activator) is available. When delivered directly to a thrombosed area through a catheter, it is effective in activating plasminogen to plasmin, which in turn can dissolve some intravascular clots. For instance, if used within the first hour or so after thrombotic occlusion of a coronary artery, the heart is often spared serious damage. Femoral Venous Thrombosis and Massive Pulmonary Embolism Because clotting almost always occurs when blood flow is blocked for many hours in any vessel of the body, the immobility of patients confined to bed plus the practice of propping the knees with pillows often causes intravascular clotting because of blood stasis in one or more of the leg veins for hours at a time. Then the clot grows, mainly in the direction of the slowly moving venous blood, sometimes growing the entire length of the leg veins and occasionally even up into the common iliac vein and inferior vena cava. Then, about 1 time out of every 10, a large part of the clot disengages from its attachments to the vessel wall and flows freely with the venous blood through the right side of the heart and into the pulmonary arteries to cause massive blockage of the pulmonary arteries, called massive pulmonary embolism. If the clot is large enough to occlude both of the pulmonary arteries at the same time, immediate death ensues. If only one pulmonary artery is blocked, death may not occur, or the embolism may lead to death a few hours to several days later because of further growth of the clot within the pulmonary vessels. But, again, t-PA therapy can be a lifesaver. Disseminated Intravascular Coagulation Occasionally the clotting mechanism becomes activated in widespread areas of the circulation, giving rise to the condition called disseminated intravascular coagulation. This often results from the presence of large amounts of traumatized or dying tissue in the body that releases great quantities of tissue factor into the blood. Frequently, the clots are small but numerous, and they plug a large share of the small peripheral blood vessels. This occurs especially in patients with widespread septicemia, in which either circulating bacteria or bacterial toxins—especially endotoxins—activate the clotting mechanisms. Plugging of small peripheral vessels greatly diminishes delivery of oxygen and other nutrients to the tissues—a situation that leads to or exacerbates circulatory shock. It is partly for this reason that septicemic shock is lethal in 85 per cent or more of patients. A peculiar effect of disseminated intravascular coagulation is that the patient on occasion begins to bleed. The reason for this is that so many of the clotting factors are removed by the widespread clotting that too few procoagulants remain to allow normal hemostasis of the remaining blood. Anticoagulants for Clinical Use In some thromboembolic conditions, it is desirable to delay the coagulation process. Various anticoagulants have been developed for this purpose. The ones most useful clinically are heparin and the coumarins. Heparin as an Intravenous Anticoagulant Commercial heparin is extracted from several different animal tissues and prepared in almost pure form. Injection of relatively small quantities, about 0.5 to 1 mg/kg of body weight, causes the blood-clotting time to increase from a normal of about 6 minutes to 30 or more minutes. Furthermore, this change in clotting time occurs instantaneously, thereby immediately preventing or slowing further development of a thromboembolic condition. The action of heparin lasts about 1.5 to 4 hours. The injected heparin is destroyed by an enzyme in the blood known as heparinase. Coumarins as Anticoagulants When a coumarin, such as warfarin, is given to a patient, the plasma levels of prothrombin and Factors VII, IX, and X, all formed by the liver, begin to fall, indicating that warfarin has a potent depressant effect on liver formation of these compounds. Warfarin causes this effect by competing with vitamin K for reactive sites in the enzymatic processes for formation of prothrombin and the other three clotting factors, thereby blocking the action of vitamin K. After administration of an effective dose of warfarin, the coagulant activity of the blood decreases to about 50 per cent of normal by the end of 12 hours and to about 20 per cent of normal by the end of 24 hours. In other words, the coagulation process is not blocked immediately but must await the natural consumption of the prothrombin and the other affected coagulation factors already present in the plasma. Normal coagulation usually returns 1 to 3 days after discontinuing coumarin therapy. Prevention of Blood Coagulation Outside the Body Although blood removed from the body and held in a glass test tube normally clots in about 6 minutes, blood collected in siliconized containers often does not clot for 1 hour or more. The reason for this delay is that preparing the surfaces of the containers with silicone 467 Hemostasis and Blood Coagulation prevents contact activation of platelets and Factor XII, the two principal factors that initiate the intrinsic clotting mechanism. Conversely, untreated glass containers allow contact activation of the platelets and Factor XII, with rapid development of clots. Heparin can be used for preventing coagulation of blood outside the body as well as in the body. Heparin is especially used in surgical procedures in which the blood must be passed through a heart-lung machine or artificial kidney machine and then back into the person. Various substances that decrease the concentration of calcium ions in the blood can also be used for preventing blood coagulation outside the body. For instance, a soluble oxalate compound mixed in a very small quantity with a sample of blood causes precipitation of calcium oxalate from the plasma and thereby decreases the ionic calcium level so much that blood coagulation is blocked. Any substance that deionizes the blood calcium will prevent coagulation. The negatively charged citrate ion is especially valuable for this purpose, mixed with blood usually in the form of sodium, ammonium, or potassium citrate. The citrate ion combines with calcium in the blood to cause an un-ionized calcium compound, and the lack of ionic calcium prevents coagulation. Citrate anticoagulants have an important advantage over the oxalate anticoagulants because oxalate is toxic to the body, whereas moderate quantities of citrate can be injected intravenously. After injection, the citrate ion is removed from the blood within a few minutes by the liver and is polymerized into glucose or metabolized directly for energy. Consequently, 500 milliliters of blood that has been rendered incoagulable by citrate can ordinarily be transfused into a recipient within a few minutes without dire consequences. But if the liver is damaged or if large quantities of citrated blood or plasma are given too rapidly (within fractions of a minute), the citrate ion may not be removed quickly enough, and the citrate can, under these conditions, greatly depress the level of calcium ion in the blood, which can result in tetany and convulsive death. Blood Coagulation Tests Bleeding Time When a sharp-pointed knife is used to pierce the tip of the finger or lobe of the ear, bleeding ordinarily lasts for 1 to 6 minutes. The time depends largely on the depth of the wound and the degree of hyperemia in the finger or ear lobe at the time of the test. Lack of any one of several of the clotting factors can prolong the bleeding time, but it is especially prolonged by lack of platelets. Clotting Time Many methods have been devised for determining blood clotting times. The one most widely used is to collect blood in a chemically clean glass test tube and then to tip the tube back and forth about every 30 seconds until the blood has clotted. By this method, the normal clotting time is 6 to 10 minutes. Procedures using multiple test tubes have also been devised for determining clotting time more accurately. Unfortunately, the clotting time varies widely, depending on the method used for measuring it, so it is no longer used in many clinics. Instead, measurements of the clotting factors themselves are made, using sophisticated chemical procedures. Prothrombin Time Prothrombin time gives an indication of the concentration of prothrombin in the blood. Figure 36–5 shows the relation of prothrombin concentration to prothrombin time. The method for determining prothrombin time is the following. Blood removed from the patient is immediately oxalated so that none of the prothrombin can change into thrombin. Then, a large excess of calcium ion and tissue factor is quickly mixed with the oxalated blood. The excess calcium nullifies the effect of the oxalate, and the tissue factor activates the prothrombin-tothrombin reaction by means of the extrinsic clotting pathway. The time required for coagulation to take place is known as the prothrombin time. The shortness of the time is determined mainly by prothrombin concentration. The normal prothrombin time is about 12 seconds. In each laboratory, a curve relating prothrombin concentration to prothrombin time, such as 100 Concentration (per cent of normal) Chapter 36 50.0 25.0 12.5 6.25 0 0 10 20 30 40 50 60 Prothrombin time (seconds) Figure 36–5 Relation of prothrombin concentration in the blood to “prothrombin time.” 468 Unit VI Blood Cells, Immunity, and Blood Clotting that shown in Figure 36–5, is drawn for the method used so that the prothrombin in the blood can be quantified. Tests similar to that for prothrombin time have been devised to determine the quantities of other blood clotting factors. In each of these tests, excesses of calcium ions and all the other factors besides the one being tested are added to oxalated blood all at once. Then the time required for coagulation is determined in the same manner as for prothrombin time. If the factor being tested is deficient, the coagulation time is prolonged. The time itself can then be used to quantitate the concentration of the factor. References Brass LF: Thrombin and platelet activation. Chest 124(3 Suppl):18S, 2003. Caprini JA, Glase CJ, Anderson CB, Hathaway K: Laboratory markers in the diagnosis of venous thromboembolism. Circulation 109(12 Suppl 1):I4, 2004. Dorsam RT, Kunapuli SP: Central role of the P2Y12 receptor in platelet activation. J Clin Invest 113:340, 2004. Fisher M, Brott TG: Emerging therapies for acute ischemic stroke: new therapies on trial. Stroke 34:359, 2003. Geddis AE, Kaushansky K: Inherited thrombocytopenias: toward a molecular understanding of disorders of platelet production. Curr Opin Pediatr 16:15, 2004. Kahn SR, Ginsberg JS: Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med 164:17, 2004. Koreth R, Weinert C, Weisdorf DJ, Key NS: Measurement of bleeding severity: a critical review. Transfusion 44:605, 2004. Levi M: Current understanding of disseminated intravascular coagulation. Br J Haematol 124:567, 2004. Lindsberg PJ, Kaste M: Thrombolysis for acute stroke. Curr Opin Neurol 16:73, 2003. Moake JL: Thrombotic microangiopathies. N Engl J Med 347:589, 2002. Roberts HR, Monroe DM, Escobar MA: Current concepts of hemostasis: implications for therapy. Anesthesiology 100:722, 2004. Saenko EL, Ananyeva NM, Shima M, et al: The future of recombinant coagulation factors. J Thromb Haemost 1:922, 2003. Solum NO: Procoagulant expression in platelets and defects leading to clinical disorders. Arterioscler Thromb Vasc Biol 19:2841, 1999. Toh CH, Dennis M: Disseminated intravascular coagulation: old disease, new hope. BMJ 327:974, 2003. Tsai HM: Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 14:1072, 2003. Tsai HM: Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura. Arterioscler Thromb Vasc Biol 23:388, 2003. VandenDriessche T, Collen D, Chuah MK: Gene therapy for the hemophilias. J Thromb Haemost 1:1550, 2003. Vesely SK, Perdue JJ, Rizvi MA, et al: Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review. Ann Intern Med 140:112, 2004. White RH, Ginsberg JS: Low-molecular-weight heparins: are they all the same? Br J Haematol 121:12, 2003. U N Respiration 37. Pulmonary Ventilation 38. Pulmonary Circulation, Pulmonary Edema, Pleural Fluid 39. Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Through the Respiratory Membrane 40. Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids 41. Regulation of Respiration 42. Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy I T VII C H A P T E R 3 7 Pulmonary Ventilation The goals of respiration are to provide oxygen to the tissues and to remove carbon dioxide. To achieve these goals, respiration can be divided into four major functions: (1) pulmonary ventilation, which means the inflow and outflow of air between the atmosphere and the lung alveoli; (2) diffusion of oxygen and carbon dioxide between the alveoli and the blood; (3) transport of oxygen and carbon dioxide in the blood and body fluids to and from the body’s tissue cells; and (4) regulation of ventilation and other facets of respiration. This chapter is a discussion of pulmonary ventilation, and the subsequent five chapters cover other respiratory functions plus the physiology of special respiratory abnormalities. Mechanics of Pulmonary Ventilation Muscles That Cause Lung Expansion and Contraction The lungs can be expanded and contracted in two ways: (1) by downward and upward movement of the diaphragm to lengthen or shorten the chest cavity, and (2) by elevation and depression of the ribs to increase and decrease the anteroposterior diameter of the chest cavity. Figure 37–1 shows these two methods. Normal quiet breathing is accomplished almost entirely by the first method, that is, by movement of the diaphragm. During inspiration, contraction of the diaphragm pulls the lower surfaces of the lungs downward. Then, during expiration, the diaphragm simply relaxes, and the elastic recoil of the lungs, chest wall, and abdominal structures compresses the lungs and expels the air. During heavy breathing, however, the elastic forces are not powerful enough to cause the necessary rapid expiration, so that extra force is achieved mainly by contraction of the abdominal muscles, which pushes the abdominal contents upward against the bottom of the diaphragm, thereby compressing the lungs. The second method for expanding the lungs is to raise the rib cage. This expands the lungs because, in the natural resting position, the ribs slant downward, as shown on the left side of Figure 37–1, thus allowing the sternum to fall backward toward the vertebral column. But when the rib cage is elevated, the ribs project almost directly forward, so that the sternum also moves forward, away from the spine, making the anteroposterior thickness of the chest about 20 per cent greater during maximum inspiration than during expiration. Therefore, all the muscles that elevate the chest cage are classified as muscles of inspiration, and those muscles that depress the chest cage are classified as muscles of expiration. The most important muscles that raise the rib cage are the external intercostals, but others that help are the (1) sternocleidomastoid muscles, which lift upward on the sternum; (2) anterior serrati, which lift many of the ribs; and (3) scaleni, which lift the first two ribs. The muscles that pull the rib cage downward during expiration are mainly the (1) abdominal recti, which have the powerful effect of pulling downward on the lower ribs at the same time that they and other abdominal muscles also compress the abdominal contents upward against the diaphragm, and (2) internal intercostals. 471 472 Unit VII Respiration Increased A–P diameter Elevated rib cage External intercostals contracted Internal intercostals relaxed Diaphragmatic contraction Abdominals contracted 0.25 Contraction and expansion of the thoracic cage during expiration and inspiration, demonstrating diaphragmatic contraction, function of the intercostal muscles, and elevation and depression of the rib cage. Figure 37–1 also shows the mechanism by which the external and internal intercostals act to cause inspiration and expiration. To the left, the ribs during expiration are angled downward, and the external intercostals are elongated forward and downward. As they contract, they pull the upper ribs forward in relation to the lower ribs, and this causes leverage on the ribs to raise them upward, thereby causing inspiration. The internal intercostals function exactly in the opposite manner, functioning as expiratory muscles because they angle between the ribs in the opposite direction and cause opposite leverage. Movement of Air In and Out of the Lungs and the Pressures That Cause the Movement The lung is an elastic structure that collapses like a balloon and expels all its air through the trachea whenever there is no force to keep it inflated. Also, there are no attachments between the lung and the walls of the chest cage, except where it is suspended at its hilum from the mediastinum. Instead, the lung “floats” in the thoracic cavity, surrounded by a thin layer of pleural fluid that lubricates movement of the lungs within the cavity. Further, continual suction of excess fluid into lymphatic channels maintains a slight suction between the visceral surface of the lung pleura and the parietal pleural surface of the thoracic cavity. Therefore, the lungs are held to the thoracic wall as if glued there, except that they are well lubricated and can slide freely as the chest expands and contracts. Pleural Pressure and Its Changes During Respiration Pleural pressure is the pressure of the fluid in the thin space between the lung pleura and the chest wall pleura. As noted earlier, this is normally a slight suction, which means a slightly negative pressure. The normal pleural pressure at the beginning of inspiration 0 Alveolar pressure +2 INSPIRATION Figure 37–1 Lung volume 0.50 0 Pressure (cm H2O) EXPIRATION Volume change (liters) Increased vertical diameter –2 Transpulmonary pressure –4 –6 Pleural pressure –8 Inspiration Expiration Figure 37–2 Changes in lung volume, alveolar pressure, pleural pressure, and transpulmonary pressure during normal breathing. is about –5 centimeters of water, which is the amount of suction required to hold the lungs open to their resting level. Then, during normal inspiration, expansion of the chest cage pulls outward on the lungs with greater force and creates more negative pressure, to an average of about –7.5 centimeters of water. These relationships between pleural pressure and changing lung volume are demonstrated in Figure 37–2, showing in the lower panel the increasing negativity of the pleural pressure from –5 to –7.5 during inspiration and in the upper panel an increase in lung volume of 0.5 liter. Then, during expiration, the events are essentially reversed. Alveolar Pressure Alveolar pressure is the pressure of the air inside the lung alveoli. When the glottis is open and no air is flowing into or out of the lungs, the pressures in all parts of the respiratory tree, all the way to the alveoli, are equal to atmospheric pressure, which is considered to be zero reference pressure in the airways—that is, 0 centimeters water pressure. To cause inward flow of air into the alveoli during inspiration, the pressure in the alveoli must fall to a value slightly below atmospheric pressure (below 0). The second curve (labeled “alveolar pressure”) of Figure 37–2 demonstrates that during normal inspiration, alveolar pressure decreases to about –1 centimeter of water. This slight negative Chapter 37 pressure is enough to pull 0.5 liter of air into the lungs in the 2 seconds required for normal quiet inspiration. During expiration, opposite pressures occur: The alveolar pressure rises to about +1 centimeter of water, and this forces the 0.5 liter of inspired air out of the lungs during the 2 to 3 seconds of expiration. Transpulmonary Pressure. Finally, note in Figure 37–2 the difference between the alveolar pressure and the pleural pressure. This is called the transpulmonary pressure. It is the pressure difference between that in the alveoli and that on the outer surfaces of the lungs, and it is a measure of the elastic forces in the lungs that tend to collapse the lungs at each instant of respiration, called the recoil pressure. Compliance of the Lungs The extent to which the lungs will expand for each unit increase in transpulmonary pressure (if enough time is allowed to reach equilibrium) is called the lung compliance. The total compliance of both lungs together in the normal adult human being averages about 200 milliliters of air per centimeter of water transpulmonary pressure. That is, every time the transpulmonary pressure increases 1 centimeter of water, the lung volume, after 10 to 20 seconds, will expand 200 milliliters. Compliance Diagram of the Lungs. Figure 37–3 is a diagram relating lung volume changes to changes in transpulmonary pressure. Note that the relation is different for inspiration and expiration. Each curve is recorded by changing the transpulmonary pressure in small steps and allowing the lung volume to come to a steady level between successive steps. The two curves are called, respectively, the inspiratory compliance curve and the expiratory compliance curve, and the entire diagram is called the compliance diagram of the lungs. The characteristics of the compliance diagram are determined by the elastic forces of the lungs. These can be divided into two parts: (1) elastic forces of the lung tissue itself and (2) elastic forces caused by surface tension of the fluid that lines the inside walls of the alveoli and other lung air spaces. The elastic forces of the lung tissue are determined mainly by elastin and collagen fibers interwoven among the lung parenchyma. In deflated lungs, these fibers are in an elastically contracted and kinked state; then, when the lungs expand, the fibers become stretched and unkinked, thereby elongating and exerting even more elastic force. The elastic forces caused by surface tension are much more complex. The significance of surface tension is shown in Figure 37–4, which compares the compliance diagram of the lungs when filled with saline solution and when filled with air.When the lungs are filled with air, there is an interface between the alveolar fluid and the air in the alveoli. In the case of the saline solution–filled lungs, there is no air-fluid interface; therefore, the surface tension effect is not present—only tissue elastic forces are operative in the saline solution–filled lung. Note that transpleural pressures required to expand air-filled lungs are about three times as great as those required to expand saline solution–filled lungs. Thus, one can conclude that the tissue elastic forces tending to cause collapse of the air-filled lung represent only about one third of the total lung elasticity, whereas the Saline-filled Lung volume change (liters) Lung volume change (liters) 473 Pulmonary Ventilation 0.50 Expiration 0.25 Inspiration Expiration 0.25 Inspiration 0 0 0 –4 –5 Pleural pressure (cm H2O) Air-filled 0.50 –6 –2 –4 –6 Pleural pressure (cm H2O) –8 Figure 37–4 Figure 37–3 Compliance diagram in a healthy person. This diagram shows compliance of the lungs alone. Comparison of the compliance diagrams of saline-filled and airfilled lungs when the alveolar pressure is maintained at atmospheric pressure (0 cm H2O) and pleural pressure is changed. 474 Unit VII fluid-air surface tension forces in the alveoli represent about two thirds. The fluid-air surface tension elastic forces of the lungs also increase tremendously when the substance called surfactant is not present in the alveolar fluid. Let us now discuss surfactant and its relation to the surface tension forces. Surfactant, Surface Tension, and Collapse of the Alveoli Principle of Surface Tension. When water forms a surface with air, the water molecules on the surface of the water have an especially strong attraction for one another. As a result, the water surface is always attempting to contract. This is what holds raindrops together: that is, there is a tight contractile membrane of water molecules around the entire surface of the raindrop. Now let us reverse these principles and see what happens on the inner surfaces of the alveoli. Here, the water surface is also attempting to contract. This results in an attempt to force the air out of the alveoli through the bronchi and, in doing so, causes the alveoli to try to collapse. The net effect is to cause an elastic contractile force of the entire lungs, which is called the surface tension elastic force. Surfactant and Its Effect on Surface Tension. Surfactant is a surface active agent in water, which means that it greatly reduces the surface tension of water. It is secreted by special surfactant-secreting epithelial cells called type II alveolar epithelial cells, which constitute about 10 per cent of the surface area of the alveoli. These cells are granular, containing lipid inclusions that are secreted in the surfactant into the alveoli. Surfactant is a complex mixture of several phospholipids, proteins, and ions. The most important components are the phospholipid dipalmitoylphosphatidylcholine, surfactant apoproteins, and calcium ions. The dipalmitoylphosphatidylcholine, along with several less important phospholipids, is responsible for reducing the surface tension. It does this by not dissolving uniformly in the fluid lining the alveolar surface. Instead, part of the molecule dissolves, while the remainder spreads over the surface of the water in the alveoli. This surface has from one twelfth to one half the surface tension of a pure water surface. In quantitative terms, the surface tension of different water fluids is approximately the following: pure water, 72 dynes/cm; normal fluids lining the alveoli but without surfactant, 50 dynes/cm; normal fluids lining the alveoli and with normal amounts of surfactant included, between 5 and 30 dynes/cm. Pressure in Occluded Alveoli Caused by Surface Tension. If the air passages leading from the alveoli of the lungs are blocked, the surface tension in the alveoli tends to collapse the alveoli. This creates positive pressure in the alveoli, attempting to push the air out. The amount of pressure generated in this way in an alveolus can be calculated from the following formula: Respiration Pressure = 2 ¥ Surface tension Radius of alveolus For the average-sized alveolus with a radius of about 100 micrometers and lined with normal surfactant, this calculates to be about 4 centimeters of water pressure (3 mm Hg). If the alveoli were lined with pure water without any surfactant, the pressure would calculate to be about 18 centimeters of water pressure, 4.5 times as great. Thus, one sees how important surfactant is in reducing alveolar surface tension and therefore also reducing the effort required by the respiratory muscles to expand the lungs. Effect of Alveolar Radius on the Pressure Caused by Surface Tension. Note from the preceding formula that the pres- sure generated as a result of surface tension in the alveoli is inversely affected by the radius of the alveolus, which means that the smaller the alveolus, the greater the alveolar pressure caused by the surface tension. Thus, when the alveoli have half the normal radius (50 instead of 100 micrometers), the pressures noted earlier are doubled. This is especially significant in small premature babies, many of whom have alveoli with radii less than one quarter that of an adult person. Further, surfactant does not normally begin to be secreted into the alveoli until between the sixth and seventh months of gestation, and in some cases, even later than that. Therefore, many premature babies have little or no surfactant in the alveoli when they are born, and their lungs have an extreme tendency to collapse, sometimes as great as six to eight times that in a normal adult person. This causes the condition called respiratory distress syndrome of the newborn. It is fatal if not treated with strong measures, especially properly applied continuous positive pressure breathing. Effect of the Thoracic Cage on Lung Expansibility Thus far, we have discussed the expansibility of the lungs alone, without considering the thoracic cage. The thoracic cage has its own elastic and viscous characteristics, similar to those of the lungs; even if the lungs were not present in the thorax, muscular effort would still be required to expand the thoracic cage. Compliance of the Thorax and the Lungs Together The compliance of the entire pulmonary system (the lungs and thoracic cage together) is measured while expanding the lungs of a totally relaxed or paralyzed person. To do this, air is forced into the lungs a little at a time while recording lung pressures and volumes. To inflate this total pulmonary system, almost twice as much pressure is needed as to inflate the same lungs after removal from the chest cage. Therefore, the compliance of the combined lung-thorax system is almost exactly one half that of the lungs alone—110 milliliters of volume per centimeter of water pressure for the combined system, compared with 200 ml/cm for the lungs alone. Furthermore, when the lungs are expanded to high volumes or compressed to low volumes, the limitations of the chest become extreme; Chapter 37 475 Pulmonary Ventilation when near these limits, the compliance of the combined lung-thorax system can be less than one fifth that of the lungs alone. “Work” of Breathing We have already pointed out that during normal quiet breathing, all respiratory muscle contraction occurs during inspiration; expiration is almost entirely a passive process caused by elastic recoil of the lungs and chest cage. Thus, under resting conditions, the respiratory muscles normally perform “work” to cause inspiration but not to cause expiration. The work of inspiration can be divided into three fractions: (1) that required to expand the lungs against the lung and chest elastic forces, called compliance work or elastic work; (2) that required to overcome the viscosity of the lung and chest wall structures, called tissue resistance work; and (3) that required to overcome airway resistance to movement of air into the lungs, called airway resistance work. Energy Required for Respiration. During normal quiet respi- ration, only 3 to 5 per cent of the total energy expended by the body is required for pulmonary ventilation. But during heavy exercise, the amount of energy required can increase as much as 50-fold, especially if the person has any degree of increased airway resistance or decreased pulmonary compliance. Therefore, one of the major limitations on the intensity of exercise that can be performed is the person’s ability to provide enough muscle energy for the respiratory process alone. Pulmonary Volumes and Capacities Recording Changes in Pulmonary Volume—Spirometry A simple method for studying pulmonary ventilation is to record the volume movement of air into and out of the lungs, a process called spirometry. A typical basic spirometer is shown in Figure 37–5. It consists of a drum inverted over a chamber of water, with the drum counterbalanced by a weight. In the drum is a breathing gas, usually air or oxygen; a tube connects the mouth with the gas chamber. When one breathes into and out of the chamber, the drum rises and falls, and an appropriate recording is made on a moving sheet of paper. Figure 37–6 shows a spirogram indicating changes in lung volume under different conditions of breathing. For ease in describing the events of pulmonary ventilation, the air in the lungs has been subdivided in this diagram into four volumes and four capacities, which are the average for a young adult man. Pulmonary Volumes To the left in Figure 37–6 are listed four pulmonary lung volumes that, when added together, equal the maximum volume to which the lungs can be expanded. The significance of each of these volumes is the following: Floating drum Oxygen chamber Recording drum Water Mouthpiece Counterbalancing weight Figure 37–5 Spirometer. 1. The tidal volume is the volume of air inspired or expired with each normal breath; it amounts to about 500 milliliters in the adult male. 2. The inspiratory reserve volume is the extra volume of air that can be inspired over and above the normal tidal volume when the person inspires with full force; it is usually equal to about 3000 milliliters. 3. The expiratory reserve volume is the maximum extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration; this normally amounts to about 1100 milliliters. 4. The residual volume is the volume of air remaining in the lungs after the most forceful expiration; this volume averages about 1200 milliliters. Pulmonary Capacities In describing events in the pulmonary cycle, it is sometimes desirable to consider two or more of the volumes together. Such combinations are called pulmonary capacities. To the right in Figure 37–6 are listed the important pulmonary capacities, which can be described as follows: 1. The inspiratory capacity equals the tidal volume plus the inspiratory reserve volume. This is the amount of air (about 3500 milliliters) a person can breathe in, beginning at the normal expiratory level and distending the lungs to the maximum amount. 2. The functional residual capacity equals the expiratory reserve volume plus the residual volume. This is the amount of air that remains in the lungs at the end of normal expiration (about 2300 milliliters). 3. The vital capacity equals the inspiratory reserve volume plus the tidal volume plus the expiratory reserve volume. This is the maximum amount of air a person can expel from the lungs after first filling the lungs to their maximum extent and then 476 Unit VII 6000 Respiration Inspiration Lung volume (ml) 5000 4000 Vital capacity Total lung capacity Tidal volume 3000 2000 Inspiratory capacity Inspiratory reserve volume Functional residual capacity Expiratory reserve volume 1000 Residual volume Expiration Figure 37–6 Time expiring to the maximum extent (about 4600 milliliters). 4. The total lung capacity is the maximum volume to which the lungs can be expanded with the greatest possible effort (about 5800 milliliters); it is equal to the vital capacity plus the residual volume. All pulmonary volumes and capacities are about 20 to 25 per cent less in women than in men, and they are greater in large and athletic people than in small and asthenic people. Abbreviations and Symbols Used in Pulmonary Function Studies Spirometry is only one of many measurement procedures that the pulmonary physician uses daily. Many of these measurement procedures depend heavily on mathematical computations. To simplify these calculations as well as the presentation of pulmonary function data, a number of abbreviations and symbols have become standardized. The more important of these are given in Table 37–1. Using these symbols, we present here a few simple algebraic exercises showing some of the interrelations among the pulmonary volumes and capacities; the student should think through and verify these interrelations. VC = IRV + VT + ERV VC = IC + ERV TLC = VC + RV TLC = IC + FRC FRC = ERV + RV Diagram showing respiratory excursions during normal breathing and during maximal inspiration and maximal expiration. Determination of Functional Residual Capacity, Residual Volume, and Total Lung Capacity— Helium Dilution Method The functional residual capacity (FRC), which is the volume of air that remains in the lungs at the end of each normal expiration, is important to lung function. Because its value changes markedly in some types of pulmonary disease, it is often desirable to measure this capacity. The spirometer cannot be used in a direct way to measure the functional residual capacity, because the air in the residual volume of the lungs cannot be expired into the spirometer, and this volume constitutes about one half of the functional residual capacity. To measure functional residual capacity, the spirometer must be used in an indirect manner, usually by means of a helium dilution method, as follows. A spirometer of known volume is filled with air mixed with helium at a known concentration. Before breathing from the spirometer, the person expires normally. At the end of this expiration, the remaining volume in the lungs is equal to the functional residual capacity. At this point, the subject immediately begins to breathe from the spirometer, and the gases of the spirometer mix with the gases of the lungs. As a result, the helium becomes diluted by the functional residual capacity gases, and the volume of the functional residual capacity can be calculated from the degree of dilution of the helium, using the following formula: Ci He FRC = Ê - 1ˆ Vi Spir Ë CfHe ¯ Chapter 37 477 Pulmonary Ventilation Table 37–1 Abbreviations and Symbols for Pulmonary Function VT FRC ERV RV IC IRV TLC VC Raw C VD V .A V .I V .E V .s V .A V . o2 Vco2 . Vco Dlo2 DlCO tidal volume functional residual capacity expiratory reserve volume residual volume inspiratory capacity inspiratory reserve volume total lung capacity vital capacity resistance of the airways to flow of air into the lung compliance volume of dead space gas volume of alveolar gas inspired volume of ventilation per minute expired volume of ventilation per minute shunt flow alveolar ventilation per minute rate of oxygen uptake per minute amount of carbon dioxide eliminated per minute rate of carbon monoxide uptake per minute PB Palv Ppl PO2 PCO2 PN2 PaO2 PaCO2 PAO2 atmospheric pressure alveolar pressure pleural pressure partial pressure of oxygen partial pressure of carbon dioxide partial pressure of nitrogen partial pressure of oxygen in arterial blood partial pressure of carbon dioxide in arterial blood partial pressure of oxygen in alveolar gas PACO2 PAH2O R Q̇ partial pressure of carbon dioxide in alveolar gas partial pressure of water in alveolar gas respiratory exchange ratio cardiac output CaO2 Cv̄o2 SO2 concentration of oxygen in arterial blood concentration of oxygen in mixed venous blood percentage saturation of hemoglobin with oxygen SaO2 percentage saturation of hemoglobin with oxygen in arterial blood diffusing capacity of the lungs for oxygen diffusing capacity of the lungs for carbon monoxide where FRC is functional residual capacity, CiHe is initial concentration of helium in the spirometer, CfHe is final concentration of helium in the spirometer, and ViSpir is initial volume of the spirometer. Once the FRC has been determined, the residual volume (RV) can be determined by subtracting expiratory reserve volume (ERV), as measured by normal spirometry, from the FRC. Also, the total lung capacity (TLC) can be determined by adding the inspiratory capacity (IC) to the FRC. That is, RV = FRC – ERV and TLC = FRC + IC Minute Respiratory Volume Equals Respiratory Rate Times Tidal Volume The minute respiratory volume is the total amount of new air moved into the respiratory passages each minute; this is equal to the tidal volume times the respiratory rate per minute. The normal tidal volume is about 500 milliliters, and the normal respiratory rate is about 12 breaths per minute. Therefore, the minute respiratory volume averages about 6 L/min. A person can live for a short period with a minute respiratory volume as low as 1.5 L/min and a respiratory rate of only 2 to 4 breaths per minute. The respiratory rate occasionally rises to 40 to 50 per minute, and the tidal volume can become as great as the vital capacity, about 4600 milliliters in a young adult man. This can give a minute respiratory volume greater than 200 L/min, or more than 30 times normal. Most people cannot sustain more than one half to two thirds these values for longer than 1 minute. Alveolar Ventilation The ultimate importance of pulmonary ventilation is to continually renew the air in the gas exchange areas of the lungs, where air is in proximity to the pulmonary blood. These areas include the alveoli, alveolar sacs, alveolar ducts, and respiratory bronchioles. The rate at which new air reaches these areas is called alveolar ventilation. “Dead Space” and Its Effect on Alveolar Ventilation Some of the air a person breathes never reaches the gas exchange areas but simply fills respiratory passages where gas exchange does not occur, such as the nose, pharynx, and trachea.This air is called dead space air because it is not useful for gas exchange. On expiration, the air in the dead space is expired first, before any of the air from the alveoli reaches the atmosphere. Therefore, the dead space is very disadvantageous for removing the expiratory gases from the lungs. Measurement of the Dead Space Volume. A simple method for measuring dead space volume is demonstrated by the graph in Figure 37–7. In making this measurement, the subject suddenly takes a deep breath of oxygen. This 478 Unit VII Respiration Anatomic Versus Physiologic Dead Space. The method just 40 20 nitro concentration gen Reco rded 60 Inspiration of pure oxygen Per cent nitrogen 80 0 0 100 200 300 400 Air expired (ml) 500 Figure 37–7 Record of the changes in nitrogen concentration in the expired air after a single previous inspiration of pure oxygen. This record can be used to calculate dead space, as discussed in the text. fills the entire dead space with pure oxygen. Some oxygen also mixes with the alveolar air but does not completely replace this air. Then the person expires through a rapidly recording nitrogen meter, which makes the record shown in the figure. The first portion of the expired air comes from the dead space regions of the respiratory passageways, where the air has been completely replaced by oxygen. Therefore, in the early part of the record, only oxygen appears, and the nitrogen concentration is zero. Then, when alveolar air begins to reach the nitrogen meter, the nitrogen concentration rises rapidly, because alveolar air containing large amounts of nitrogen begins to mix with the dead space air. After still more air has been expired, all the dead space air has been washed from the passages, and only alveolar air remains. Therefore, the recorded nitrogen concentration reaches a plateau level equal to its concentration in the alveoli, as shown to the right in the figure. With a little thought, the student can see that the gray area represents the air that has no nitrogen in it; this area is a measure of the volume of dead space air. For exact quantification, the following equation is used: Gray area ¥ VE VD = Pink area + Gray area where VD is dead space air and VE is the total volume of expired air. Let us assume, for instance, that the gray area on the graph is 30 square centimeters, the pink area is 70 square centimeters, and the total volume expired is 500 milliliters. The dead space would be 30 ¥ 500, or 150 ml 30 + 70 Normal Dead Space Volume. The normal dead space air in a young adult man is about 150 milliliters. This increases slightly with age. described for measuring the dead space measures the volume of all the space of the respiratory system other than the alveoli and their other closely related gas exchange areas; this space is called the anatomic dead space. On occasion, some of the alveoli themselves are nonfunctional or only partially functional because of absent or poor blood flow through the adjacent pulmonary capillaries. Therefore, from a functional point of view, these alveoli must also be considered dead space. When the alveolar dead space is included in the total measurement of dead space, this is called the physiologic dead space, in contradistinction to the anatomic dead space. In a normal person, the anatomic and physiologic dead spaces are nearly equal because all alveoli are functional in the normal lung, but in a person with partially functional or nonfunctional alveoli in some parts of the lungs, the physiologic dead space may be as much as 10 times the volume of the anatomic dead space, or 1 to 2 liters. These problems are discussed further in Chapter 39 in relation to pulmonary gaseous exchange and in Chapter 42 in relation to certain pulmonary diseases. Rate of Alveolar Ventilation Alveolar ventilation per minute is the total volume of new air entering the alveoli and adjacent gas exchange areas each minute. It is equal to the respiratory rate times the amount of new air that enters these areas with each breath. . V A = Freq • (VT – VD) . where V A is the volume of alveolar ventilation per minute, Freq is the frequency of respiration per minute, VT is the tidal volume, and VD is the physiologic dead space volume. Thus, with a normal tidal volume of 500 milliliters, a normal dead space of 150 milliliters, and a respiratory rate of 12 breaths per minute, alveolar ventilation equals 12 ¥ (500 – 150), or 4200 ml/min. Alveolar ventilation is one of the major factors determining the concentrations of oxygen and carbon dioxide in the alveoli. Therefore, almost all discussions of gaseous exchange in the following chapters on the respiratory system emphasize alveolar ventilation. Functions of the Respiratory Passageways Trachea, Bronchi, and Bronchioles Figure 37–8 shows the respiratory system, demonstrating especially the respiratory passageways.The air is distributed to the lungs by way of the trachea, bronchi, and bronchioles. One of the most important problems in all the respiratory passageways is to keep them open and allow easy passage of air to and from the alveoli. To keep the trachea from collapsing, multiple cartilage rings extend about five sixths of the way around the trachea. In the walls of the bronchi, less extensive curved cartilage plates also maintain a reasonable amount of rigidity yet allow sufficient motion for the lungs to expand and Chapter 37 479 Pulmonary Ventilation Conchae CO2 O2 Alveolus Glottis Larynx, vocal cords Trachea Epiglottis Pharynx Esophagus O2 O2 CO2 CO2 Pulmonary capillary Pulmonary arteries Pulmonary veins Alveoli Figure 37–8 Respiratory passages. contract. These plates become progressively less extensive in the later generations of bronchi and are gone in the bronchioles, which usually have diameters less than 1.5 millimeters. The bronchioles are not prevented from collapsing by the rigidity of their walls. Instead, they are kept expanded mainly by the same transpulmonary pressures that expand the alveoli. That is, as the alveoli enlarge, the bronchioles also enlarge, but not as much. Muscular Wall of the Bronchi and Bronchioles and Its Control. In all areas of the trachea and bronchi not occupied by cartilage plates, the walls are composed mainly of smooth muscle. Also, the walls of the bronchioles are almost entirely smooth muscle, with the exception of the most terminal bronchiole, called the respiratory bronchiole, which is mainly pulmonary epithelium and underlying fibrous tissue plus a few smooth muscle fibers. Many obstructive diseases of the lung result from narrowing of the smaller bronchi and larger bronchioles, often because of excessive contraction of the smooth muscle itself. Resistance to Airflow in the Bronchial Tree. Under normal respiratory conditions, air flows through the respiratory passageways so easily that less than 1 centimeter of water pressure gradient from the alveoli to the atmosphere is sufficient to cause enough airflow for quiet breathing. The greatest amount of resistance to airflow occurs not in the minute air passages of the terminal bronchioles but in some of the larger bronchioles and bronchi near the trachea. The reason for this high resistance is that there are relatively few of these larger bronchi in comparison with the approximately 65,000 parallel terminal bronchioles, through each of which only a minute amount of air must pass. Yet in disease conditions, the smaller bronchioles often play a far greater role in determining airflow resistance because of their small size and because they are easily occluded by (1) muscle contraction in their walls, (2) edema occurring in the walls, or (3) mucus collecting in the lumens of the bronchioles. Nervous and Local Control of the Bronchiolar Musculature— “Sympathetic” Dilation of the Bronchioles. Direct control of the bronchioles by sympathetic nerve fibers is relatively weak because few of these fibers penetrate to the central portions of the lung. However, the bronchial tree is very much exposed to norepinephrine and epinephrine released into the blood by sympathetic stimulation of the adrenal gland medullae. Both these hormones— especially epinephrine, because of its greater stimulation of beta-adrenergic receptors—cause dilation of the bronchial tree. Parasympathetic Constriction of the Bronchioles. A few parasympathetic nerve fibers derived from the vagus nerves penetrate the lung parenchyma. These nerves secrete acetylcholine and, when activated, cause mild to moderate constriction of the bronchioles. When a disease process such as asthma has already caused some bronchiolar constriction, superimposed parasympathetic nervous stimulation often worsens the condition. When this occurs, administration of drugs that block the effects of acetylcholine, such as atropine, can sometimes relax the respiratory passages enough to relieve the obstruction. Sometimes the parasympathetic nerves are also activated by reflexes that originate in the lungs. Most of these begin with irritation of the epithelial membrane of the respiratory passageways themselves, initiated by noxious gases, dust, cigarette smoke, or bronchial infection. Also, a bronchiolar constrictor reflex often occurs when microemboli occlude small pulmonary arteries. Local Secretory Factors Often Cause Bronchiolar Constriction. Several substances formed in the lungs themselves are 480 Unit VII often quite active in causing bronchiolar constriction. Two of the most important of these are histamine and slow reactive substance of anaphylaxis. Both of these are released in the lung tissues by mast cells during allergic reactions, especially those caused by pollen in the air. Therefore, they play key roles in causing the airway obstruction that occurs in allergic asthma; this is especially true of the slow reactive substance of anaphylaxis. The same irritants that cause parasympathetic constrictor reflexes of the airways—smoke, dust, sulfur dioxide, and some of the acidic elements in smog—often act directly on the lung tissues to initiate local, nonnervous reactions that cause obstructive constriction of the airways. Mucus Lining the Respiratory Passageways, and Action of Cilia to Clear the Passageways All the respiratory passages, from the nose to the terminal bronchioles, are kept moist by a layer of mucus that coats the entire surface. The mucus is secreted partly by individual mucous goblet cells in the epithelial lining of the passages and partly by small submucosal glands. In addition to keeping the surfaces moist, the mucus traps small particles out of the inspired air and keeps most of these from ever reaching the alveoli. The mucus itself is removed from the passages in the following manner. The entire surface of the respiratory passages, both in the nose and in the lower passages down as far as the terminal bronchioles, is lined with ciliated epithelium, with about 200 cilia on each epithelial cell. These cilia beat continually at a rate of 10 to 20 times per second by the mechanism explained in Chapter 2, and the direction of their “power stroke” is always toward the pharynx. That is, the cilia in the lungs beat upward, whereas those in the nose beat downward. This continual beating causes the coat of mucus to flow slowly, at a velocity of a few millimeters per minute, toward the pharynx. Then the mucus and its entrapped particles are either swallowed or coughed to the exterior. Cough Reflex The bronchi and trachea are so sensitive to light touch that very slight amounts of foreign matter or other causes of irritation initiate the cough reflex. The larynx and carina (the point where the trachea divides into the bronchi) are especially sensitive, and the terminal bronchioles and even the alveoli are sensitive to corrosive chemical stimuli such as sulfur dioxide gas or chlorine gas. Afferent nerve impulses pass from the respiratory passages mainly through the vagus nerves to the medulla of the brain. There, an automatic sequence of events is triggered by the neuronal circuits of the medulla, causing the following effect. First, up to 2.5 liters of air are rapidly inspired. Second, the epiglottis closes, and the vocal cords shut tightly to entrap the air within the lungs. Third, the abdominal muscles contract forcefully, pushing against the diaphragm while other expiratory muscles, such as the internal intercostals, also contract forcefully. Consequently, the pressure in the lungs rises rapidly to as much as 100 mm Hg or more. Fourth, the vocal cords and the epiglottis suddenly open widely, so that air under this high pressure in the lungs explodes outward. Indeed, sometimes this air is expelled at velocities ranging from 75 to 100 miles per hour. Importantly, the strong compression of the lungs collapses the bronchi and trachea by causing their noncartilaginous parts to Respiration invaginate inward, so that the exploding air actually passes through bronchial and tracheal slits. The rapidly moving air usually carries with it any foreign matter that is present in the bronchi or trachea. Sneeze Reflex The sneeze reflex is very much like the cough reflex, except that it applies to the nasal passageways instead of the lower respiratory passages. The initiating stimulus of the sneeze reflex is irritation in the nasal passageways; the afferent impulses pass in the fifth cranial nerve to the medulla, where the reflex is triggered. A series of reactions similar to those for the cough reflex takes place; however, the uvula is depressed, so that large amounts of air pass rapidly through the nose, thus helping to clear the nasal passages of foreign matter. Normal Respiratory Functions of the Nose As air passes through the nose, three distinct normal respiratory functions are performed by the nasal cavities: (1) the air is warmed by the extensive surfaces of the conchae and septum, a total area of about 160 square centimeters (see Figure 37–8); (2) the air is almost completely humidified even before it passes beyond the nose; and (3) the air is partially filtered. These functions together are called the air conditioning function of the upper respiratory passageways. Ordinarily, the temperature of the inspired air rises to within 1°F of body temperature and to within 2 to 3 per cent of full saturation with water vapor before it reaches the trachea. When a person breathes air through a tube directly into the trachea (as through a tracheostomy), the cooling and especially the drying effect in the lower lung can lead to serious lung crusting and infection. Filtration Function of the Nose. The hairs at the entrance to the nostrils are important for filtering out large particles. Much more important, though, is the removal of particles by turbulent precipitation. That is, the air passing through the nasal passageways hits many obstructing vanes: the conchae (also called turbinates, because they cause turbulence of the air), the septum, and the pharyngeal wall. Each time air hits one of these obstructions, it must change its direction of movement. The particles suspended in the air, having far more mass and momentum than air, cannot change their direction of travel as rapidly as the air can. Therefore, they continue forward, striking the surfaces of the obstructions, and are entrapped in the mucous coating and transported by the cilia to the pharynx to be swallowed. Size of Particles Entrapped in the Respiratory Passages. The nasal turbulence mechanism for removing particles from air is so effective that almost no particles larger than 6 micrometers in diameter enter the lungs through the nose. This size is smaller than the size of red blood cells. Of the remaining particles, many that are between 1 and 5 micrometers settle in the smaller bronchioles as a result of gravitational precipitation. For instance, terminal bronchiolar disease is common in coal miners because of settled dust particles. Some of the still smaller particles (smaller than 1 micrometer in diameter) diffuse against the walls of the alveoli and adhere to the alveolar fluid. But many particles smaller than 0.5 Chapter 37 481 Pulmonary Ventilation Thyroid cartilage Thyroarytenoid muscle Vocal ligament Lateral cricoarytenoid muscle Figure 37–9 A, Anatomy of the larynx. B, Laryngeal function in phonation, showing the positions of the vocal cords during different types of phonation. (Modified from Greene MC: The Voice and Its Disorders, 4th ed. Philadelphia: JB Lippincott, 1980.) Arytenoid cartilage A Transverse arytenoid muscle micrometer in diameter remain suspended in the alveolar air and are expelled by expiration. For instance, the particles of cigarette smoke are about 0.3 micrometer. Almost none of these particles are precipitated in the respiratory passageways before they reach the alveoli. Unfortunately, up to one third of them do precipitate in the alveoli by the diffusion process, with the balance remaining suspended and expelled in the expired air. Many of the particles that become entrapped in the alveoli are removed by alveolar macrophages, as explained in Chapter 33, and others are carried away by the lung lymphatics. An excess of particles can cause growth of fibrous tissue in the alveolar septa, leading to permanent debility. Vocalization Speech involves not only the respiratory system but also (1) specific speech nervous control centers in the cerebral cortex, which are discussed in Chapter 57; (2) respiratory control centers of the brain; and (3) the articulation and resonance structures of the mouth and nasal cavities. Speech is composed of two mechanical functions: (1) phonation, which is achieved by the larynx, and (2) articulation, which is achieved by the structures of the mouth. Phonation. The larynx, shown in Figure 37–9A, is especially adapted to act as a vibrator. The vibrating element is the vocal folds, commonly called the vocal cords. The vocal cords protrude from the lateral walls of the larynx toward the center of the glottis; they are stretched and positioned by several specific muscles of the larynx itself. Figure 37–9B shows the vocal cords as they are seen when looking into the glottis with a laryngoscope. During normal breathing, the cords are wide open to allow easy passage of air. During phonation, the cords move together so that passage of air between them will cause vibration. The pitch of the vibration is determined mainly by the degree of stretch of the cords, but also by how tightly the cords are approximated to one another and by the mass of their edges. Figure 37–9A shows a dissected view of the vocal folds after removal of the mucous epithelial lining. Immediately inside each cord is a strong elastic ligament called the vocal ligament. This is attached anteriorly to the large thyroid cartilage, which is the cartilage that projects forward from the anterior surface of the neck and is called the “Adam’s apple.” Posteriorly, the vocal Full abduction Posterior cricoarytenoid muscle Gentle Intermediate position– abduction loud whisper Stage whisper Phonation B ligament is attached to the vocal processes of two arytenoid cartilages. The thyroid cartilage and the arytenoid cartilages articulate from below with another cartilage not shown in Figure 37–9, the cricoid cartilage. The vocal cords can be stretched by either forward rotation of the thyroid cartilage or posterior rotation of the arytenoid cartilages, activated by muscles stretching from the thyroid cartilage and arytenoid cartilages to the cricoid cartilage. Muscles located within the vocal cords lateral to the vocal ligaments, the thyroarytenoid muscles, can pull the arytenoid cartilages toward the thyroid cartilage and, therefore, loosen the vocal cords. Also, slips of these muscles within the vocal cords can change the shapes and masses of the vocal cord edges, sharpening them to emit high-pitched sounds and blunting them for the more bass sounds. Finally, several other sets of small laryngeal muscles lie between the arytenoid cartilages and the cricoid cartilage and can rotate these cartilages inward or outward or pull their bases together or apart to give the various configurations of the vocal cords shown in Figure 37–9B. Articulation and Resonance. The three major organs of articulation are the lips, tongue, and soft palate. They need not be discussed in detail because we are all familiar with their movements during speech and other vocalizations. The resonators include the mouth, the nose and associated nasal sinuses, the pharynx, and even the chest cavity. Again, we are all familiar with the resonating qualities of these structures. For instance, the function of the nasal resonators is demonstrated by the change in voice quality when a person has a severe cold that blocks the air passages to these resonators. References Carr MJ, Undem BJ: Bronchopulmonary afferent nerves. Respirology 8:291, 2003. Coulson FR, Fryer AD: Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther 98:59, 2003. Daniels CB, Orgeig S: Pulmonary surfactant: the key to the evolution of air breathing. News Physiol Sci 18:151, 2003. Foster WM: Mucociliary transport and cough in humans. Pulm Pharmacol Ther 15:277, 2002. Haitsma JJ, Papadakos PJ, Lachmann B: Surfactant therapy for acute lung injury/acute respiratory distress syndrome. Curr Opin Crit Care 10:18, 2004. Hilaire G, Duron B: Maturation of the mammalian respiratory system. Physiol Rev 79:325, 1999. 482 Unit VII Lai-Fook SJ: Pleural mechanics and fluid exchange. Physiol Rev 84:385, 2004. Mason RJ, Greene K, Voelker DR: Surfactant protein A and surfactant protein D in health and disease. Am J Physiol Lung Cell Mol Physiol 275:L1, 1998. Massaro D, Massaro GD: Pulmonary alveoli: formation, the “call for oxygen,” and other regulators. Am J Physiol Lung Cell Mol Physiol 282:L345, 2002. Maxfield RA: New and emerging minimally invasive techniques for lung volume reduction. Chest 125:777, 2004. McConnell AK, Romer LM: Dyspnoea in health and obstructive pulmonary disease: the role of respiratory muscle function and training. Sports Med 34:117, 2004. Paton JF, Dutschmann M: Central control of upper airway resistance regulating respiratory airflow in mammals. J Anat 201:319, 2002. Respiration Powell FL, Hopkins SR: Comparative physiology of lung complexity: implications for gas exchange. News Physiol Sci 19:55, 2004. Sant’Ambrogio G, Widdicombe J: Reflexes from airway rapidly adapting receptors. Respir Physiol 125:33, 2001. Uhlig S, Taylor AE: Methods in Pulmonary Research. Basel: Birkhauser Verlag, 1998. West JB: Respiratory Physiology. New York: Oxford University Press, 1996. West JB: Why doesn’t the elephant have a pleural space? News Physiol Sci 17:47, 2002. Widdicombe J: Neuroregulation of cough: implications for drug therapy. Curr Opin Pharmacol 2:256, 2002. Wright JR: Pulmonary surfactant: a front line of lung host defense. J Clin Invest 111:1453, 2003. Zeitels SM, Healy GB: Laryngology and phonosurgery. N Engl J Med 349:882, 2003. C H A P T E R 3 8 Pulmonary Circulation, Pulmonary Edema, Pleural Fluid Some aspects of blood flow distribution and other hemodynamics are particular to the pulmonary circulation and are especially important for gas exchange in the lungs. The present discussion is concerned with these special features of the pulmonary circulation. Physiologic Anatomy of the Pulmonary Circulatory System Pulmonary Vessels. The pulmonary artery extends only 5 centimeters beyond the apex of the right ventricle and then divides into right and left main branches that supply blood to the two respective lungs. The pulmonary artery is thin, with a wall thickness one third that of the aorta. The pulmonary arterial branches are very short, and all the pulmonary arteries, even the smaller arteries and arterioles, have larger diameters than their counterpart systemic arteries. This, combined with the fact that the vessels are thin and distensible, gives the pulmonary arterial tree a large compliance, averaging almost 7 ml/mm Hg, which is similar to that of the entire systemic arterial tree. This large compliance allows the pulmonary arteries to accommodate the stroke volume output of the right ventricle. The pulmonary veins, like the pulmonary arteries, are also short. They immediately empty their effluent blood into the left atrium, to be pumped by the left heart through the systemic circulation. Bronchial Vessels. Blood also flows to the lungs through small bronchial arteries that originate from the systemic circulation, amounting to about 1 to 2 per cent of the total cardiac output. This bronchial arterial blood is oxygenated blood, in contrast to the partially deoxygenated blood in the pulmonary arteries. It supplies the supporting tissues of the lungs, including the connective tissue, septa, and large and small bronchi. After this bronchial and arterial blood has passed through the supporting tissues, it empties into the pulmonary veins and enters the left atrium, rather than passing back to the right atrium. Therefore, the flow into the left atrium and the left ventricular output are about 1 to 2 per cent greater than the right ventricular output. Lymphatics. Lymph vessels are present in all the supportive tissues of the lung, beginning in the connective tissue spaces that surround the terminal bronchioles, coursing to the hilum of the lung, and thence mainly into the right thoracic lymph duct. Particulate matter entering the alveoli is partly removed by way of these channels, and plasma protein leaking from the lung capillaries is also removed from the lung tissues, thereby helping to prevent pulmonary edema. Pressures in the Pulmonary System Pressure Pulse Curve in the Right Ventricle. The pressure pulse curves of the right ventricle and pulmonary artery are shown in the lower portion of Figure 38–1. These curves are contrasted with the much higher aortic pressure curve shown in the upper portion of the figure. The systolic pressure in the right ventricle of the normal human being averages about 25 mm Hg, and the diastolic pressure 483 484 Unit VII Respiration normal human being, the diastolic pulmonary arterial pressure is about 8 mm Hg, and the mean pulmonary arterial pressure is 15 mm Hg. Aortic pressure curve 120 Pressure (mm Hg) Pulmonary Capillary Pressure. The mean pulmonary cap- illary pressure, as diagrammed in Figure 38–2, is about 7 mm Hg. The importance of this low capillary pressure is discussed in detail later in the chapter in relation to fluid exchange functions of the pulmonary capillaries. 75 Right ventricular curve Pulmonary artery curve 25 8 0 0 1 Seconds 2 Figure 38–1 mm Hg Pressure pulse contours in the right ventricle, pulmonary artery, and aorta. 25 S 15 M 8 7 D Pulmonary capillaries Left atrium 2 0 Pulmonary artery Pulmonary capillaries Left atrium Figure 38–2 Pressures in the different vessels of the lungs. D, diastolic; M, mean; S, systolic; red curve, arterial pulsations. averages about 0 to 1 mm Hg, values that are only one fifth those for the left ventricle. Pressures in the Pulmonary Artery. During systole, the pressure in the pulmonary artery is essentially equal to the pressure in the right ventricle, as also shown in Figure 38–1. However, after the pulmonary valve closes at the end of systole, the ventricular pressure falls precipitously, whereas the pulmonary arterial pressure falls more slowly as blood flows through the capillaries of the lungs. As shown in Figure 38–2, the systolic pulmonary arterial pressure averages about 25 mm Hg in the Left Atrial and Pulmonary Venous Pressures. The mean pressure in the left atrium and the major pulmonary veins averages about 2 mm Hg in the recumbent human being, varying from as low as 1 mm Hg to as high as 5 mm Hg. It usually is not feasible to measure a human being’s left atrial pressure using a direct measuring device because it is difficult to pass a catheter through the heart chambers into the left atrium. However, the left atrial pressure can often be estimated with moderate accuracy by measuring the so-called pulmonary wedge pressure. This is achieved by inserting a catheter first through a peripheral vein to the right atrium, then through the right side of the heart and through the pulmonary artery into one of the small branches of the pulmonary artery, finally pushing the catheter until it wedges tightly in the small branch. The pressure measured through the catheter, called the “wedge pressure,” is about 5 mm Hg. Because all blood flow has been stopped in the small wedged artery, and because the blood vessels extending beyond this artery make a direct connection with the pulmonary capillaries, this wedge pressure is usually only 2 to 3 mm Hg greater than the left atrial pressure. When the left atrial pressure rises to high values, the pulmonary wedge pressure also rises. Therefore, wedge pressure measurements can be used to clinically study changes in pulmonary capillary pressure and left atrial pressure in patients with congestive heart failure. Blood Volume of the Lungs The blood volume of the lungs is about 450 milliliters, about 9 per cent of the total blood volume of the entire circulatory system. Approximately 70 milliliters of this pulmonary blood volume is in the pulmonary capillaries, and the remainder is divided about equally between the pulmonary arteries and the veins. Lungs as a Blood Reservoir. Under various physiological and pathological conditions, the quantity of blood in the lungs can vary from as little as one half normal up to twice normal. For instance, when a person blows out air so hard that high pressure is built up in the lungs— such as when blowing a trumpet—as much as 250 milliliters of blood can be expelled from the pulmonary circulatory system into the systemic circulation. Also, loss of blood from the systemic circulation by hemorrhage can be partly compensated for by the Chapter 38 485 Pulmonary Circulation, Pulmonary Edema, Pleural Fluid automatic shift of blood from the lungs into the systemic vessels. Shift of Blood Between the Pulmonary and Systemic Circulatory Systems as a Result of Cardiac Pathology. Failure of the left side of the heart or increased resistance to blood flow through the mitral valve as a result of mitral stenosis or mitral regurgitation causes blood to dam up in the pulmonary circulation, sometimes increasing the pulmonary blood volume as much as 100 per cent and causing large increases in the pulmonary vascular pressures. Because the volume of the systemic circulation is about nine times that of the pulmonary system, a shift of blood from one system to the other affects the pulmonary system greatly but usually has only mild systemic circulatory effects. Blood Flow Through the Lungs and Its Distribution The blood flow through the lungs is essentially equal to the cardiac output. Therefore, the factors that control cardiac output—mainly peripheral factors, as discussed in Chapter 20—also control pulmonary blood flow. Under most conditions, the pulmonary vessels act as passive, distensible tubes that enlarge with increasing pressure and narrow with decreasing pressure. For adequate aeration of the blood to occur, it is important for the blood to be distributed to those segments of the lungs where the alveoli are best oxygenated. This is achieved by the following mechanism. Effect of Hydrostatic Pressure Gradients in the Lungs on Regional Pulmonary Blood Flow In Chapter 15, it was pointed out that the blood pressure in the foot of a standing person can be as much as 90 mm Hg greater than the pressure at the level of the heart. This is caused by hydrostatic pressure—that is, by the weight of the blood itself in the blood vessels. The same effect, but to a lesser degree, occurs in the lungs. In the normal, upright adult, the lowest point in the lungs is about 30 centimeters below the highest point. This represents a 23 mm Hg pressure difference, about 15 mm Hg of which is above the heart and 8 below. That is, the pulmonary arterial pressure in the uppermost portion of the lung of a standing person is about 15 mm Hg less than the pulmonary arterial pressure at the level of the heart, and the pressure in the lowest portion of the lungs is about 8 mm Hg greater. Such pressure differences have profound effects on blood flow through the different areas of the lungs. This is demonstrated by the lower curve in Figure 38–3, which depicts blood flow per unit of lung tissue at different levels of the lung in the upright person. Note that in the standing position at rest, there is little flow in the top of the lung but about five times as much flow in the bottom. To help explain these differences, one often describes the lung as being divided into three zones, as shown in Figure 38–4. In each zone, the patterns of blood flow are quite different. Zones 1, 2, and 3 of Pulmonary Blood Flow The capillaries in the alveolar walls are distended by the blood pressure inside them, but simultaneously, they are When the concentration of oxygen in the air of the alveoli decreases below normal—especially when it falls below 70 per cent of normal (below 73 mm Hg Po2)—the adjacent blood vessels constrict, with the vascular resistance increasing more than fivefold at extremely low oxygen levels. This is opposite to the effect observed in systemic vessels, which dilate rather than constrict in response to low oxygen. It is believed that the low oxygen concentration causes some yet undiscovered vasoconstrictor substance to be released from the lung tissue; this substance promotes constriction of the small arteries and arterioles. It has been suggested that this vasoconstrictor might be secreted by the alveolar epithelial cells when they become hypoxic. This effect of low oxygen on pulmonary vascular resistance has an important function: to distribute blood flow where it is most effective. That is, if some alveoli are poorly ventilated so that their oxygen concentration becomes low, the local vessels constrict.This causes the blood to flow through other areas of the lungs that are better aerated, thus providing an automatic control system for distributing blood flow to the pulmonary areas in proportion to their alveolar oxygen pressures. Blood flow (per unit of tissue) Effect of Diminished Alveolar Oxygen on Local Alveolar Blood Flow—Automatic Control of Pulmonary Blood Flow Distribution. Top Exercise Standing at rest Middle Lung level Bottom Figure 38–3 Blood flow at different levels in the lung of an upright person at rest and during exercise. Note that when the person is at rest, the blood flow is very low at the top of the lungs; most of the flow is through the bottom of the lung. 486 Unit VII ZONE 1 Artery PALV Vein Ppc ZONE 2 Artery PALV Vein Ppc ZONE 3 Artery PALV Vein Respiration during cardiac systole. Conversely, during diastole, the 8 mm Hg diastolic pressure at the level of the heart is not sufficient to push the blood up the 15 mm Hg hydrostatic pressure gradient required to cause diastolic capillary flow. Therefore, blood flow through the apical part of the lung is intermittent, with flow during systole but cessation of flow during diastole; this is called zone 2 blood flow. Zone 2 blood flow begins in the normal lungs about 10 centimeters above the midlevel of the heart and extends from there to the top of the lungs. In the lower regions of the lungs, from about 10 centimeters above the level of the heart all the way to the bottom of the lungs, the pulmonary arterial pressure during both systole and diastole remains greater than the zero alveolar air pressure. Therefore, there is continuous flow through the alveolar capillaries, or zone 3 blood flow. Also, when a person is lying down, no part of the lung is more than a few centimeters above the level of the heart. In this case, blood flow in a normal person is entirely zone 3 blood flow, including the lung apices. Zone 1 Blood Flow Occurs Only Under Abnormal Conditions. Ppc Figure 38–4 Mechanics of blood flow in the three blood flow zones of the lung: zone 1, no flow—alveolar air pressure (PALV) is greater than arterial pressure; zone 2, intermittent flow—systolic arterial pressure rises higher than alveolar air pressure, but diastolic arterial pressure falls below alveolar air pressure; and zone 3, continuous flow—arterial pressure and pulmonary capillary pressure (Ppc) remain greater than alveolar air pressure at all times. compressed by the alveolar air pressure on their outsides. Therefore, any time the lung alveolar air pressure becomes greater than the capillary blood pressure, the capillaries close and there is no blood flow. Under different normal and pathological lung conditions, one may find any one of three possible zones of pulmonary blood flow, as follows: Zone 1: No blood flow during all portions of the cardiac cycle because the local alveolar capillary pressure in that area of the lung never rises higher than the alveolar air pressure during any part of the cardiac cycle Zone 2: Intermittent blood flow only during the pulmonary arterial pressure peaks because the systolic pressure is then greater than the alveolar air pressure, but the diastolic pressure is less than the alveolar air pressure Zone 3: Continuous blood flow because the alveolar capillary pressure remains greater than alveolar air pressure during the entire cardiac cycle Normally, the lungs have only zones 2 and 3 blood flow—zone 2 (intermittent flow) in the apices, and zone 3 (continuous flow) in all the lower areas. For example, when a person is in the upright position, the pulmonary arterial pressure at the lung apex is about 15 mm Hg less than the pressure at the level of the heart. Therefore, the apical systolic pressure is only 10 mm Hg (25 mm Hg at heart level minus 15 mm Hg hydrostatic pressure difference). This 10 mm Hg apical blood pressure is greater than the zero alveolar air pressure, so that blood flows through the pulmonary apical capillaries Zone 1 blood flow, which is blood flow at no time during the cardiac cycle, occurs when either the pulmonary systolic arterial pressure is too low or the alveolar pressure is too high to allow flow. For instance, if an upright person is breathing against a positive air pressure so that the intra-alveolar air pressure is at least 10 mm Hg greater than normal but the pulmonary systolic blood pressure is normal, one would expect zone 1 blood flow—no blood flow—in the lung apices. Another instance in which zone 1 blood flow occurs is in an upright person whose pulmonary systolic arterial pressure is exceedingly low, as might occur after severe blood loss. Effect of Exercise on Blood Flow Through the Different Parts of the Lungs. Referring again to Figure 38–3, one sees that the blood flow in all parts of the lung increases during exercise. The increase in flow in the top of the lung may be 700 to 800 per cent, whereas the increase in the lower part of the lung may be no more than 200 to 300 per cent. The reason for these differences is that the pulmonary vascular pressures rise enough during exercise to convert the lung apices from a zone 2 pattern into a zone 3 pattern of flow. Effect of Increased Cardiac Output on Pulmonary Blood Flow and Pulmonary Arterial Pressure During Heavy Exercise During heavy exercise, blood flow through the lungs increases fourfold to sevenfold. This extra flow is accommodated in the lungs in three ways: (1) by increasing the number of open capillaries, sometimes as much as threefold; (2) by distending all the capillaries and increasing the rate of flow through each capillary more than twofold; and (3) by increasing the pulmonary arterial pressure. In the normal person, the first two changes decrease pulmonary vascular resistance so much that the pulmonary arterial pressure rises very little, even during maximum exercise; this effect is shown in Figure 38–5. Chapter 38 Pulmonary Circulation, Pulmonary Edema, Pleural Fluid 487 above 30 mm Hg, causing similar increases in capillary pressure, pulmonary edema is likely to develop, as we discuss later in the chapter. 30 Pulmonary arterial pressure (mm Hg) Pulmonary Capillary Dynamics Normal value Exchange of gases between the alveolar air and the pulmonary capillary blood is discussed in the next chapter. However, it is important for us to note here that the alveolar walls are lined with so many capillaries that, in most places, the capillaries almost touch one another side by side. Therefore, it is often said that the capillary blood flows in the alveolar walls as a “sheet of flow,” rather than in individual capillaries. 20 10 0 0 4 8 12 16 20 Cardiac output (L/min) 24 Figure 38–5 Effect on mean pulmonary arterial pressure caused by increasing the cardiac output during exercise. The ability of the lungs to accommodate greatly increased blood flow during exercise without increasing the pulmonary arterial pressure conserves the energy of the right side of the heart. This ability also prevents a significant rise in pulmonary capillary pressure, thus also preventing the development of pulmonary edema. Function of the Pulmonary Circulation When the Left Atrial Pressure Rises as a Result of Left-Sided Heart Failure The left atrial pressure in a healthy person almost never rises above +6 mm Hg, even during the most strenuous exercise. These small changes in left atrial pressure have virtually no effect on pulmonary circulatory function because this merely expands the pulmonary venules and opens up more capillaries so that blood continues to flow with almost equal ease from the pulmonary arteries. When the left side of the heart fails, however, blood begins to dam up in the left atrium. As a result, the left atrial pressure can rise on occasion from its normal value of 1 to 5 mm Hg all the way up to 40 to 50 mm Hg. The initial rise in atrial pressure, up to about 7 mm Hg, has very little effect on pulmonary circulatory function. But when the left atrial pressure rises to greater than 7 or 8 mm Hg, further increases in left atrial pressure above these levels cause almost equally great increases in pulmonary arterial pressure, thus causing a concomitant increased load on the right heart. Any increase in left atrial pressure above 7 or 8 mm Hg increases the capillary pressure almost equally as much.When the left atrial pressure has risen Pulmonary Capillary Pressure. No direct measurements of pulmonary capillary pressure have ever been made. However, “isogravimetric” measurement of pulmonary capillary pressure, using a technique described in Chapter 16, has given a value of 7 mm Hg. This is probably nearly correct, because the mean left atrial pressure is about 2 mm Hg and the mean pulmonary arterial pressure is only 15 mm Hg, so the mean pulmonary capillary pressure must lie somewhere between these two values. Length of Time Blood Stays in the Pulmonary Capillaries. From histological study of the total cross-sectional area of all the pulmonary capillaries, it can be calculated that when the cardiac output is normal, blood passes through the pulmonary capillaries in about 0.8 second. When the cardiac output increases, this can shorten to as little as 0.3 second. The shortening would be much greater were it not for the fact that additional capillaries, which normally are collapsed, open up to accommodate the increased blood flow. Thus, in only a fraction of a second, blood passing through the alveolar capillaries becomes oxygenated and loses its excess carbon dioxide. Capillary Exchange of Fluid in the Lungs, and Pulmonary Interstitial Fluid Dynamics The dynamics of fluid exchange across the lung capillary membranes are qualitatively the same as for peripheral tissues. However, quantitatively, there are important differences, as follows: 1. The pulmonary capillary pressure is low, about 7 mm Hg, in comparison with a considerably higher functional capillary pressure in the peripheral tissues of about 17 mm Hg. 2. The interstitial fluid pressure in the lung is slightly more negative than that in the peripheral subcutaneous tissue. (This has been measured in two ways: by a micropipette inserted into the pulmonary interstitium, giving a value of about –5 mm Hg, and by measuring the absorption pressure of fluid from the alveoli, giving a value of about –8 mm Hg.) 488 Unit VII Respiration 3. The pulmonary capillaries are relatively leaky to protein molecules, so that the colloid osmotic pressure of the pulmonary interstitial fluid is about 14 mm Hg, in comparison with less than half this value in the peripheral tissues. 4. The alveolar walls are extremely thin, and the alveolar epithelium covering the alveolar surfaces is so weak that it can be ruptured by any positive pressure in the interstitial spaces greater than alveolar air pressure (greater than 0 mm Hg), which allows dumping of fluid from the interstitial spaces into the alveoli. Now let us see how these quantitative differences affect pulmonary fluid dynamics. pressure at the pulmonary capillary membrane; this can be calculated as follows: Interrelations Between Interstitial Fluid Pressure and Other Pressures in the Lung. Figure 38–6 shows a pulmonary Negative Pulmonary Interstitial Pressure and the Mechanism for Keeping the Alveoli “Dry.” One of the most important capillary, a pulmonary alveolus, and a lymphatic capillary draining the interstitial space between the blood capillary and the alveolus. Note the balance of forces at the blood capillary membrane, as follows: problems in lung function is to understand why the alveoli do not normally fill with fluid. One’s first inclination is to think that the alveolar epithelium is strong enough and continuous enough to keep fluid from leaking out of the interstitial spaces into the alveoli. This is not true, because experiments have shown that there are always openings between the alveolar epithelial cells through which even large protein molecules, as well as water and electrolytes, can pass. However, if one remembers that the pulmonary capillaries and the pulmonary lymphatic system normally maintain a slight negative pressure in the interstitial spaces, it is clear that whenever extra fluid appears in the alveoli, it will simply be sucked mechanically into the lung interstitium through the small openings between the alveolar epithelial cells. Then the excess fluid is either carried away through the pulmonary lymphatics or absorbed into the pulmonary capillaries. Thus, under normal conditions, the alveoli are kept “dry,” except for a small amount of fluid that seeps from the epithelium onto the lining surfaces of the alveoli to keep them moist. mm Hg Forces tending to cause movement of fluid outward from the capillaries and into the pulmonary interstitium: Capillary pressure Interstitial fluid colloid osmotic pressure Negative interstitial fluid pressure TOTAL OUTWARD FORCE 7 14 8 29 Forces tending to cause absorption of fluid into the capillaries: Plasma colloid osmotic pressure 28 TOTAL INWARD FORCE 28 Thus, the normal outward forces are slightly greater than the inward forces, providing a mean filtration Pressures Causing Fluid Movement CAPILLARY mm Hg Total outward force Total inward force MEAN FILTRATION PRESSURE +29 –28 +1 This filtration pressure causes a slight continual flow of fluid from the pulmonary capillaries into the interstitial spaces, and except for a small amount that evaporates in the alveoli, this fluid is pumped back to the circulation through the pulmonary lymphatic system. ALVEOLUS Pulmonary Edema Hydrostatic pressure Osmotic pressure Net pressure +7 - 28 -8 -8 - 8 (Surface tension at pore) - 14 (+ 1) -5 ( 0) (Evaporation) -4 Lymphatic pump Figure 38–6 Hydrostatic and osmotic forces at the capillary (left) and alveolar membrane (right) of the lungs. Also shown is the tip end of a lymphatic vessel (center) that pumps fluid from the pulmonary interstitial spaces. (Modified from Guyton AC, Taylor AE, Granger HJ: Circulatory Physiology II: Dynamics and Control of the Body Fluids. Philadelphia: WB Saunders, 1975.) Pulmonary edema occurs in the same way that edema occurs elsewhere in the body. Any factor that causes the pulmonary interstitial fluid pressure to rise from the negative range into the positive range will cause rapid filling of the pulmonary interstitial spaces and alveoli with large amounts of free fluid. The most common causes of pulmonary edema are as follows: 1. Left-sided heart failure or mitral valve disease, with consequent great increases in pulmonary venous pressure and pulmonary capillary pressure and flooding of the interstitial spaces and alveoli. 2. Damage to the pulmonary blood capillary membranes caused by infections such as pneumonia or by breathing noxious substances such as chlorine gas or sulfur dioxide gas. Each of these causes rapid leakage of both plasma proteins and fluid out of the capillaries and into both the lung interstitial spaces and the alveoli. “Pulmonary Edema Safety Factor.” Experiments in animals have shown that the pulmonary capillary pressure nor- 489 Pulmonary Circulation, Pulmonary Edema, Pleural Fluid Figure 38–7 Rate of fluid loss into the lung tissues when the left atrial pressure (and pulmonary capillary pressure) is increased. (From Guyton AC, Lindsey AW: Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res 7:649, 1959.) mally must rise to a value at least equal to the colloid osmotic pressure of the plasma inside the capillaries before significant pulmonary edema will occur. To give an example, Figure 38–7 shows how different levels of left atrial pressure increase the rate of pulmonary edema formation in dogs. Remember that every time the left atrial pressure rises to high values, the pulmonary capillary pressure rises to a level 1 to 2 mm Hg greater than the left atrial pressure. In these experiments, as soon as the left atrial pressure rose above 23 mm Hg (causing the pulmonary capillary pressure to rise above 25 mm Hg), fluid began to accumulate in the lungs. This fluid accumulation increased even more rapidly with further increases in capillary pressure. The plasma colloid osmotic pressure during these experiments was equal to this 25 mm Hg critical pressure level. Therefore, in the human being, whose normal plasma colloid osmotic pressure is 28 mm Hg, one can predict that the pulmonary capillary pressure must rise from the normal level of 7 mm Hg to more than 28 mm Hg to cause pulmonary edema, giving an acute safety factor against pulmonary edema of 21 mm Hg. Safety Factor in Chronic Conditions. When the pulmonary capillary pressure remains elevated chronically (for at least 2 weeks), the lungs become even more resistant to pulmonary edema because the lymph vessels expand greatly, increasing their capability of carrying fluid away from the interstitial spaces perhaps as much as 10-fold. Therefore, in patients with chronic mitral stenosis, pulmonary capillary pressures of 40 to 45 mm Hg have been measured without the development of lethal pulmonary edema. Rapidity of Death in Acute Pulmonary Edema. When the pul- monary capillary pressure rises even slightly above the safety factor level, lethal pulmonary edema can occur within hours, or even within 20 to 30 minutes if the capillary pressure rises 25 to 30 mm Hg above the safety factor level. Thus, in acute left-sided heart failure, in Rate of edema formation = edema fluid per hour dry weight of lung Chapter 38 10 9 x x 8 7 x 6 x 5 4 x x x x x 10 15 20 25 30 35 40 Left atrial pressure (mm Hg) 45 3 x 2 x 1 0 x x 0 5 x x x x xx x x x x x x 50 which the pulmonary capillary pressure occasionally does rise to 50 mm Hg, death frequently ensues in less than 30 minutes from acute pulmonary edema. Fluid in the Pleural Cavity When the lungs expand and contract during normal breathing, they slide back and forth within the pleural cavity. To facilitate this, a thin layer of mucoid fluid lies between the parietal and visceral pleurae. Figure 38–8 shows the dynamics of fluid exchange in the pleural space. The pleural membrane is a porous, mesenchymal, serous membrane through which small amounts of interstitial fluid transude continually into the pleural space. These fluids carry with them tissue proteins, giving the pleural fluid a mucoid characteristic, which is what allows extremely easy slippage of the moving lungs. The total amount of fluid in each pleural cavity is normally slight, only a few milliliters. Whenever the quantity becomes more than barely enough to begin flowing in the pleural cavity, the excess fluid is pumped away by lymphatic vessels opening directly from the pleural cavity into (1) the mediastinum, (2) the superior surface of the diaphragm, and (3) the lateral surfaces of the parietal pleura. Therefore, the pleural space—the space between the parietal and visceral pleurae—is called a potential space because it normally is so narrow that it is not obviously a physical space. “Negative Pressure” in Pleural Fluid. A negative force is always required on the outside of the lungs to keep the lungs expanded. This is provided by negative pressure in the normal pleural space. The basic cause of this negative pressure is pumping of fluid from the space by the lymphatics (which is also the basis of the negative pressure found in most tissue spaces of the body). Because the normal collapse tendency of the lungs is about –4 mm Hg, the pleural fluid pressure must always be at 490 Unit VII Venous system Lymphatics Artery Respiration (3) greatly reduced plasma colloid osmotic pressure, thus allowing excessive transudation of fluid; and (4) infection or any other cause of inflammation of the surfaces of the pleural cavity, which breaks down the capillary membranes and allows rapid dumping of both plasma proteins and fluid into the cavity. References Vein Figure 38–8 Dynamics of fluid exchange in the intrapleural space. least as negative as –4 mm Hg to keep the lungs expanded. Actual measurements have shown that the pressure is usually about –7 mm Hg, which is a few millimeters of mercury more negative than the collapse pressure of the lungs. Thus, the negativity of the pleural fluid keeps the normal lungs pulled against the parietal pleura of the chest cavity, except for an extremely thin layer of mucoid fluid that acts as a lubricant. Pleural Effusion. Pleural effusion means the collection of large amounts of free fluid in the pleural space.The effusion is analogous to edema fluid in the tissues and can be called “edema of the pleural cavity.” The causes of the effusion are the same as the causes of edema in other tissues (discussed in Chapter 25), including (1) blockage of lymphatic drainage from the pleural cavity; (2) cardiac failure, which causes excessively high peripheral and pulmonary capillary pressures, leading to excessive transudation of fluid into the pleural cavity; Gehlbach BK, Geppert E: The pulmonary manifestations of left heart failure. Chest 125:669, 2004. Guazzi M: Alveolar-capillary membrane dysfunction in heart failure: evidence of a pathophysiologic role. Chest 124:1090, 2003. Guyton AC, Lindsey AW: Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res 7:649, 1959. Guyton AC, Parker JC, Taylor AE, et al: Forces governing water movement in the lung. In: Fishman AP, Renkin EM (eds): Pulmonary Edema. Baltimore: Waverly Press, 1979, p 65. Guyton AC, Taylor AE, Granger HJ: Circulatory Physiology. II. Dynamics and Control of the Body Fluids. Philadelphia: WB Saunders, 1975. Hoschele S, Mairbaurl H: Alveolar flooding at high altitude: failure of reabsorption? News Physiol Sci 18:55, 2003. Lai-Fook SJ: Pleural mechanics and fluid exchange. Physiol Rev 84:385, 2004. Matalon S, Hardiman KM, Jain L, et al: Regulation of ion channel structure and function by reactive oxygennitrogen species. Am J Physiol Lung Cell Mol Physiol 285:L1184, 2003. Miserocchi G, Negrini D, Passi A, De Luca G: Development of lung edema: interstitial fluid dynamics and molecular structure. News Physiol Sci 16:66, 2001. Schoene RB: Limits of human lung function at high altitude. J Exp Biol 204:3121, 2001. Taylor AE, Guyton AC, Bishop VS: Permeability of the alveolar membrane to solutes. Circ Res 16:353, 1965. Wallace J: Update in pulmonary diseases. Ann Intern Med 139:499, 2003. West JB: Respiratory Physiology—The Essentials, 5th ed. Baltimore: Williams & Wilkins, 1994. West JB: Invited review: pulmonary capillary stress failure. J Appl Physiol 89:2483, 2000. C H A P T E R 3 9 Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Through the Respiratory Membrane After the alveoli are ventilated with fresh air, the next step in the respiratory process is diffusion of oxygen from the alveoli into the pulmonary blood and diffusion of carbon dioxide in the opposite direction, out of the blood. The process of diffusion is simply the random motion of molecules intertwining their way in all directions through the respiratory membrane and adjacent fluids. However, in respiratory physiology, one is concerned not only with the basic mechanism by which diffusion occurs but also with the rate at which it occurs; this is a much more complex problem, requiring a deeper understanding of the physics of diffusion and gas exchange. Physics of Gas Diffusion and Gas Partial Pressures Molecular Basis of Gas Diffusion All the gases of concern in respiratory physiology are simple molecules that are free to move among one another, which is the process called “diffusion.” This is also true of gases dissolved in the fluids and tissues of the body. For diffusion to occur, there must be a source of energy. This is provided by the kinetic motion of the molecules themselves. Except at absolute zero temperature, all molecules of all matter are continually undergoing motion. For free molecules that are not physically attached to others, this means linear movement at high velocity until they strike other molecules. Then they bounce away in new directions and continue until striking other molecules again. In this way, the molecules move rapidly and randomly among one another. Net Diffusion of a Gas in One Direction—Effect of a Concentration Gradient. If a gas chamber or a solution has a high concentration of a particular gas at one end of the chamber and a low concentration at the other end, as shown in Figure 39–1, net diffusion of the gas will occur from the high-concentration area toward the low-concentration area. The reason is obvious: There are far more molecules at end A of the chamber to diffuse toward end B than there are molecules to diffuse in the opposite direction. Therefore, the rates of diffusion in each of the two directions are proportionately different, as demonstrated by the lengths of the arrows in the figure. Gas Pressures in a Mixture of Gases—“Partial Pressures” of Individual Gases Pressure is caused by multiple impacts of moving molecules against a surface. Therefore, the pressure of a gas acting on the surfaces of the respiratory passages and alveoli is proportional to the summated force of impact of all the molecules of that gas striking the surface at any given instant. This means that the pressure is directly proportional to the concentration of the gas molecules. 491 492 Unit VII When partial pressure is expressed in atmospheres (1 atmosphere pressure equals 760 mm Hg) and concentration is expressed in volume of gas dissolved in each volume of water, the solubility coefficients for important respiratory gases at body temperature are the following: Dissolved gas molecules A B Figure 39–1 Diffusion of oxygen from one end of a chamber (A) to the other (B). The difference between the lengths of the arrows represents net diffusion. In respiratory physiology, one deals with mixtures of gases, mainly of oxygen, nitrogen, and carbon dioxide. The rate of diffusion of each of these gases is directly proportional to the pressure caused by that gas alone, which is called the partial pressure of that gas. The concept of partial pressure can be explained as follows. Consider air, which has an approximate composition of 79 per cent nitrogen and 21 per cent oxygen. The total pressure of this mixture at sea level averages 760 mm Hg. It is clear from the preceding description of the molecular basis of pressure that each gas contributes to the total pressure in direct proportion to its concentration. Therefore, 79 per cent of the 760 mm Hg is caused by nitrogen (600 mm Hg) and 21 per cent by oxygen (160 mm Hg). Thus, the “partial pressure” of nitrogen in the mixture is 600 mm Hg, and the “partial pressure” of oxygen is 160 mm Hg; the total pressure is 760 mm Hg, the sum of the individual partial pressures. The partial pressures of individual gases in a mixture are designated by the symbols Po2, Pco2, Pn2, Ph2o, Phe, and so forth. Pressures of Gases Dissolved in Water and Tissues Gases dissolved in water or in body tissues also exert pressure, because the dissolved gas molecules are moving randomly and have kinetic energy. Further, when the gas dissolved in fluid encounters a surface, such as the membrane of a cell, it exerts its own partial pressure in the same way that a gas in the gas phase does. The partial pressures of the separate dissolved gases are designated the same as the partial pressures in the gas state, that is, Po2, Pco2, Pn2, Phe, and so forth. Factors That Determine the Partial Pressure of a Gas Dissolved in a Fluid. The partial pressure of a gas in a solution is determined not only by its concentration but also by the solubility coefficient of the gas. That is, some types of molecules, especially carbon dioxide, are physically or chemically attracted to water molecules, whereas others are repelled. When molecules are attracted, far more of them can be dissolved without building up excess partial pressure within the solution. Conversely, in the case of those that are repelled, high partial pressure will develop with fewer dissolved molecules. These relations are expressed by the following formula, which is Henry’s law: Partial pressure = Respiration Concentration of dissolved gas Solubility coefficient Oxygen Carbon dioxide Carbon monoxide Nitrogen Helium 0.024 0.57 0.018 0.012 0.008 From this table, one can see that carbon dioxide is more than 20 times as soluble as oxygen. Therefore, the partial pressure of carbon dioxide (for a given concentration) is less than one twentieth that exerted by oxygen. Diffusion of Gases Between the Gas Phase in the Alveoli and the Dissolved Phase in the Pulmonary Blood. The partial pressure of each gas in the alveolar respiratory gas mixture tends to force molecules of that gas into solution in the blood of the alveolar capillaries. Conversely, the molecules of the same gas that are already dissolved in the blood are bouncing randomly in the fluid of the blood, and some of these bouncing molecules escape back into the alveoli. The rate at which they escape is directly proportional to their partial pressure in the blood. But in which direction will net diffusion of the gas occur? The answer is that net diffusion is determined by the difference between the two partial pressures. If the partial pressure is greater in the gas phase in the alveoli, as is normally true for oxygen, then more molecules will diffuse into the blood than in the other direction. Alternatively, if the partial pressure of the gas is greater in the dissolved state in the blood, which is normally true for carbon dioxide, then net diffusion will occur toward the gas phase in the alveoli. Vapor Pressure of Water When nonhumidified air is breathed into the respiratory passageways, water immediately evaporates from the surfaces of these passages and humidifies the air. This results from the fact that water molecules, like the different dissolved gas molecules, are continually escaping from the water surface into the gas phase. The partial pressure that the water molecules exert to escape through the surface is called the vapor pressure of the water. At normal body temperature, 37°C, this vapor pressure is 47 mm Hg. Therefore, once the gas mixture has become fully humidified—that is, once it is in “equilibrium” with the water—the partial pressure of the water vapor in the gas mixture is 47 mm Hg. This partial pressure, like the other partial pressures, is designated Ph2o. The vapor pressure of water depends entirely on the temperature of the water. The greater the temperature, the greater the kinetic activity of the molecules and, therefore, the greater the likelihood that the water molecules will escape from the surface of the water into the gas phase. For instance, the water vapor pressure at 0°C is 5 mm Hg, and at 100°C it is 760 mm Hg. But the most important value to remember is the vapor pressure at body temperature, 47 mm Hg; this value appears in many of our subsequent discussions. Chapter 39 Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Diffusion of Gases Through Fluids—Pressure Difference Causes Net Diffusion Now, let us return to the problem of diffusion. From the preceding discussion, it is clear that when the partial pressure of a gas is greater in one area than in another area, there will be net diffusion from the high-pressure area toward the low-pressure area. For instance, returning to Figure 39–1, one can readily see that the molecules in the area of high pressure, because of their greater number, have a greater statistical chance of moving randomly into the area of low pressure than do molecules attempting to go in the other direction. However, some molecules do bounce randomly from the area of low pressure toward the area of high pressure. Therefore, the net diffusion of gas from the area of high pressure to the area of low pressure is equal to the number of molecules bouncing in this forward direction minus the number bouncing in the opposite direction; this is proportional to the gas partial pressure difference between the two areas, called simply the pressure difference for causing diffusion. Quantifying the Net Rate of Diffusion in Fluids. In addition to the pressure difference, several other factors affect the rate of gas diffusion in a fluid. They are (1) the solubility of the gas in the fluid, (2) the cross-sectional area of the fluid, (3) the distance through which the gas must diffuse, (4) the molecular weight of the gas, and (5) the temperature of the fluid. In the body, the last of these factors, the temperature, remains reasonably constant and usually need not be considered. The greater the solubility of the gas, the greater the number of molecules available to diffuse for any given partial pressure difference. The greater the crosssectional area of the diffusion pathway, the greater the total number of molecules that diffuse. Conversely, the greater the distance the molecules must diffuse, the longer it will take the molecules to diffuse the entire distance. Finally, the greater the velocity of kinetic movement of the molecules, which is inversely proportional to the square root of the molecular weight, the greater the rate of diffusion of the gas. All these factors can be expressed in a single formula, as follows: Dµ DP ¥ A ¥ S , d ¥ MW in which D is the diffusion rate, DP is the partial pressure difference between the two ends of the diffusion 493 pathway, A is the cross-sectional area of the pathway, S is the solubility of the gas, d is the distance of diffusion, and MW is the molecular weight of the gas. It is obvious from this formula that the characteristics of the gas itself determine two factors of the formula: solubility and molecular weight. Together, these two factors determine the diffusion coefficient of the gas, which is proportional to S/ MW . That is, the relative rates at which different gases at the same partial pressure levels will diffuse are proportional to their diffusion coefficients. Assuming that the diffusion coefficient for oxygen is 1, the relative diffusion coefficients for different gases of respiratory importance in the body fluids are as follows: Oxygen Carbon dioxide Carbon monoxide Nitrogen Helium 1.0 20.3 0.81 0.53 0.95 Diffusion of Gases Through Tissues The gases that are of respiratory importance are all highly soluble in lipids and, consequently, are highly soluble in cell membranes. Because of this, the major limitation to the movement of gases in tissues is the rate at which the gases can diffuse through the tissue water instead of through the cell membranes. Therefore, diffusion of gases through the tissues, including through the respiratory membrane, is almost equal to the diffusion of gases in water, as given in the preceding list. Composition of Alveolar Air—Its Relation to Atmospheric Air Alveolar air does not have the same concentrations of gases as atmospheric air by any means, which can readily be seen by comparing the alveolar air composition in Table 39–1 with that of atmospheric air. There are several reasons for the differences. First, the alveolar air is only partially replaced by atmospheric air with each breath. Second, oxygen is constantly being absorbed into the pulmonary blood from the alveolar air. Third, carbon dioxide is constantly diffusing from the pulmonary blood into the alveoli. And fourth, dry Table 39–1 Partial Pressures of Respiratory Gases as They Enter and Leave the Lungs (at Sea Level) Atmospheric Air* (mm Hg) N2 O2 CO2 H2O TOTAL 597.0 159.0 0.3 3.7 760.0 * On an average cool, clear day. Humidified Air (mm Hg) (78.62%) (20.84%) (0.04%) (0.50%) (100.0%) 563.4 149.3 0.3 47.0 760.0 Alveolar Air (mm Hg) (74.09%) (19.67%) (0.04%) (6.20%) (100.0%) 569.0 104.0 40.0 47.0 760.0 Expired Air (mm Hg) (74.9%) (13.6%) (5.3%) (6.2%) (100.0%) 566.0 120.0 27.0 47.0 760.0 (74.5%) (15.7%) (3.6%) (6.2%) (100.0%) Unit VII atmospheric air that enters the respiratory passages is humidified even before it reaches the alveoli. Humidification of the Air in the Respiratory Passages. Table 39–1 shows that atmospheric air is composed almost entirely of nitrogen and oxygen; it normally contains almost no carbon dioxide and little water vapor. However, as soon as the atmospheric air enters the respiratory passages, it is exposed to the fluids that cover the respiratory surfaces. Even before the air enters the alveoli, it becomes (for all practical purposes) totally humidified. The partial pressure of water vapor at a normal body temperature of 37°C is 47 mm Hg, which is therefore the partial pressure of water vapor in the alveolar air. Because the total pressure in the alveoli cannot rise to more than the atmospheric pressure (760 mm Hg at sea level), this water vapor simply dilutes all the other gases in the inspired air. Table 39–1 also shows that humidification of the air dilutes the oxygen partial pressure at sea level from an average of 159 mm Hg in atmospheric air to 149 mm Hg in the humidified air, and it dilutes the nitrogen partial pressure from 597 to 563 mm Hg. Rate at Which Alveolar Air Is Renewed by Atmospheric Air In Chapter 37, it was pointed out that the average male functional residual capacity of the lungs (the volume of air remaining in the lungs at the end of normal expiration) measures about 2300 milliliters. Yet only 350 milliliters of new air is brought into the alveoli with each normal inspiration, and this same amount of old alveolar air is expired. Therefore, the volume of alveolar air replaced by new atmospheric air with each breath is only one seventh of the total, so that multiple breaths are required to exchange most of the alveolar air. Figure 39–2 shows this slow rate of renewal of the alveolar air. In the first alveolus of the figure, an excess amount of a gas is present in the alveoli, but note that even at the end of 16 breaths, the excess Oxygen is continually being absorbed from the alveoli into the blood of the lungs, and new oxygen is continually being breathed into the alveoli from the atmosphere. The more rapidly oxygen is absorbed, the lower its concentration in the alveoli becomes; conversely, the more rapidly new oxygen is breathed into the alveoli from the atmosphere, the higher its concentration becomes. Therefore, oxygen concentration in the alveoli, and its partial pressure as well, is controlled by (1) the rate of absorption of oxygen into the blood and (2) the rate of entry of new oxygen into the lungs by the ventilatory process. 100 1/2 80 no 60 rm 40 al al rm no al ve a lv o la al 20 ve eo rv al 12th breath Oxygen Concentration and Partial Pressure in the Alveoli 2¥ 8th breath 3rd breath Importance of the Slow Replacement of Alveolar Air. The slow replacement of alveolar air is of particular importance in preventing sudden changes in gas concentrations in the blood. This makes the respiratory control mechanism much more stable than it would be otherwise, and it helps prevent excessive increases and decreases in tissue oxygenation, tissue carbon dioxide concentration, and tissue pH when respiration is temporarily interrupted. rm 4th breath 2nd breath gas still has not been completely removed from the alveoli. Figure 39–3 demonstrates graphically the rate at which excess gas in the alveoli is normally removed, showing that with normal alveolar ventilation, about one half the gas is removed in 17 seconds. When a person’s rate of alveolar ventilation is only one half normal, one half the gas is removed in 34 seconds, and when the rate of ventilation is twice normal, one half is removed in about 8 seconds. No 1st breath Respiration Concentration of gas (per cent of original concentration) 494 ola la r en ven t ila r ven tilat io n ti o n tilation 0 0 10 20 30 40 Time (seconds) 50 16th breath Figure 39–2 Expiration of a gas from an alveolus with successive breaths. Figure 39–3 Rate of removal of excess gas from alveoli. 60 Chapter 39 495 Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Upper limit at maximum ventilation Alveolar partial pressure of oxygen (mm Hg) 150 Figure 39–4 250 ml O2/min 125 100 A Normal alveolar PO2 75 50 1000 ml O2/min 25 0 0 5 Effect of alveolar ventilation on the alveolar PO2 at two rates of oxygen absorption from the alveoli— 250 ml/min and 1000 ml/min. Point A is the normal operating point. 35 40 175 Alveolar partial pressure of CO2 (mm Hg) Figure 39–4 shows the effect of both alveolar ventilation and rate of oxygen absorption into the blood on the alveolar partial pressure of oxygen (Po2). One curve represents oxygen absorption at a rate of 250 ml/min, and the other curve represents a rate of 1000 ml/min. At a normal ventilatory rate of 4.2 L/min and an oxygen consumption of 250 ml/min, the normal operating point in Figure 39–4 is point A. The figure also shows that when 1000 milliliters of oxygen is being absorbed each minute, as occurs during moderate exercise, the rate of alveolar ventilation must increase fourfold to maintain the alveolar Po2 at the normal value of 104 mm Hg. Another effect shown in Figure 39–4 is that an extremely marked increase in alveolar ventilation can never increase the alveolar Po2 above 149 mm Hg as long as the person is breathing normal atmospheric air at sea level pressure, because this is the maximum Po2 in humidified air at this pressure. If the person breathes gases that contain partial pressures of oxygen higher than 149 mm Hg, the alveolar Po2 can approach these higher pressures at high rates of ventilation. 10 15 20 25 30 Alveolar ventilation (L/min) 150 125 800 ml CO2/min 100 75 50 Normal alveolar PCO2 A 25 200 ml CO2/min 0 0 5 10 15 20 25 30 35 Alveolar ventilation (L/min) 40 Figure 39–5 Effect of alveolar ventilation on the alveolar PCO2 at two rates of carbon dioxide excretion from the blood—800 ml/min and 200 ml/ min. Point A is the normal operating point. CO2 Concentration and Partial Pressure in the Alveoli Carbon dioxide is continually being formed in the body and then carried in the blood to the alveoli; it is continually being removed from the alveoli by ventilation. Figure 39–5 shows the effects on the alveolar partial pressure of carbon dioxide (Pco2) of both alveolar ventilation and two rates of carbon dioxide excretion, 200 and 800 ml/min. One curve represents a normal rate of carbon dioxide excretion of 200 ml/min. At the normal rate of alveolar ventilation of 4.2 L/min, the operating point for alveolar Pco2 is at point A in Figure 39–5—that is, 40 mm Hg. Two other facts are also evident from Figure 39–5: First, the alveolar PCO2 increases directly in proportion to the rate of carbon dioxide excretion, as represented by the fourfold elevation of the curve (when 800 milliliters of CO2 are excreted per minute). Second, the alveolar PCO2 decreases in inverse proportion to alveolar ventilation. Therefore, the concentrations and partial pressures of both oxygen and carbon dioxide in the alveoli are determined by the rates of absorption or excretion of the two gases and by the amount of alveolar ventilation. Expired Air Expired air is a combination of dead space air and alveolar air; its overall composition is therefore determined 496 Unit VII Respiration 160 Pressures of O2 and CO2 (mm Hg) 140 120 Oxygen (PO2) 100 Alveolar air and dead space air Dead space air 80 60 Alveolar air Carbon dioxide (PCO2) 40 20 0 0 100 300 200 Milliliters of air expired 400 500 Figure 39–6 Oxygen and carbon dioxide partial pressures in the various portions of normal expired air. by (1) the amount of the expired air that is dead space air and (2) the amount that is alveolar air. Figure 39–6 shows the progressive changes in oxygen and carbon dioxide partial pressures in the expired air during the course of expiration. The first portion of this air, the dead space air from the respiratory passageways, is typical humidified air, as shown in Table 39–1.Then, progressively more and more alveolar air becomes mixed with the dead space air until all the dead space air has finally been washed out and nothing but alveolar air is expired at the end of expiration. Therefore, the method of collecting alveolar air for study is simply to collect a sample of the last portion of the expired air after forceful expiration has removed all the dead space air. Normal expired air, containing both dead space air and alveolar air, has gas concentrations and partial pressures approximately as shown in Table 39–1—that is, concentrations between those of alveolar air and humidified atmospheric air. Terminal bronchiole Respiratory bronchiole Atrium Alveolar duct Alveoli Diffusion of Gases Through the Respiratory Membrane Alveolar sacs Respiratory Unit. Figure 39–7 shows the respiratory unit (also called “respiratory lobule”), which is composed of a respiratory bronchiole, alveolar ducts, atria, and alveoli. There are about 300 million alveoli in the two lungs, and each alveolus has an average diameter of about 0.2 millimeter. The alveolar walls are extremely thin, and between the alveoli is an almost solid network of interconnecting capillaries, shown in Figure 39–8. Indeed, because of the extensiveness of the capillary plexus, the flow of blood in the alveolar wall has been described as a “sheet” of flowing blood. Thus, it is obvious that the alveolar gases are in very close proximity to the blood of the pulmonary capillaries. Further, gas exchange between the alveolar air Figure 39–7 Respiratory unit. (Redrawn from Miller WS: The Lung. Springfield, Ill: Charles C Thomas, 1947.) and the pulmonary blood occurs through the membranes of all the terminal portions of the lungs, not merely in the alveoli themselves. All these membranes are collectively known as the respiratory membrane, also called the pulmonary membrane. Chapter 39 Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide 497 Epithelial basement Alveolar epithelium membrane Fluid and surfactant layer Alveolus Capillary Diffusion Oxygen Diffusion Carbon dioxide A Alveolus Alveolus Red blood cell Interstitial space Capillaries Lymphatic vessel Alveolus Interstitial space Capillary endothelium Capillary basement membrane Figure 39–9 Vein Artery Perivascular interstitial space Alveolus B Figure 39–8 A, Surface view of capillaries in an alveolar wall. B, Cross-sectional view of alveolar walls and their vascular supply. (A, From Maloney JE, Castle BL: Pressure-diameter relations of capillaries and small blood vessels in frog lung. Respir Physiol 7:150, 1969. Reproduced by permission of ASP Biological and Medical Press, North-Holland Division.) Respiratory Membrane. Figure 39–9 shows the ultrastructure of the respiratory membrane drawn in cross section on the left and a red blood cell on the right. It also shows the diffusion of oxygen from the alveolus into the red blood cell and diffusion of carbon dioxide in the opposite direction. Note the following different layers of the respiratory membrane: 1. A layer of fluid lining the alveolus and containing surfactant that reduces the surface tension of the alveolar fluid 2. The alveolar epithelium composed of thin epithelial cells 3. An epithelial basement membrane 4. A thin interstitial space between the alveolar epithelium and the capillary membrane Ultrastructure of the alveolar respiratory membrane, shown in cross section. 5. A capillary basement membrane that in many places fuses with the alveolar epithelial basement membrane 6. The capillary endothelial membrane Despite the large number of layers, the overall thickness of the respiratory membrane in some areas is as little as 0.2 micrometer, and it averages about 0.6 micrometer, except where there are cell nuclei. From histological studies, it has been estimated that the total surface area of the respiratory membrane is about 70 square meters in the normal adult human male. This is equivalent to the floor area of a 25–by-30–foot room. The total quantity of blood in the capillaries of the lungs at any given instant is 60 to 140 milliliters. Now imagine this small amount of blood spread over the entire surface of a 25–by-30–foot floor, and it is easy to understand the rapidity of the respiratory exchange of oxygen and carbon dioxide. The average diameter of the pulmonary capillaries is only about 5 micrometers, which means that red blood cells must squeeze through them. The red blood cell membrane usually touches the capillary wall, so that oxygen and carbon dioxide need not pass through significant amounts of plasma as they diffuse between the alveolus and the red cell. This, too, increases the rapidity of diffusion. 498 Unit VII Factors That Affect the Rate of Gas Diffusion Through the Respiratory Membrane Referring to the earlier discussion of diffusion of gases in water, one can apply the same principles and mathematical formulas to diffusion of gases through the respiratory membrane. Thus, the factors that determine how rapidly a gas will pass through the membrane are (1) the thickness of the membrane, (2) the surface area of the membrane, (3) the diffusion coefficient of the gas in the substance of the membrane, and (4) the partial pressure difference of the gas between the two sides of the membrane. The thickness of the respiratory membrane occasionally increases—for instance, as a result of edema fluid in the interstitial space of the membrane and in the alveoli—so that the respiratory gases must then diffuse not only through the membrane but also through this fluid. Also, some pulmonary diseases cause fibrosis of the lungs, which can increase the thickness of some portions of the respiratory membrane. Because the rate of diffusion through the membrane is inversely proportional to the thickness of the membrane, any factor that increases the thickness to more than two to three times normal can interfere significantly with normal respiratory exchange of gases. The surface area of the respiratory membrane can be greatly decreased by many conditions. For instance, removal of an entire lung decreases the total surface area to one half normal. Also, in emphysema, many of the alveoli coalesce, with dissolution of many alveolar walls. Therefore, the new alveolar chambers are much larger than the original alveoli, but the total surface area of the respiratory membrane is often decreased as much as fivefold because of loss of the alveolar walls. When the total surface area is decreased to about one third to one fourth normal, exchange of gases through the membrane is impeded to a significant degree, even under resting conditions, and during competitive sports and other strenuous exercise, even the slightest decrease in surface area of the lungs can be a serious detriment to respiratory exchange of gases. The diffusion coefficient for transfer of each gas through the respiratory membrane depends on the gas’s solubility in the membrane and, inversely, on the square root of the gas’s molecular weight. The rate of diffusion in the respiratory membrane is almost exactly the same as that in water, for reasons explained earlier. Therefore, for a given pressure difference, carbon dioxide diffuses about 20 times as rapidly as oxygen. Oxygen diffuses about twice as rapidly as nitrogen. The pressure difference across the respiratory membrane is the difference between the partial pressure of the gas in the alveoli and the partial pressure of the gas in the pulmonary capillary blood. The partial pressure represents a measure of the total number of molecules of a particular gas striking a unit area of the alveolar surface of the membrane in unit time, and the Respiration pressure of the gas in the blood represents the number of molecules that attempt to escape from the blood in the opposite direction. Therefore, the difference between these two pressures is a measure of the net tendency for the gas molecules to move through the membrane. When the partial pressure of a gas in the alveoli is greater than the pressure of the gas in the blood, as is true for oxygen, net diffusion from the alveoli into the blood occurs; when the pressure of the gas in the blood is greater than the partial pressure in the alveoli, as is true for carbon dioxide, net diffusion from the blood into the alveoli occurs. Diffusing Capacity of the Respiratory Membrane The ability of the respiratory membrane to exchange a gas between the alveoli and the pulmonary blood is expressed in quantitative terms by the respiratory membrane’s diffusing capacity, which is defined as the volume of a gas that will diffuse through the membrane each minute for a partial pressure difference of 1 mm Hg. All the factors discussed earlier that affect diffusion through the respiratory membrane can affect this diffusing capacity. Diffusing Capacity for Oxygen. In the average young man, the diffusing capacity for oxygen under resting conditions averages 21 ml/min/mm Hg. In functional terms, what does this mean? The mean oxygen pressure difference across the respiratory membrane during normal, quiet breathing is about 11 mm Hg. Multiplication of this pressure by the diffusing capacity (11 ¥ 21) gives a total of about 230 milliliters of oxygen diffusing through the respiratory membrane each minute; this is equal to the rate at which the resting body uses oxygen. Change in Oxygen Diffusing Capacity During Exercise. During strenuous exercise or other conditions that greatly increase pulmonary blood flow and alveolar ventilation, the diffusing capacity for oxygen increases in young men to a maximum of about 65 ml/min/ mm Hg, which is three times the diffusing capacity under resting conditions. This increase is caused by several factors, among which are (1) opening up of many previously dormant pulmonary capillaries or extra dilation of already open capillaries, thereby increasing the surface area of the blood into which the oxygen can diffuse; and (2) a better match between the ventilation of the alveoli and the perfusion of the alveolar capillaries with blood, called the ventilationperfusion ratio, which is explained in detail later in this chapter. Therefore, during exercise, oxygenation of the blood is increased not only by increased alveolar ventilation but also by greater diffusing capacity of the respiratory membrane for transporting oxygen into the blood. Diffusing Capacity for Carbon Dioxide. The diffusing capacity for carbon dioxide has never been measured Chapter 39 Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide because of the following technical difficulty: Carbon dioxide diffuses through the respiratory membrane so rapidly that the average Pco2 in the pulmonary blood is not far different from the Pco2 in the alveoli—the average difference is less than 1 mm Hg—and with the available techniques, this difference is too small to be measured. Nevertheless, measurements of diffusion of other gases have shown that the diffusing capacity varies directly with the diffusion coefficient of the particular gas. Because the diffusion coefficient of carbon dioxide is slightly more than 20 times that of oxygen, one would expect a diffusing capacity for carbon dioxide under resting conditions of about 400 to 450 ml/min/ mm Hg and during exercise of about 1200 to 1300 ml/ min/mm Hg. Figure 39–10 compares the measured or calculated diffusing capacities of carbon monoxide, oxygen, and carbon dioxide at rest and during exercise, showing the extreme diffusing capacity of carbon dioxide and the effect of exercise on the diffusing capacity of each of these gases. Measurement of Diffusing Capacity—The Carbon Monoxide Method. The oxygen diffusing capacity can be calculated from measurements of (1) alveolar Po2, (2) Po2 in the pulmonary capillary blood, and (3) the rate of oxygen uptake by the blood. However, measuring the Po2 in the pulmonary capillary blood is so difficult and so imprecise that it is not practical to measure oxygen diffusing 1300 1200 Resting Exercise Diffusing capacity (ml/min/mm Hg) 1100 1000 900 800 700 600 500 400 300 200 100 0 CO O2 CO2 Figure 39–10 Diffusing capacities for carbon monoxide, oxygen, and carbon dioxide in the normal lungs under resting conditions and during exercise. 499 capacity by such a direct procedure, except on an experimental basis. To obviate the difficulties encountered in measuring oxygen diffusing capacity directly, physiologists usually measure carbon monoxide diffusing capacity instead and then calculate the oxygen diffusing capacity from this. The principle of the carbon monoxide method is the following: A small amount of carbon monoxide is breathed into the alveoli, and the partial pressure of the carbon monoxide in the alveoli is measured from appropriate alveolar air samples. The carbon monoxide pressure in the blood is essentially zero, because hemoglobin combines with this gas so rapidly that its pressure never has time to build up. Therefore, the pressure difference of carbon monoxide across the respiratory membrane is equal to its partial pressure in the alveolar air sample. Then, by measuring the volume of carbon monoxide absorbed in a short period and dividing this by the alveolar carbon monoxide partial pressure, one can determine accurately the carbon monoxide diffusing capacity. To convert carbon monoxide diffusing capacity to oxygen diffusing capacity, the value is multiplied by a factor of 1.23 because the diffusion coefficient for oxygen is 1.23 times that for carbon monoxide. Thus, the average diffusing capacity for carbon monoxide in young men at rest is 17 ml/min/mm Hg, and the diffusing capacity for oxygen is 1.23 times this, or 21 ml/min/mm Hg. Effect of the VentilationPerfusion Ratio on Alveolar Gas Concentration In the early part of this chapter, we learned that two factors determine the Po2 and the Pco2 in the alveoli: (1) the rate of alveolar ventilation and (2) the rate of transfer of oxygen and carbon dioxide through the respiratory membrane. These earlier discussions made the assumption that all the alveoli are ventilated equally and that blood flow through the alveolar capillaries is the same for each alveolus. However, even normally to some extent, and especially in many lung diseases, some areas of the lungs are well ventilated but have almost no blood flow, whereas other areas may have excellent blood flow but little or no ventilation. In either of these conditions, gas exchange through the respiratory membrane is seriously impaired, and the person may suffer severe respiratory distress despite both normal total ventilation and normal total pulmonary blood flow, but with the ventilation and blood flow going to different parts of the lungs. Therefore, a highly quantitative concept has been developed to help us understand respiratory exchange when there is imbalance between alveolar ventilation and alveolar blood flow. This concept is called the ventilation-perfusion ratio. In quantitative. terms, the ventilation-perfusion ratio . . is expressed as Va/Q. When Va (alveolar ventilation) is . normal for a given alveolus and Q (blood flow) is also normal. for. the same alveolus, the ventilation-perfusion ratio (Va/Q . ) is also said to be normal. When the . ventilation (Va) is zero, . . yet there is still perfusion (Q) of the alveolus, the Va/Q is zero. Or, at the . other extreme, when there is adequate . . .ventilation (Va) but zero perfusion (Q), the ratio Va/Q is infinity. At a ratio of either zero or infinity, there is no exchange of gases through the respiratory membrane of the affected alveoli, which 500 Unit VII Respiration explains the importance of this concept. Therefore, let us explain the respiratory consequences of these two extremes. any alveolar ventilation—the air in the alveolus comes to equilibrium with the blood oxygen and carbon dioxide because these gases diffuse between the blood and the alveolar air. Because the blood that perfuses the capillaries is venous blood returning to the lungs from the systemic circulation, it is the gases in this blood with which the alveolar gases equilibrate. In Chapter 40, we will learn that the normal venous blood (v̄) has a Po2 of 40 mm Hg and a Pco2 of 45 mm Hg. Therefore, these are also the normal partial pressures of these two gases in alveoli that have blood flow but no ventilation. . . Alveolar Oxygen and Carbon Dioxide Partial Pressures When VA/Q Equals Infinity. .The. effect on the alveolar gas partial pres- sures when Va/Q equals is entirely different . infinity . from the effect when Va/Q equals zero because now there is no capillary blood flow to carry oxygen away or to bring carbon dioxide to the alveoli. Therefore, instead of the alveolar gases coming to equilibrium with the venous blood, the alveolar air becomes equal to the humidified inspired air. That is, the air that is inspired loses no oxygen to the blood and gains no carbon dioxide from the blood. And because normal inspired and humidified air has a Po2 of 149 mm Hg and a Pco2 of 0 mm Hg, these will be the partial pressures of these two gases in the alveoli. . . Gas Exchange and Alveolar Partial Pressures When VA/Q Is Normal. When there is both normal alveolar ventilation and normal alveolar capillary blood flow (normal alveolar perfusion), exchange of oxygen and carbon dioxide through the respiratory membrane is nearly optimal, and alveolar Po2 is normally at a level of 104 mm Hg, which lies between that of the inspired air (149 mm Hg) and that of venous blood (40 mm Hg). Likewise, alveolar Pco2 lies between two extremes; it is normally 40 mm Hg, in contrast to 45 mm Hg in venous blood and 0 mm Hg in inspired air. Thus, under normal conditions, the alveolar air Po2 averages 104 mm Hg and the Pco2 averages 40 mm Hg. . . PO2-PCO2, VA/Q Diagram The concepts presented in the preceding sections can be shown in graphical form, as in Figure . demonstrated . 39–11, called the Po2-Pco2, Va/Q diagram. The curve in the diagram represents all possible . Po . 2 and Pco2 combinations between the limits of Va/Q equals zero and . . Va/Q equals infinity when the gas pressures in the venous blood are normal and the person is breathing air at sea-level pressure. Thus, point v̄ is the plot of Po2 . . and Pco2 when Va/Q equals zero. At this point, the Po2 is 40 mm Hg and the Pco2 is 45 mm Hg, which are the values in normal venous blood. . . At the other end of the curve, when Va/Q equals infinity, point I represents inspired air, showing Po2 to be 149 mm Hg while Pco2 is zero. Also plotted on the curve is. the . point that represents normal alveolar air when Va/Q is normal. At this point, Po2 is 104 mm Hg and Pco2 is 40 mm Hg. 50 v VA /Q = 0 VA /Q = Normal (PO2 = 40) (PCO2 = 45) 40 PCO2 (mm Hg) . . Alveolar Oxygen and Carbon . . Dioxide Partial Pressures When VA/Q Equals Zero. When Va/Q is equal to zero—that is, without Normal alveolar air (PO2 = 104) (PCO2 = 40) 30 20 10 (PO2 = 149) (PCO2 = 0) I 0 20 40 VA /Q = ∞ 60 80 100 120 140 160 PO2 (mm Hg) Figure 39–11 . . Normal PO2-PCO2, VA/Q diagram. Concept. of. “Physiologic Shunt” (When VA/Q Is Below Normal) . . Whenever Va/Q is below normal, there is inadequate ventilation to provide the oxygen needed to fully oxygenate the blood flowing through the alveolar capillaries. Therefore, a certain fraction of the venous blood passing through the pulmonary capillaries does not become oxygenated. This fraction is called shunted blood. Also, some additional blood flows through bronchial vessels rather than through alveolar capillaries, normally about 2 per cent of the cardiac output; this, too, is unoxygenated, shunted blood. The total quantitative amount of shunted blood per minute is called the physiologic shunt. This physiologic shunt is measured in clinical pulmonary function laboratories by analyzing the concentration of oxygen in both mixed venous blood and arterial blood, along with simultaneous measurement of cardiac output. From these values, the physiologic shunt can be calculated by the following equation: . Q ps Ci O2 - CaO2 . = . Qt Ci O2 - C v O2 . in which . Qps is the physiologic shunt blood flow per minute, Qt is cardiac output per minute, CiO is the concentration of oxygen in the arterial blood if there is an “ideal” ventilation-perfusion ratio, CaO is the measured concentration of oxygen in the arterial blood, and Cv̄O is the measured concentration of oxygen in the mixed venous blood. The greater the physiologic shunt, the greater the amount of blood that fails to be oxygenated as it passes through the lungs. 2 2 2 Concept of the .“Physiologic Dead . Space” (When VA/Q Is Greater Than Normal) When ventilation of some of the alveoli is great but alveolar blood flow is low, there is far more available oxygen in the alveoli than can be transported away from Chapter 39 Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide the alveoli by the flowing blood. Thus, the ventilation of these alveoli is said to be wasted. The ventilation of the anatomical dead space areas of the respiratory passageways is also wasted. The sum of these two types of wasted ventilation is called the physiologic dead space. This is measured in the clinical pulmonary function laboratory by making appropriate blood and expiratory gas measurements and using the following equation, called the Bohr equation: Vdphys PaCO2 - Pe CO2 = , Vt PaCO2 in which Vdphys is the physiologic dead space, Vt is the tidal volume, PaCO is the partial pressure of carbon dioxide in the arterial blood, and Pe CO2 is the average partial pressure of carbon dioxide in the entire expired air. When the physiologic dead space is great, much of the work of ventilation is wasted effort because so much of the ventilating air never reaches the blood. 2 Abnormalities of VentilationPerfusion Ratio . . Abnormal VA/Q in the Upper and Lower Normal Lung. In a normal person in the upright position, both pulmonary capillary blood flow and alveolar ventilation are considerably less in the upper part of the lung than in the lower part; however, blood flow is decreased considerably more. than . ventilation is. Therefore, at the top of the lung, Va/Q is as much as 2.5 times as great as the ideal value, which causes a moderate degree of physiologic dead space in this area of the lung. At the other extreme, in the bottom of the lung, there is slightly . . too little ventilation in relation to blood flow, with Va/Q as low as 0.6 times the ideal value. In this area, a small fraction of the blood fails to become normally oxygenated, and this represents a physiologic shunt. In both extremes, inequalities of ventilation and perfusion decrease slightly the lung’s effectiveness for exchanging oxygen and carbon dioxide. However, during exercise, blood flow to the upper part of the lung increases markedly, so that far less physiologic dead space occurs, and the effectiveness of gas exchange now approaches optimum. . . Abnormal VA/Q in Chronic Obstructive Lung Disease. Most people who smoke for many years develop various degrees of bronchial obstruction; in a large share of these persons, this condition eventually becomes so severe that they develop serious alveolar air trapping and resultant emphysema. The emphysema in turn causes many of the alveolar walls to be destroyed. Thus, 501 two . .abnormalities occur in smokers to cause abnormal Va/Q. First, because many of the small bronchioles are obstructed, the alveoli beyond the obstructions are . . unventilated, causing a Va/Q that approaches zero. Second, in those areas of the lung where the alveolar walls have been mainly destroyed but there is still alveolar ventilation, most of the ventilation is wasted because of inadequate blood flow to transport the blood gases. Thus, in chronic obstructive lung disease, some areas of the lung exhibit serious physiologic shunt, and other areas exhibit serious physiologic dead space. Both these conditions tremendously decrease the effectiveness of the lungs as gas exchange organs, sometimes reducing their effectiveness to as little as one tenth normal. In fact, this is the most prevalent cause of pulmonary disability today. References Albert R, Spiro S, Jett J: Comprehensive Respiratory Medicine. Philadelphia: Mosby, 2002. Cole RP: CO2 and lung mechanical or gas exchange function. Crit Care Med 32:1240, 2004. Guazzi M: Alveolar-capillary membrane dysfunction in heart failure: evidence of a pathophysiologic role. Chest 124:1090, 2003. Hsia CC: Recruitment of lung diffusing capacity: update of concept and application. Chest 122:1774, 2002. Knight DA, Holgate ST: The airway epithelium: structural and functional properties in health and disease. Respirology 8:432, 2003. Otis AB: Quantitative relationships in steady-state gas exchange. In: Fenn WQ, Rahn H (eds): Handbook of Physiology. Sec 3, Vol 1. Baltimore: Williams & Wilkins, 1964, p 681. Parker JC,Townsley MI: Evaluation of lung injury in rats and mice. Am J Physiol Lung Cell Mol Physiol 286:L231, 2004. Powell FL, Hopkins SR: Comparative physiology of lung complexity: implications for gas exchange. News Physiol Sci 19:55, 2004. Rahn H, Farhi EE: Ventilation, perfusion, and gas exchange—the Va/Q concept. In: Fenn WO, Rahn H (eds): Handbook of Physiology. Sec 3, Vol 1. Baltimore: Williams & Wilkins, 1964, p 125. Uhlig S, Taylor AE: Methods in Pulmonary Research. Basel: Birkhauser Verlag, 1998. West JB: Pulmonary Physiology and Pathophysiology: An Integrated, Case-Based Approach. Philadelphia: Lippincott Williams & Wilkins, 2001. West JB: Pulmonary Physiology—The Essentials. Baltimore: Lippincott Williams & Wilkins, 2003. Williams MC:Alveolar type I cells: molecular phenotype and development. Annu Rev Physiol 65:669, 2003. C H A P T E R 4 0 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids Once oxygen has diffused from the alveoli into the pulmonary blood, it is transported to the peripheral tissue capillaries almost entirely in combination with hemoglobin. The presence of hemoglobin in the red blood cells allows the blood to transport 30 to 100 times as much oxygen as could be transported in the form of dissolved oxygen in the water of the blood. In the body’s tissue cells, oxygen reacts with various foodstuffs to form large quantities of carbon dioxide. This carbon dioxide enters the tissue capillaries and is transported back to the lungs. Carbon dioxide, like oxygen, also combines with chemical substances in the blood that increase carbon dioxide transport 15- to 20-fold. The purpose of this chapter is to present both qualitatively and quantitatively the physical and chemical principles of oxygen and carbon dioxide transport in the blood and tissue fluids. Transport of Oxygen from the Lungs to the Body Tissues In Chapter 39, we pointed out that gases can move from one point to another by diffusion and that the cause of this movement is always a partial pressure difference from the first point to the next. Thus, oxygen diffuses from the alveoli into the pulmonary capillary blood because the oxygen partial pressure (Po2) in the alveoli is greater than the Po2 in the pulmonary capillary blood. In the other tissues of the body, a higher Po2 in the capillary blood than in the tissues causes oxygen to diffuse into the surrounding cells. Conversely, when oxygen is metabolized in the cells to form carbon dioxide, the intracellular carbon dioxide pressure (Pco2) rises to a high value, which causes carbon dioxide to diffuse into the tissue capillaries. After blood flows to the lungs, the carbon dioxide diffuses out of the blood into the alveoli, because the Pco2 in the pulmonary capillary blood is greater than that in the alveoli. Thus, the transport of oxygen and carbon dioxide by the blood depends on both diffusion and the flow of blood. We now consider quantitatively the factors responsible for these effects. Diffusion of Oxygen from the Alveoli to the Pulmonary Capillary Blood The top part of Figure 40–1 shows a pulmonary alveolus adjacent to a pulmonary capillary, demonstrating diffusion of oxygen molecules between the alveolar air and the pulmonary blood. The Po2 of the gaseous oxygen in the alveolus averages 104 mm Hg, whereas the Po2 of the venous blood entering the pulmonary capillary at its arterial end averages only 40 mm Hg because a large amount of oxygen was removed from this blood as it passed through the peripheral tissues. Therefore, the initial pressure difference that causes oxygen to diffuse into the pulmonary capillary is 104 – 40, or 64 mm Hg. In the graph at 502 Chapter 40 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids Mixed with pulmonary shunt blood Alveolus PO2 = 104 mm Hg 100 Pulmonary Capillary PO2 = 104 mm Hg PO2 = 40 mm Hg Arterial End Venous End Alveolar oxygen partial pressure Systemic venous blood 60 Pulmonary Systemic capillaries arterial blood Systemic Systemic capillaries venous blood 40 O 2 90 80 70 Blo od P Blood PO2 (mm Hg) 100 PO2 110 80 503 20 0 60 50 40 Figure 40–2 Changes in PO2 in the pulmonary capillary blood, systemic arterial blood, and systemic capillary blood, demonstrating the effect of “venous admixture.” Figure 40–1 Uptake of oxygen by the pulmonary capillary blood. (The curve in this figure was constructed from data in Milhorn HT Jr, Pulley PE Jr: A theoretical study of pulmonary capillary gas exchange and venous admixture. Biophys J 8:337, 1968.) Therefore, during exercise, even with a shortened time of exposure in the capillaries, the blood can still become fully oxygenated, or nearly so. Transport of Oxygen in the Arterial Blood the bottom of the figure, the curve shows the rapid rise in blood Po2 as the blood passes through the capillary; the blood Po2 rises almost to that of the alveolar air by the time the blood has moved a third of the distance through the capillary, becoming almost 104 mm Hg. Uptake of Oxygen by the Pulmonary Blood During Exercise. During strenuous exercise, a person’s body may require as much as 20 times the normal amount of oxygen. Also, because of increased cardiac output during exercise, the time that the blood remains in the pulmonary capillary may be reduced to less than one half normal. Yet, because of the great safety factor for diffusion of oxygen through the pulmonary membrane, the blood still becomes almost saturated with oxygen by the time it leaves the pulmonary capillaries. This can be explained as follows. First, it was pointed out in Chapter 39 that the diffusing capacity for oxygen increases almost threefold during exercise; this results mainly from increased surface area of capillaries participating in the diffusion and also from a more nearly ideal ventilation-perfusion ratio in the upper part of the lungs. Second, note in the curve of Figure 40–1 that under nonexercising conditions, the blood becomes almost saturated with oxygen by the time it has passed through one third of the pulmonary capillary, and little additional oxygen normally enters the blood during the latter two thirds of its transit. That is, the blood normally stays in the lung capillaries about three times as long as necessary to cause full oxygenation. About 98 per cent of the blood that enters the left atrium from the lungs has just passed through the alveolar capillaries and has become oxygenated up to a Po2 of about 104 mm Hg. Another 2 per cent of the blood has passed from the aorta through the bronchial circulation, which supplies mainly the deep tissues of the lungs and is not exposed to lung air. This blood flow is called “shunt flow,” meaning that blood is shunted past the gas exchange areas. On leaving the lungs, the Po2 of the shunt blood is about that of normal systemic venous blood, about 40 mm Hg. When this blood combines in the pulmonary veins with the oxygenated blood from the alveolar capillaries, this so-called venous admixture of blood causes the Po2 of the blood entering the left heart and pumped into the aorta to fall to about 95 mm Hg. These changes in blood Po2 at different points in the circulatory system are shown in Figure 40–2. Diffusion of Oxygen from the Peripheral Capillaries into the Tissue Fluid When the arterial blood reaches the peripheral tissues, its Po2 in the capillaries is still 95 mm Hg.Yet, as shown in Figure 40–3, the Po2 in the interstitial fluid that surrounds the tissue cells averages only 40 mm Hg. Thus, there is a tremendous initial pressure difference that causes oxygen to diffuse rapidly from the capillary 504 Unit VII Arterial end of capillary Venous end of capillary 40 mm Hg PO2 = 95 mm Hg PO2 = 40 mm Hg 23 mm Hg Figure 40–3 Diffusion of oxygen from a tissue capillary to the cells. (PO2 in interstitial fluid = 40 mm Hg, and in tissue cells = 23 mm Hg.) Upper limit of infinite blood flow 80 p ti o n sum con nor ma l O2 1/ 4 60 No rm Interstitial fluid PO2 (mm Hg) 100 40 O al A 4 2 s co n ump tion al O 2 orm n ¥ B ption sum con 20 C 0 0 100 200 300 400 500 600 Blood flow (per cent of normal) 700 Figure 40–4 Effect of blood flow and rate of oxygen consumption on tissue PO2. blood into the tissues—so rapidly that the capillary Po2 falls almost to equal the 40 mm Hg pressure in the interstitium. Therefore, the Po2 of the blood leaving the tissue capillaries and entering the systemic veins is also about 40 mm Hg. Effect of Rate of Blood Flow on Interstitial Fluid PO2. If the blood flow through a particular tissue is increased, greater quantities of oxygen are transported into the tissue, and the tissue Po2 becomes correspondingly higher. This is shown in Figure 40–4. Note that an increase in flow to 400 per cent of normal increases the Po2 from 40 mm Hg (at point A in the figure) to 66 mm Hg (at point B). However, the upper limit to which the Po2 can rise, even with maximal blood flow, is 95 mm Hg, because this is the oxygen pressure in the arterial blood. Conversely, if blood flow through the tissue decreases, the tissue Po2 also decreases, as shown at point C. Effect of Rate of Tissue Metabolism on Interstitial Fluid PO2. If the cells use more oxygen for metabolism than normally, this reduces the interstitial fluid Po2. Figure 40–4 also demonstrates this effect, showing reduced interstitial fluid Po2 when the cellular oxygen consumption is increased, and increased Po2 when consumption is decreased. Respiration In summary, tissue Po2 is determined by a balance between (1) the rate of oxygen transport to the tissues in the blood and (2) the rate at which the oxygen is used by the tissues. Diffusion of Oxygen from the Peripheral Capillaries to the Tissue Cells Oxygen is always being used by the cells. Therefore, the intracellular Po2 in the peripheral tissue cells remains lower than the Po2 in the peripheral capillaries. Also, in many instances, there is considerable physical distance between the capillaries and the cells. Therefore, the normal intracellular Po2 ranges from as low as 5 mm Hg to as high as 40 mm Hg, averaging (by direct measurement in lower animals) 23 mm Hg. Because only 1 to 3 mm Hg of oxygen pressure is normally required for full support of the chemical processes that use oxygen in the cell, one can see that even this low intracellular Po2 of 23 mm Hg is more than adequate and provides a large safety factor. Diffusion of Carbon Dioxide from the Peripheral Tissue Cells into the Capillaries and from the Pulmonary Capillaries into the Alveoli When oxygen is used by the cells, virtually all of it becomes carbon dioxide, and this increases the intracellular Pco2; because of this high tissue cell Pco2, carbon dioxide diffuses from the cells into the tissue capillaries and is then carried by the blood to the lungs. In the lungs, it diffuses from the pulmonary capillaries into the alveoli and is expired. Thus, at each point in the gas transport chain, carbon dioxide diffuses in the direction exactly opposite to the diffusion of oxygen. Yet there is one major difference between diffusion of carbon dioxide and of oxygen: carbon dioxide can diffuse about 20 times as rapidly as oxygen. Therefore, the pressure differences required to cause carbon dioxide diffusion are, in each instance, far less than the pressure differences required to cause oxygen diffusion. The CO2 pressures are approximately the following: 1. Intracellular Pco2, 46 mm Hg; interstitial Pco2, 45 mm Hg. Thus, there is only a 1 mm Hg pressure differential, as shown in Figure 40–5. 2. Pco2 of the arterial blood entering the tissues, 40 mm Hg; Pco2 of the venous blood leaving the tissues, 45 mm Hg. Thus, as shown in Figure 40–5, the tissue capillary blood comes almost exactly to equilibrium with the interstitial Pco2 of 45 mm Hg. 3. Pco2 of the blood entering the pulmonary capillaries at the arterial end, 45 mm Hg; Pco2 of the alveolar air, 40 mm Hg. Thus, only a 5 mm Hg pressure difference causes all the required carbon dioxide diffusion out of the pulmonary capillaries Arterial end of capillary PCO2 = 40 mm Hg Venous end of capillary 45 mm Hg 46 mm Hg 505 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids 120 PCO2 = 45 mm Hg Interstitial fluid PCO2 (mm Hg) Chapter 40 100 Figure 40–5 Uptake of carbon dioxide by the blood in the tissue capillaries. (PCO2 in tissue cells = 46 mm Hg, and in interstitial fluid = 45 mm Hg.) Alveolus PCO2 = 40 mm Hg 80 10⫻ normal metabolism B 60 A Normal metabolism 40 1/4 Lower limit of infinite blood flow normal metabolism C 20 0 0 Pulmonary Capillary PCO2 = 40 mm Hg PCO2 = 45 mm Hg Arterial End Venous End 100 200 300 400 500 Blood flow (per cent of normal) 600 Blood PCO2 (mm Hg) 45 Figure 40–7 44 Effect of blood flow and metabolic rate on peripheral tissue PCO2. 43 42 41 Pulmonary capillary blood 40 Alveolar carbon dioxide partial pressure Figure 40–6 Diffusion of carbon dioxide from the pulmonary blood into the alveolus. (This curve was constructed from data in Milhorn HT Jr, Pulley PE Jr: A theoretical study of pulmonary capillary gas exchange and venous admixture. Biophys J 8:337, 1968.) Pco2 from the normal value of 45 mm Hg to 41 mm Hg, down to a level almost equal to the Pco2 in the arterial blood (40 mm Hg) entering the tissue capillaries. 2. Note also that a 10-fold increase in tissue metabolic rate greatly elevates the interstitial fluid Pco2 at all rates of blood flow, whereas decreasing the metabolism to one quarter normal causes the interstitial fluid Pco2 to fall to about 41 mm Hg, closely approaching that of the arterial blood, 40 mm Hg. Role of Hemoglobin in Oxygen Transport into the alveoli. Furthermore, as shown in Figure 40–6, the Pco2 of the pulmonary capillary blood falls to almost exactly equal the alveolar Pco2 of 40 mm Hg before it has passed more than about one third the distance through the capillaries. This is the same effect that was observed earlier for oxygen diffusion, except that it is in the opposite direction. Effect of Rate of Tissue Metabolism and Tissue Blood Flow on Interstitial PCO2. Tissue capillary blood flow and tissue metabolism affect the Pco2 in ways exactly opposite to their effect on tissue Po2. Figure 40–7 shows these effects, as follows: 1. A decrease in blood flow from normal (point A) to one quarter normal (point B) increases peripheral tissue Pco2 from the normal value of 45 mm Hg to an elevated level of 60 mm Hg. Conversely, increasing the blood flow to six times normal (point C) decreases the interstitial Normally, about 97 per cent of the oxygen transported from the lungs to the tissues is carried in chemical combination with hemoglobin in the red blood cells. The remaining 3 per cent is transported in the dissolved state in the water of the plasma and blood cells. Thus, under normal conditions, oxygen is carried to the tissues almost entirely by hemoglobin. Reversible Combination of Oxygen with Hemoglobin The chemistry of hemoglobin is presented in Chapter 32, where it was pointed out that the oxygen molecule combines loosely and reversibly with the heme portion of hemoglobin. When Po2 is high, as in the pulmonary capillaries, oxygen binds with the hemoglobin, but when Po2 is low, as in the tissue capillaries, oxygen is released from the hemoglobin. This is the basis for 506 Unit VII Respiration 20 Hemoglobin saturation (%) 90 Oxygenated blood leaving the lungs 80 18 16 70 14 60 12 10 50 Reduced blood returning from tissues 40 8 30 6 20 4 10 2 Volumes (%) 100 0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 Pressure of oxygen in blood (PO2) (mm Hg) Figure 40–8 Oxygen-hemoglobin dissociation curve. O2 wi und bo oglobin th hem Normal arterial blood 20 18 16 14 12 10 8 6 4 2 0 Normal venous blood the oxygen-hemoglobin dissociation curve, which demonstrates a progressive increase in the percentage of hemoglobin bound with oxygen as blood Po2 increases, which is called the per cent saturation of hemoglobin. Because the blood leaving the lungs and entering the systemic arteries usually has a Po2 of about 95 mm Hg, one can see from the dissociation curve that the usual oxygen saturation of systemic arterial blood averages 97 per cent. Conversely, in normal venous blood returning from the peripheral tissues, the Po2 is about 40 mm Hg, and the saturation of hemoglobin averages 75 per cent. Venous blood in exercise Oxygen-Hemoglobin Dissociation Curve. Figure 40–8 shows Oxygen in blood (volumes %) almost all oxygen transport from the lungs to the tissues. 20 40 0 60 80 100 120 140 Pressure of oxygen in blood (PO2) (mm Hg) Maximum Amount of Oxygen That Can Combine with the Hemoglobin of the Blood. The blood of a normal person contains about 15 grams of hemoglobin in each 100 milliliters of blood, and each gram of hemoglobin can bind with a maximum of 1.34 milliliters of oxygen (1.39 milliliters when the hemoglobin is chemically pure, but impurities such as methemoglobin reduce this). Therefore, 15 times 1.34 equals 20.1, which means that, on average, the 15 grams of hemoglobin in 100 milliliters of blood can combine with a total of almost exactly 20 milliliters of oxygen if the hemoglobin is 100 per cent saturated. This is usually expressed as 20 volumes per cent. The oxygen-hemoglobin dissociation curve for the normal person can also be expressed in terms of volume per cent of oxygen, as shown by the far right scale in Figure 40–8, instead of per cent saturation of hemoglobin. Amount of Oxygen Released from the Hemoglobin When Systemic Arterial Blood Flows Through the Tissues. The total quantity of oxygen bound with hemoglobin in normal Figure 40–9 Effect of blood PO2 on the quantity of oxygen bound with hemoglobin in each 100 milliliters of blood. systemic arterial blood, which is 97 per cent saturated, is about 19.4 milliliters per 100 milliliters of blood. This is shown in Figure 40–9. On passing through the tissue capillaries, this amount is reduced, on average, to 14.4 milliliters (Po2 of 40 mm Hg, 75 per cent saturated hemoglobin). Thus, under normal conditions, about 5 milliliters of oxygen are transported from the lungs to the tissues by each 100 milliliters of blood flow. Transport of Oxygen During Strenuous Exercise. During heavy exercise, the muscle cells use oxygen at a rapid rate, which, in extreme cases, can cause the muscle interstitial fluid Po2 to fall from the normal 40 mm Hg Chapter 40 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids to as low as 15 mm Hg. At this low pressure, only 4.4 milliliters of oxygen remain bound with the hemoglobin in each 100 milliliters of blood, as shown in Figure 40–9. Thus, 19.4 – 4.4, or 15 milliliters, is the quantity of oxygen actually delivered to the tissues by each 100 milliliters of blood flow. Thus, three times as much oxygen as normal is delivered in each volume of blood that passes through the tissues. And keep in mind that the cardiac output can increase to six to seven times normal in well-trained marathon runners. Thus, multiplying the increase in cardiac output (six- to sevenfold) by the increase in oxygen transport in each volume of blood (threefold) gives a 20-fold increase in oxygen transport to the tissues. We see later in the chapter that several other factors facilitate delivery of oxygen into muscles during exercise, so that muscle tissue Po2 often falls very little below normal even during very strenuous exercise. Utilization Coefficient. The percentage of the blood that gives up its oxygen as it passes through the tissue capillaries is called the utilization coefficient. The normal value for this is about 25 per cent, as is evident from the preceding discussion—that is, 25 per cent of the oxygenated hemoglobin gives its oxygen to the tissues. During strenuous exercise, the utilization coefficient in the entire body can increase to 75 to 85 per cent. And in local tissue areas where blood flow is extremely slow or the metabolic rate is very high, utilization coefficients approaching 100 per cent have been recorded—that is, essentially all the oxygen is given to the tissues. Effect of Hemoglobin to “Buffer” the Tissue PO2 Although hemoglobin is necessary for the transport of oxygen to the tissues, it performs another function essential to life. This is its function as a “tissue oxygen buffer” system. That is, the hemoglobin in the blood is mainly responsible for stabilizing the oxygen pressure in the tissues. This can be explained as follows. Role of Hemoglobin in Maintaining Nearly Constant PO2 in the Tissues. Under basal conditions, the tissues require about 5 milliliters of oxygen from each 100 milliliters of blood passing through the tissue capillaries. Referring back to the oxygen-hemoglobin dissociation curve in Figure 40–9, one can see that for the normal 5 milliliters of oxygen to be released per 100 milliliters of blood flow, the Po2 must fall to about 40 mm Hg. Therefore, the tissue Po2 normally cannot rise above this 40 mm Hg level, because if it did, the amount of oxygen needed by the tissues would not be released from the hemoglobin. In this way, the hemoglobin normally sets an upper limit on the oxygen pressure in the tissues at about 40 mm Hg. Conversely, during heavy exercise, extra amounts of oxygen (as much as 20 times normal) must be delivered from the hemoglobin to the tissues. But this can be achieved with little further decrease in tissue Po2 507 because of (1) the steep slope of the dissociation curve and (2) the increase in tissue blood flow caused by the decreased Po2; that is, a very small fall in Po2 causes large amounts of extra oxygen to be released from the hemoglobin. It can be seen, then, that the hemoglobin in the blood automatically delivers oxygen to the tissues at a pressure that is held rather tightly between about 15 and 40 mm Hg. When Atmospheric Oxygen Concentration Changes Markedly, the Buffer Effect of Hemoglobin Still Maintains Almost Constant Tissue PO2. The normal Po2 in the alveoli is about 104 mm Hg, but as one ascends a mountain or ascends in an airplane, the Po2 can easily fall to less than half this amount. Alternatively, when one enters areas of compressed air, such as deep in the sea or in pressurized chambers, the Po2 may rise to 10 times this level. Even so, the tissue Po2 changes little. It can be seen from the oxygen-hemoglobin dissociation curve in Figure 40–8 that when the alveolar Po2 is decreased to as low as 60 mm Hg, the arterial hemoglobin is still 89 per cent saturated with oxygen—only 8 per cent below the normal saturation of 97 per cent. Further, the tissues still remove about 5 milliliters of oxygen from each 100 milliliters of blood passing through the tissues; to remove this oxygen, the Po2 of the venous blood falls to 35 mm Hg—only 5 mm Hg below the normal value of 40 mm Hg. Thus, the tissue Po2 hardly changes, despite the marked fall in alveolar Po2 from 104 to 60 mm Hg. Conversely, when the alveolar Po2 rises as high as 500 mm Hg, the maximum oxygen saturation of hemoglobin can never rise above 100 per cent, which is only 3 per cent above the normal level of 97 per cent. Only a small amount of additional oxygen dissolves in the fluid of the blood, as will be discussed subsequently. Then, when the blood passes through the tissue capillaries and loses several milliliters of oxygen to the tissues, this reduces the Po2 of the capillary blood to a value only a few millimeters greater than the normal 40 mm Hg. Consequently, the level of alveolar oxygen may vary greatly—from 60 to more than 500 mm Hg Po2—and still the Po2 in the peripheral tissues does not vary more than a few millimeters from normal, demonstrating beautifully the tissue “oxygen buffer” function of the blood hemoglobin system. Factors That Shift the OxygenHemoglobin Dissociation Curve— Their Importance for Oxygen Transport The oxygen-hemoglobin dissociation curves of Figures 40–8 and 40–9 are for normal, average blood. However, a number of factors can displace the dissociation curve in one direction or the other in the manner shown in Figure 40–10. This figure shows that when the blood becomes slightly acidic, with the pH decreasing from the normal value of 7.4 to 7.2, the oxygen-hemoglobin dissociation curve shifts, on 508 Unit VII oxygen-hemoglobin dissociation curve to the left and upward. Therefore, the quantity of oxygen that binds with the hemoglobin at any given alveolar Po2 becomes considerably increased, thus allowing greater oxygen transport to the tissues. 100 90 80 pH 70 60 Effect of BPG to Shift the Oxygen-Hemoglobin Dissociation Curve. The normal BPG in the blood keeps the 7.6 7. 7.2 4 Hemoglobin saturation (%) Respiration Shift to right: (1) Increased hydrogen ions (2) Increased CO2 (3) Increased temperature (4) Increased BPG 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100110 120130 140 Pressure of oxygen in blood (PO2) (mm Hg) Figure 40–10 Shift of the oxygen-hemoglobin dissociation curve to the right caused by an increase in hydrogen ion concentration (decrease in pH). BPG, 2,3-biphosphoglycerate. average, about 15 per cent to the right. Conversely, an increase in pH from the normal 7.4 to 7.6 shifts the curve a similar amount to the left. In addition to pH changes, several other factors are known to shift the curve. Three of these, all of which shift the curve to the right, are (1) increased carbon dioxide concentration, (2) increased blood temperature, and (3) increased 2,3-biphosphoglycerate (BPG), a metabolically important phosphate compound present in the blood in different concentrations under different metabolic conditions. Increased Delivery of Oxygen to the Tissues When Carbon Dioxide and Hydrogen Ions Shift the Oxygen-Hemoglobin Dissociation Curve—The Bohr Effect. A shift of the oxygen- hemoglobin dissociation curve to the right in response to increases in blood carbon dioxide and hydrogen ions has a significant effect by enhancing the release of oxygen from the blood in the tissues and enhancing oxygenation of the blood in the lungs. This is called the Bohr effect, which can be explained as follows: As the blood passes through the tissues, carbon dioxide diffuses from the tissue cells into the blood.This increases the blood Po2, which in turn raises the blood H2CO3 (carbonic acid) and the hydrogen ion concentration. These effects shift the oxygen-hemoglobin dissociation curve to the right and downward, as shown in Figure 40–10, forcing oxygen away from the hemoglobin and therefore delivering increased amounts of oxygen to the tissues. Exactly the opposite effects occur in the lungs, where carbon dioxide diffuses from the blood into the alveoli. This reduces the blood Pco2 and decreases the hydrogen ion concentration, shifting the oxygen-hemoglobin dissociation curve shifted slightly to the right all the time. In hypoxic conditions that last longer than a few hours, the quantity of BPG in the blood increases considerably, thus shifting the oxygen-hemoglobin dissociation curve even farther to the right. This causes oxygen to be released to the tissues at as much as 10 mm Hg higher tissue oxygen pressure than would be the case without this increased BPG. Therefore, under some conditions, the BPG mechanism can be important for adaptation to hypoxia, especially to hypoxia caused by poor tissue blood flow. Shift of the Dissociation Curve During Exercise. During exercise, several factors shift the dissociation curve considerably to the right, thus delivering extra amounts of oxygen to the active, exercising muscle fibers. The exercising muscles, in turn, release large quantities of carbon dioxide; this and several other acids released by the muscles increase the hydrogen ion concentration in the muscle capillary blood. In addition, the temperature of the muscle often rises 2° to 3°C, which can increase oxygen delivery to the muscle fibers even more.All these factors act together to shift the oxygenhemoglobin dissociation curve of the muscle capillary blood considerably to the right. This right-hand shift of the curve forces oxygen to be released from the blood hemoglobin to the muscle at Po2 levels as great as 40 mm Hg, even when 70 per cent of the oxygen has already been removed from the hemoglobin. Then, in the lungs, the shift occurs in the opposite direction, allowing the pickup of extra amounts of oxygen from the alveoli. Metabolic Use of Oxygen by the Cells Effect of Intracellular PO2 on Rate of Oxygen Usage. Only a minute level of oxygen pressure is required in the cells for normal intracellular chemical reactions to take place. The reason for this is that the respiratory enzyme systems of the cell, which are discussed in Chapter 67, are geared so that when the cellular Po2 is more than 1 mm Hg, oxygen availability is no longer a limiting factor in the rates of the chemical reactions. Instead, the main limiting factor is the concentration of adenosine diphosphate (ADP) in the cells. This effect is demonstrated in Figure 40–11, which shows the relation between intracellular Po2 and the rate of oxygen usage at different concentrations of ADP. Note that whenever the intracellular Po2 is above 1 mm Hg, the rate of oxygen usage becomes constant for any given concentration of ADP in the cell. Conversely, when the ADP concentration is altered, the rate of Chapter 40 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids oxygen that can be transported to the tissue in each 100 milliliters of blood and (2) the rate of blood flow. If the rate of blood flow falls to zero, the amount of available oxygen also falls to zero. Thus, there are times when the rate of blood flow through a tissue can be so low that tissue Po2 falls below the critical 1 mm Hg required for intracellular metabolism. Under these conditions, the rate of tissue usage of oxygen is blood flow limited. Neither diffusion-limited nor blood flow–limited oxygen states can continue for long, because the cells receive less oxygen than is required to continue the life of the cells. ADP = 11/2 normal 1.5 Rate of oxygen usage (times normal resting level) 509 ADP = Normal resting level 1.0 ADP = 1/2 normal 0.5 Transport of Oxygen in the Dissolved State 0 0 2 3 1 Intracellular PO2 (mm Hg) 4 Figure 40–11 Effect of intracellular adenosine diphosphate (ADP) and PO2 on rate of oxygen usage by the cells. Note that as long as the intracellular PO2 remains above 1 mm Hg, the controlling factor for the rate of oxygen usage is the intracellular concentration of ADP. oxygen usage changes in proportion to the change in ADP concentration. As explained in Chapter 3, when adenosine triphosphate (ATP) is used in the cells to provide energy, it is converted into ADP. The increasing concentration of ADP increases the metabolic usage of oxygen as it combines with the various cell nutrients, releasing energy that reconverts the ADP back to ATP. Under normal operating conditions, the rate of oxygen usage by the cells is controlled ultimately by the rate of energy expenditure within the cells—that is, by the rate at which ADP is formed from ATP. Effect of Diffusion Distance from the Capillary to the Cell on Oxygen Usage. Tissue cells are seldom more than 50 micrometers away from a capillary, and oxygen normally can diffuse readily enough from the capillary to the cell to supply all the required amounts of oxygen for metabolism. However, occasionally, cells are located farther from the capillaries, and the rate of oxygen diffusion to these cells can become so low that intracellular Po2 falls below the critical level required to maintain maximal intracellular metabolism. Thus, under these conditions, oxygen usage by the cells is said to be diffusion limited and is no longer determined by the amount of ADP formed in the cells. But this almost never occurs, except in pathological states. Effect of Blood Flow on Metabolic Use of Oxygen. The total amount of oxygen available each minute for use in any given tissue is determined by (1) the quantity of At the normal arterial Po2 of 95 mm Hg, about 0.29 milliliter of oxygen is dissolved in every 100 milliliters of water in the blood, and when the Po2 of the blood falls to the normal 40 mm Hg in the tissue capillaries, only 0.12 milliliter of oxygen remains dissolved. In other words, 0.17 milliliter of oxygen is normally transported in the dissolved state to the tissues by each 100 milliliters of arterial blood flow. This compares with almost 5 milliliters of oxygen transported by the red cell hemoglobin. Therefore, the amount of oxygen transported to the tissues in the dissolved state is normally slight, only about 3 per cent of the total, as compared with 97 per cent transported by the hemoglobin. During strenuous exercise, when hemoglobin release of oxygen to the tissues increases another threefold, the relative quantity of oxygen transported in the dissolved state falls to as little as 1.5 per cent. But if a person breathes oxygen at very high alveolar Po2 levels, the amount transported in the dissolved state can become much greater, sometimes so much so that a serious excess of oxygen occurs in the tissues, and “oxygen poisoning” ensues. This often leads to brain convulsions and even death, as discussed in detail in Chapter 44 in relation to the high-pressure breathing of oxygen among deep-sea divers. Combination of Hemoglobin with Carbon Monoxide—Displacement of Oxygen Carbon monoxide combines with hemoglobin at the same point on the hemoglobin molecule as does oxygen; it can therefore displace oxygen from the hemoglobin, thereby decreasing the oxygen carrying capacity of blood. Further, it binds with about 250 times as much tenacity as oxygen, which is demonstrated by the carbon monoxide–hemoglobin dissociation curve in Figure 40–12. This curve is almost identical to the oxygenhemoglobin dissociation curve, except that the carbon monoxide partial pressures, shown on the abscissa, are at a level 1/250 of those for the oxygen-hemoglobin dissociation curve of Figure 40–8. Therefore, a carbon monoxide partial pressure of only 0.4 mm Hg in the alveoli, 1/250 that of normal alveolar oxygen (100 mm Hg Po2), allows the carbon monoxide to compete equally with the oxygen for combination with the hemoglobin and causes half the hemoglobin in the blood to become bound with carbon monoxide instead of with oxygen. Therefore, a carbon monoxide pressure of only 510 Unit VII Respiration Capillary Hemoglobin saturation (%) Interstitial fluid Red blood cell 100 90 Cell Hgb • CO2 80 Carbonic Hgb anhydrase + H2CO3 H2O + CO2 70 60 HCO3– + H+ + H2O Hgb Cl 50 40 30 H2O 20 Cl 10 HHgb HCO3– Plasma 0 0.1 0.3 0.4 0 0.2 Gas pressure of carbon monoxide (mm Hg) CO2 CO2 CO2 CO2 transported as: 1. CO2 = 7% 2. Hgb • CO2 = 23% 3. HCO3ⴚ = 70% Figure 40–13 Transport of carbon dioxide in the blood. Figure 40–12 Carbon monoxide–hemoglobin dissociation curve. Note the extremely low carbon monoxide pressures at which carbon monoxide combines with hemoglobin. 0.6 mm Hg (a volume concentration of less than one part per thousand in air) can be lethal. Even though the oxygen content of blood is greatly reduced in carbon monoxide poisoning, the Po2 of the blood may be normal. This makes exposure to carbon monoxide especially dangerous, because the blood is bright red and there are no obvious signs of hypoxemia, such as a bluish color of the fingertips or lips (cyanosis). Also, Po2 is not reduced, and the feedback mechanism that usually stimulates increased respiration rate in response to lack of oxygen (usually reflected by a low Po2) is absent. Because the brain is one of the first organs affected by lack of oxygen, the person may become disoriented and unconscious before becoming aware of the danger. A patient severely poisoned with carbon monoxide can be treated by administering pure oxygen, because oxygen at high alveolar pressure can displace carbon monoxide rapidly from its combination with hemoglobin. The patient can also benefit from simultaneous administration of 5 per cent carbon dioxide, because this strongly stimulates the respiratory center, which increases alveolar ventilation and reduces the alveolar carbon monoxide. With intensive oxygen and carbon dioxide therapy, carbon monoxide can be removed from the blood as much as 10 times as rapidly as without therapy. Transport of Carbon Dioxide in the Blood Transport of carbon dioxide by the blood is not nearly as problematical as transport of oxygen is, because even in the most abnormal conditions, carbon dioxide can usually be transported in far greater quantities than oxygen can be. However, the amount of carbon dioxide in the blood has a lot to do with the acid-base balance of the body fluids, which is discussed in Chapter 30. Under normal resting conditions, an average of 4 milliliters of carbon dioxide is transported from the tissues to the lungs in each 100 milliliters of blood. Chemical Forms in Which Carbon Dioxide Is Transported To begin the process of carbon dioxide transport, carbon dioxide diffuses out of the tissue cells in the dissolved molecular carbon dioxide form. On entering the tissue capillaries, the carbon dioxide initiates a host of almost instantaneous physical and chemical reactions, shown in Figure 40–13, which are essential for carbon dioxide transport. Transport of Carbon Dioxide in the Dissolved State. A small portion of the carbon dioxide is transported in the dissolved state to the lungs. Recall that the Pco2 of venous blood is 45 mm Hg and that of arterial blood is 40 mm Hg. The amount of carbon dioxide dissolved in the fluid of the blood at 45 mm Hg is about 2.7 ml/dl (2.7 volumes per cent). The amount dissolved at 40 mm Hg is about 2.4 milliliters, or a difference of 0.3 milliliter. Therefore, only about 0.3 milliliter of carbon dioxide is transported in the dissolved form by each 100 milliliters of blood flow. This is about 7 per cent of all the carbon dioxide normally transported. Transport of Carbon Dioxide in the Form of Bicarbonate Ion Reaction of Carbon Dioxide with Water in the Red Blood Cells—Effect of Carbonic Anhydrase. The dis- solved carbon dioxide in the blood reacts with water to form carbonic acid. This reaction would occur much too slowly to be of importance were it not for the fact that inside the red blood cells is a protein enzyme called carbonic anhydrase, which catalyzes the Chapter 40 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids reaction between carbon dioxide and water and accelerates its reaction rate about 5000-fold. Therefore, instead of requiring many seconds or minutes to occur, as is true in the plasma, the reaction occurs so rapidly in the red blood cells that it reaches almost complete equilibrium within a very small fraction of a second. This allows tremendous amounts of carbon dioxide to react with the red blood cell water even before the blood leaves the tissue capillaries. Dissociation of Carbonic Acid into Bicarbonate and Hydrogen Ions. In another fraction of a second, the carbonic acid formed in the red cells (H2CO3) dissociates into hydrogen and bicarbonate ions (H+ and HCO3–). Most of the hydrogen ions then combine with the hemoglobin in the red blood cells, because the hemoglobin protein is a powerful acid-base buffer. In turn, many of the bicarbonate ions diffuse from the red cells into the plasma, while chloride ions diffuse into the red cells to take their place. This is made possible by the presence of a special bicarbonate-chloride carrier protein in the red cell membrane that shuttles these two ions in opposite directions at rapid velocities. Thus, the chloride content of venous red blood cells is greater than that of arterial red cells, a phenomenon called the chloride shift. The reversible combination of carbon dioxide with water in the red blood cells under the influence of carbonic anhydrase accounts for about 70 per cent of the carbon dioxide transported from the tissues to the lungs. Thus, this means of transporting carbon dioxide is by far the most important. Indeed, when a carbonic anhydrase inhibitor (acetazolamide) is administered to an animal to block the action of carbonic anhydrase in the red blood cells, carbon dioxide transport from the tissues becomes so poor that the tissue Pco2 can be made to rise to 80 mm Hg instead of the normal 45 mm Hg. dioxide with water inside the red blood cells, it is doubtful that under normal conditions this carbamino mechanism transports more than 20 per cent of the total carbon dioxide. Carbon Dioxide Dissociation Curve The curve shown in Figure 40–14—called the carbon dioxide dissociation curve—depicts the dependence of total blood carbon dioxide in all its forms on Pco2. Note that the normal blood Pco2 ranges between the limits of 40 mm Hg in arterial blood and 45 mm Hg in venous blood, which is a very narrow range. Note also that the normal concentration of carbon dioxide in the blood in all its different forms is about 50 volumes per cent, but only 4 volumes per cent of this is exchanged during normal transport of carbon dioxide from the tissues to the lungs. That is, the concentration rises to about 52 volumes per cent as the blood passes through the tissues and falls to about 48 volumes per cent as it passes through the lungs. When Oxygen Binds with Hemoglobin, Carbon Dioxide Is Released (the Haldane Effect) to Increase CO2 Transport Earlier in the chapter, it was pointed out that an increase in carbon dioxide in the blood causes oxygen to be displaced from the hemoglobin (the Bohr effect), which is an important factor in increasing oxygen transport. The reverse is also true: binding of oxygen with hemoglobin tends to displace carbon dioxide from the blood. Indeed, this effect, called the Haldane effect, is quantitatively far more important in CO2 in blood (volumes per cent) Transport of Carbon Dioxide in Combination with Hemoglobin and Plasma Proteins—Carbaminohemoglobin. In addition to 80 70 60 50 40 30 20 10 Normal operating range reacting with water, carbon dioxide reacts directly with amine radicals of the hemoglobin molecule to form the compound carbaminohemoglobin (CO2Hgb). This combination of carbon dioxide and hemoglobin is a reversible reaction that occurs with a loose bond, so that the carbon dioxide is easily released into the alveoli, where the Pco2 is lower than in the pulmonary capillaries. A small amount of carbon dioxide also reacts in the same way with the plasma proteins in the tissue capillaries. This is much less significant for the transport of carbon dioxide because the quantity of these proteins in the blood is only one fourth as great as the quantity of hemoglobin. The quantity of carbon dioxide that can be carried from the peripheral tissues to the lungs by carbamino combination with hemoglobin and plasma proteins is about 30 per cent of the total quantity transported— that is, normally about 1.5 milliliters of carbon dioxide in each 100 milliliters of blood. However, because this reaction is much slower than the reaction of carbon 511 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Gas pressure of carbon dioxide (mm Hg) Figure 40–14 Carbon dioxide dissociation curve. 512 Unit VII falls to 48 volumes per cent (point B). This represents an additional 2 volumes per cent loss of carbon dioxide. Thus, the Haldane effect approximately doubles the amount of carbon dioxide released from the blood in the lungs and approximately doubles the pickup of carbon dioxide in the tissues. 55 CO2 in blood (volumes per cent) Respiration A PO2 = 40 mm Hg Change in Blood Acidity During Carbon Dioxide Transport 50 PO2 = 100 mm Hg B 45 35 40 45 50 PCO2 Figure 40–15 Portions of the carbon dioxide dissociation curve when the PO2 is 100 mm Hg or 40 mm Hg. The arrow represents the Haldane effect on the transport of carbon dioxide, as discussed in the text. promoting carbon dioxide transport than is the Bohr effect in promoting oxygen transport. The Haldane effect results from the simple fact that the combination of oxygen with hemoglobin in the lungs causes the hemoglobin to become a stronger acid. This displaces carbon dioxide from the blood and into the alveoli in two ways: (1) The more highly acidic hemoglobin has less tendency to combine with carbon dioxide to form carbaminohemoglobin, thus displacing much of the carbon dioxide that is present in the carbamino form from the blood. (2) The increased acidity of the hemoglobin also causes it to release an excess of hydrogen ions, and these bind with bicarbonate ions to form carbonic acid; this then dissociates into water and carbon dioxide, and the carbon dioxide is released from the blood into the alveoli and, finally, into the air. Figure 40–15 demonstrates quantitatively the significance of the Haldane effect on the transport of carbon dioxide from the tissues to the lungs. This figure shows small portions of two carbon dioxide dissociation curves: (1) when the Po2 is 100 mm Hg, which is the case in the blood capillaries of the lungs, and (2) when the Po2 is 40 mm Hg, which is the case in the tissue capillaries. Point A shows that the normal Pco2 of 45 mm Hg in the tissues causes 52 volumes per cent of carbon dioxide to combine with the blood. On entering the lungs, the Pco2 falls to 40 mm Hg and the Po2 rises to 100 mm Hg. If the carbon dioxide dissociation curve did not shift because of the Haldane effect, the carbon dioxide content of the blood would fall only to 50 volumes per cent, which would be a loss of only 2 volumes per cent of carbon dioxide. However, the increase in Po2 in the lungs lowers the carbon dioxide dissociation curve from the top curve to the lower curve of the figure, so that the carbon dioxide content The carbonic acid formed when carbon dioxide enters the blood in the peripheral tissues decreases the blood pH. However, reaction of this acid with the acid-base buffers of the blood prevents the hydrogen ion concentration from rising greatly (and the pH from falling greatly). Ordinarily, arterial blood has a pH of about 7.41, and as the blood acquires carbon dioxide in the tissue capillaries, the pH falls to a venous value of about 7.37. In other words, a pH change of 0.04 unit takes place. The reverse occurs when carbon dioxide is released from the blood in the lungs, with the pH rising to the arterial value of 7.41 once again. In heavy exercise or other conditions of high metabolic activity, or when blood flow through the tissues is sluggish, the decrease in pH in the tissue blood (and in the tissues themselves) can be as much as 0.50, about 12 times normal, thus causing significant tissue acidosis. Respiratory Exchange Ratio The discerning student will have noted that normal transport of oxygen from the lungs to the tissues by each 100 milliliters of blood is about 5 milliliters, whereas normal transport of carbon dioxide from the tissues to the lungs is about 4 milliliters. Thus, under normal resting conditions, only about 82 per cent as much carbon dioxide is expired from the lungs as oxygen is taken up by the lungs. The ratio of carbon dioxide output to oxygen uptake is called the respiratory exchange ratio (R). That is, R= Rate of carbon dioxide output Rate of oxygen uptake The value for R changes under different metabolic conditions. When a person is using exclusively carbohydrates for body metabolism, R rises to 1.00. Conversely, when a person is using exclusively fats for metabolic energy, the R level falls to as low as 0.7. The reason for this difference is that when oxygen is metabolized with carbohydrates, one molecule of carbon dioxide is formed for each molecule of oxygen consumed; when oxygen reacts with fats, a large share of the oxygen combines with hydrogen atoms from the fats to form water instead of carbon dioxide. In other words, when fats are metabolized, the respiratory quotient of the chemical reactions in the tissues is about 0.70 instead of 1.00. (The tissue respiratory quotient is discussed in Chapter 71.) For a person on a normal diet consuming average amounts of carbohydrates, fats, and proteins, the average value for R is considered to be 0.825. References Albert R, Spiro S, Jett J: Comprehensive Respiratory Medicine. Philadelphia: Mosby, 2002. Chapter 40 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids Dempsey JA, Wagner PD: Exercise-induced arterial hypoxemia. J Appl Physiol 87:1997, 1999. Geers C, Gros G: Carbon dioxide transport and carbonic anhydrase in blood and muscle. Physiol Rev 80:681, 2000. Henry RP, Swenson ER: The distribution and physiological significance of carbonic anhydrase in vertebrate gas exchange organs. Respir Physiol 121:1, 2000. Jones AM, Koppo K, Burnley M: Effects of prior exercise on metabolic and gas exchange responses to exercise. Sports Med 33:949, 2003. Nikinmaa M: Membrane transport and control of hemoglobin-oxygen affinity in nucleated erythrocytes. Physiol Rev 72:301, 1992. Piiper J: Perfusion, diffusion and their heterogeneities limiting blood-tissue O2 transfer in muscle. Acta Physiol Scand 168:603, 2000. 513 Richardson RS: Oxygen transport and utilization: an integration of the muscle systems. Adv Physiol Educ 27:183, 2003. Roy TK, Popel AS: Theoretical predictions of end-capillary Po2 in muscles of athletic and nonathletic animals at Vo2max. Am J Physiol 271:H721, 1996. Spahn DR, Pasch T: Physiological properties of blood substitutes. News Physiol Sci 16:38, 2001. Tsai AG, Johnson PC, Intaglietta M: Oxygen gradients in the microcirculation. Physiol Rev 83:933, 2003. Wagner PD: Diffusive resistance to O2 transport in muscle. Acta Physiol Scand 168:609, 2000. West JB: Pulmonary Physiology and Pathophysiology: An Integrated, Case-Based Approach. Philadelphia: Lippincott Williams & Wilkins, 2001. West JB: Pulmonary Physiology—The Essentials. Baltimore: Lippincott Williams & Wilkins, 2003. C H A P T E R 4 Regulation of Respiration The nervous system normally adjusts the rate of alveolar ventilation almost exactly to the demands of the body so that the oxygen pressure (Po2) and carbon dioxide pressure (Pco2) in the arterial blood are hardly altered even during heavy exercise and most other types of respiratory stress. This chapter describes the function of this neurogenic system for regulation of respiration. Respiratory Center The respiratory center is composed of several groups of neurons located bilaterally in the medulla oblongata and pons of the brain stem, as shown in Figure 41–1. It is divided into three major collections of neurons: (1) a dorsal respiratory group, located in the dorsal portion of the medulla, which mainly causes inspiration; (2) a ventral respiratory group, located in the ventrolateral part of the medulla, which mainly causes expiration; and (3) the pneumotaxic center, located dorsally in the superior portion of the pons, which mainly controls rate and depth of breathing. The dorsal respiratory group of neurons plays the most fundamental role in the control of respiration. Therefore, let us discuss its function first. Dorsal Respiratory Group of Neurons—Its Control of Inspiration and of Respiratory Rhythm The dorsal respiratory group of neurons extends most of the length of the medulla. Most of its neurons are located within the nucleus of the tractus solitarius, although additional neurons in the adjacent reticular substance of the medulla also play important roles in respiratory control. The nucleus of the tractus solitarius is the sensory termination of both the vagal and the glossopharyngeal nerves, which transmit sensory signals into the respiratory center from (1) peripheral chemoreceptors, (2) baroreceptors, and (3) several types of receptors in the lungs. Rhythmical Inspiratory Discharges from the Dorsal Respiratory Group. The basic rhythm of respiration is generated mainly in the dorsal respiratory group of neurons. Even when all the peripheral nerves entering the medulla have been sectioned and the brain stem transected both above and below the medulla, this group of neurons still emits repetitive bursts of inspiratory neuronal action potentials. The basic cause of these repetitive discharges is unknown. In primitive animals, neural networks have been found in which activity of one set of neurons excites a second set, which in turn inhibits the first. Then, after a period of time, the mechanism repeats itself, continuing throughout the life of the animal. Therefore, most respiratory physiologists believe that some similar network of neurons is present in the human being, located entirely within the medulla; it probably involves not only the dorsal respiratory group but adjacent areas of the medulla as well, and is responsible for the basic rhythm of respiration. Inspiratory “Ramp” Signal. The nervous signal that is transmitted to the inspiratory muscles, mainly the diaphragm, is not an instantaneous burst of action 514 1 Chapter 41 Regulation of Respiration Pneumotaxic center Fourth ventricle Inhibits ? Apneustic center Dorsal respiratory group (inspiration) Vagus and glossopharyngeal Ventral respiratory group (expiration and inspiration) Respiratory motor pathways Figure 41–1 Organization of the respiratory center. potentials. Instead, in normal respiration, it begins weakly and increases steadily in a ramp manner for about 2 seconds. Then it ceases abruptly for approximately the next 3 seconds, which turns off the excitation of the diaphragm and allows elastic recoil of the lungs and the chest wall to cause expiration. Next, the inspiratory signal begins again for another cycle; this cycle repeats again and again, with expiration occurring in between. Thus, the inspiratory signal is a ramp signal. The obvious advantage of the ramp is that it causes a steady increase in the volume of the lungs during inspiration, rather than inspiratory gasps. There are two qualities of the inspiratory ramp that are controlled, as follows: 1. Control of the rate of increase of the ramp signal, so that during heavy respiration, the ramp increases rapidly and therefore fills the lungs rapidly. 2. Control of the limiting point at which the ramp suddenly ceases. This is the usual method for controlling the rate of respiration; that is, the earlier the ramp ceases, the shorter the duration of inspiration. This also shortens the duration of expiration. Thus, the frequency of respiration is increased. A Pneumotaxic Center Limits the Duration of Inspiration and Increases the Respiratory Rate A pneumotaxic center, located dorsally in the nucleus parabrachialis of the upper pons, transmits signals to the inspiratory area. The primary effect of this center is to control the “switch-off” point of the inspiratory ramp, thus controlling the duration of the filling phase of the lung cycle. When the pneumotaxic signal is strong, inspiration might last for as little as 0.5 second, thus filling the lungs only slightly; when the pneumotaxic signal is weak, inspiration might continue for 5 515 or more seconds, thus filling the lungs with a great excess of air. The function of the pneumotaxic center is primarily to limit inspiration. This has a secondary effect of increasing the rate of breathing, because limitation of inspiration also shortens expiration and the entire period of each respiration. A strong pneumotaxic signal can increase the rate of breathing to 30 to 40 breaths per minute, whereas a weak pneumotaxic signal may reduce the rate to only 3 to 5 breaths per minute. Ventral Respiratory Group of Neurons—Functions in Both Inspiration and Expiration Located in each side of the medulla, about 5 millimeters anterior and lateral to the dorsal respiratory group of neurons, is the ventral respiratory group of neurons, found in the nucleus ambiguus rostrally and the nucleus retroambiguus caudally. The function of this neuronal group differs from that of the dorsal respiratory group in several important ways: 1. The neurons of the ventral respiratory group remain almost totally inactive during normal quiet respiration. Therefore, normal quiet breathing is caused only by repetitive inspiratory signals from the dorsal respiratory group transmitted mainly to the diaphragm, and expiration results from elastic recoil of the lungs and thoracic cage. 2. There is no evidence that the ventral respiratory neurons participate in the basic rhythmical oscillation that controls respiration. 3. When the respiratory drive for increased pulmonary ventilation becomes greater than normal, respiratory signals spill over into the ventral respiratory neurons from the basic oscillating mechanism of the dorsal respiratory area. As a consequence, the ventral respiratory area contributes extra respiratory drive as well. 4. Electrical stimulation of a few of the neurons in the ventral group causes inspiration, whereas stimulation of others causes expiration. Therefore, these neurons contribute to both inspiration and expiration. They are especially important in providing the powerful expiratory signals to the abdominal muscles during very heavy expiration. Thus, this area operates more or less as an overdrive mechanism when high levels of pulmonary ventilation are required, especially during heavy exercise. Lung Inflation Signals Limit Inspiration—The Hering-Breuer Inflation Reflex In addition to the central nervous system respiratory control mechanisms operating entirely within the brain stem, sensory nerve signals from the lungs also 516 Unit VII help control respiration. Most important, located in the muscular portions of the walls of the bronchi and bronchioles throughout the lungs are stretch receptors that transmit signals through the vagi into the dorsal respiratory group of neurons when the lungs become overstretched. These signals affect inspiration in much the same way as signals from the pneumotaxic center; that is, when the lungs become overly inflated, the stretch receptors activate an appropriate feedback response that “switches off” the inspiratory ramp and thus stops further inspiration. This is called the HeringBreuer inflation reflex. This reflex also increases the rate of respiration, as is true for signals from the pneumotaxic center. In human beings, the Hering-Breuer reflex probably is not activated until the tidal volume increases to more than three times normal (greater than about 1.5 liters per breath). Therefore, this reflex appears to be mainly a protective mechanism for preventing excess lung inflation rather than an important ingredient in normal control of ventilation. Control of Overall Respiratory Center Activity Up to this point, we have discussed the basic mechanisms for causing inspiration and expiration, but it is also important to know how the intensity of the respiratory control signals is increased or decreased to match the ventilatory needs of the body. For example, during heavy exercise, the rates of oxygen usage and carbon dioxide formation are often increased to as much as 20 times normal, requiring commensurate increases in pulmonary ventilation. The major purpose of the remainder of this chapter is to discuss this control of ventilation in accord with the respiratory needs of the body. Respiration Direct Chemical Control of Respiratory Center Activity by Carbon Dioxide and Hydrogen Ions Chemosensitive Area of the Respiratory Center. We have discussed mainly three areas of the respiratory center: the dorsal respiratory group of neurons, the ventral respiratory group, and the pneumotaxic center. It is believed that none of these is affected directly by changes in blood carbon dioxide concentration or hydrogen ion concentration. Instead, an additional neuronal area, a chemosensitive area, shown in Figure 41–2, is located bilaterally, lying only 0.2 millimeter beneath the ventral surface of the medulla. This area is highly sensitive to changes in either blood Pco2 or hydrogen ion concentration, and it in turn excites the other portions of the respiratory center. Excitation of the Chemosensitive Neurons by Hydrogen Ions Is Likely the Primary Stimulus The sensor neurons in the chemosensitive area are especially excited by hydrogen ions; in fact, it is believed that hydrogen ions may be the only important direct stimulus for these neurons. However, hydrogen ions do not easily cross the blood-brain barrier. For this reason, changes in hydrogen ion concentration in the blood have considerably less effect in stimulating the chemosensitive neurons than do changes in blood carbon dioxide, even though carbon dioxide is believed to stimulate these neurons secondarily by changing the hydrogen ion concentration, as explained in the following section. Carbon Dioxide Stimulates the Chemosensitive Area Although carbon dioxide has little direct effect in stimulating the neurons in the chemosensitive area, it Chemical Control of Respiration The ultimate goal of respiration is to maintain proper concentrations of oxygen, carbon dioxide, and hydrogen ions in the tissues. It is fortunate, therefore, that respiratory activity is highly responsive to changes in each of these. Excess carbon dioxide or excess hydrogen ions in the blood mainly act directly on the respiratory center itself, causing greatly increased strength of both the inspiratory and the expiratory motor signals to the respiratory muscles. Oxygen, in contrast, does not have a significant direct effect on the respiratory center of the brain in controlling respiration. Instead, it acts almost entirely on peripheral chemoreceptors located in the carotid and aortic bodies, and these in turn transmit appropriate nervous signals to the respiratory center for control of respiration. Let us discuss first the stimulation of the respiratory center itself by carbon dioxide and hydrogen ions. Chemosensitive area Inspiratory area H+ + HCO3- H2CO3 CO2 + H2O Figure 41–2 Stimulation of the brain stem inspiratory area by signals from the chemosensitive area located bilaterally in the medulla, lying only a fraction of a millimeter beneath the ventral medullary surface. Note also that hydrogen ions stimulate the chemosensitive area, but carbon dioxide in the fluid gives rise to most of the hydrogen ions. 517 Regulation of Respiration 11 10 9 8 7 Normal does have a potent indirect effect. It does this by reacting with the water of the tissues to form carbonic acid, which dissociates into hydrogen and bicarbonate ions; the hydrogen ions then have a potent direct stimulatory effect on respiration. These reactions are shown in Figure 41–2. Why does blood carbon dioxide have a more potent effect in stimulating the chemosensitive neurons than do blood hydrogen ions? The answer is that the bloodbrain barrier is not very permeable to hydrogen ions, but carbon dioxide passes through this barrier almost as if the barrier did not exist. Consequently, whenever the blood Pco2 increases, so does the Pco2 of both the interstitial fluid of the medulla and the cerebrospinal fluid. In both these fluids, the carbon dioxide immediately reacts with the water to form new hydrogen ions. Thus, paradoxically, more hydrogen ions are released into the respiratory chemosensitive sensory area of the medulla when the blood carbon dioxide concentration increases than when the blood hydrogen ion concentration increases. For this reason, respiratory center activity is increased very strongly by changes in blood carbon dioxide, a fact that we subsequently discuss quantitatively. Alveolar ventilation (basal rate = 1) Chapter 41 6 5 4 3 2 PCO2 pH 1 0 20 30 40 50 60 70 80 PCO2 (mm Hg) 7.6 7.5 7.4 7.3 Decreased Stimulatory Effect of Carbon Dioxide After the First 1 to 2 Days. Excitation of the respiratory center by carbon dioxide is great the first few hours after the blood carbon dioxide first increases, but then it gradually declines over the next 1 to 2 days, decreasing to about one fifth the initial effect. Part of this decline results from renal readjustment of the hydrogen ion concentration in the circulating blood back toward normal after the carbon dioxide first increases the hydrogen concentration. The kidneys achieve this by increasing the blood bicarbonate, which binds with the hydrogen ions in the blood and cerebrospinal fluid to reduce their concentrations. But even more important, over a period of hours, the bicarbonate ions also slowly diffuse through the blood-brain and blood– cerebrospinal fluid barriers and combine directly with the hydrogen ions adjacent to the respiratory neurons as well, thus reducing the hydrogen ions back to near normal. A change in blood carbon dioxide concentration therefore has a potent acute effect on controlling respiratory drive but only a weak chronic effect after a few days’ adaptation. Quantitative Effects of Blood PCO2 and Hydrogen Ion Concentration on Alveolar Ventilation Figure 41–3 shows quantitatively the approximate effects of blood Pco2 and blood pH (which is an inverse logarithmic measure of hydrogen ion concentration) on alveolar ventilation. Note especially the very marked increase in ventilation caused by an increase in Pco2 in the normal range between 35 and 75 mm Hg. This demonstrates the tremendous effect that carbon dioxide changes have in controlling respiration. By contrast, the change in respiration in the normal blood pH range between 7.3 and 7.5 is less than one tenth as great. 90 100 7.2 7.1 7.0 6.9 pH Figure 41–3 Effects of increased arterial blood PCO2 and decreased arterial pH (increased hydrogen ion concentration) on the rate of alveolar ventilation. Unimportance of Oxygen for Control of the Respiratory Center Changes in oxygen concentration have virtually no direct effect on the respiratory center itself to alter respiratory drive (although oxygen changes do have an indirect effect, acting through the peripheral chemoreceptors, as explained in the next section). We learned in Chapter 40 that the hemoglobinoxygen buffer system delivers almost exactly normal amounts of oxygen to the tissues even when the pulmonary Po2 changes from a value as low as 60 mm Hg up to a value as high as 1000 mm Hg. Therefore, except under special conditions, adequate delivery of oxygen can occur despite changes in lung ventilation ranging from slightly below one half normal to as high as 20 or more times normal. This is not true for carbon dioxide, because both the blood and tissue Pco2 changes inversely with the rate of pulmonary ventilation; thus, the processes of animal evolution have made carbon dioxide the major controller of respiration, not oxygen. Yet, for those special conditions in which the tissues get into trouble for lack of oxygen, the body has a special mechanism for respiratory control located in the peripheral chemoreceptors, outside the brain respiratory center; this mechanism responds when the blood oxygen falls too low, mainly below a Po2 of 70 mm Hg, as explained in the next section. 518 Unit VII Peripheral Chemoreceptor System for Control of Respiratory Activity—Role of Oxygen in Respiratory Control In addition to control of respiratory activity by the respiratory center itself, still another mechanism is available for controlling respiration. This is the peripheral chemoreceptor system, shown in Figure 41–4. Special nervous chemical receptors, called chemoreceptors, are located in several areas outside the brain. They are especially important for detecting changes in oxygen in the blood, although they also respond to a lesser extent to changes in carbon dioxide and hydrogen ion concentrations. The chemoreceptors transmit nervous signals to the respiratory center in the brain to help regulate respiratory activity. Most of the chemoreceptors are in the carotid bodies. However, a few are also in the aortic bodies, shown in the lower part of Figure 41–4, and a very few are located elsewhere in association with other arteries of the thoracic and abdominal regions. The carotid bodies are located bilaterally in the bifurcations of the common carotid arteries. Their afferent nerve fibers pass through Hering’s nerves to the glossopharyngeal nerves and then to the dorsal respiratory area of the medulla. The aortic bodies are located along the arch of the aorta; their afferent nerve fibers pass through the vagi, also to the dorsal medullary respiratory area. Each of the chemoreceptor bodies receives its own special blood supply through a minute artery directly from the adjacent arterial trunk. Further, blood flow through these bodies is extreme, 20 times the weight of the bodies themselves each minute. Therefore, the percentage of oxygen removed from the flowing blood is virtually zero. This means that the chemoreceptors Respiration are exposed at all times to arterial blood, not venous blood, and their Po2s are arterial Po2s. Stimulation of the Chemoreceptors by Decreased Arterial Oxygen. When the oxygen concentration in the arterial blood falls below normal, the chemoreceptors become strongly stimulated. This is demonstrated in Figure 41–5, which shows the effect of different levels of arterial Po2 on the rate of nerve impulse transmission from a carotid body. Note that the impulse rate is particularly sensitive to changes in arterial Po2 in the range of 60 down to 30 mm Hg, a range in which hemoglobin saturation with oxygen decreases rapidly. Effect of Carbon Dioxide and Hydrogen Ion Concentration on Chemoreceptor Activity. An increase in either carbon dioxide concentration or hydrogen ion concentration also excites the chemoreceptors and, in this way, indirectly increases respiratory activity. However, the direct effects of both these factors in the respiratory center itself are so much more powerful than their effects mediated through the chemoreceptors (about seven times as powerful) that, for practical purposes, the indirect effects of carbon dioxide and hydrogen ions through the chemoreceptors do not need to be considered. Yet there is one difference between the peripheral and central effects of carbon dioxide: the stimulation by way of the peripheral chemoreceptors occurs as much as five times as rapidly as central stimulation, so that the peripheral chemoreceptors might be especially important in increasing the rapidity of response to carbon dioxide at the onset of exercise. Basic Mechanism of Stimulation of the Chemoreceptors by Oxygen Deficiency. The exact means by which low Po2 excites the nerve endings in the carotid and aortic bodies is still unknown. However, these bodies have Medulla Glossopharyngeal nerve Carotid body Carotid body nerve impulses per second Vagus nerve 800 600 400 200 0 0 Aortic bodies Figure 41–4 Respiratory control by peripheral chemoreceptors in the carotid and aortic bodies. 100 200 300 400 Arterial PO2 (mm Hg) 500 Figure 41–5 Effect of arterial PO2 on impulse rate from the carotid body of a cat. Chapter 41 519 Regulation of Respiration multiple highly characteristic glandular-like cells, called glomus cells, that synapse directly or indirectly with the nerve endings. Some investigators have suggested that these glomus cells might function as the chemoreceptors and then stimulate the nerve endings. But other studies suggest that the nerve endings themselves are directly sensitive to the low Po2. Effect of Low Arterial PO2 to Stimulate Alveolar Ventilation When Arterial Carbon Dioxide and Hydrogen Ion Concentrations Remain Normal Figure 41–6 shows the effect of low arterial Po2 on alveolar ventilation when the Pco2 and the hydrogen ion concentration are kept constant at their normal levels. In other words, in this figure, only the ventilatory drive due to the effect of low oxygen on the chemoreceptors is active. The figure shows almost no effect on ventilation as long as the arterial Po2 remains greater than 100 mm Hg. But at pressures lower than 100 mm Hg, ventilation approximately doubles when the arterial Po2 falls to 60 mm Hg and can increase as much as fivefold at very low Po2s. Under these conditions, low arterial Po2 obviously drives the ventilatory process quite strongly. Chronic Breathing of Low Oxygen Stimulates Respiration Even More—The Phenomenon of “Acclimatization” Mountain climbers have found that when they ascend a mountain slowly, over a period of days rather than a period of hours, they breathe much more deeply and therefore can withstand far lower atmospheric oxygen concentrations than when they ascend rapidly. This is called acclimatization. The reason for acclimatization is that, within 2 to 3 days, the respiratory center in the brain stem loses about four fifths of its sensitivity to changes in Pco2 and hydrogen ions. Therefore, the excess ventilatory blow-off of carbon dioxide that normally would inhibit an increase in respiration fails to occur, and low oxygen can drive the respiratory system to a much higher level of alveolar ventilation than under acute conditions. Instead of the 70 per cent increase in ventilation that might occur after acute exposure to low oxygen, the alveolar ventilation often increases 400 to 500 per cent after 2 to 3 days of low oxygen; this helps immensely in supplying additional oxygen to the mountain climber. Composite Effects of PCO2, pH, and PO2 on Alveolar Ventilation Figure 41–7 gives a quick overview of the manner in which the chemical factors Po2, Pco2, and pH— together—affect alveolar ventilation. To understand this diagram, first observe the four red curves. These curves were recorded at different levels of arterial Po2—40 mm Hg, 50 mm Hg, 60 mm Hg, and 100 mm Hg. For each of these curves, the Pco2 was changed from lower to higher levels. Thus, this 7 4 30 3 2 20 PCO2 Ventilation 0 160 140 120 100 80 60 40 Arterial PO2 (mm Hg) Alveolar ventilation (L/min) 5 1 60 40 Arterial PCO2 (mm Hg) Alveolar ventilation (normal = 1) 6 pH = 7.4 pH = 7.3 50 40 PO2 (mm Hg) 40 50 40 50 60 100 60 30 100 20 10 0 20 0 0 0 10 20 30 40 50 Alveolar PCO2 (mm Hg) 60 Figure 41–6 The lower curve demonstrates the effect of different levels of arterial PO2 on alveolar ventilation, showing a sixfold increase in ventilation as the PO2 decreases from the normal level of 100 mm Hg to 20 mm Hg. The upper line shows that the arterial PCO2 was kept at a constant level during the measurements of this study; pH also was kept constant. Figure 41–7 Composite diagram showing the interrelated effects of PCO2, PO2, and pH on alveolar ventilation. (Drawn from data in Cunningham DJC, Lloyd BB: The Regulation of Human Respiration. Oxford: Blackwell Scientific Publications, 1963.) 520 Unit VII Respiration “family” of red curves represents the combined effects of alveolar Pco2 and Po2 on ventilation. Now observe the green curves. The red curves were measured at a blood pH of 7.4; the green curves were measured at a pH of 7.3. We now have two families of curves representing the combined effects of Pco2 and Po2 on ventilation at two different pH values. Still other families of curves would be displaced to the right at higher pHs and displaced to the left at lower pHs. Thus, using this diagram, one can predict the level of alveolar ventilation for most combinations of alveolar Pco2, alveolar Po2, and arterial pH. to transmit at the same time collateral impulses into the brain stem to excite the respiratory center. This is analogous to the stimulation of the vasomotor center of the brain stem during exercise that causes a simultaneous increase in arterial pressure. Actually, when a person begins to exercise, a large share of the total increase in ventilation begins immediately on initiation of the exercise, before any blood chemicals have had time to change. It is likely that most of the increase in respiration results from neurogenic signals transmitted directly into the brain stem respiratory center at the same time that signals go to the body muscles to cause muscle contraction. Regulation of Respiration During Exercise Interrelation Between Chemical Factors and Nervous: Factors in the Control of Respiration During Exercise. When a In strenuous exercise, oxygen consumption and carbon dioxide formation can increase as much as 20-fold.Yet, as illustrated in Figure 41–8, in the healthy athlete, alveolar ventilation ordinarily increases almost exactly in step with the increased level of oxygen metabolism. The arterial Po2, Pco2, and pH remain almost exactly normal. In trying to analyze what causes the increased ventilation during exercise, one is tempted to ascribe this to increases in blood carbon dioxide and hydrogen ions, plus a decrease in blood oxygen. However, this is questionable, because measurements of arterial Pco2, pH, and Po2 show that none of these values changes significantly during exercise, so that none of them becomes abnormal enough to stimulate respiration. Therefore, the question must be asked: What causes intense ventilation during exercise? At least one effect seems to be predominant. The brain, on transmitting motor impulses to the exercising muscles, is believed person exercises, direct nervous signals presumably stimulate the respiratory center almost the proper amount to supply the extra oxygen required for exercise and to blow off extra carbon dioxide. Occasionally, however, the nervous respiratory control signals are either too strong or too weak. Then chemical factors play a significant role in bringing about the final adjustment of respiration required to keep the oxygen, carbon dioxide, and hydrogen ion concentrations of the body fluids as nearly normal as possible. This is demonstrated in Figure 41–9, which shows in the lower curve changes in alveolar ventilation during a 1-minute period of exercise and in the upper curve changes in arterial Pco2. Note that at the onset of exercise, the alveolar ventilation increases instantaneously, without an initial increase in arterial Pco2. In fact, this Arterial PCO2 (mm Hg) 44 40 38 36 110 Alveolar ventilation (L/min) Total ventilation (L/min) 120 42 100 80 60 40 20 Moderate exercise 0 0 1.0 Exercise 18 14 10 6 2 Severe exercise 0 1 Minutes 2 2.0 3.0 4.0 O2 consumption (L/min) Figure 41–9 Figure 41–8 Effect of exercise on oxygen consumption and ventilatory rate. (From Gray JS: Pulmonary Ventilation and Its Physiological Regulation. Springfield, Ill: Charles C Thomas, 1950.) Changes in alveolar ventilation (bottom curve) and arterial PCO2 (top curve) during a 1-minute period of exercise and also after termination of exercise. (Extrapolated to the human being from data in dogs in Bainton CR: Effect of speed vs grade and shivering on ventilation in dogs during active exercise. J Appl Physiol 33:778, 1972.) Chapter 41 Regulation of Respiration the rate of carbon dioxide release, thus keeping arterial Pco2 near its normal value. The upper curve of Figure 41–10 also shows that if, during exercise, the arterial Pco2 does change from its normal value of 40 mm Hg, it has an extra stimulatory effect on ventilation at a Pco2 greater than 40 mm Hg and a depressant effect at a Pco2 less than 40 mm Hg. 140 120 Alveolar ventilation (L/min) 521 Possibility That the Neurogenic Factor for Control of Ventilation During Exercise Is a Learned Response. Many experi- 100 ments suggest that the brain’s ability to shift the ventilatory response curve during exercise, as shown in Figure 41–10, is at least partly a learned response. That is, with repeated periods of exercise, the brain becomes progressively more able to provide the proper signals required to keep the blood Pco2 at its normal level. Also, there is reason to believe that even the cerebral cortex is involved in this learning, because experiments that block only the cortex also block the learned response. 80 60 40 Exercise Resting Normal 20 0 20 30 40 50 60 80 Arterial PCO2 (mm Hg) 100 Figure 41–10 Approximate effect of maximum exercise in an athlete to shift the alveolar PCO2-ventilation response curve to a level much higher than normal. The shift, believed to be caused by neurogenic factors, is almost exactly the right amount to maintain arterial PCO2 at the normal level of 40 mm Hg both in the resting state and during heavy exercise. increase in ventilation is usually great enough so that at first it actually decreases arterial Pco2 below normal, as shown in the figure. The presumed reason that the ventilation forges ahead of the buildup of blood carbon dioxide is that the brain provides an “anticipatory” stimulation of respiration at the onset of exercise, causing extra alveolar ventilation even before it is needed. However, after about 30 to 40 seconds, the amount of carbon dioxide released into the blood from the active muscles approximately matches the increased rate of ventilation, and the arterial Pco2 returns essentially to normal even as the exercise continues, as shown toward the end of the 1-minute period of exercise in the figure. Figure 41–10 summarizes the control of respiration during exercise in still another way, this time more quantitatively. The lower curve of this figure shows the effect of different levels of arterial Pco2 on alveolar ventilation when the body is at rest—that is, not exercising. The upper curve shows the approximate shift of this ventilatory curve caused by neurogenic drive from the respiratory center that occurs during heavy exercise. The points indicated on the two curves show the arterial Pco2 first in the resting state and then in the exercising state. Note in both instances that the Pco2 is at the normal level of 40 mm Hg. In other words, the neurogenic factor shifts the curve about 20-fold in the upward direction, so that ventilation almost matches Other Factors That Affect Respiration Voluntary Control of Respiration. Thus far, we have dis- cussed the involuntary system for the control of respiration. However, we all know that for short periods of time, respiration can be controlled voluntarily and that one can hyperventilate or hypoventilate to such an extent that serious derangements in Pco2, pH, and Po2 can occur in the blood. Effect of Irritant Receptors in the Airways. The epithelium of the trachea, bronchi, and bronchioles is supplied with sensory nerve endings called pulmonary irritant receptors that are stimulated by many incidents. These cause coughing and sneezing, as discussed in Chapter 39. They may also cause bronchial constriction in such diseases as asthma and emphysema. Function of Lung “J Receptors.” A few sensory nerve endings have been described in the alveolar walls in juxtaposition to the pulmonary capillaries—hence the name “J receptors.”They are stimulated especially when the pulmonary capillaries become engorged with blood or when pulmonary edema occurs in such conditions as congestive heart failure. Although the functional role of the J receptors is not clear, their excitation may give the person a feeling of dyspnea. Effect of Brain Edema. The activity of the respiratory center may be depressed or even inactivated by acute brain edema resulting from brain concussion. For instance, the head might be struck against some solid object, after which the damaged brain tissues swell, compressing the cerebral arteries against the cranial vault and thus partially blocking cerebral blood supply. Occasionally, respiratory depression resulting from brain edema can be relieved temporarily by intravenous injection of hypertonic solutions such as highly concentrated mannitol solution. These solutions osmotically remove some of the fluids of the brain, thus relieving intracranial pressure and sometimes re-establishing respiration within a few minutes. 522 Unit VII Anesthesia. Perhaps the most prevalent cause of respiratory depression and respiratory arrest is overdosage with anesthetics or narcotics. For instance, sodium pentobarbital depresses the respiratory center considerably more than many other anesthetics, such as halothane. At one time, morphine was used as an anesthetic, but this drug is now used only as an adjunct to anesthetics because it greatly depresses the respiratory center while having less ability to anesthetize the cerebral cortex. Periodic Breathing An abnormality of respiration called periodic breathing occurs in a number of disease conditions. The person breathes deeply for a short interval and then breathes slightly or not at all for an additional interval, with the cycle repeating itself over and over. One type of periodic breathing, Cheyne-Stokes breathing, is characterized by slowly waxing and waning respiration occurring about every 40 to 60 seconds, as illustrated in Figure 41–11. Basic Mechanism of Cheyne-Stokes Breathing. The basic cause of Cheyne-Stokes breathing is the following: When a person overbreathes, thus blowing off too much carbon dioxide from the pulmonary blood while at the same time increasing blood oxygen, it takes several seconds before the changed pulmonary blood can be transported to the brain and inhibit the excess ventilation. By this time, the person has already overventilated for an extra few seconds. Therefore, when the overventilated blood finally reaches the brain respiratory center, the center becomes depressed an excessive amount. Then the opposite cycle begins. That is, carbon dioxide increases and oxygen decreases in the alveoli. Again, it takes a few seconds before the brain can respond to these new changes. When the brain does respond, the person breathes hard once again, and the cycle repeats. The basic cause of Cheyne-Stokes breathing occurs in everyone. However, under normal conditions, this mechanism is highly “damped.” That is, the fluids of the blood and the respiratory center control areas have large amounts of dissolved and chemically bound Depth of respiration PCO2 of respiratory neurons Respiration carbon dioxide and oxygen. Therefore, normally, the lungs cannot build up enough extra carbon dioxide or depress the oxygen sufficiently in a few seconds to cause the next cycle of the periodic breathing. But under two separate conditions, the damping factors can be overridden, and Cheyne-Stokes breathing does occur: 1. When a long delay occurs for transport of blood from the lungs to the brain, changes in carbon dioxide and oxygen in the alveoli can continue for many more seconds than usual. Under these conditions, the storage capacities of the alveoli and pulmonary blood for these gases are exceeded; then, after a few more seconds, the periodic respiratory drive becomes extreme, and CheyneStokes breathing begins. This type of CheyneStokes breathing often occurs in patients with severe cardiac failure because blood flow is slow, thus delaying the transport of blood gases from the lungs to the brain. In fact, in patients with chronic heart failure, Cheyne-Stokes breathing can sometimes occur on and off for months. 2. A second cause of Cheyne-Stokes breathing is increased negative feedback gain in the respiratory control areas. This means that a change in blood carbon dioxide or oxygen causes a far greater change in ventilation than normally. For instance, instead of the normal 2- to 3-fold increase in ventilation that occurs when the Pco2 rises 3 mm Hg, the same 3 mm Hg rise might increase ventilation 10- to 20-fold. The brain feedback tendency for periodic breathing is now strong enough to cause Cheyne-Stokes breathing without extra blood flow delay between the lungs and brain. This type of Cheyne-Stokes breathing occurs mainly in patients with brain damage. The brain damage often turns off the respiratory drive entirely for a few seconds; then an extra intense increase in blood carbon dioxide turns it back on with great force. Cheyne-Stokes breathing of this type is frequently a prelude to death from brain malfunction. Typical records of changes in pulmonary and respiratory center Pco2 during Cheyne-Stokes breathing are shown in Figure 41–11. Note that the Pco2 of the pulmonary blood changes in advance of the Pco2 of the respiratory neurons. But the depth of respiration corresponds with the Pco2 in the brain, not with the Pco2 in the pulmonary blood where the ventilation is occurring. Sleep Apnea Respiratory center excited PCO2 of lung blood Figure 41–11 Cheyne-Stokes breathing, showing changing PCO2 in the pulmonary blood (red line) and delayed changes in the PCO2 of the fluids of the respiratory center (blue line). The term apnea means absence of spontaneous breathing. Occasional apneas occur during normal sleep, but in persons with sleep apnea, the frequency and duration are greatly increased, with episodes of apnea lasting for 10 seconds or longer and occurring 300 to 500 times each night. Sleep apneas can be caused by obstruction of the upper airways, especially the pharynx, or by impaired central nervous system respiratory drive. Obstructive Sleep Apnea Is Caused by Blockage of the Upper Airway. The muscles of the pharynx normally keep this passage open to allow air to flow into the lungs during inspiration. During sleep, these muscles usually relax, but the airway passage remains open enough to permit adequate airflow. Some individuals have an especially Chapter 41 Regulation of Respiration narrow passage, and relaxation of these muscles during sleep causes the pharynx to completely close so that air cannot flow into the lungs. In persons with sleep apnea, loud snoring and labored breathing occur soon after falling asleep. The snoring proceeds, often becoming louder, and is then interrupted by a long silent period during which no breathing (apnea) occurs. These periods of apnea result in significant decreases in Po2 and increases in Pco2, which greatly stimulate respiration. This, in turn, causes sudden attempts to breathe, which result in loud snorts and gasps followed by snoring and repeated episodes of apnea. The periods of apnea and labored breathing are repeated several hundred times during the night, resulting in fragmented, restless sleep. Therefore, patients with sleep apnea usually have excessive daytime drowsiness as well as other disorders, including increased sympathetic activity, high heart rates, pulmonary and systemic hypertension, and a greatly elevated risk for cardiovascular disease. Obstructive sleep apnea most commonly occurs in older, obese persons in whom there is increased fat deposition in the soft tissues of the pharynx or compression of the pharynx due to excessive fat masses in the neck. In a few individuals, sleep apnea may be associated with nasal obstruction, a very large tongue, enlarged tonsils, or certain shapes of the palate that greatly increase resistance to the flow of air to the lungs during inspiration. The most common treatments of obstructive sleep apnea include (1) surgery to remove excess fat tissue at the back of the throat (a procedure called uvulopalatopharyngoplasty), to remove enlarged tonsils or adenoids, or to create an opening in the trachea (tracheostomy) to bypass the obstructed airway during sleep, and (2) nasal ventilation with continuous positive airway pressure (CPAP). “Central” Sleep Apnea Occurs When the Neural Drive to Respiratory Muscles Is Transiently Abolished. In a few persons with sleep apnea, the central nervous system drive to the ventilatory muscles transiently ceases. Disorders that can cause cessation of the ventilatory drive during sleep include damage to the central respiratory centers or abnormalities of the respiratory neuromuscular apparatus. Patients affected by central sleep apnea may have decreased ventilation when they are awake, although they are fully capable of normal voluntary breathing. During sleep, their breathing disorders usually worsen, resulting in more frequent episodes of apnea that decrease Po2 and increase Pco2 until a critical level is reached that eventually stimulates respiration. These transient instabilities of respiration cause restless sleep and clinical features similar to those observed in obstructive sleep apnea. In most patients, the cause of central sleep apnea is unknown, although instability of the respiratory drive can result from strokes or other disorders that make the respiratory centers of the brain less responsive to the 523 stimulatory effects of carbon dioxide and hydrogen ions. Patients with this disease are extremely sensitive to even small doses of sedatives or narcotics, which further reduce the responsiveness of the respiratory centers to the stimulatory effects of carbon dioxide. Medications that stimulate the respiratory centers can sometimes be helpful, but ventilation with CPAP at night is usually necessary. References Dean JB, Ballantyne D, Cardone DL, et al: Role of gap junctions in CO2 chemoreception and respiratory control. Am J Physiol Lung Cell Mol Physiol 283:L665, 2002. Dutschmann M, Paton JF: Inhibitory synaptic mechanisms regulating upper airway patency. Respir Physiol Neurobiol 131:57, 2002. Feldman JL, Mitchell GS, Nattie EE: Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26:239, 2003. Forster HV: Plasticity in the control of breathing following sensory denervation. J Appl Physiol 94:784, 2003. Hilaire G, Pasaro R: Genesis and control of the respiratory rhythm in adult mammals. News Physiol Sci 18:23, 2003. Howard RS, Rudd AG, Wolfe CD, Williams AJ: Pathophysiological and clinical aspects of breathing after stroke. Postgrad Med J 77:700, 2001. Jordan D: Central nervous pathways and control of the airways. Respir Physiol 125:67, 2001. Kara T, Narkiewicz K, Somers VK: Chemoreflexes—physiology and clinical implications. Acta Physiol Scand 177: 377, 2003. Morris KF, Baekey DM, Nuding SC, et al: Neural network plasticity in respiratory control. J Appl Physiol 94:1242, 2003. Mortola JP, Frappell PB: Ventilatory responses to changes in temperature in mammals and other vertebrates.Annu Rev Physiol 62:847, 2000. Richerson GB: Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 5:449, 2004. Semenza GL: O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1. J Appl Physiol 96:1173, 2004. Sharp FR, Bernaudin M: HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5:437, 2004. Taylor EW, Jordan D, Coote JH: Central control of the cardiovascular and respiratory systems and their interactions in vertebrates. Physiol Rev 79:855, 1999. West JB: Pulmonary Physiology—The Essentials. Baltimore: Lippincott Williams & Wilkins, 2003. Wolk R, Shamsuzzaman AS, Somers VK: Obesity, sleep apnea, and hypertension. Hypertension 42:1067, 2003. Young T, Skatrud J, Peppard PE: Risk factors for obstructive sleep apnea in adults. JAMA 291:2013, 2004. Zuperku EJ, McCrimmon DR: Gain modulation of respiratory neurons. Respir Physiol Neurobiol 131:121, 2002. C H A P T E R 4 Respiratory Insufficiency— Pathophysiology, Diagnosis, Oxygen Therapy Diagnosis and treatment of most respiratory disorders depend heavily on understanding the basic physiologic principles of respiration and gas exchange. Some respiratory diseases result from inadequate ventilation. Others result from abnormalities of diffusion through the pulmonary membrane or abnormal blood transport of gases between the lungs and tissues. Therapy is often entirely different for these diseases, so it is no longer satisfactory simply to make a diagnosis of “respiratory insufficiency.” Useful Methods for Studying Respiratory Abnormalities In the previous few chapters, we have discussed a number of methods for studying respiratory abnormalities, including measuring vital capacity, tidal air, functional residual capacity, dead space, physiologic shunt, and physiologic dead space. This array of measurements is only part of the armamentarium of the clinical pulmonary physiologist. Some other interesting tools are described here. Study of Blood Gases and Blood pH Among the most fundamental of all tests of pulmonary performance are determinations of the blood Po2, CO2, and pH. It is often important to make these measurements rapidly as an aid in determining appropriate therapy for acute respiratory distress or acute abnormalities of acid-base balance. Several simple and rapid methods have been developed to make these measurements within minutes, using no more than a few drops of blood. They are the following. Determination of Blood pH. Blood pH is measured using a glass pH electrode of the type used in all chemical laboratories. However, the electrodes used for this purpose are miniaturized. The voltage generated by the glass electrode is a direct measure of pH, and this is generally read directly from a voltmeter scale, or it is recorded on a chart. Determination of Blood CO2. A glass electrode pH meter can also be used to deter- mine blood CO2 in the following way: When a weak solution of sodium bicarbonate is exposed to carbon dioxide gas, the carbon dioxide dissolves in the solution until an equilibrium state is established. In this equilibrium state, the pH of the solution is a function of the carbon dioxide and bicarbonate ion concentrations in accordance with the Henderson-Hasselbalch equation that is explained in Chapter 30; that is, pH = 6.1 + log HCO3 CO 2 When the glass electrode is used to measure CO2 in blood, a miniature glass electrode is surrounded by a thin plastic membrane. In the space between the electrode and plastic membrane is a solution of sodium bicarbonate of known 524 2 525 Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy concentration. Blood is then superfused onto the outer surface of the plastic membrane, allowing carbon dioxide to diffuse from the blood into the bicarbonate solution. Only a drop or so of blood is required. Next, the pH is measured by the glass electrode, and the CO2 is calculated by use of the above formula. 300 ry to ra pi ex 200 w flo In many respiratory diseases, particularly in asthma, the resistance to airflow becomes especially great during expiration, sometimes causing tremendous difficulty in breathing. This has led to the concept called maximum expiratory flow, which can be defined as follows: When a person expires with great force, the expiratory airflow reaches a maximum flow beyond which the flow cannot be increased any more even with greatly increased additional force. This is the maximum expiratory flow. The maximum expiratory flow is much greater when the lungs are filled with a large volume of air than when they are almost empty. These principles can be understood by referring to Figure 42–1. Figure 42–1A shows the effect of increased pressure applied to the outsides of the alveoli and air passageways caused by compressing the chest cage.The arrows indicate that the same pressure compresses the outsides of both the alveoli and the bronchioles.Therefore, not only does this pressure force air from the alveoli toward the bronchioles, but it also tends to collapse the bronchioles at the same time, which will oppose movement of air to the exterior. Once the bronchioles have almost completely collapsed, further expiratory force can still greatly increase the alveolar pressure, but it also increases the degree of bronchiolar collapse and airway resistance by an equal amount, thus preventing further increase in flow. um Measurement of Maximum Expiratory Flow 400 im ax in a fluid can be measured by a technique called polarography. Electric current is made to flow between a small negative electrode and the solution. If the voltage of the electrode is more than -0.6 volt different from the voltage of the solution, oxygen will deposit on the electrode. Furthermore, the rate of current flow through the electrode will be directly proportional to the concentration of oxygen (and therefore to PO2 as well). In practice, a negative platinum electrode with a surface area of about 1 square millimeter is used, and this is separated from the blood by a thin plastic membrane that allows diffusion of oxygen but not diffusion of proteins or other substances that will “poison” the electrode. Often all three of the measuring devices for pH, CO2, and Po2 are built into the same apparatus, and all these measurements can be made within a minute or so using a single, droplet-size sample of blood. Thus, changes in the blood gases and pH can be followed almost moment by moment at the bedside. 500 M Determination of Blood PO2. The concentration of oxygen A Expiratory air flow (L/min) Chapter 42 Total lung capacity 100 Residual volume 0 6 B 5 4 3 2 Lung volume (liters) 1 0 Figure 42–1 A, Collapse of the respiratory passageway during maximum expiratory effort, an effect that limits expiratory flow rate. B, Effect of lung volume on the maximum expiratory air flow, showing decreasing maximum expiratory air flow as the lung volume becomes smaller. Therefore, beyond a critical degree of expiratory force, a maximum expiratory flow has been reached. Figure 42–1B shows the effect of different degrees of lung collapse (and therefore of bronchiolar collapse as well) on the maximum expiratory flow. The curve recorded in this section shows the maximum expiratory flow at all levels of lung volume after a healthy person first inhales as much air as possible and then expires with maximum expiratory effort until he or she can expire at no greater rate. Note that the person quickly reaches a maximum expiratory airflow of more than 400 L/min. But regardless of how much additional expiratory effort the person exerts, this is still the maximum flow rate that he or she can achieve. Note also that as the lung volume becomes smaller, the maximum expiratory flow rate also becomes less. The main reason for this is that in the enlarged lung the bronchi and bronchioles are held open partially by way of elastic pull on their outsides by lung structural elements; however, as the lung becomes smaller, these structures are relaxed, so that the bronchi and bronchioles are collapsed more easily by external chest pressure, thus progressively reducing the maximum expiratory flow rate as well. Abnormalities of the Maximum Expiratory Flow-Volume Curve. Figure 42–2 shows the normal maximum expiratory flow-volume curve, along with two additional flowvolume curves recorded in two types of lung diseases: constricted lungs and partial airway obstruction. Note that the constricted lungs have both reduced total lung capacity (TLC) and reduced residual volume (RV). 526 Unit VII NORMAL Normal Airway obstruction Constricted lungs 400 A Maximum inspiration 4 300 FEV1 3 200 100 TLC RV 0 7 6 5 4 3 2 Lung volume (liters) 1 0 Figure 42–2 Effect of two respiratory abnormalities—constricted lungs and airway obstruction—-on the maximum expiratory flow-volume curve. TLC, total lung capacity; RV, residual volume. Furthermore, because the lung cannot expand to a normal maximum volume, even with the greatest possible expiratory effort, the maximal expiratory flow cannot rise to equal that of the normal curve. Constricted lung diseases include fibrotic diseases of the lung itself, such as tuberculosis and silicosis, and diseases that constrict the chest cage, such as kyphosis, scoliosis, and fibrotic pleurisy. In diseases with airway obstruction, it is usually much more difficult to expire than to inspire because the closing tendency of the airways is greatly increased by the extra positive pressure required in the chest to cause expiration. By contrast, the extra negative pleural pressure that occurs during inspiration actually “pulls” the airways open at the same time that it expands the alveoli. Therefore, air tends to enter the lung easily but then becomes trapped in the lungs. Over a period of months or years, this effect increases both the TLC and the RV, as shown by the green curve in Figure 42–2. Also, because of the obstruction of the airways and because they collapse more easily than normal airways, the maximum expiratory flow rate is greatly reduced. The classic disease that causes severe airway obstruction is asthma. Serious airway obstruction also occurs in some stages of emphysema. Forced Expiratory Vital Capacity and Forced Expiratory Volume Another exceedingly useful clinical pulmonary test, and one that is also simple, is to make a record on a spirometer of the forced expiratory vital capacity (FVC). Such a record is shown in Figure 42–3A for a person with normal lungs and in Figure 42–3B for a person with partial airway obstruction. In performing the FVC maneuver, the person first inspires maximally to the total lung capacity, then exhales into the Lung volume change (liters) Expiratory air flow (L/min) 500 Respiration FVC 2 FEV1/FVC% = 80% 1 0 0 B 1 2 3 4 5 6 7 AIRWAY OBSTRUCTION 4 3 FEV1 2 FEV1/FVC% FVC = 47% 1 0 0 1 2 3 4 Seconds 5 6 7 Figure 42–3 Recordings during the forced vital capacity maneuver: A, in a healthy person and B, in a person with partial airway obstruction. (The “zero” on the volume scale is residual volume.) spirometer with maximum expiratory effort as rapidly and as completely as possible. The total distance of the downslope of the lung volume record represents the FVC, as shown in the figure. Now, study the difference between the two records (1) for normal lungs and (2) for partial airway obstruction. The total volume changes of the FVCs are not greatly different, indicating only a moderate difference in basic lung volumes in the two persons. There is, however, a major difference in the amounts of air that these persons can expire each second, especially during the first second. Therefore, it is customary to compare the recorded forced expiratory volume during the first second (FEV1) with the normal. In the normal person (see Figure 42–3A), the percentage of the FVC that is expired in the first second divided by the total FVC (FEV1/FVC%) is 80 per cent. However, note in Figure 42–3B that, with airway obstruction, this value decreased to only 47 per cent. In serious airway obstruction, as often occurs in acute asthma, this can decrease to less than 20 per cent. Physiologic Peculiarities of Specific Pulmonary Abnormalities Chronic Pulmonary Emphysema The term pulmonary emphysema literally means excess air in the lungs. However, this term is usually Chapter 42 Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy used to describe complex obstructive and destructive process of the lungs caused by many years of smoking. It results from the following major pathophysiologic changes in the lungs: 1. Chronic infection, caused by inhaling smoke or other substances that irritate the bronchi and bronchioles. The chronic infection seriously deranges the normal protective mechanisms of the airways, including partial paralysis of the cilia of the respiratory epithelium, an effect caused by nicotine. As a result, mucus cannot be moved easily out of the passageways. Also, stimulation of excess mucus secretion occurs, which further exacerbates the condition. Too, inhibition of the alveolar macrophages occurs, so that they become less effective in combating infection. 2. The infection, excess mucus, and inflammatory edema of the bronchiolar epithelium together cause chronic obstruction of many of the smaller airways. 3. The obstruction of the airways makes it especially difficult to expire, thus causing entrapment of air in the alveoli and overstretching them. This, combined with the lung infection, causes marked destruction of as much as 50 to 80 per cent of the alveolar walls. Therefore, the final picture of the emphysematous lung is that shown in Figures 42–4 (top) and 42–5. The physiologic effects of chronic emphysema are extremely varied, depending on the severity of the disease and the relative degrees of bronchiolar obstruction versus lung parenchymal destruction.Among the different abnormalities are the following: 1. The bronchiolar obstruction increases airway resistance and results in greatly increased work of breathing. It is especially difficult for the person to move air through the bronchioles during expiration because the compressive force on the outside of the lung not only compresses the alveoli but also compresses the bronchioles, which further increases their resistance during expiration. 2. The marked loss of alveolar walls greatly decreases the diffusing capacity of the lung, which reduces the ability of the lungs to oxygenate the blood and remove carbon dioxide from the blood. 3. The obstructive process is frequently much worse in some parts of the lungs than in other parts, so that some portions of the lungs are well ventilated, while other portions are poorly ventilated. This often causes extremely abnormal ventilation-perfusion ratios, with a very low . . Va/Q in some parts (physiologic shunt), resulting . . in poor aeration of the blood, and very high Va/Q in other parts (physiologic dead space), resulting in wasted ventilation, both effects occurring in the same lungs. 4. Loss of large portions of the alveolar walls also decreases the number of pulmonary capillaries through which blood can pass. As a result, the pulmonary vascular resistance often increases markedly, causing pulmonary hypertension. This in 527 Figure 42–4 Contrast of the emphysematous lung (top figure) with the normal lung (bottom figure), showing extensive alveolar destruction in emphysema. (Reproduced with permission of Patricia Delaney and the Department of Anatomy, The Medical College of Wisconsin.) turn overloads the right side of the heart and frequently causes right-sided heart failure. Chronic emphysema usually progresses slowly over many years. The person develops both hypoxia and hypercapnia because of hypoventilation of many alveoli plus loss of alveolar walls. The net result of all these effects is severe, prolonged, devastating air hunger that can last for years until the hypoxia and hypercapnia cause death—a high penalty to pay for smoking. Pneumonia The term pneumonia includes any inflammatory condition of the lung in which some or all of the alveoli are filled with fluid and blood cells, as shown in Figure 42–5. A common type of pneumonia is bacterial pneumonia, caused most frequently by pneumococci. This disease begins with infection in the alveoli; the pulmonary membrane becomes inflamed and highly porous so that fluid and even red and white blood cells 528 Unit VII Respiration Fluid and blood cells Confluent alveoli Edema Normal Pneumonia Emphysema Figure 42–5 Lung alveolar changes in pneumonia and emphysema. leak out of the blood into the alveoli.Thus, the infected alveoli become progressively filled with fluid and cells, and the infection spreads by extension of bacteria or virus from alveolus to alveolus. Eventually, large areas of the lungs, sometimes whole lobes or even a whole lung, become “consolidated,” which means that they are filled with fluid and cellular debris. In pneumonia, the gas exchange functions of the lungs change in different stages of the disease. In early stages, the pneumonia process might well be localized to only one lung, with alveolar ventilation reduced while blood flow through the lung continues normally. This results in two major pulmonary abnormalities: (1) reduction in the total available surface area of the respiratory membrane and (2) decreased ventilationperfusion ratio. Both these effects cause hypoxemia (low blood oxygen) and hypercapnia (high blood carbon dioxide). Figure 42–6 shows the effect of the decreased ventilation-perfusion ratio in pneumonia, showing that the blood passing through the aerated lung becomes 97 per cent saturated with oxygen, whereas that passing through the unaerated lung is about 60 per cent saturated.Therefore, the average saturation of the blood pumped by the left heart into the aorta is only about 78 per cent, which is far below normal. Atelectasis Atelectasis means collapse of the alveoli. It can occur in localized areas of a lung or in an entire lung. Its most common causes are (1) total obstruction of the airway or (2) lack of surfactant in the fluids lining the alveoli. Airway Obstruction. The airway obstruction type of atelectasis usually results from (1) blockage of many small bronchi with mucus or (2) obstruction of a major bronchus by either a large mucus plug or some solid object such as a tumor. The air entrapped beyond the block is absorbed within minutes to hours by the blood flowing in the pulmonary capillaries. If the lung tissue Pulmonary arterial blood 60% saturated with O2 Pneumonia Right pulmonary vein 97% saturated Left pulmonary vein 60% saturated Aorta: Blood 1/2 = 97% 1/2 = 60% Mean = 78% Figure 42–6 Effect of pneumonia on percentage saturation of oxygen in the pulmonary artery, the right and left pulmonary veins, and the aorta. is pliable enough, this will lead simply to collapse of the alveoli. However, if the lung is rigid because of fibrotic tissue and cannot collapse, absorption of air from the alveoli creates very negative pressures within the alveoli, which pull fluid out of the pulmonary capillaries into the alveoli, thus causing the alveoli to fill completely with edema fluid. This almost always is the effect that occurs when an entire lung becomes atelectatic, a condition called massive collapse of the lung. The effects on overall pulmonary function caused by massive collapse (atelectasis) of an entire lung are shown in Figure 42–7. Collapse of the lung tissue not only occludes the alveoli but also almost always increases the resistance to blood flow through the pulmonary vessels of the collapsed lung. This resistance Chapter 42 Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy Asthma Pulmonary arterial blood 60% saturated with O2 Atelectasis Right pulmonary vein 97% saturated 529 Left pulmonary vein 60% saturatedflow 1/5 normal Aorta: Blood 5/6 = 97% 1/6 = 60% Mean saturation = 91% Figure 42–7 Effect of atelectasis on aortic blood oxygen saturation. increase occurs partially because of the lung collapse itself, which compresses and folds the vessels as the volume of the lung decreases. In addition, hypoxia in the collapsed alveoli causes additional vasoconstriction, as explained in Chapter 38. Because of the vascular constriction, blood flow through the atelectatic lung becomes slight. Fortunately, most of the blood is routed through the ventilated lung and therefore becomes well aerated. In the situation shown in Figure 42–7, five sixths of the blood passes through the aerated lung and only one sixth through the unaerated lung. As a result, the overall ventilation-perfusion ratio is only moderately compromised, so that the aortic blood has only mild oxygen desaturation despite total loss of ventilation in an entire lung. Lack of “Surfactant” as a Cause of Lung Collapse. The secretion and function of surfactant in the alveoli were discussed in Chapter 37. It was pointed out that the surfactant is secreted by special alveolar epithelial cells into the fluids that coat the inside surface of the alveoli. The surfactant in turn decreases the surface tension in the alveoli 2- to 10-fold, which normally plays a major role in preventing alveolar collapse. However, in a number of conditions, such as in hyaline membrane disease (also called respiratory distress syndrome), which often occurs in newborn premature babies, the quantity of surfactant secreted by the alveoli is so greatly depressed that the surface tension of the alveolar fluid becomes several times normal. This causes a serious tendency for the lungs of these babies to collapse or to become filled with fluid. As explained in Chapter 37, many of these infants die of suffocation when large portions of the lungs become atelectatic. Asthma is characterized by spastic contraction of the smooth muscle in the bronchioles, which partially obstructs the bronchioles and causes extremely difficult breathing. It occurs in 3 to 5 per cent of all people at some time in life. The usual cause of asthma is contractile hypersensitivity of the bronchioles in response to foreign substances in the air. In about 70 per cent of patients younger than age 30 years, the asthma is caused by allergic hypersensitivity, especially sensitivity to plant pollens. In older people, the cause is almost always hypersensitivity to nonallergenic types of irritants in the air, such as irritants in smog. The allergic reaction that occurs in the allergic type of asthma is believed to occur in the following way: The typical allergic person has a tendency to form abnormally large amounts of IgE antibodies, and these antibodies cause allergic reactions when they react with the specific antigens that have caused them to develop in the first place, as explained in Chapter 34. In asthma, these antibodies are mainly attached to mast cells that are present in the lung interstitium in close association with the bronchioles and small bronchi. When the asthmatic person breathes in pollen to which he or she is sensitive (that is, to which the person has developed IgE antibodies), the pollen reacts with the mast cell– attached antibodies and causes the mast cells to release several different substances. Among them are (a) histamine, (b) slow-reacting substance of anaphylaxis (which is a mixture of leukotrienes), (c) eosinophilic chemotactic factor, and (d) bradykinin. The combined effects of all these factors, especially the slow-reacting substance of anaphylaxis, are to produce (1) localized edema in the walls of the small bronchioles, as well as secretion of thick mucus into the bronchiolar lumens, and (2) spasm of the bronchiolar smooth muscle. Therefore, the airway resistance increases greatly. As discussed earlier in this chapter, the bronchiolar diameter becomes more reduced during expiration than during inspiration in asthma, caused by bronchiolar collapse during expiratory effort that compresses the outsides of the bronchioles. Because the bronchioles of the asthmatic lungs are already partially occluded, further occlusion resulting from the external pressure creates especially severe obstruction during expiration. That is, the asthmatic person often can inspire quite adequately but has great difficulty expiring. Clinical measurements show (1) greatly reduced maximum expiratory rate and (2) reduced timed expiratory volume. Also, all of this together results in dyspnea, or “air hunger,” which is discussed later in this chapter. The functional residual capacity and residual volume of the lung become especially increased during the acute asthmatic attack because of the difficulty in expiring air from the lungs. Also, over a period of years, the chest cage becomes permanently enlarged, causing a “barrel chest,” and both the functional residual capacity and lung residual volume become permanently increased. 530 Unit VII Tuberculosis In tuberculosis, the tubercle bacilli cause a peculiar tissue reaction in the lungs, including (1) invasion of the infected tissue by macrophages and (2) “walling off” of the lesion by fibrous tissue to form the so-called tubercle. This walling-off process helps to limit further transmission of the tubercle bacilli in the lungs and therefore is part of the protective process against extension of the infection. However, in about 3 per cent of all people who develop tuberculosis, if untreated, the walling-off process fails and tubercle bacilli spread throughout the lungs, often causing extreme destruction of lung tissue with formation of large abscess cavities. Thus, tuberculosis in its late stages is characterized by many areas of fibrosis throughout the lungs, as well as reduced total amount of functional lung tissue. These effects cause (1) increased “work” on the part of the respiratory muscles to cause pulmonary ventilation and reduced vital capacity and breathing capacity; (2) reduced total respiratory membrane surface area and increased thickness of the respiratory membrane, causing progressively diminished pulmonary diffusing capacity; and (3) abnormal ventilation-perfusion ratio in the lungs, further reducing overall pulmonary diffusion of oxygen and carbon dioxide. Hypoxia and Oxygen Therapy Almost any of the conditions discussed in the past few sections of this chapter can cause serious degrees of bodywide cellular hypoxia. Sometimes, oxygen therapy is of great value; other times, it is of moderate value; and, at still other times, it is of almost no value. Therefore, it is important to understand the different types of hypoxia; then we can discuss the physiologic principles of oxygen therapy. The following is a descriptive classification of the causes of hypoxia: 1. Inadequate oxygenation of the blood in the lungs because of extrinsic reasons a. Deficiency of oxygen in the atmosphere b. Hypoventilation (neuromuscular disorders) 2. Pulmonary disease a. Hypoventilation caused by increased airway resistance or decreased pulmonary compliance b. Abnormal alveolar ventilation-perfusion ratio (including either increased physiologic dead space or increased physiologic shunt) c. Diminished respiratory membrane diffusion 3. Venous-to-arterial shunts (“right-to-left” cardiac shunts) 4. Inadequate oxygen transport to the tissues by the blood a. Anemia or abnormal hemoglobin b. General circulatory deficiency c. Localized circulatory deficiency (peripheral, cerebral, coronary vessels) d. Tissue edema 5. Inadequate tissue capability of using oxygen a. Poisoning of cellular oxidation enzymes Respiration b. Diminished cellular metabolic capacity for using oxygen, because of toxicity, vitamin deficiency, or other factors This classification of the types of hypoxia is mainly self-evident from the discussions earlier in the chapter. Only one of the types of hypoxia in the classification needs further elaboration: this is the hypoxia caused by inadequate capability of the body’s tissue cells to use oxygen. Inadequate Tissue Capability to Use Oxygen. The classic cause of inability of the tissues to use oxygen is cyanide poisoning, in which the action of the enzyme cytochrome oxidase is completely blocked by the cyanide—to such an extent that the tissues simply cannot use oxygen even when plenty is available. Also, deficiencies of some of the tissue cellular oxidative enzymes or of other elements in the tissue oxidative system can lead to this type of hypoxia. A special example occurs in the disease beriberi, in which several important steps in tissue utilization of oxygen and formation of carbon dioxide are compromised because of vitamin B deficiency. Effects of Hypoxia on the Body. Hypoxia, if severe enough, can cause death of cells throughout the body, but in less severe degrees it causes principally (1) depressed mental activity, sometimes culminating in coma, and (2) reduced work capacity of the muscles. These effects are specifically discussed in Chapter 43 in relation to high-altitude physiology. Oxygen Therapy in Different Types of Hypoxia Oxygen can be administered by (1) placing the patient’s head in a “tent” that contains air fortified with oxygen, (2) allowing the patient to breathe either pure oxygen or high concentrations of oxygen from a mask, or (3) administering oxygen through an intranasal tube. Recalling the basic physiologic principles of the different types of hypoxia, one can readily decide when oxygen therapy will be of value and, if so, how valuable. In atmospheric hypoxia, oxygen therapy can completely correct the depressed oxygen level in the inspired gases and, therefore, provide 100 per cent effective therapy. In hypoventilation hypoxia, a person breathing 100 per cent oxygen can move five times as much oxygen into the alveoli with each breath as when breathing normal air. Therefore, here again oxygen therapy can be extremely beneficial. (However, this provides no benefit for the excess blood carbon dioxide also caused by the hypoventilation.) In hypoxia caused by impaired alveolar membrane diffusion, essentially the same result occurs as in hypoventilation hypoxia, because oxygen therapy can increase the Po2 in the lung alveoli from the normal value of about 100 mm Hg to as high as 600 mm Hg. PO2 in alveoli and blood (mm Hg) Chapter 42 Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy 300 200 Alveolar PO2 with tent therapy Normal alveolar PO2 Pulmonary edema + O2 therapy Pulmonary edema with no therapy 100 Capillary blood 0 Arterial end Venous end Blood in pulmonary capillary Figure 42–8 Absorption of oxygen into the pulmonary capillary blood in pulmonary edema with and without oxygen tent therapy. This raises the oxygen pressure gradient for diffusion of oxygen from the alveoli to the blood from the normal value of 60 mm Hg to as high as 560 mm Hg, an increase of more than 800 per cent. This highly beneficial effect of oxygen therapy in diffusion hypoxia is demonstrated in Figure 42–8, which shows that the pulmonary blood in this patient with pulmonary edema picks up oxygen three to four times as rapidly as would occur with no therapy. In hypoxia caused by anemia, abnormal hemoglobin transport of oxygen, circulatory deficiency, or physiologic shunt, oxygen therapy is of much less value because normal oxygen is already available in the alveoli. The problem instead is that one or more of the mechanisms for transporting oxygen from the lungs to the tissues is deficient. Even so, a small amount of extra oxygen, between 7 and 30 per cent, can be transported in the dissolved state in the blood when alveolar oxygen is increased to maximum even though the amount transported by the hemoglobin is hardly altered. This small amount of extra oxygen may be the difference between life and death. In the different types of hypoxia caused by inadequate tissue use of oxygen, there is abnormality neither of oxygen pickup by the lungs nor of transport to the tissues. Instead, the tissue metabolic enzyme system is simply incapable of using the oxygen that is delivered. Therefore, oxygen therapy is of hardly any measurable benefit. Cyanosis The term cyanosis means blueness of the skin, and its cause is excessive amounts of deoxygenated hemoglobin in the skin blood vessels, especially in the capillaries. This deoxygenated hemoglobin has an intense 531 dark blue-purple color that is transmitted through the skin. In general, definite cyanosis appears whenever the arterial blood contains more than 5 grams of deoxygenated hemoglobin in each 100 milliliters of blood. A person with anemia almost never becomes cyanotic because there is not enough hemoglobin for 5 grams to be deoxygenated in 100 milliliters of arterial blood. Conversely, in a person with excess red blood cells, as occurs in polycythemia vera, the great excess of available hemoglobin that can become deoxygenated leads frequently to cyanosis, even under otherwise normal conditions. Hypercapnia Hypercapnia means excess carbon dioxide in the body fluids. One might suspect, on first thought, that any respiratory condition that causes hypoxia would also cause hypercapnia. However, hypercapnia usually occurs in association with hypoxia only when the hypoxia is caused by hypoventilation or circulatory deficiency. The reasons for this are the following. Hypoxia caused by too little oxygen in the air, too little hemoglobin, or poisoning of the oxidative enzymes has to do only with the availability of oxygen or use of oxygen by the tissues. Therefore, it is readily understandable that hypercapnia is not a concomitant of these types of hypoxia. In hypoxia resulting from poor diffusion through the pulmonary membrane or through the tissues, serious hypercapnia usually does not occur at the same time because carbon dioxide diffuses 20 times as rapidly as oxygen. If hypercapnia does begin to occur, this immediately stimulates pulmonary ventilation, which corrects the hypercapnia but not necessarily the hypoxia. Conversely, in hypoxia caused by hypoventilation, carbon dioxide transfer between the alveoli and the atmosphere is affected as much as is oxygen transfer. Hypercapnia then occurs along with the hypoxia. And in circulatory deficiency, diminished flow of blood decreases carbon dioxide removal from the tissues, resulting in tissue hypercapnia in addition to tissue hypoxia. However, the transport capacity of the blood for carbon dioxide is more than three times that for oxygen, so that the resulting tissue hypercapnia is much less than the tissue hypoxia. When the alveolar Pco2 rises above about 60 to 75 mm Hg, an otherwise normal person by then is breathing about as rapidly and deeply as he or she can, and “air hunger,” also called dyspnea, becomes severe. If the Pco2 rises to 80 to 100 mm Hg, the person becomes lethargic and sometimes even semicomatose. Anesthesia and death can result when the Pco2 rises to 120 to 150 mm Hg. At these higher levels of Pco2, the excess carbon dioxide now begins to depress respiration rather than stimulate it, thus causing a vicious circle: (1) more carbon dioxide, (2) further decrease in 532 Unit VII Respiration respiration, (3) then more carbon dioxide, and so forth—culminating rapidly in a respiratory death. A Mechanism for applying positive and negative pressure Dyspnea Dyspnea means mental anguish associated with inability to ventilate enough to satisfy the demand for air. A common synonym is air hunger. At least three factors often enter into the development of the sensation of dyspnea. They are (1) abnormality of respiratory gases in the body fluids, especially hypercapnia and, to a much less extent, hypoxia; (2) the amount of work that must be performed by the respiratory muscles to provide adequate ventilation; and (3) state of mind. A person becomes very dyspneic especially from excess buildup of carbon dioxide in the body fluids. At times, however, the levels of both carbon dioxide and oxygen in the body fluids are normal, but to attain this normality of the respiratory gases, the person has to breathe forcefully. In these instances, the forceful activity of the respiratory muscles frequently gives the person a sensation of dyspnea. Finally, the person’s respiratory functions may be normal and still dyspnea may be experienced because of an abnormal state of mind. This is called neurogenic dyspnea or emotional dyspnea. For instance, almost anyone momentarily thinking about the act of breathing may suddenly start taking breaths a little more deeply than ordinarily because of a feeling of mild dyspnea. This feeling is greatly enhanced in people who have a psychological fear of not being able to receive a sufficient quantity of air, such as on entering small or crowded rooms. Artificial Respiration Resuscitator. Many types of respiratory resuscitators are available, and each has its own characteristic principles of operation. The resuscitator shown in Figure 42–9A consists of a tank supply of oxygen or air; a mechanism for applying intermittent positive pressure and, with some machines, negative pressure as well; and a mask that fits over the face of the patient or a connector for joining the equipment to an endotracheal tube. This apparatus forces air through the mask or endotracheal tube into the lungs of the patient during the positive-pressure cycle of the resuscitator and then usually allows the air to flow passively out of the lungs during the remainder of the cycle. Earlier resuscitators often caused damage to the lungs because of excessive positive pressure. Their usage was at one time greatly decried. However, resuscitators now have adjustable positive-pressure limits that are commonly set at 12 to 15 cm H2O pressure for normal lungs (but sometimes much higher for noncompliant lungs). Tank Respirator (the “Iron-Lung”). Figure 42–9B shows the tank respirator with a patient’s body inside the tank B Positive pressure valve Negative pressure valve Leather diaphragm Figure 42–9 A, Resuscitator. B, Tank respirator. and the head protruding through a flexible but airtight collar. At the end of the tank opposite the patient’s head a motor-driven leather diaphragm moves back and forth with sufficient excursion to raise and lower the pressure inside the tank. As the leather diaphragm moves inward, positive pressure develops around the body and causes expiration; as the diaphragm moves outward, negative pressure causes inspiration. Check valves on the respirator control the positive and negative pressures. Ordinarily these pressures are adjusted so that the negative pressure that causes inspiration falls to -10 to -20 cm H2O and the positive pressure rises to 0 to +5 cm H2O. Effect of the Resuscitator and the Tank Respirator on Venous Return. When air is forced into the lungs under posi- tive pressure by a resuscitator, or when the pressure around the patient’s body is reduced by the tank respirator, the pressure inside the lungs becomes greater than pressure everywhere else in the body. Flow of blood into the chest and heart from the peripheral veins becomes impeded. As a result, use of excessive pressures with either the resuscitator or the tank respirator can reduce the cardiac output— sometimes to lethal levels. For instance, continuous exposure for more than a few minutes to greater than 30 mm Hg positive pressure in the lungs can cause death because of inadequate venous return to the heart. Chapter 42 Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy References Albert R, Spiro S, Jett J: Comprehensive Respiratory Medicine. Philadelphia: Mosby, 2002. Barnes PJ, Adcock IM: How do corticosteroids work in asthma? Ann Intern Med 139:359, 2003. Basu S, Fenton MJ: Toll-like receptors: function and roles in lung disease. Am J Physiol Lung Cell Mol Physiol 286: L887, 2004. Cardoso WV: Molecular regulation of lung development. Annu Rev Physiol 63:471, 2001. Carter EP, Garat C, Imamura M: Continual emerging roles of HO-1: protection against airway inflammation. Am J Physiol Lung Cell Mol Physiol 287:L24, 2004. Dwyer TM: Cigarette smoke-induced airway inflammation as sampled by the expired breath condensate. Am J Med Sci 326:174, 2003. Knight DA, Holgate ST: The airway epithelium: structural and functional properties in health and disease. Respirology 8:432, 2003. McConnell AK, Romer LM: Dyspnoea in health and obstructive pulmonary disease: the role of respiratory muscle function and training. Sports Med 34:117, 2004. Naureckas ET, Solway J: Clinical practice. Mild asthma. N Engl J Med 345:1257, 2001. 533 Page S, Ammit AJ, Black JL, Armour CL: Human mast cell and airway smooth muscle cell interactions: implications for asthma. Am J Physiol Lung Cell Mol Physiol 281: L1313, 2001. Rodrigo GJ, Rodrigo C, Hall JB: Acute asthma in adults: a review. Chest 125:1081, 2004. Schwiebert LM: Cystic fibrosis, gene therapy, and lung inflammation: for better or worse? Am J Physiol Lung Cell Mol Physiol 286:L715, 2004. Sin DD, McAlister FA, Man SF, Anthonisen NR: Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 290:2301, 2003. Wardlaw AJ, Brightling CE, Green R, et al: New insights into the relationship between airway inflammation and asthma. Clin Sci (Lond) 103:201, 2002. West JB: Pulmonary Physiology and Pathophysiology: An Integrated, Case-Based Approach. Philadelphia: Lippincott Williams & Wilkins, 2001. Whitsett JA, Weaver TE: Hydrophobic surfactant proteins in lung function and disease. N Engl J Med 347:2141, 2002. Wills-Karp M, Ewart SL: Time to draw breath: asthmasusceptibility genes are identified. Nat Rev Genet 5:376, 2004. U N I Aviation, Space, and Deep-Sea Diving Physiology 43. Aviation, High-Altitude, and Space Physiology 44. Physiology of Deep-Sea Diving and Other Hyperbaric Conditions T VIII C H A P T E R 4 3 Aviation, High-Altitude, and Space Physiology As we have ascended to higher and higher altitudes in aviation, mountain climbing, and space vehicles, it has become progressively more important to understand the effects of altitude and low gas pressures (as well as several other factors—acceleratory forces, weightlessness, and so forth) on the human body. This chapter deals with these problems. Effects of Low Oxygen Pressure on the Body Barometric Pressures at Different Altitudes. Table 43–1 gives the approximate barometric and oxygen pressures at different altitudes, showing that at sea level, the barometric pressure is 760 mm Hg; at 10,000 feet, only 523 mm Hg; and at 50,000 feet, 87 mm Hg. This decrease in barometric pressure is the basic cause of all the hypoxia problems in high-altitude physiology because, as the barometric pressure decreases, the atmospheric oxygen partial pressure decreases proportionately, remaining at all times slightly less than 21 per cent of the total barometric pressure—Po2 at sea level about 159 mm Hg, but at 50,000 feet only 18 mm Hg. Alveolar PO2 at Different Elevations Carbon Dioxide and Water Vapor Decrease the Alveolar Oxygen. Even at high altitudes, carbon dioxide is continually excreted from the pulmonary blood into the alveoli. Also, water vaporizes into the inspired air from the respiratory surfaces. These two gases dilute the oxygen in the alveoli, thus reducing the oxygen concentration. Water vapor pressure in the alveoli remains 47 mm Hg as long as the body temperature is normal, regardless of altitude. In the case of carbon dioxide, during exposure to very high altitudes, the alveolar Pco2 falls from the sea-level value of 40 mm Hg to lower values. In the acclimatized person, who increases his or her ventilation about fivefold, the Pco2 falls to about 7 mm Hg because of increased respiration. Now let us see how the pressures of these two gases affect the alveolar oxygen. For instance, assume that the barometric pressure falls from the normal sea-level value of 760 mm Hg to 253 mm Hg, which is the usual measured value at the top of 29,028–foot Mount Everest. Forty-seven millimeters of mercury of this must be water vapor, leaving only 206 mm Hg for all the other gases. In the acclimatized person, 7 mm of the 206 mm Hg must be carbon dioxide, leaving only 199 mm Hg. If there were no use of oxygen by the body, one fifth of this 199 mm Hg would be oxygen and four fifths would be nitrogen; that is, the Po2 in the alveoli would be 40 mm Hg. However, some of this remaining alveolar oxygen is continually being absorbed into the blood, leaving about 35 mm Hg oxygen pressure in the alveoli. At the summit of Mount Everest, only the best of acclimatized people can barely survive when breathing air. But the effect is very different when the person is breathing pure oxygen, as we see in the following discussions. 537 538 Unit VIII Aviation, Space, and Deep-Sea Diving Physiology Table 43–1 Effects of Acute Exposure to Low Atmospheric Pressures on Alveolar Gas Concentrations and Arterial Oxygen Saturation* Breathing Air Altitude (ft) 0 10,000 20,000 30,000 40,000 50,000 Barometric Pressure (mm Hg) PO2 in Air (mm Hg) PCO2 in Alveoli (mm Hg) PO2 in Alveoli (mm Hg) 760 523 349 226 141 87 159 110 73 47 29 18 40 (40) 36 (23) 24 (10) 24 (7) 104 67 40 18 Breathing Pure Oxygen Arterial Oxygen Saturation (%) (104) (77) (53) (30) 97 90 73 24 (97) (92) (85) (38) PCO2 in Alveoli (mm Hg) PO2 in Alveoli (mm Hg) 40 40 40 40 36 24 673 436 262 139 58 16 Arterial Oxygen Saturation (%) 100 100 100 99 84 15 Alveolar PO2 at Different Altitudes. The fifth column of Table 43–1 shows the approximate Po2s in the alveoli at different altitudes when one is breathing air for both the unacclimatized and the acclimatized person. At sea level, the alveolar Po2 is 104 mm Hg; at 20,000 feet altitude, it falls to about 40 mm Hg in the unacclimatized person but only to 53 mm Hg in the acclimatized. The difference between these two is that alveolar ventilation increases much more in the acclimatized person than in the unacclimatized person, as we discuss later. Saturation of Hemoglobin with Oxygen at Different Altitudes. Figure 43–1 shows arterial blood oxygen saturation at different altitudes while a person is breathing air and while breathing oxygen. Up to an altitude of about 10,000 feet, even when air is breathed, the arterial oxygen saturation remains at least as high as 90 per cent. Above 10,000 feet, the arterial oxygen saturation falls rapidly, as shown by the blue curve of the figure, until it is slightly less than 70 per cent at 20,000 feet and much less at still higher altitudes. Effect of Breathing Pure Oxygen on Alveolar PO2 at Different Altitudes Arterial oxygen saturation (per cent) * Numbers in parentheses are acclimatized values. Breathing pure oxygen Breathing air 100 90 80 70 60 50 0 10 20 30 40 Altitude (thousands of feet) 50 Figure 43–1 Effect of high altitude on arterial oxygen saturation when breathing air and when breathing pure oxygen. When a person breathes pure oxygen instead of air, most of the space in the alveoli formerly occupied by nitrogen becomes occupied by oxygen. At 30,000 feet, an aviator could have an alveolar Po2 as high as 139 mm Hg instead of the 18 mm Hg when breathing air (see Table 43–1). The red curve of Figure 43–1 shows arterial blood hemoglobin oxygen saturation at different altitudes when one is breathing pure oxygen. Note that the saturation remains above 90 per cent until the aviator ascends to about 39,000 feet; then it falls rapidly to about 50 per cent at about 47,000 feet. breathing pure oxygen in an unpressurized airplane can ascend to far higher altitudes than one breathing air. For instance, the arterial saturation at 47,000 feet when one is breathing oxygen is about 50 per cent and is equivalent to the arterial oxygen saturation at 23,000 feet when one is breathing air. In addition, because an unacclimatized person usually can remain conscious until the arterial oxygen saturation falls to 50 per cent, for short exposure times the ceiling for an aviator in an unpressurized airplane when breathing air is about 23,000 feet and when breathing pure oxygen is about 47,000 feet, provided the oxygen-supplying equipment operates perfectly. The “Ceiling” When Breathing Air and When Breathing Oxygen in an Unpressurized Airplane Acute Effects of Hypoxia Comparing the two arterial blood oxygen saturation curves in Figure 43–1, one notes that an aviator Some of the important acute effects of hypoxia in the unacclimatized person breathing air, beginning at an Chapter 43 Aviation, High-Altitude, and Space Physiology altitude of about 12,000 feet, are drowsiness, lassitude, mental and muscle fatigue, sometimes headache, occasionally nausea, and sometimes euphoria.These effects progress to a stage of twitchings or seizures above 18,000 feet and end, above 23,000 feet in the unacclimatized person, in coma, followed shortly thereafter by death. One of the most important effects of hypoxia is decreased mental proficiency, which decreases judgment, memory, and performance of discrete motor movements. For instance, if an unacclimatized aviator stays at 15,000 feet for 1 hour, mental proficiency ordinarily falls to about 50 per cent of normal, and after 18 hours at this level it falls to about 20 per cent of normal. 539 An important mechanism for the gradual decrease in bicarbonate concentration is compensation by the kidneys for the respiratory alkalosis, as discussed in Chapter 30. The kidneys respond to decreased Pco2 by reducing hydrogen ion secretion and increasing bicarbonate excretion. This metabolic compensation for the respiratory alkalosis gradually reduces plasma and cerebrospinal fluid bicarbonate concentration and pH toward normal and removes part of the inhibitory effect on respiration of low hydrogen ion concentration. Thus, the respiratory centers are much more responsive to the peripheral chemoreceptor stimulus caused by the hypoxia after the kidneys compensate for the alkalosis. Increase in Red Blood Cells and Hemoglobin Concentration During Acclimatization. As discussed in Chapter 32, Acclimatization to Low PO2 A person remaining at high altitudes for days, weeks, or years becomes more and more acclimatized to the low Po2, so that it causes fewer deleterious effects on the body. And it becomes possible for the person to work harder without hypoxic effects or to ascend to still higher altitudes. The principal means by which acclimatization comes about are (1) a great increase in pulmonary ventilation, (2) increased numbers of red blood cells, (3) increased diffusing capacity of the lungs, (4) increased vascularity of the peripheral tissues, and (5) increased ability of the tissue cells to use oxygen despite low Po2. Increased Pulmonary Ventilation—Role of Arterial Chemoreceptors. Immediate exposure to low Po2 stimulates the arterial chemoreceptors, and this increases alveolar ventilation to a maximum of about 1.65 times normal. Therefore, compensation occurs within seconds for the high altitude, and it alone allows the person to rise several thousand feet higher than would be possible without the increased ventilation. Then, if the person remains at very high altitude for several days, the chemoreceptors increase ventilation still more, up to about five times normal. The immediate increase in pulmonary ventilation on rising to a high altitude blows off large quantities of carbon dioxide, reducing the Pco2 and increasing the pH of the body fluids. These changes inhibit the brain stem respiratory center and thereby oppose the effect of low PO2 to stimulate respiration by way of the peripheral arterial chemoreceptors in the carotid and aortic bodies. But during the ensuing 2 to 5 days, this inhibition fades away, allowing the respiratory center to respond with full force to the peripheral chemoreceptor stimulus from hypoxia, and ventilation increases to about five times normal. The cause of this fading inhibition is believed to be mainly a reduction of bicarbonate ion concentration in the cerebrospinal fluid as well as in the brain tissues. This in turn decreases the pH in the fluids surrounding the chemosensitive neurons of the respiratory center, thus increasing the respiratory stimulatory activity of the center. hypoxia is the principal stimulus for causing an increase in red blood cell production. Ordinarily, when a person remains exposed to low oxygen for weeks at a time, the hematocrit rises slowly from a normal value of 40 to 45 to an average of about 60, with an average increase in whole blood hemoglobin concentration from normal of 15 g/dl to about 20 g/dl. In addition, the blood volume also increases, often by 20 to 30 per cent, and this increase times the increased blood hemoglobin concentration gives an increase in total body hemoglobin of 50 or more per cent. Increased Diffusing Capacity After Acclimatization. It will be recalled that the normal diffusing capacity for oxygen through the pulmonary membrane is about 21 ml/mm Hg/min, and this diffusing capacity can increase as much as threefold during exercise. A similar increase in diffusing capacity occurs at high altitude. Part of the increase results from increased pulmonary capillary blood volume, which expands the capillaries and increases the surface area through which oxygen can diffuse into the blood. Another part results from an increase in lung air volume, which expands the surface area of the alveolar-capillary interface still more. A final part results from an increase in pulmonary arterial blood pressure; this forces blood into greater numbers of alveolar capillaries than normally—especially in the upper parts of the lungs, which are poorly perfused under usual conditions. Peripheral Circulatory System Changes During Acclimatization—Increased Tissue Capillarity. The cardiac output often increases as much as 30 per cent immediately after a person ascends to high altitude but then decreases back toward normal over a period of weeks as the blood hematocrit increases, so that the amount of oxygen transported to the peripheral body tissues remains about normal. Another circulatory adaptation is growth of increased numbers of systemic circulatory capillaries in the nonpulmonary tissues, which is called increased tissue capillarity (or angiogenesis). This occurs Unit VIII Aviation, Space, and Deep-Sea Diving Physiology especially in animals born and bred at high altitudes but less so in animals that later in life become exposed to high altitude. In active tissues exposed to chronic hypoxia, the increase in capillarity is especially marked. For instance, capillary density in right ventricular muscle increases markedly because of the combined effects of hypoxia and excess workload on the right ventricle caused by pulmonary hypertension at high altitude. Cellular Acclimatization. In animals native to altitudes of 13,000 to 17,000 feet, cell mitochondria and cellular oxidative enzyme systems are slightly more plentiful than in sea-level inhabitants. Therefore, it is presumed that the tissue cells of high altitude–acclimatized human beings also can use oxygen more effectively than can their sea-level counterparts. Natural Acclimatization of Native Human Beings Living at High Altitudes Many native human beings in the Andes and in the Himalayas live at altitudes above 13,000 feet—one group in the Peruvian Andes lives at an altitude of 17,500 feet and works a mine at an altitude of 19,000 feet. Many of these natives are born at these altitudes and live there all their lives. In all aspects of acclimatization, the natives are superior to even the bestacclimatized lowlanders, even though the lowlanders might also have lived at high altitudes for 10 or more years. Acclimatization of the natives begins in infancy. The chest size, especially, is greatly increased, whereas the body size is somewhat decreased, giving a high ratio of ventilatory capacity to body mass. In addition, their hearts, which from birth onward pump extra amounts of cardiac output, are considerably larger than the hearts of lowlanders. Delivery of oxygen by the blood to the tissues is also highly facilitated in these natives. For instance, Figure 43–2 shows oxygen-hemoglobin dissociation curves for natives who live at sea level and for their counterparts who live at 15,000 feet. Note that the arterial oxygen Po2 in the natives at high altitude is only 40 mm Hg, but because of the greater quantity of hemoglobin, the quantity of oxygen in their arterial blood is greater than that in the blood of the natives at the lower altitude. Note also that the venous Po2 in the highaltitude natives is only 15 mm Hg less than the venous Po2 for the lowlanders, despite the very low arterial Po2, indicating that oxygen transport to the tissues is exceedingly effective in the naturally acclimatized high-altitude natives. Reduced Work Capacity at High Altitudes and Positive Effect of Acclimatization In addition to the mental depression caused by hypoxia, as discussed earlier, the work capacity of all muscles is greatly decreased in hypoxia. This includes Quantity of oxygen in blood (vol %) 540 Mountain dwellers 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 (15,000 ft) (Arterial values) X X X X Sea-level dwellers (Venous values) 0 20 40 60 80 100 120 140 Pressure of oxygen in blood (PO2) (mm Hg) Figure 43–2 Oxygen-hemoglobin dissociation curves for blood of high-altitude residents (red curve) and sea-level residents (blue curve), showing the respective arterial and venous PO2 levels and oxygen contents as recorded in their native surroundings. (Data from Oxygen-dissociation curves for bloods of high-altitude and sealevel residents. PAHO Scientific Publication No. 140, Life at High Altitudes, 1966.) not only skeletal muscles but also cardiac muscles. In general, work capacity is reduced in direct proportion to the decrease in maximum rate of oxygen uptake that the body can achieve. To give an idea of the importance of acclimatization in increasing work capacity, consider this: The work capacities as per cent of normal for unacclimatized and acclimatized people at an altitude of 17,000 feet are as follows: Work capacity (per cent of normal) Unacclimatized Acclimatized for 2 months Native living at 13,200 feet but working at 17,000 feet Thus, naturally acclimatized native achieve a daily work output even at almost equal to that of a lowlander at even well-acclimatized lowlanders can achieve this result. 50 68 87 persons can high altitude sea level, but almost never Acute Mountain Sickness and High-Altitude Pulmonary Edema A small percentage of people who ascend rapidly to high altitudes become acutely sick and can die if not Chapter 43 541 Aviation, High-Altitude, and Space Physiology given oxygen or removed to a low altitude. The sickness begins from a few hours up to about 2 days after ascent. Two events frequently occur: 1. Acute cerebral edema. This is believed to result from local vasodilation of the cerebral blood vessels, caused by the hypoxia. Dilation of the arterioles increases blood flow into the capillaries, thus increasing capillary pressure, which in turn causes fluid to leak into the cerebral tissues. The cerebral edema can then lead to severe disorientation and other effects related to cerebral dysfunction. 2. Acute pulmonary edema. The cause of this is still unknown, but a suggested answer is the following: The severe hypoxia causes the pulmonary arterioles to constrict potently, but the constriction is much greater in some parts of the lungs than in other parts, so that more and more of the pulmonary blood flow is forced through fewer and fewer still unconstricted pulmonary vessels. The postulated result is that the capillary pressure in these areas of the lungs becomes especially high and local edema occurs. Extension of the process to progressively more areas of the lungs leads to spreading pulmonary edema and severe pulmonary dysfunction that can be lethal. Allowing the person to breathe oxygen usually reverses the process within hours. Effects of Acceleratory Forces on the Body in Aviation and Space Physiology Because of rapid changes in velocity and direction of motion in airplanes or spacecraft, several types of acceleratory forces affect the body during flight. At the beginning of flight, simple linear acceleration occurs; at the end of flight, deceleration; and every time the vehicle turns, centrifugal acceleration. Centrifugal Acceleratory Forces When an airplane makes a turn, the force of centrifugal acceleration is determined by the following relation: f= mv 2 r in which f is centrifugal acceleratory force, m is the mass of the object, v is velocity of travel, and r is radius of curvature of the turn. From this formula, it is obvious that as the velocity increases, the force of centrifugal acceleration increases in proportion to the square of the velocity. It is also obvious that the force of acceleration is directly proportional to the sharpness of the turn (the less the radius). Chronic Mountain Sickness of Acceleratory Force—“G.” When an aviator is simply sitting in his seat, the force with which he is pressing against the seat results from the pull of gravity and is equal to his weight. The intensity of this force is said to be +1 G because it is equal to the pull of gravity. If the force with which he presses against the seat becomes five times his normal weight during pull-out from a dive, the force acting on the seat is +5 G. If the airplane goes through an outside loop so that the person is held down by his seat belt, negative G is applied to his body; if the force with which he is held down by his belt is equal to the weight of his body, the negative force is -1 G. Measurement Occasionally, a person who remains at high altitude too long develops chronic mountain sickness, in which the following effects occur: (1) the red cell mass and hematocrit become exceptionally high, (2) the pulmonary arterial pressure becomes elevated even more than the normal elevation that occurs during acclimatization, (3) the right side of the heart becomes greatly enlarged, (4) the peripheral arterial pressure begins to fall, (5) congestive heart failure ensues, and (6) death often follows unless the person is removed to a lower altitude. The causes of this sequence of events are probably threefold: First, the red cell mass becomes so great that the blood viscosity increases severalfold; this increased viscosity tends to decrease tissue blood flow so that oxygen delivery also begins to decrease. Second, the pulmonary arterioles become vasoconstricted because of the lung hypoxia. This results from the hypoxic vascular constrictor effect that normally operates to divert blood flow from low-oxygen to high-oxygen alveoli, as explained in Chapter 38. But because all the alveoli are now in the low-oxygen state, all the arterioles become constricted, the pulmonary arterial pressure rises excessively, and the right side of the heart fails. Third, the alveolar arteriolar spasm diverts much of the blood flow through nonalveolar pulmonary vessels, thus causing an excess of pulmonary shunt blood flow where the blood is poorly oxygenated; this further compounds the problem. Most of these people recover within days or weeks when they are moved to a lower altitude. Effects of Centrifugal Acceleratory Force on the Body— (Positive G) Effects on the Circulatory System. The most impor- tant effect of centrifugal acceleration is on the circulatory system, because blood is mobile and can be translocated by centrifugal forces. When an aviator is subjected to positive G, blood is centrifuged toward the lowermost part of the body. Thus, if the centrifugal acceleratory force is +5 G and the person is in an immobilized standing position, the pressure in the veins of the feet becomes greatly increased (to about 450 mm Hg). In the sitting position, the pressure becomes nearly 300 mm Hg. And, as pressure in the vessels of the lower body increases, these vessels passively dilate so that a major portion of the blood from the upper body is translocated into the lower vessels. Because the heart cannot pump 542 Arterial pressure (mm Hg) Unit VIII Aviation, Space, and Deep-Sea Diving Physiology 100 50 0 0 5 10 15 20 25 30 Time from start of G to symptoms (sec) Figure 43–3 Changes in systolic (top of curve) and diastolic (bottom of curve) arterial pressures after abrupt and continuing exposure of a sitting person to an acceleratory force from top to bottom of 3.3. G. (Data from Martin EE, Henry JP: Effects of time and temperature upon tolerance to positive acceleration. J Aviation Med 22:382, 1951.) unless blood returns to it, the greater the quantity of blood “pooled” in this way in the lower body, the less that is available for the cardiac output. Figure 43–3 shows the changes in systolic and diastolic arterial pressures (top and bottom curves, respectively) in the upper body when a centrifugal acceleratory force of +3.3 G is suddenly applied to a sitting person. Note that both these pressures fall below 22 mm Hg for the first few seconds after the acceleration begins but then return to a systolic pressure of about 55 mm Hg and a diastolic pressure of 20 mm Hg within another 10 to 15 seconds. This secondary recovery is caused mainly by activation of the baroreceptor reflexes. Acceleration greater than 4 to 6 G causes “blackout” of vision within a few seconds and unconsciousness shortly thereafter. If this great degree of acceleration is continued, the person will die. cranium show less tendency for rupture than would be expected for the following reason: The cerebrospinal fluid is centrifuged toward the head at the same time that blood is centrifuged toward the cranial vessels, and the greatly increased pressure of the cerebrospinal fluid acts as a cushioning buffer on the outside of the brain to prevent intracerebral vascular rupture. Because the eyes are not protected by the cranium, intense hyperemia occurs in them during strong negative G. As a result, the eyes often become temporarily blinded with “red-out.” Protection of the Body Against Centrifugal Acceleratory Forces. Specific procedures and apparatus have been developed to protect aviators against the circulatory collapse that might occur during positive G. First, if the aviator tightens his or her abdominal muscles to an extreme degree and leans forward to compress the abdomen, some of the pooling of blood in the large vessels of the abdomen can be prevented, thereby delaying the onset of blackout. Also, special “antiG” suits have been devised to prevent pooling of blood in the lower abdomen and legs. The simplest of these applies positive pressure to the legs and abdomen by inflating compression bags as the G increases. Theoretically, a pilot submerged in a tank or suit of water might experience little effect of G forces on the circulation because the pressures developed in the water pressing on the outside of the body during centrifugal acceleration would almost exactly balance the forces acting in the body. However, the presence of air in the lungs still allows displacement of the heart, lung tissues, and diaphragm into seriously abnormal positions despite submersion in water. Therefore, even if this procedure were used, the limit of safety almost certainly would still be less than 10 G. Effects of Linear Acceleratory Forces on the Body Effects on the Vertebrae. Extremely high acceleratory forces for even a fraction of a second can fracture the vertebrae. The degree of positive acceleration that the average person can withstand in the sitting position before vertebral fracture occurs is about 20 G. Negative G. The effects of negative G on the body are less dramatic acutely but possibly more damaging permanently than the effects of positive G. An aviator can usually go through outside loops up to negative acceleratory forces of -4 to -5 G without causing permanent harm, although causing intense momentary hyperemia of the head. Occasionally, psychotic disturbances lasting for 15 to 20 minutes occur as a result of brain edema. Occasionally, negative G forces can be so great (-20 G, for instance) and centrifugation of the blood into the head is so great that the cerebral blood pressure reaches 300 to 400 mm Hg, sometimes causing small vessels on the surface of the head and in the brain to rupture. However, the vessels inside the Acceleratory Forces in Space Travel. Unlike an airplane, a spacecraft cannot make rapid turns; therefore, centrifugal acceleration is of little importance except when the spacecraft goes into abnormal gyrations. However, blast-off acceleration and landing deceleration can be tremendous; both of these are types of linear acceleration, one positive and the other negative. Figure 43–4 shows an approximate profile of acceleration during blast-off in a three-stage spacecraft, demonstrating that the first-stage booster causes acceleration as high as 9 G, and the second-stage booster as high as 8 G. In the standing position, the human body could not withstand this much acceleration, but in a semireclining position transverse to the axis of acceleration, this amount of acceleration can be withstood with ease despite the fact that the acceleratory forces continue for as long as several minutes at a time. Therefore, we see the reason for the reclining seats used by astronauts. Chapter 43 Aviation, High-Altitude, and Space Physiology other words, the speed of landing is about 20 feet per second, and the force of impact against the earth is 1/81 the impact force without a parachute. Even so, the force of impact is still great enough to cause considerable damage to the body unless the parachutist is properly trained in landing. Actually, the force of impact with the earth is about the same as that which would be experienced by jumping without a parachute from a height of about 6 feet. Unless forewarned, the parachutist will be tricked by his senses into striking the earth with extended legs, and this will result in tremendous deceleratory forces along the skeletal axis of the body, resulting in fracture of his pelvis, vertebrae, or leg. Consequently, the trained parachutist strikes the earth with knees bent but muscles taut to cushion the shock of landing. 10 Acceleration (G) 8 6 4 2 First booster 0 0 1 Second booster 2 3 Minutes Space ship 4 543 5 “Artificial Climate” in the Sealed Spacecraft Figure 43–4 Acceleratory forces during takeoff of a spacecraft. Problems also occur during deceleration when the spacecraft re-enters the atmosphere. A person traveling at Mach 1 (the speed of sound and of fast airplanes) can be safely decelerated in a distance of about 0.12 mile, whereas a person traveling at a speed of Mach 100 (a speed possible in interplanetary space travel) would require a distance of about 10,000 miles for safe deceleration. The principal reason for this difference is that the total amount of energy that must be dispelled during deceleration is proportional to the square of the velocity, which alone increases the required distance for decelerations between Mach 1 versus Mach 100 about 10,000-fold. But in addition to this, a human being can withstand far less deceleration if the period of deceleration lasts for a long time than for a short time. Therefore, deceleration must be accomplished much more slowly from high velocities than is necessary at lower velocities. Deceleratory Forces Associated with Parachute Jumps. When the parachuting aviator leaves the airplane, his velocity of fall is at first exactly 0 feet per second. However, because of the acceleratory force of gravity, within 1 second his velocity of fall is 32 feet per second (if there is no air resistance); in 2 seconds it is 64 feet per second; and so on. As the velocity of fall increases, the air resistance tending to slow the fall also increases. Finally, the deceleratory force of the air resistance exactly balances the acceleratory force of gravity, so that after falling for about 12 seconds, the person will be falling at a “terminal velocity” of 109 to 119 miles per hour (175 feet per second). If the parachutist has already reached terminal velocity before opening his parachute, an “opening shock load” of up to 1200 pounds can occur on the parachute shrouds. The usual-sized parachute slows the fall of the parachutist to about one ninth the terminal velocity. In Because there is no atmosphere in outer space, an artificial atmosphere and climate must be produced in a spacecraft. Most important, the oxygen concentration must remain high enough and the carbon dioxide concentration low enough to prevent suffocation. In some earlier space missions, a capsule atmosphere containing pure oxygen at about 260 mm Hg pressure was used, but in the modern space shuttle, gases about equal to those in normal air are used, with four times as much nitrogen as oxygen and a total pressure of 760 mm Hg. The presence of nitrogen in the mixture greatly diminishes the likelihood of fire and explosion. It also protects against development of local patches of lung atelectasis that often occur when breathing pure oxygen because oxygen is absorbed rapidly when small bronchi are temporarily blocked by mucous plugs. For space travel lasting more than several months, it is impractical to carry along an adequate oxygen supply. For this reason, recycling techniques have been proposed for use of the same oxygen over and over again. Some recycling processes depend on purely physical procedures, such as electrolysis of water to release oxygen. Others depend on biological methods, such as use of algae with their large store of chlorophyll to release oxygen from carbon dioxide by the process of photosynthesis. A completely satisfactory system for recycling has yet to be achieved. Weightlessness in Space A person in an orbiting satellite or a nonpropelled spacecraft experiences weightlessness, or a state of near-zero G force, which is sometimes called microgravity. That is, the person is not drawn toward the bottom, sides, or top of the spacecraft but simply floats inside its chambers. The cause of this is not failure of gravity to pull on the body, because gravity from any nearby heavenly body is still active. However, the gravity acts on both the spacecraft and the person at 544 Unit VIII Aviation, Space, and Deep-Sea Diving Physiology the same time, so that both are pulled with exactly the same acceleratory forces and in the same direction. For this reason, the person simply is not attracted toward any specific wall of the spacecraft. Physiologic Problems of Weightlessness (Microgravity). The physiologic problems of weightlessness have not proved to be of much significance, as long as the period of weightlessness is not too long. Most of the problems that do occur are related to three effects of the weightlessness: (1) motion sickness during the first few days of travel, (2) translocation of fluids within the body because of failure of gravity to cause normal hydrostatic pressures, and (3) diminished physical activity because no strength of muscle contraction is required to oppose the force of gravity. Almost 50 per cent of astronauts experience motion sickness, with nausea and sometimes vomiting, during the first 2 to 5 days of space travel. This probably results from an unfamiliar pattern of motion signals arriving in the equilibrium centers of the brain, and at the same time lack of gravitational signals. The observed effects of prolonged stay in space are the following: (1) decrease in blood volume, (2) decrease in red blood cell mass, (3) decrease in muscle strength and work capacity, (4) decrease in maximum cardiac output, and (5) loss of calcium and phosphate from the bones, as well as loss of bone mass. Most of these same effects also occur in people who lie in bed for an extended period of time. For this reason, exercise programs are carried out by astronauts during prolonged space missions. In previous space laboratory expeditions in which the exercise program had been less vigorous, the astronauts had severely decreased work capacities for the first few days after returning to earth. They also had a tendency to faint (and still do, to some extent) when they stood up during the first day or so after return to gravity because of diminished blood volume and diminished responses of the arterial pressure control mechanisms. Cardiovascular, Muscle, and Bone “Deconditioning” During Prolonged Exposure to Weightlessness. During very long space flights and prolonged exposure to microgravity, gradual “deconditioning” effects occur on the cardiovascular system, skeletal muscles, and bone despite rigorous exercise during the flight. Studies of astronauts on space flights lasting several months have shown that they may lose as much 1.0 percent of their bone mass each month even though they continue to exercise. Substantial atrophy of cardiac and skeletal muscles also occurs during prolonged exposure to a microgravity environment. One of the most serious effects is cardiovascular “deconditioning”, which includes decreased work capacity, reduced blood volume, impaired baroreceptor reflexes, and reduced orthostatic tolerance. These changes greatly limit the astronauts’ ability to stand upright or perform normal daily activities after returning to the full gravity of Earth. Astronauts returning from space flights lasting 4 to 6 months are also susceptible to bone fractures and may require several weeks before they return to pre-flight cardiovascular, bone, and muscle fitness. As space flights become longer in preparation for possible human exploration of other planets, such as Mars, the effects of prolonged microgravity could pose a very serious threat to astronauts after they land, especially in the event of an emergency landing. Therefore, considerable research effort has been directed toward developing countermeasures, in addition to exercise, that can prevent or more effectively attenuate these changes. One such countermeasure that is being tested is the application of intermittent “artificial gravity” caused by short periods (e.g., 1 hour each day) of centrifugal acceleration of the astronauts while they sit in specially designed short-arm centrifuges that create forces of up to 2 to 3 G. References Adams GR, Caiozzo VJ, Baldwin KM: Skeletal muscle unweighting: spaceflight and ground-based models. J Appl Physiol 95:2185, 2003. Alfrey CP, Udden MM, Leach-Huntoon C, et al: Control of red blood cell mass in spaceflight. J Appl Physiol 81:98, 1996. Basnyat B, Murdoch DR: High-altitude illness. Lancet 361:1967, 2003. Convertino VA: Mechanisms of microgravity induced orthostatic intolerance: implications for effective countermeasures. J Gravit Physiol 9:1, 2002. Eckberg DL: Bursting into space: alterations of sympathetic control by space travel. Acta Physiol Scand 177:299, 2003. Hackett PH, Roach RC: High-altitude illness. N Engl J Med 345:107, 2001. Harm DL, Jennings RT, Meck JV, et al: Gender issues related to spaceflight: a NASA perspective. J Appl Physiol 91:2374, 2001. Hochachka PW, Beatty CL, Burelle Y, et al: The lactate paradox in human high-altitude physiological performance. News Physiol Sci 17:122, 2002. Hoschele S, Mairbaurl H: Alveolar flooding at high altitude: failure of reabsorption? News Physiol Sci 18:55, 2003. Hultgren HN: High-altitude pulmonary edema: current concepts. Annu Rev Med 47:267, 1996. Rupert JL, Hochachka PW: Genetic approaches to understanding human adaptation to altitude in the Andes. J Exp Biol 204(Pt 18):3151, 2001. Smith SM, Heer M: Calcium and bone metabolism during space flight. Nutrition 18:849, 2002. West JB: Climbing Mount Everest without oxygen. News Physiol Sci 1:25, 1986. West JB: Man in space. News Physiol Sci 1:198, 1986. West JB: High Life—History of High-Altitude Physiology and Medicine. Bethesda, MD: American Physiological Society, 1998. Zhang LF: Vascular adaptation to microgravity: what have we learned? J Appl Physiol 91:2415, 2001. C H A P T E R 4 4 Physiology of Deep-Sea Diving and Other Hyperbaric Conditions When human beings descend beneath the sea, the pressure around them increases tremendously. To keep the lungs from collapsing, air must be supplied at very high pressure to keep them inflated. This exposes the blood in the lungs also to extremely high alveolar gas pressure, a condition called hyperbarism. Beyond certain limits, these high pressures can cause tremendous alterations in body physiology and can be lethal. Relationship of Pressure to Sea Depth. A column of seawater 33 feet deep exerts the same pressure at its bottom as the pressure of the atmosphere above the sea. Therefore, a person 33 feet beneath the ocean surface is exposed to 2 atmospheres pressure, 1 atmosphere of pressure caused by the weight of the air above the water and the second atmosphere by the weight of the water itself. At 66 feet the pressure is 3 atmospheres, and so forth, in accord with the table in Figure 44–1. Effect of Sea Depth on the Volume of Gases-Boyle’s Law. Another important effect of depth is compression of gases to smaller and smaller volumes. The lower part of Figure 44–1 shows a bell jar at sea level containing 1 liter of air. At 33 feet beneath the sea, where the pressure is 2 atmospheres, the volume has been compressed to only one-half liter, and at 8 atmospheres (233 feet) to one-eighth liter.Thus, the volume to which a given quantity of gas is compressed is inversely proportional to the pressure. This is a principle of physics called Boyle’s law, which is extremely important in diving physiology because increased pressure can collapse the air chambers of the diver’s body, especially the lungs, and often causes serious damage. Many times in this chapter it is necessary to refer to actual volume versus sea-level volume. For instance, we might speak of an actual volume of 1 liter at a depth of 300 feet; this is the same quantity of air as a sea-level volume of 10 liters. Effect of High Partial Pressures of Individual Gases on the Body The individual gases to which a diver is exposed when breathing air are nitrogen, oxygen, and carbon dioxide; each of these at times can cause significant physiologic effects at high pressures. Nitrogen Narcosis at High Nitrogen Pressures About four fifths of the air is nitrogen. At sea-level pressure, the nitrogen has no significant effect on bodily function, but at high pressures it can cause varying degrees of narcosis. When the diver remains beneath the sea for an hour or more and is breathing compressed air, the depth at which the first symptoms of mild narcosis appear is about 120 feet. At this level the diver begins to exhibit 545 Unit VIII Depth (feet) Sea level 33 66 100 133 166 200 300 400 500 Aviation, Space, and Deep-Sea Diving Physiology Atmosphere(s) 1 2 3 4 5 6 7 10 13 16 1 liter Sea level 1/2 1/4 liter liter 33 ft 100 ft 30 A Oxygen in blood (volumes per cent) 546 25 B 20 Oxygen-hemoglobin dissociation curve Total O2 in blood Combined with hemoglobin Dissolved in water of blood Normal alveolar oxygen pressure 15 10 Oxygen poisoning 5 0 0 1560 2280 3040 760 Oxygen partial pressure in lungs (mm Hg) Figure 44–2 Quantity of oxygen dissolved in the fluid of the blood and in combination with hemoglobin at very high PO2s. Oxygen Toxicity at High Pressures 1/8 liter 233 ft Figure 44–1 Effect of sea depth on pressure (top table) and on gas volume (bottom). joviality and to lose many of his or her cares. At 150 to 200 feet, the diver becomes drowsy. At 200 to 250 feet, his or her strength wanes considerably, and the diver often becomes too clumsy to perform the work required. Beyond 250 feet (8.5 atmospheres pressure), the diver usually becomes almost useless as a result of nitrogen narcosis if he or she remains at these depths too long. Nitrogen narcosis has characteristics similar to those of alcohol intoxication, and for this reason it has frequently been called “raptures of the depths.” The mechanism of the narcotic effect is believed to be the same as that of most other gas anesthetics. That is, it dissolves in the fatty substances in neuronal membranes and, because of its physical effect on altering ionic conductance through the membranes, reduces neuronal excitability. Effect of Very High PO2 on Blood Oxygen Transport. When the Po2 in the blood rises above 100 mm Hg, the amount of oxygen dissolved in the water of the blood increases markedly. This is shown in Figure 44–2, which depicts the same oxygen-hemoglobin dissociation curve as that shown in Chapter 40 but with the alveolar Po2 extended to more than 3000 mm Hg. Also depicted by the lowest curve in the figure is the volume of oxygen dissolved in the fluid of the blood at each Po2 level. Note that in the normal range of alveolar Po2 (below 120 mm Hg), almost none of the total oxygen in the blood is accounted for by dissolved oxygen, but as the oxygen pressure rises into the thousands of millimeters of mercury, a large portion of the total oxygen is then dissolved in the water of the blood, in addition to that bound with hemoglobin. Effect of High Alveolar PO2 on Tissue PO2. Let us assume that the Po2 in the lungs is about 3000 mm Hg (4 atmospheres pressure). Referring to Figure 44–2, one finds that this represents a total oxygen content in each 100 milliliters of blood of about 29 volumes per cent, as demonstrated by point A in the figure—this means 20 volumes per cent bound with hemoglobin and 9 volumes per cent dissolved in the blood water. As this blood passes through the tissue capillaries and the tissues use their normal amount of oxygen, about 5 milliliters from each 100 milliliters of blood, the Chapter 44 Physiology of Deep-Sea Diving and Other Hyperbaric Conditions oxygen content on leaving the tissue capillaries is still 24 volumes per cent (point B in the figure). At this point, the Po2 is approximately 1200 mm Hg, which means that oxygen is delivered to the tissues at this extremely high pressure instead of at the normal value of 40 mm Hg. Thus, once the alveolar Po2 rises above a critical level, the hemoglobin-oxygen buffer mechanism (discussed in Chapter 40) is no longer capable of keeping the tissue Po2 in the normal, safe range between 20 and 60 mm Hg. Acute Oxygen Poisoning. The extremely high tissue Po2 that occurs when oxygen is breathed at very high alveolar oxygen pressure can be detrimental to many of the body’s tissues. For instance, breathing oxygen at 4 atmospheres pressure of oxygen (Po2 = 3040 mm Hg) will cause brain seizures followed by coma in most people within 30 to 60 minutes. The seizures often occur without warning and, for obvious reasons, are likely to be lethal to divers submerged beneath the sea. Other symptoms encountered in acute oxygen poisoning include nausea, muscle twitchings, dizziness, disturbances of vision, irritability, and disorientation. Exercise greatly increases the diver’s susceptibility to oxygen toxicity, causing symptoms to appear much earlier and with far greater severity than in the resting person. Excessive Intracellular Oxidation as a Cause of Nervous System Oxygen Toxicity—“Oxidizing Free Radicals.” Molecular oxygen (O2) has little capability of oxidizing other chemical compounds. Instead, it must first be converted into an “active” form of oxygen. There are several forms of active oxygen called oxygen free radicals. One of the most important _ of these is the superoxide free radical O2 , and another is the peroxide radical in the form of hydrogen peroxide. Even when the tissue Po2 is normal at the level of 40 mm Hg, small amounts of free radicals are continually being formed from the dissolved molecular oxygen. Fortunately, the tissues also contain multiple enzymes that rapidly remove these free radicals, including peroxidases, catalases, and superoxide dismutases. Therefore, so long as the hemoglobin-oxygen buffering mechanism maintains a normal tissue Po2, the oxidizing free radicals are removed rapidly enough that they have little or no effect in the tissues. Above a critical alveolar Po2 (above about 2 atmospheres Po2), the hemoglobin-oxygen buffering mechanism fails, and the tissue Po2 can then rise to hundreds or thousands of millimeters of mercury. At these high levels, the amounts of oxidizing free radicals literally swamp the enzyme systems designed to remove them, and now they can have serious destructive and even lethal effects on the cells. One of the principal effects is to oxidize the polyunsaturated fatty acids that are essential components of many of the cell membranes. Another effect is to oxidize some of the cellular enzymes, thus damaging severely the cellular metabolic systems. The nervous tissues are especially susceptible because of their high lipid content. 547 Therefore, most of the acute lethal effects of acute oxygen toxicity are caused by brain dysfunction. Chronic Oxygen Poisoning Causes Pulmonary Disability. A person can be exposed to only 1 atmosphere pressure of oxygen almost indefinitely without developing the acute oxygen toxicity of the nervous system just described. However, after only about 12 hours of 1 atmosphere oxygen exposure, lung passageway congestion, pulmonary edema, and atelectasis caused by damage to the linings of the bronchi and alveoli begin to develop. The reason for this effect in the lungs but not in other tissues is that the air spaces of the lungs are directly exposed to the high oxygen pressure, but oxygen is delivered to the other body tissues at almost normal Po2 because of the hemoglobin-oxygen buffer system. Carbon Dioxide Toxicity at Great Depths in the Sea If the diving gear is properly designed and functions properly, the diver has no problem due to carbon dioxide toxicity because depth alone does not increase the carbon dioxide partial pressure in the alveoli. This is true because depth does not increase the rate of carbon dioxide production in the body, and as long as the diver continues to breathe a normal tidal volume and expires the carbon dioxide as it is formed, alveolar carbon dioxide pressure will be maintained at a normal value. In certain types of diving gear, however, such as the diving helmet and some types of rebreathing apparatuses, carbon dioxide can build up in the dead space air of the apparatus and be rebreathed by the diver. Up to an alveolar carbon dioxide pressure (Pco2) of about 80 mm Hg, twice that in normal alveoli, the diver usually tolerates this buildup by increasing the minute respiratory volume a maximum of 8- to 11-fold to compensate for the increased carbon dioxide. Beyond 80-mm Hg alveolar Pco2, the situation becomes intolerable, and eventually the respiratory center begins to be depressed, rather than excited, because of the negative tissue metabolic effects of high Pco2. The diver’s respiration then begins to fail rather than to compensate. In addition, the diver develops severe respiratory acidosis, and varying degrees of lethargy, narcosis, and finally even anesthesia, as discussed in Chapter 42. Decompression of the Diver After Excess Exposure to High Pressure When a person breathes air under high pressure for a long time, the amount of nitrogen dissolved in the body fluids increases. The reason for this is the following: Blood flowing through the pulmonary capillaries becomes saturated with nitrogen to the same high pressure as that in the alveolar breathing mixture. And over several more hours, enough nitrogen is 548 Unit VIII Aviation, Space, and Deep-Sea Diving Physiology carried to all the tissues of the body to raise their tissue Pn2 also to equal the Pn2 in the breathing air. Because nitrogen is not metabolized by the body, it remains dissolved in all the body tissues until the nitrogen pressure in the lungs is decreased back to some lower level, at which time the nitrogen can be removed by the reverse respiratory process; however, this removal often takes hours to occur and is the source of multiple problems collectively called decompression sickness. Pressure Outside Body Before decompression After sudden decompression O2 = 1044 mm Hg N2 = 3956 O2 = 159 mm Hg N2 = 601 Total = 5000 mm Hg Total = 760 mm Hg Body Gaseous pressure in the body fluids H2O = 47 mm Hg CO2 = 40 O2 = 60 N2 = 3918 Body Gaseous pressure in the body fluids H2O = 47 mm Hg CO2 = 40 O2 = 60 N2 = 3918 Volume of Nitrogen Dissolved in the Body Fluids at Different Depths. At sea level, almost exactly 1 liter of nitrogen is dissolved in the entire body. Slightly less than one half of this is dissolved in the water of the body and a little more than one half in the fat of the body. This is true because nitrogen is five times as soluble in fat as in water. After the diver has become saturated with nitrogen, the sea-level volume of nitrogen dissolved in the body at different depths is as follows: Total = 4065 A Feet Liters 0 33 100 200 300 1 2 4 7 10 Several hours are required for the gas pressures of nitrogen in all the body tissues to come nearly to equilibrium with the gas pressure of nitrogen in the alveoli. The reason for this is that the blood does not flow rapidly enough and the nitrogen does not diffuse rapidly enough to cause instantaneous equilibrium. The nitrogen dissolved in the water of the body comes to almost complete equilibrium in less than 1 hour, but the fat tissue, requiring five times as much transport of nitrogen and having a relatively poor blood supply, reaches equilibrium only after several hours. For this reason, if a person remains at deep levels for only a few minutes, not much nitrogen dissolves in the body fluids and tissues, whereas if the person remains at a deep level for several hours, both the body water and body fat become saturated with nitrogen. Decompression Sickness (Synonyms: Bends, Compressed Air Sickness, Caisson Disease, Diver’s Paralysis, Dysbarism). If a diver has been beneath the sea long enough that large amounts of nitrogen have dissolved in his or her body and the diver then suddenly comes back to the surface of the sea, significant quantities of nitrogen bubbles can develop in the body fluids either intracellularly or extracellularly and can cause minor or serious damage in almost any area of the body, depending on the number and sizes of bubbles formed; this is called decompression sickness. The principles underlying bubble formation are shown in Figure 44–3. In Figure 44–3A, the diver’s tissues have become equilibrated to a high dissolved Total = 4065 B Figure 44–3 Gaseous pressures both inside and outside the body, showing (A) saturation of the body to high gas pressures when breathing air at a total pressure of 5000 mm Hg, and (B) the great excesses of intra-body pressures that are responsible for bubble formation in the tissues when the lung intra-alveolar pressure body is suddenly returned from 5000 mm Hg to normal pressure of 760 mm Hg. nitrogen pressure (Pn2 = 3918 mm Hg), about 6.5 times the normal amount of nitrogen in the tissues. As long as the diver remains deep beneath the sea, the pressure against the outside of his or her body (5000 mm Hg) compresses all the body tissues sufficiently to keep the excess nitrogen gas dissolved. But when the diver suddenly rises to sea level (Figure 44–3B), the pressure on the outside of the body becomes only 1 atmosphere (760 mm Hg), while the gas pressure inside the body fluids is the sum of the pressures of water vapor, carbon dioxide, oxygen, and nitrogen, or a total of 4065 mm Hg, 97 per cent of which is caused by the nitrogen. Obviously, this total value of 4065 mm Hg is far greater than the 760 mm Hg pressure on the outside of the body. Therefore, the gases can escape from the dissolved state and form actual bubbles, composed almost entirely of nitrogen, both in the tissues and in the blood where they plug many small blood vessels. The bubbles may not appear for many minutes to hours, because sometimes the gases can remain dissolved in the “supersaturated” state for hours before bubbling. Symptoms of Decompression Sickness (“Bends”). The symptoms of decompression sickness are caused by gas bubbles blocking many blood vessels in different tissues. At first, only the smallest vessels are blocked by minute bubbles, but as the bubbles coalesce, progressively larger vessels are affected. Chapter 44 Physiology of Deep-Sea Diving and Other Hyperbaric Conditions Tissue ischemia and sometimes tissue death are the result. In most people with decompression sickness, the symptoms are pain in the joints and muscles of the legs and arms, affecting 85 to 90 per cent of those persons who develop decompression sickness. The joint pain accounts for the term “bends” that is often applied to this condition. In 5 to 10 per cent of people with decompression sickness, nervous system symptoms occur, ranging from dizziness in about 5 per cent to paralysis or collapse and unconsciousness in as many as 3 per cent. The paralysis may be temporary, but in some instances, damage is permanent. Finally, about 2 per cent of people with decompression sickness develop “the chokes,” caused by massive numbers of microbubbles plugging the capillaries of the lungs; this is characterized by serious shortness of breath, often followed by severe pulmonary edema and, occasionally, death. Nitrogen Elimination from the Body; Decompression Tables. If a diver is brought to the surface slowly, enough of the dissolved nitrogen can usually be eliminated by expiration through the lungs to prevent decompression sickness. About two thirds of the total nitrogen is liberated in 1 hour and about 90 per cent in 6 hours. Decompression tables have been prepared by the U.S. Navy that detail procedures for safe decompression. To give the student an idea of the decompression process, a diver who has been breathing air and has been on the sea bottom for 60 minutes at a depth of 190 feet is decompressed according to the following schedule: 10 minutes at 50 feet depth 17 minutes at 40 feet depth 19 minutes at 30 feet depth 50 minutes at 20 feet depth 84 minutes at 10 feet depth Thus, for a work period on the bottom of only 1 hour, the total time for decompression is about 3 hours. Tank Decompression and Treatment of Decompression Sickness. Another procedure widely used for decompres- sion of professional divers is to put the diver into a pressurized tank and then to lower the pressure gradually back to normal atmospheric pressure, using essentially the same time schedule as noted above. Tank decompression is even more important for treating people in whom symptoms of decompression sickness develop minutes or even hours after they have returned to the surface. In this case, the diver is recompressed immediately to a deep level. Then decompression is carried out over a period several times as long as the usual decompression period. “Saturation Diving” and Use of Helium-Oxygen Mixtures in Deep Dives. When divers must work at very deep levels— between 250 feet and nearly 1000 feet—they frequently live in a large compression tank for days or weeks at a time, remaining compressed at a pressure 549 level near that at which they will be working. This keeps the tissues and fluids of the body saturated with the gases to which they will be exposed while diving. Then, when they return to the same tank after working, there are no significant changes in pressure, so that decompression bubbles do not occur. In very deep dives, especially during saturation diving, helium is usually used in the gas mixture instead of nitrogen for three reasons: (1) it has only about one fifth the narcotic effect of nitrogen; (2) only about one half as much volume of helium dissolves in the body tissues as nitrogen, and the volume that does dissolve diffuses out of the tissues during decompression several times as rapidly as does nitrogen, thus reducing the problem of decompression sickness; and (3) the low density of helium (one seventh the density of nitrogen) keeps the airway resistance for breathing at a minimum, which is very important because highly compressed nitrogen is so dense that airway resistance can become extreme, sometimes making the work of breathing beyond endurance. Finally, in very deep dives it is important to reduce the oxygen concentration in the gaseous mixture because otherwise oxygen toxicity would result. For instance, at a depth of 700 feet (22 atmospheres of pressure), a 1 per cent oxygen mixture will provide all the oxygen required by the diver, whereas a 21 per cent mixture of oxygen (the percentage in air) delivers a Po2 to the lungs of more than 4 atmospheres, a level very likely to cause seizures in as little as 30 minutes. Scuba (Self-Contained Underwater Breathing Apparatus) Diving Before the 1940s, almost all diving was done using a diving helmet connected to a hose through which air was pumped to the diver from the surface. Then, in 1943, Jacques Cousteau popularized a self-contained underwater breathing apparatus, known as the SCUBA apparatus. The type of SCUBA apparatus used in more than 99 per cent of all sports and commercial diving is the open-circuit demand system shown in Figure 44–4. This system consists of the following components: (1) one or more tanks of compressed air or some other breathing mixture, (2) a first-stage “reducing” valve for reducing the very high pressure from the tanks to a low pressure level, (3) a combination inhalation “demand” valve and exhalation valve that allows air to be pulled into the lungs with slight negative pressure of breathing and then to be exhaled into the sea at a pressure level slightly positive to the surrounding water pressure, and (4) a mask and tube system with small “dead space.” The demand system operates as follows: The firststage reducing valve reduces the pressure from the tanks so that the air delivered to the mask has a pressure only a few mm Hg greater than the surrounding water pressure. The breathing mixture does not flow continually into the mask. Instead, with each 550 Unit VIII Aviation, Space, and Deep-Sea Diving Physiology Mask Hose Demand valve First stage valve devices, especially when using helium, theoretically can allow escape from as deep as 600 feet or perhaps more. One of the major problems of escape is prevention of air embolism. As the person ascends, the gases in the lungs expand and sometimes rupture a pulmonary blood vessel, forcing the gases to enter the vessel and cause air embolism of the circulation. Therefore, as the person ascends, he or she must make a special effort to exhale continually. Health Problems in the Submarine Internal Environment. Air cylinders Except for escape, submarine medicine generally centers around several engineering problems to keep hazards out of the internal environment. First, in atomic submarines, there exists the problem of radiation hazards, but with appropriate shielding, the amount of radiation received by the crew submerged beneath the sea has been less than normal radiation received above the surface of the sea from cosmic rays. Second, poisonous gases on occasion escape into the atmosphere of the submarine and must be controlled rapidly. For instance, during several weeks’ submergence, cigarette smoking by the crew can liberate enough carbon monoxide, if not removed rapidly, to cause carbon monoxide poisoning. And, on occasion, even freon gas has been found to diffuse out of refrigeration systems in sufficient quantity to cause toxicity. Figure 44–4 Open-circuit demand type of SCUBA apparatus. inspiration, slight extra negative pressure in the demand valve of the mask pulls the diaphragm of the valve open, and this automatically releases air from the tank into the mask and lungs. In this way, only the amount of air needed for inhalation enters the mask. Then, on expiration, the air cannot go back into the tank but instead is expired into the sea. The most important problem in use of the selfcontained underwater breathing apparatus is the limited amount of time one can remain beneath the sea surface; for instance, only a few minutes are possible at a 200-foot depth. The reason for this is that tremendous airflow from the tanks is required to wash carbon dioxide out of the lungs—the greater the depth, the greater the airflow in terms of quantity of air per minute that is required, because the volumes have been compressed to small sizes. Special Physiologic Problems in Submarines Escape from Submarines. Essentially the same problems encountered in deep-sea diving are often met in relation to submarines, especially when it is necessary to escape from a submerged submarine. Escape is possible from as deep as 300 feet without using any apparatus. However, proper use of rebreathing Hyperbaric Oxygen Therapy The intense oxidizing properties of high-pressure oxygen (hyperbaric oxygen) can have valuable therapeutic effects in several important clinical conditions. Therefore, large pressure tanks are now available in many medical centers into which patients can be placed and treated with hyperbaric oxygen. The oxygen is usually administered at Po2s of 2 to 3 atmospheres of pressure through a mask or intratracheal tube, whereas the gas around the body is normal air compressed to the same high-pressure level. It is believed that the same oxidizing free radicals responsible for oxygen toxicity are also responsible for at least some of the therapeutic benefits. Some of the conditions in which hyperbaric oxygen therapy has been especially beneficial follow. Probably the most successful use of hyperbaric oxygen has been for treatment of gas gangrene. The bacteria that cause this condition, clostridial organisms, grow best under anaerobic conditions and stop growing at oxygen pressures greater than about 70 mm Hg. Therefore, hyperbaric oxygenation of the tissues can frequently stop the infectious process entirely and thus convert a condition that formerly was almost 100 per cent fatal into one that is cured in most instances by early treatment with hyperbaric therapy. Other conditions in which hyperbaric oxygen therapy has been either valuable or possibly valuable include decompression sickness, arterial gas embolism, Chapter 44 Physiology of Deep-Sea Diving and Other Hyperbaric Conditions carbon monoxide poisoning, osteomyelitis, and myocardial infarction. References Butler PJ: Diving beyond the limits. News Physiol Sci 16:222, 2001. Kooyman GL, Ponganis PJ: The physiological basis of diving to depth: birds and mammals. Annu Rev Physiol 60:19, 1998. Leach RM, Rees PJ, Wilmshurst P: Hyperbaric oxygen therapy. BMJ 317:1140, 1998. Neuman TS: Arterial gas embolism and decompression sickness. News Physiol Sci 17:77, 2002. 551 Nilsson GE: Surviving anoxia with the brain turned on. News Physiol Sci 16:217, 2001. Russi EW: Diving and the risk of barotrauma. Thorax 53(Suppl 2):S20, 1998. Wang C, Schwaitzberg S, Berliner E, et al: Hyperbaric oxygen for treating wounds: a systematic review of the literature. Arch Surg 138:272, 2003. Wang J, Li F, Calhoun JH, Mader JT: The role and effectiveness of adjunctive hyperbaric oxygen therapy in the management of musculoskeletal disorders. J Postgrad Med 48:226, 2002 West JB, Fu Z, Gaeth AP, Short RV: Fetal lung development in the elephant reflects the adaptations required for snorkeling in adult life. Respir Physiol Neurobiol 138:325, 2003. U N I The Nervous System: A. General Principles and Sensory Physiology 45. Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” 46. Sensory Receptors, Neuronal Circuits for Processing Information 47. Somatic Sensations: I. General Organization, the Tactile and Position Senses 48. Somatic Sensations: II. Pain, Headache, and Thermal Sensations T IX C H A P T E R 4 5 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” The nervous system is unique in the vast complexity of thought processes and control actions it can perform. It receives each minute literally millions of bits of information from the different sensory nerves and sensory organs and then integrates all these to determine responses to be made by the body. However, before beginning this discussion of the nervous system, the reader should review Chapters 5 and 7, which present the principles of membrane potentials and transmission of signals in nerves and through neuromuscular junctions. General Design of the Nervous System Central Nervous System Neuron: The Basic Functional Unit The central nervous system contains more than 100 billion neurons. Figure 45–1 shows a typical neuron of a type found in the brain motor cortex. Incoming signals enter this neuron through synapses located mostly on the neuronal dendrites, but also on the cell body. For different types of neurons, there may be only a few hundred or as many as 200,000 such synaptic connections from input fibers. Conversely, the output signal travels by way of a single axon leaving the neuron. Then, this axon has many separate branches to other parts of the nervous system or peripheral body. A special feature of most synapses is that the signal normally passes only in the forward direction (from the axon of a preceding neuron to dendrites on cell membranes of subsequent neurons). This forces the signal to travel in required directions for performing specific nervous functions. Sensory Part of the Nervous System—Sensory Receptors Most activities of the nervous system are initiated by sensory experience exciting sensory receptors, whether visual receptors in the eyes, auditory receptors in the ears, tactile receptors on the surface of the body, or other kinds of receptors. This sensory experience can either cause immediate reaction from the brain, or memory of the experience can be stored in the brain for minutes, weeks, or years and determine bodily reactions at some future date. Figure 45–2 shows the somatic portion of the sensory system, which transmits sensory information from the receptors of the entire body surface and from some deep structures. This information enters the central nervous system through peripheral nerves and is conducted immediately to multiple sensory areas in (1) the spinal cord at all levels; (2) the reticular substance of the medulla, pons, and mesencephalon of the brain; (3) the cerebellum; (4) the thalamus; and (5) areas of the cerebral cortex. 555 556 Unit IX The Nervous System: A. General Principles and Sensory Physiology Somesthetic areas Motor cortex Dendrites Thalamus Brain Pons Cell body Medulla Cerebellum Spinal cord Bulboreticular formation Skin Pain, cold, warmth (Free nerve ending) Pressure (Pacinian corpuscle) (Expanded tip receptor) Touch (Meissner's corpuscle) Axon Muscle spindle Golgi tendon apparatus Muscle Kinesthetic receptor Synapses Joint Spinal cord Second-order neurons Figure 45–2 Somatosensory axis of the nervous system. Figure 45–1 Structure of a large neuron in the brain, showing its important functional parts. (Redrawn from Guyton AC: Basic Neuroscience: Anatomy and Physiology. Philadelphia: WB Saunders Co, 1987.) Motor Part of the Nervous System— Effectors The most important eventual role of the nervous system is to control the various bodily activities. This is achieved by controlling (1) contraction of appropriate skeletal muscles throughout the body, (2) contraction of smooth muscle in the internal organs, and (3) secretion of active chemical substances by both exocrine and endocrine glands in many parts of the body. These activities are collectively called motor functions of the nervous system, and the muscles and glands are called effectors because they are the actual anatomical structures that perform the functions dictated by the nerve signals. Figure 45–3 shows the “skeletal” motor nerve axis of the nervous system for controlling skeletal muscle contraction. Operating parallel to this axis is another system, called the autonomic nervous system, for con- trolling smooth muscles, glands, and other internal bodily systems; this is discussed in Chapter 60. Note in Figure 45–3 that the skeletal muscles can be controlled from many levels of the central nervous system, including (1) the spinal cord; (2) the reticular substance of the medulla, pons, and mesencephalon; (3) the basal ganglia; (4) the cerebellum; and (5) the motor cortex. Each of these areas plays its own specific role, the lower regions concerned primarily with automatic, instantaneous muscle responses to sensory stimuli, and the higher regions with deliberate complex muscle movements controlled by the thought processes of the brain. Processing of Information— “Integrative” Function of the Nervous System One of the most important functions of the nervous system is to process incoming information in such a way that appropriate mental and motor responses will occur. More than 99 per cent of all sensory information is discarded by the brain as irrelevant and unimportant. For instance, one is ordinarily unaware of the Chapter 45 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” Motor nerve to muscles Motor area Caudate nucleus Thalamus Putamen Globus pallidus Subthalamic nucleus Cerebellum Bulboreticular formation Gamma motor fiber Alpha motor fiber Muscle spindle Figure 45–3 Skeletal motor nerve axis of the nervous system. parts of the body that are in contact with clothing, as well as of the seat pressure when sitting. Likewise, attention is drawn only to an occasional object in one’s field of vision, and even the perpetual noise of our surroundings is usually relegated to the subconscious. But, when important sensory information excites the mind, it is immediately channeled into proper integrative and motor regions of the brain to cause desired responses. This channeling and processing of information is called the integrative function of the nervous system. Thus, if a person places a hand on a hot stove, the desired instantaneous response is to lift the hand. And other associated responses follow, such as moving the entire body away from the stove, and perhaps even shouting with pain. Role of Synapses in Processing Information. The synapse is the junction point from one neuron to the next. Later in this chapter, we will discuss the details of synaptic function. However, it is important to point out here that synapses determine the directions that the nervous signals will spread through the nervous system. Some synapses transmit signals from one neuron to the next with ease, whereas others transmit signals only with difficulty. Also, facilitatory and inhibitory signals from other areas in the nervous 557 system can control synaptic transmission, sometimes opening the synapses for transmission and at other times closing them. In addition, some postsynaptic neurons respond with large numbers of output impulses, and others respond with only a few. Thus, the synapses perform a selective action, often blocking weak signals while allowing strong signals to pass, but at other times selecting and amplifying certain weak signals, and often channeling these signals in many directions rather than only one direction. Storage of Information—Memory Only a small fraction of even the most important sensory information usually causes immediate motor response. But much of the information is stored for future control of motor activities and for use in the thinking processes. Most storage occurs in the cerebral cortex, but even the basal regions of the brain and the spinal cord can store small amounts of information. The storage of information is the process we call memory, and this, too, is a function of the synapses. That is, each time certain types of sensory signals pass through sequences of synapses, these synapses become more capable of transmitting the same type of signal the next time, a process called facilitation. After the sensory signals have passed through the synapses a large number of times, the synapses become so facilitated that signals generated within the brain itself can also cause transmission of impulses through the same sequences of synapses, even when the sensory input is not excited. This gives the person a perception of experiencing the original sensations, although the perceptions are only memories of the sensations. We know little about the precise mechanisms by which long-term facilitation of synapses occurs in the memory process, but what is known about this and other details of the sensory memory process are discussed in Chapter 57. Once memories have been stored in the nervous system, they become part of the brain processing mechanism for future “thinking.” That is, the thinking processes of the brain compare new sensory experiences with stored memories; the memories then help to select the important new sensory information and to channel this into appropriate memory storage areas for future use or into motor areas to cause immediate bodily responses. Major Levels of Central Nervous System Function The human nervous system has inherited special functional capabilities from each stage of human evolutionary development. From this heritage, three major levels of the central nervous system have specific functional characteristics: (1) the spinal cord level, (2) the lower brain or subcortical level, and (3) the higher brain or cortical level. 558 Unit IX The Nervous System: A. General Principles and Sensory Physiology Spinal Cord Level We often think of the spinal cord as being only a conduit for signals from the periphery of the body to the brain, or in the opposite direction from the brain back to the body. This is far from the truth. Even after the spinal cord has been cut in the high neck region, many highly organized spinal cord functions still occur. For instance, neuronal circuits in the cord can cause (1) walking movements, (2) reflexes that withdraw portions of the body from painful objects, (3) reflexes that stiffen the legs to support the body against gravity, and (4) reflexes that control local blood vessels, gastrointestinal movements, or urinary excretion. In fact, the upper levels of the nervous system often operate not by sending signals directly to the periphery of the body but by sending signals to the control centers of the cord, simply “commanding” the cord centers to perform their functions. Lower Brain or Subcortical Level Many, if not most, of what we call subconscious activities of the body are controlled in the lower areas of the brain—in the medulla, pons, mesencephalon, hypothalamus, thalamus, cerebellum, and basal ganglia. For instance, subconscious control of arterial pressure and respiration is achieved mainly in the medulla and pons. Control of equilibrium is a combined function of the older portions of the cerebellum and the reticular substance of the medulla, pons, and mesencephalon. Feeding reflexes, such as salivation and licking of the lips in response to the taste of food, are controlled by areas in the medulla, pons, mesencephalon, amygdala, and hypothalamus. And many emotional patterns, such as anger, excitement, sexual response, reaction to pain, and reaction to pleasure, can still occur after destruction of much of the cerebral cortex. system performs specific functions. But it is the cortex that opens a world of stored information for use by the mind. Comparison of the Nervous System with a Computer When computers were first developed, it soon became apparent that these machines have many features in common with the nervous system. First, all computers have input circuits that are comparable to the sensory portion of the nervous system, and output circuits that are comparable to the motor portion of the nervous system. In simple computers, the output signals are controlled directly by the input signals, operating in a manner similar to that of simple reflexes of the spinal cord. In more complex computers, the output is determined both by input signals and by information that has already been stored in memory in the computer, which is analogous to the more complex reflex and processing mechanisms of our higher nervous system. Furthermore, as computers become even more complex, it is necessary to add still another unit, called the central processing unit, that determines the sequence of all operations. This unit is analogous to the control mechanisms in our brain that direct our attention first to one thought or sensation or motor activity, then to another, and so forth, until complex sequences of thought or action take place. Figure 45–4 is a simple block diagram of a computer. Even a rapid study of this diagram demonstrates its similarity to the nervous system. The fact that the basic components of the general-purpose computer are analogous to those of the human nervous system demonstrates that the brain is basically a computer that continuously collects sensory information and uses this along with stored information to compute the daily course of bodily activity. Higher Brain or Cortical Level After the preceding account of the many nervous system functions that occur at the cord and lower brain levels, one may ask, what is left for the cerebral cortex to do? The answer to this is complex, but it begins with the fact that the cerebral cortex is an extremely large memory storehouse. The cortex never functions alone but always in association with lower centers of the nervous system. Without the cerebral cortex, the functions of the lower brain centers are often imprecise. The vast storehouse of cortical information usually converts these functions to determinative and precise operations. Finally, the cerebral cortex is essential for most of our thought processes, but it cannot function by itself. In fact, it is the lower brain centers, not the cortex, that initiate wakefulness in the cerebral cortex, thus opening its bank of memories to the thinking machinery of the brain. Thus, each portion of the nervous Problem Input Procedure for solution Central processing unit Output Initial data Result of operations Answer Information storage Computational unit Figure 45–4 Block diagram of a general-purpose computer, showing the basic components and their interrelations. Chapter 45 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” Central Nervous System Synapses Every medical student is aware that information is transmitted in the central nervous system mainly in the form of nerve action potentials, called simply “nerve impulses,” through a succession of neurons, one after another. However, in addition, each impulse (1) may be blocked in its transmission from one neuron to the next, (2) may be changed from a single impulse into repetitive impulses, or (3) may be integrated with impulses from other neurons to cause highly intricate patterns of impulses in successive neurons. All these functions can be classified as synaptic functions of neurons. Types of Synapses—Chemical and Electrical There are two major types of synapses: (1) the chemical synapse and (2) the electrical synapse. Almost all the synapses used for signal transmission in the central nervous system of the human being are chemical synapses. In these, the first neuron secretes at its nerve ending synapse a chemical substance called a neurotransmitter (or often called simply transmitter substance), and this transmitter in turn acts on receptor proteins in the membrane of the next neuron to excite the neuron, inhibit it, or modify its sensitivity in some other way. More than 40 important transmitter substances have been discovered thus far. Some of the best known are acetylcholine, norepinephrine, epinephrine, histamine, gamma-aminobutyric acid (GABA), glycine, serotonin, and glutamate. Electrical synapses, in contrast, are characterized by direct open fluid channels that conduct electricity from one cell to the next. Most of these consist of small protein tubular structures called gap junctions that allow free movement of ions from the interior of one cell to the interior of the next. Such junctions were discussed in Chapter 4. Only a few examples of gap junctions have been found in the central nervous system. However, it is by way of gap junctions and other similar junctions that action potentials are transmitted from one smooth muscle fiber to the next in visceral smooth muscle (Chapter 8) and from one cardiac muscle cell to the next in cardiac muscle (Chapter 10). “One-Way” Conduction at Chemical Synapses. Chemical synapses have one exceedingly important characteristic that makes them highly desirable for transmitting most nervous system signals: they always transmit the signals in one direction: that is, from the neuron that secretes the transmitter substance, called the presynaptic neuron, to the neuron on which the transmitter acts, called the postsynaptic neuron. This is the principle of one-way conduction at chemical synapses, and it is quite different from conduction through electrical synapses, which often transmit signals in either direction. 559 Think for a moment about the extreme importance of the one-way conduction mechanism. It allows signals to be directed toward specific goals. Indeed, it is this specific transmission of signals to discrete and highly focused areas both within the nervous system and at the terminals of the peripheral nerves that allows the nervous system to perform its myriad functions of sensation, motor control, memory, and many others. Physiologic Anatomy of the Synapse Figure 45–5 shows a typical anterior motor neuron in the anterior horn of the spinal cord. It is composed of three major parts: the soma, which is the main body of the neuron; a single axon, which extends from the soma into a peripheral nerve that leaves the spinal cord; and the dendrites, which are great numbers of branching projections of the soma that extend as much as 1 millimeter into the surrounding areas of the cord. As many as 10,000 to 200,000 minute synaptic knobs called presynaptic terminals lie on the surfaces of the dendrites and soma of the motor neuron, about 80 to 95 per cent of them on the dendrites and only 5 to 20 per cent on the soma. These presynaptic terminals are the ends of nerve fibrils that originate from many other neurons. Later, it will become evident that many Dendrites Axon Soma Figure 45–5 Typical anterior motor neuron, showing presynaptic terminals on the neuronal soma and dendrites. Note also the single axon. 560 Unit IX The Nervous System: A. General Principles and Sensory Physiology of these presynaptic terminals are excitatory—that is, they secrete a transmitter substance that excites the postsynaptic neuron. But other presynaptic terminals are inhibitory—they secrete a transmitter substance that inhibits the postsynaptic neuron. Neurons in other parts of the cord and brain differ from the anterior motor neuron in (1) the size of the cell body; (2) the length, size, and number of dendrites, ranging in length from almost zero to many centimeters; (3) the length and size of the axon; and (4) the number of presynaptic terminals, which may range from only a few to as many as 200,000. These differences make neurons in different parts of the nervous system react differently to incoming synaptic signals and, therefore, perform many different functions. Presynaptic Terminals. Electron microscopic studies of the presynaptic terminals show that they have varied anatomical forms, but most resemble small round or oval knobs and, therefore, are sometimes called terminal knobs, boutons, end-feet, or synaptic knobs. Figure 45–6 illustrates the basic structure of a synapse, showing a single presynaptic terminal on the membrane surface of a postsomatic neuron.The presynaptic terminal is separated from the postsynaptic neuronal soma by a synaptic cleft having a width usually of 200 to 300 angstroms. The terminal has two internal structures important to the excitatory or inhibitory function of the synapse: the transmitter vesicles and the mitochondria. The transmitter vesicles contain the transmitter substance that, when released into the synaptic cleft, either excites or inhibits the postsynaptic neuron—excites if the neuronal membrane contains excitatory receptors, inhibits if the membrane contains inhibitory receptors. The mitochondria provide adenosine triphosphate (ATP), which in turn supplies the energy for synethesizing new transmitter substance. When an action potential spreads over a presynaptic terminal, depolarization of its membrane causes a small number of vesicles to empty into the cleft. The released transmitter in turn causes an immediate change in permeability characteristics of the postsynaptic neuronal membrane, and this leads to excitation or inhibition of the postsynaptic neuron, depending on the neuronal receptor characteristics. Mechanism by Which an Action Potential Causes Transmitter Release from the Presynaptic Terminals—Role of Calcium Ions The membrane of the presynaptic terminal is called the presynaptic membrane. It contains large numbers of voltage-gated calcium channels. When an action potential depolarizes the presynaptic membrane, these calcium channels open and allow large numbers of calcium ions to flow into the terminal. The quantity of transmitter substance that is then released from the terminal into the synaptic cleft is directly related to the number of calcium ions that enter. The precise mechanism by which the calcium ions cause this release is not known, but it is believed to be the following. When the calcium ions enter the presynaptic terminal, it is believed that they bind with special protein molecules on the inside surface of the presynaptic membrane, called release sites. This binding in turn causes the release sites to open through the membrane, allowing a few transmitter vesicles to release their transmitter into the cleft after each single action potential. For those vesicles that store the neurotransmitter acetylcholine, between 2000 and 10,000 molecules of acetylcholine are present in each vesicle, and there are enough vesicles in the presynaptic terminal to transmit from a few hundred to more than 10,000 action potentials. Action of the Transmitter Substance on the Postsynaptic Neuron—Function of “Receptor Proteins” Transmitter vesicles Mitochondria Presynaptic terminal Synaptic cleft (200-300 angstroms) Receptor proteins Soma of neuron Figure 45–6 Physiologic anatomy of the synapse. The membrane of the postsynaptic neuron contains large numbers of receptor proteins, also shown in Figure 45–6. The molecules of these receptors have two important components: (1) a binding component that protrudes outward from the membrane into the synaptic cleft—here it binds the neurotransmitter coming from the presynaptic terminal—and (2) an ionophore component that passes all the way through the postsynaptic membrane to the interior of the postsynaptic neuron. The ionophore in turn is one of two types: (1) an ion channel that allows passage of specified types of ions through the membrane or (2) a “second messenger” activator that is not an ion channel but instead is a molecule that protrudes into the cell cytoplasm and activates one or more substances inside the postsynaptic neuron. These substances in turn serve as “second messengers” to increase or decrease specific cellular functions. Chapter 45 561 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” the process of memory—require prolonged changes in neurons for seconds to months after the initial transmitter substance is gone. The ion channels are not suitable for causing prolonged postsynaptic neuronal changes because these channels close within milliseconds after the transmitter substance is no longer present. However, in many instances, prolonged postsynaptic neuronal excitation or inhibition is achieved by activating a “second messenger” chemical system inside the postsynaptic neuronal cell itself, and then it is the second messenger that causes the prolonged effect. There are several types of second messenger systems. One of the most common types uses a group of proteins called G-proteins. Figure 45–7 shows in the upper left corner a membrane receptor protein. A G-protein is attached to the portion of the receptor that protrudes into the interior of the cell. The G-protein in turn consists of three components: an alpha (a) component that is the activator portion of the G-protein, and beta (b) and gamma (g) components that are attached to the alpha component and also to the inside of the cell membrane adjacent to the receptor protein. On activation by a nerve impulse, the alpha portion of the G-protein separates from the beta and gamma portions and then is free to move within the cytoplasm of the cell. Inside the cytoplasm, the separated alpha component performs one or more of multiple functions, depending on the specific characteristic of each type of neuron. Shown in Figure 45–7 are four changes that can occur. They are as follows: 1. Opening specific ion channels through the postsynaptic cell membrane. Shown in the upper right of the figure is a potassium channel that is opened in response to the G-protein; this channel often stays open for a prolonged time, in contrast to rapid closure of directly activated ion channels that do not use the second messenger system. Ion Channels. The ion channels in the postsynaptic neuronal membrane are usually of two types: (1) cation channels that most often allow sodium ions to pass when opened, but sometimes allow potassium and/or calcium ions as well, and (2) anion channels that allow mainly chloride ions to pass but also minute quantities of other anions. The cation channels that conduct sodium ions are lined with negative charges. These charges attract the positively charged sodium ions into the channel when the channel diameter increases to a size larger than that of the hydrated sodium ion. But those same negative charges repel chloride ions and other anions and prevent their passage. For the anion channels, when the channel diameters become large enough, chloride ions pass into the channels and on through to the opposite side, whereas sodium, potassium, and calcium cations are blocked, mainly because their hydrated ions are too large to pass. We will learn later that when cation channels open and allow positively charged sodium ions to enter, the positive electrical charges of the sodium ions will in turn excite this neuron. Therefore, a transmitter substance that opens cation channels is called an excitatory transmitter. Conversely, opening anion channels allows negative electrical charges to enter, which inhibits the neuron. Therefore, transmitter substances that open these channels are called inhibitory transmitters. When a transmitter substance activates an ion channel, the channel usually opens within a fraction of a millisecond; when the transmitter substance is no longer present, the channel closes equally rapidly. The opening and closing of ion channels provide a means for very rapid control of postsynaptic neurons. “Second Messenger” System in the Postsynaptic Neuron. Many functions of the nervous system—for instance, Transmitter substance Receptor protein Figure 45–7 “Second messenger” system by which a transmitter substance from an initial neuron can activate a second neuron by first releasing a “G-protein” into the second neuron’s cytoplasm. Four subsequent possible effects of the G-protein are shown, including 1, opening an ion channel in the membrane of the second neuron; 2, activating an enzyme system in the neuron’s membrane; 3, activating an intracellular enzyme system; and/or 4, causing gene transcription in the second neuron. g Potassium channel b a G-protein 1 Opens channel K+ Membrane enzyme 2 a 3 Activates one or more intracellular enzymes Activates gene transcription 4 Activates enzymes ATP GTP or cAMP Specific cellular chemical activators Proteins and structural changes cGMP 562 Unit IX The Nervous System: A. General Principles and Sensory Physiology 2. Activation of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) in the neuronal cell. Recall that either cyclic AMP or cyclic GMP can activate highly specific metabolic machinery in the neuron and, therefore, can initiate any one of many chemical results, including long-term changes in cell structure itself, which in turn alters long-term excitability of the neuron. 3. Activation of one or more intracellular enzymes. The G-protein can directly activate one or more intracellular enzymes. In turn the enzymes can cause any one of many specific chemical functions in the cell. 4. Activation of gene transcription. This is one of the most important effects of activation of the second messenger systems because gene transcription can cause formation of new proteins within the neuron, thereby changing its metabolic machinery or its structure. Indeed, it is well known that structural changes of appropriately activated neurons do occur, especially in long-term memory processes. It is clear that activation of second messenger systems within the neuron, whether they be of the G-protein type or of other types, is extremely important for changing the long-term response characteristics of different neuronal pathways. We will return to this subject in more detail in Chapter 57 when we discuss memory functions of the nervous system. Excitatory or Inhibitory Receptors in the Postsynaptic Membrane Some postsynaptic receptors, when activated, cause excitation of the postsynaptic neuron, and others cause inhibition. The importance of having inhibitory as well as excitatory types of receptors is that this gives an additional dimension to nervous function, allowing restraint of nervous action as well as excitation. The different molecular and membrane mechanisms used by the different receptors to cause excitation or inhibition include the following. excitatory membrane receptors or decrease the number of inhibitory membrane receptors. Inhibition 1. Opening of chloride ion channels through the postsynaptic neuronal membrane. This allows rapid diffusion of negatively charged chloride ions from outside the postsynaptic neuron to the inside, thereby carrying negative charges inward and increasing the negativity inside, which is inhibitory. 2. Increase in conductance of potassium ions out of the neuron. This allows positive ions to diffuse to the exterior, which causes increased negativity inside the neuron; this is inhibitory. 3. Activation of receptor enzymes that inhibit cellular metabolic functions that increase the number of inhibitory synaptic receptors or decrease the number of excitatory receptors. Chemical Substances That Function as Synaptic Transmitters More than 50 chemical substances have been proved or postulated to function as synaptic transmitters. Many of them are listed in Tables 45–1 and 45–2, which give two groups of synaptic transmitters. One group comprises small-molecule, rapidly acting transmitters. The other is made up of a large number of neuropeptides of much larger molecular size that are usually much more slowly acting. The small-molecule, rapidly acting transmitters are the ones that cause most acute responses of the nervous system, such as transmission of sensory signals to the brain and of motor signals back to the muscles. The neuropeptides, in contrast, usually cause more prolonged actions, such as long-term changes in numbers of neuronal receptors, long-term opening or closure of certain ion channels, and possibly even longterm changes in numbers of synapses or sizes of synapses. Excitation 1. Opening of sodium channels to allow large numbers of positive electrical charges to flow to the interior of the postsynaptic cell. This raises the intracellular membrane potential in the positive direction up toward the threshold level for excitation. It is by far the most widely used means for causing excitation. 2. Depressed conduction through chloride or potassium channels, or both. This decreases the diffusion of negatively charged chloride ions to the inside of the postsynaptic neuron or decreases the diffusion of positively charged potassium ions to the outside. In either instance, the effect is to make the internal membrane potential more positive than normal, which is excitatory. 3. Various changes in the internal metabolism of the postsynaptic neuron to excite cell activity or, in some instances, to increase the number of Table 45–1 Small-Molecule, Rapidly Acting Transmitters Class I Acetylcholine Class II: The Amines Norepinephrine Epinephrine Dopamine Serotonin Histamine Class III: Amino Acids Gamma-aminobutyric acid (GABA) Glycine Glutamate Aspartate Class IV Nitric oxide (NO) Chapter 45 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” Table 45–2 Neuropeptide, Slowly Acting Transmitters or Growth Factors Hypothalamic-releasing hormones Thyrotropin-releasing hormone Luteinizing hormone–releasing hormone Somatostatin (growth hormone inhibitory factor) Pituitary peptides Adrenocorticotropic hormone (ACTH) b-Endorphin a-Melanocyte-stimulating hormone Prolactin Luteinizing hormone Thyrotropin Growth hormone Vasopressin Oxytocin Peptides that act on gut and brain Leucine enkephalin Methionine enkephalin Substance P Gastrin Cholecystokinin Vasoactive intestinal polypeptide (VIP) Nerve growth factor Brain-derived neurotropic factor Neurotensin Insulin Glucagon From other tissues Angiotensin II Bradykinin Carnosine Sleep peptides Calcitonin Small-Molecule, Rapidly Acting Transmitters In most cases, the small-molecule types of transmitters are synthesized in the cytosol of the presynaptic terminal and are absorbed by means of active transport into the many transmitter vesicles in the terminal. Then, each time an action potential reaches the presynaptic terminal, a few vesicles at a time release their transmitter into the synaptic cleft. This usually occurs within a millisecond or less by the mechanism described earlier. The subsequent action of the smallmolecule type of transmitter on the membrane receptors of the postsynaptic neuron usually also occurs within another millisecond or less. Most often the effect is to increase or decrease conductance through ion channels; an example is to increase sodium conductance, which causes excitation, or to increase potassium or chloride conductance, which causes inhibition. Recycling of the Small-Molecule Types of Vesicles. The vesicles that store and release small-molecule transmitters are continually recycled and used over and over again. After they fuse with the synaptic membrane and open to release their transmitter substance, the vesicle membrane at first simply becomes part of the synaptic membrane. However, within seconds to minutes, the vesicle portion of the membrane invaginates back to the inside of the presynaptic terminal and pinches off to form a new vesicle. And the new vesicular 563 membrane still contains appropriate enzyme proteins or transport proteins required for synthesizing and/or concentrating new transmitter substance inside the vesicle. Acetylcholine is a typical small-molecule transmitter that obeys the principles of synthesis and release stated earlier. This transmitter substance is synthesized in the presynaptic terminal from acetyl coenzyme A and choline in the presence of the enzyme choline acetyltransferase. Then it is transported into its specific vesicles. When the vesicles later release the acetylcholine into the synaptic cleft during synaptic neuronal signal transmission, the acetylcholine is rapidly split again to acetate and choline by the enzyme cholinesterase, which is present in the proteoglycan reticulum that fills the space of the synaptic cleft. And then again, inside the presynaptic terminal, the vesicles are recycled; choline is actively transported back into the terminal to be used again for synthesis of new acetylcholine. Characteristics of Some of the More Important Small-Molecule Transmitters. The most important of the small-molecule transmitters are the following. Acetylcholine is secreted by neurons in many areas of the nervous system but specifically by (1) the terminals of the large pyramidal cells from the motor cortex, (2) several different types of neurons in the basal ganglia, (3) the motor neurons that innervate the skeletal muscles, (4) the preganglionic neurons of the autonomic nervous system, (5) the postganglionic neurons of the parasympathetic nervous system, and (6) some of the postganglionic neurons of the sympathetic nervous system. In most instances, acetylcholine has an excitatory effect; however, it is known to have inhibitory effects at some peripheral parasympathetic nerve endings, such as inhibition of the heart by the vagus nerves. Norepinephrine is secreted by the terminals of many neurons whose cell bodies are located in the brain stem and hypothalamus. Specifically, norepinephrinesecreting neurons located in the locus ceruleus in the pons send nerve fibers to widespread areas of the brain to help control overall activity and mood of the mind, such as increasing the level of wakefulness. In most of these areas, norepinephrine probably activates excitatory receptors, but in a few areas, it activates inhibitory receptors instead. Norepinephrine is also secreted by most postganglionic neurons of the sympathetic nervous system, where it excites some organs but inhibits others. Dopamine is secreted by neurons that originate in the substantia nigra. The termination of these neurons is mainly in the striatal region of the basal ganglia. The effect of dopamine is usually inhibition. Glycine is secreted mainly at synapses in the spinal cord. It is believed to always act as an inhibitory transmitter. GABA (gamma-aminobutyric acid) is secreted by nerve terminals in the spinal cord, cerebellum, basal ganglia, and many areas of the cortex. It is believed always to cause inhibition. 564 Unit IX The Nervous System: A. General Principles and Sensory Physiology Glutamate is secreted by the presynaptic terminals in many of the sensory pathways entering the central nervous system, as well as in many areas of the cerebral cortex. It probably always causes excitation. Serotonin is secreted by nuclei that originate in the median raphe of the brain stem and project to many brain and spinal cord areas, especially to the dorsal horns of the spinal cord and to the hypothalamus. Serotonin acts as an inhibitor of pain pathways in the cord, and an inhibitor action in the higher regions of the nervous system is believed to help control the mood of the person, perhaps even to cause sleep. Nitric oxide is especially secreted by nerve terminals in areas of the brain responsible for long-term behavior and for memory. Therefore, this transmitter system might in the future explain some behavior and memory functions that thus far have defied understanding. Nitric oxide is different from other smallmolecule transmitters in its mechanism of formation in the presynaptic terminal and in its actions on the postsynaptic neuron. It is not preformed and stored in vesicles in the presynaptic terminal as are other transmitters. Instead, it is synthesized almost instantly as needed, and it then diffuses out of the presynaptic terminals over a period of seconds rather than being released in vesicular packets. Next, it diffuses into postsynaptic neurons nearby. In the postsynaptic neuron, it usually does not greatly alter the membrane potential but instead changes intracellular metabolic functions that modify neuronal excitability for seconds, minutes, or perhaps even longer. Neuropeptides The neuropeptides are an entirely different class of transmitters that are synthesized differently and whose actions are usually slow and in other ways quite different from those of the small-molecule transmitters. The neuropeptides are not synthesized in the cytosol of the presynaptic terminals. Instead, they are synthesized as integral parts of large-protein molecules by ribosomes in the neuronal cell body. The protein molecules then enter the spaces inside the endoplasmic reticulum of the cell body and subsequently inside the Golgi apparatus, where two changes occur: First, the neuropeptide-forming protein is enzymatically split into smaller fragments, some of which are either the neuropeptide itself or a precursor of it. Second, the Golgi apparatus packages the neuropeptide into minute transmitter vesicles that are released into the cytoplasm. Then the transmitter vesicles are transported all the way to the tips of the nerve fibers by axonal streaming of the axon cytoplasm, traveling at the slow rate of only a few centimeters per day. Finally, these vesicles release their transmitter at the neuronal terminals in response to action potentials in the same manner as for small-molecule transmitters. However, the vesicle is autolyzed and is not reused. Because of this laborious method of forming the neuropeptides, much smaller quantities of them are usually released than of the small-molecule transmitters. This is partly compensated for by the fact that the neuropeptides are generally a thousand or more times as potent as the small-molecule transmitters. Another important characteristic of the neuropeptides is that they often cause much more prolonged actions. Some of these actions include prolonged closure of calcium channels, prolonged changes in the metabolic machinery of cells, prolonged changes in activation or deactivation of specific genes in the cell nucleus, and/or prolonged alterations in numbers of excitatory or inhibitory receptors. Some of these effects last for days, but others perhaps for months or years. Our knowledge of the functions of the neuropeptides is only beginning to develop. Electrical Events During Neuronal Excitation The electrical events in neuronal excitation have been studied especially in the large motor neurons of the anterior horns of the spinal cord. Therefore, the events described in the next few sections pertain essentially to these neurons. Except for quantitative differences, they apply to most other neurons of the nervous system as well. Resting Membrane Potential of the Neuronal Soma. Figure 45–8 shows the soma of a spinal motor neuron, indicating a resting membrane potential of about -65 millivolts. This is somewhat less negative than the -90 millivolts found in large peripheral nerve fibers and in skeletal muscle fibers; the lower voltage is important because it allows both positive and negative control of the degree of excitability of the neuron. That is, decreasing the voltage to a less negative value makes the membrane of the neuron more excitable, whereas increasing this voltage to a more negative value makes the neuron less excitable. This is the basis for the two Dendrite Na+: 142 mEq/L K+: 4.5 mEq/L Cl-: 107 mEq/L 14 mEq/L (Pumps) 120 mEq/L 8 mEq/L ? Pump -65 mV Axon Axon hillock Figure 45–8 Distribution of sodium, potassium, and chloride ions across the neuronal somal membrane; origin of the intrasomal membrane potential. Chapter 45 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” modes of function of the neuron—either excitation or inhibition—as explained in detail in the next sections. Concentration Differences of Ions Across the Neuronal Somal Membrane. Figure 45–8 also shows the concen- tration differences across the neuronal somal membrane of the three ions that are most important for neuronal function: sodium ions, potassium ions, and chloride ions. At the top, the sodium ion concentration is shown to be high in the extracellular fluid (142 mEq/L) but low inside the neuron (14 mEq/L). This sodium concentration gradient is caused by a strong somal membrane sodium pump that continually pumps sodium out of the neuron. The figure also shows that potassium ion concentration is high inside the neuronal soma (120 mEq/L) but low in the extracellular fluid (4.5 mEq/L). It shows that there is a potassium pump (the other half of the Na+K+ pump) that pumps potassium to the interior. Figure 45–8 shows the chloride ion to be of high concentration in the extracellular fluid but low concentration inside the neuron. It also shows that the membrane is quite permeable to chloride ions and that there may be a weak chloride pump. Yet most of the reason for the low concentration of chloride ions inside the neuron is the -65 millivolts in the neuron. That is, this negative voltage repels the negatively charged chloride ions, forcing them outward through the pores until the concentration is much less inside the membrane than outside. Let us recall at this point what we learned in Chapters 4 and 5 about the relation of ionic concentration differences to membrane potentials. It will be recalled that an electrical potential across the cell membrane can oppose movement of ions through a membrane if the potential is of proper polarity and magnitude. A potential that exactly opposes movement of an ion is called the Nernst potential for that ion; the equation for this is the following: EMF (mV) = ± 61 ¥ log Ê Concentration inside ˆ Ë Concentration outside ¯ where EMF is the Nernst potential in millivolts on the inside of the membrane. The potential will be negative (-) for positive ions and positive (+) for negative ions. Now, let us calculate the Nernst potential that will exactly oppose the movement of each of the three separate ions: sodium, potassium, and chloride. For the sodium concentration difference shown in Figure 45–8, 142 mEq/L on the exterior and 14 mEq/L on the interior, the membrane potential that will exactly oppose sodium ion movement through the sodium channels calculates to be +61 millivolts. However, the actual membrane potential is -65 millivolts, not +61 millivolts. Therefore, those sodium ions that leak to the interior are immediately pumped back to the exterior by the sodium pump, thus maintaining the -65 millivolt negative potential inside the neuron. For potassium ions, the concentration gradient is 120 mEq/L inside the neuron and 4.5 mEq/L outside. This calculates to a Nernst potential of -86 millivolts inside the neuron, which is more negative than the 565 -65 that actually exists. Therefore, because of the high intracellular potassium ion concentration, there is a net tendency for potassium ions to diffuse to the outside of the neuron, but this is opposed by continual pumping of these potassium ions back to the interior. Finally, the chloride ion gradient, 107 mEq/L outside and 8 mEq/L inside, yields a Nernst potential of -70 millivolts inside the neuron, which is only slightly more negative than the actual measured value of -65 millivolts. Therefore, chloride ions tend to leak very slightly to the interior of the neuron, but those few that do leak are moved back to the exterior, perhaps by an active chloride pump. Keep these three Nernst potentials in mind and remember the direction in which the different ions tend to diffuse because this information is important in understanding both excitation and inhibition of the neuron by synapse activation or inactivation of ion channels. Uniform Distribution of Electrical Potential Inside the Soma. The interior of the neuronal soma contains a highly conductive electrolytic solution, the intracellular fluid of the neuron. Furthermore, the diameter of the neuronal soma is large (from 10 to 80 micrometers), causing almost no resistance to conduction of electric current from one part of the somal interior to another part. Therefore, any change in potential in any part of the intrasomal fluid causes an almost exactly equal change in potential at all other points inside the soma (that is, as long as the neuron is not transmitting an action potential). This is an important principle, because it plays a major role in “summation” of signals entering the neuron from multiple sources, as we shall see in subsequent sections of this chapter. Effect of Synaptic Excitation on the Postsynaptic Membrane— Excitatory Postsynaptic Potential. Figure 45–9A shows the resting neuron with an unexcited presynaptic terminal resting on its surface. The resting membrane potential everywhere in the soma is -65 millivolts. Figure 45–9B shows a presynaptic terminal that has secreted an excitatory transmitter into the cleft between the terminal and the neuronal somal membrane. This transmitter acts on the membrane excitatory receptor to increase the membrane’s permeability to Na+. Because of the large sodium concentration gradient and large electrical negativity inside the neuron, sodium ions diffuse rapidly to the inside of the membrane. The rapid influx of positively charged sodium ions to the interior neutralizes part of the negativity of the resting membrane potential. Thus, in Figure 45–9B, the resting membrane potential has increased in the positive direction from -65 to -45 millivolts. This positive increase in voltage above the normal resting neuronal potential—that is, to a less negative value—is called the excitatory postsynaptic potential (or EPSP), because if this potential rises high enough in the positive direction, it will elicit an action potential in the postsynaptic neuron, thus exciting it. (In this case, the 566 Unit IX The Nervous System: A. General Principles and Sensory Physiology A -65 mV Resting Neuron Initial segment of axon B Excitatory -45 mV Na+ influx Excited Neuron C Spread of action potential Cl- influx times as great a concentration of voltage-gated sodium channels as does the soma and, therefore, can generate an action potential with much greater ease than can the soma. The EPSP that will elicit an action potential in the axon initial segment is between +10 and +20 millivolts. This is in contrast to the +30 or +40 millivolts or more required on the soma. Once the action potential begins, it travels peripherally along the axon and usually also backward over the soma. In some instances, it travels backward into the dendrites, too, but not into all of them, because they, like the neuronal soma, have very few voltagegated sodium channels and therefore frequently cannot generate action potentials at all. Thus, in Figure 45–9B, the threshold for excitation of the neuron is shown to be about -45 millivolts, which represents an EPSP of +20 millivolts—that is, 20 millivolts more positive than the normal resting neuronal potential of -65 millivolts. Inhibitory -70 mV K+ efflux Inhibited Neuron Figure 45–9 Three states of a neuron. A, Resting neuron, with a normal intraneuronal potential of -65 millivolts. B, Neuron in an excited state, with a less negative intraneuronal potential (-45 millivolts) caused by sodium influx. C, Neuron in an inhibited state, with a more negative intraneuronal membrane potential (-70 millivolts) caused by potassium ion efflux, chloride ion influx, or both. EPSP is +20 millivolts—that is, 20 millivolts more positive than the resting value.) However, we must issue a word of warning. Discharge of a single presynaptic terminal can never increase the neuronal potential from -65 millivolts all the way up to -45 millivolts. An increase of this magnitude requires simultaneous discharge of many terminals—about 40 to 80 for the usual anterior motor neuron—at the same time or in rapid succession. This occurs by a process called summation, which is discussed in detail in the next sections. Generation of Action Potentials in the Initial Segment of the Axon Leaving the Neuron—Threshold for Excitation. When the EPSP rises high enough in the positive direction, there comes a point at which this initiates an action potential in the neuron. However, the action potential does not begin adjacent to the excitatory synapses. Instead, it begins in the initial segment of the axon where the axon leaves the neuronal soma. The main reason for this point of origin of the action potential is that the soma has relatively few voltage-gated sodium channels in its membrane, which makes it difficult for the EPSP to open the required number of sodium channels to elicit an action potential. Conversely, the membrane of the initial segment has seven Electrical Events During Neuronal Inhibition Effect of Inhibitory Synapses on the Postsynaptic Membrane— Inhibitory Postsynaptic Potential. The inhibitory synapses open mainly chloride channels, allowing easy passage of chloride ions. Now, to understand how the inhibitory synapses inhibit the postsynaptic neuron, we must recall what we learned about the Nernst potential for chloride ions. We calculated the Nernst potential for chloride ions to be about -70 millivolts. This potential is more negative than the -65 millivolts normally present inside the resting neuronal membrane. Therefore, opening the chloride channels will allow negatively charged chloride ions to move from the extracellular fluid to the interior, which will make the interior membrane potential more negative than normal, approaching the -70 millivolt level. Opening potassium channels will allow positively charged potassium ions to move to the exterior, and this will also make the interior membrane potential more negative than usual. Thus, both chloride influx and potassium efflux increase the degree of intracellular negativity, which is called hyperpolarization. This inhibits the neuron because the membrane potential is even more negative than the normal intracellular potential. Therefore, an increase in negativity beyond the normal resting membrane potential level is called an inhibitory postsynaptic potential (IPSP). Figure 45–9C shows the effect on the membrane potential caused by activation of inhibitory synapses, allowing chloride influx into the cell and/or potassium efflux out of the cell, with the membrane potential decreasing from its normal value of -65 millivolts to the more negative value of -70 millivolts. This membrane potential is 5 millivolts more negative than normal and is therefore an IPSP of -5 millivolts, which inhibits transmission of the nerve signal through the synapse. Chapter 45 567 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” Presynaptic Inhibition In addition to inhibition caused by inhibitory synapses operating at the neuronal membrane, which is called postsynaptic inhibition, another type of inhibition often occurs at the presynaptic terminals before the signal ever reaches the synapse. This type of inhibition, called presynaptic inhibition, occurs in the following way. Presynaptic inhibition is caused by release of an inhibitory substance onto the outsides of the presynaptic nerve fibrils before their own endings terminate on the postsynaptic neuron. In most instances, the inhibitory transmitter substance is GABA (gammaaminobutyric acid). This has a specific effect of opening anion channels, allowing large numbers of chloride ions to diffuse into the terminal fibril. The negative charges of these ions inhibit synaptic transmission because they cancel much of the excitatory effect of the positively charged sodium ions that also enter the terminal fibrils when an action potential arrives. Presynaptic inhibition occurs in many of the sensory pathways in the nervous system. In fact, adjacent sensory nerve fibers often mutually inhibit one another, which minimizes sideways spread and mixing of signals in sensory tracts. We discuss the importance of this phenomenon more fully in subsequent chapters. Time Course of Postsynaptic Potentials When an excitatory synapse excites the anterior motor neuron, the neuronal membrane becomes highly permeable to sodium ions for 1 to 2 milliseconds. During this very short time, enough sodium ions diffuse rapidly to the interior of the postsynaptic motor neuron to increase its intraneuronal potential by a few millivolts, thus creating the excitatory postsynaptic potential (EPSP) shown by the blue and green curves of Figure 45–10. This potential then slowly declines over the next 15 milliseconds because this is the time required for the excess positive charges to leak out of the excited neuron and to re-establish the normal resting membrane potential. Precisely the opposite effect occurs for an IPSP; that is, the inhibitory synapse increases the permeability of the membrane to potassium or chloride ions, or both, for 1 to 2 milliseconds, and this decreases the intraneuronal potential to a more negative value than normal, thereby creating the IPSP. This potential also dies away in about 15 milliseconds. Other types of transmitter substances can excite or inhibit the postsynaptic neuron for much longer periods—for hundreds of milliseconds or even for seconds, minutes, or hours. This is especially true for some of the neuropeptide types of transmitter substances. “Spatial Summation” in Neurons— Threshold for Firing Excitation of a single presynaptic terminal on the surface of a neuron almost never excites the neuron. The reason for this is that sufficient transmitter substance is released by a single terminal to cause an EPSP usually no greater than 0.5 to 1 millivolt, instead of the 10 to 20 millivolts normally required to reach threshold for excitation. However, many presynaptic terminals are usually stimulated at the same time. Even though these terminals are spread over wide areas of the neuron, their effects can still summate; that is, they can add to one another until neuronal excitation does occur. The reason for this is the following: It was pointed out earlier that a change in potential at any single point within the soma will cause the potential to change everywhere inside the soma almost exactly equally. This is true because of the very high electrical conductivity inside the large neuronal cell body. Therefore, for each excitatory synapse that discharges simultaneously, the total intrasomal potential becomes more positive by 0.5 to 1.0 millivolt. When +20 Action potential Millivolts 0 –20 Excitatory postsynaptic potentials, showing that simultaneous firing of only a few synapses will not cause sufficient summated potential to elicit an action potential, but that simultaneous firing of many synapses will raise the summated potential to threshold for excitation and cause a superimposed action potential. 16 synapses firing 8 8 synapses firing 4 4 synapses firing 16 –40 Excitatory postsynaptic potential 8 Figure 45–10 16 4 –60 Resting membrane potential – 80 0 2 4 6 8 Milliseconds 10 12 14 16 The Nervous System: A. General Principles and Sensory Physiology the EPSP becomes great enough, the threshold for firing will be reached and an action potential will develop spontaneously in the initial segment of the axon. This is demonstrated in Figure 45–10. The bottom postsynaptic potential in the figure was caused by simultaneous stimulation of 4 synapses; the next higher potential was caused by stimulation of 8 synapses; finally, a still higher EPSP was caused by stimulation of 16 synapses. In this last instance, the firing threshold had been reached, and an action potential was generated in the axon. This effect of summing simultaneous postsynaptic potentials by activating multiple terminals on widely spaced areas of the neuronal membrane is called spatial summation. “Temporal Summation” Each time a presynaptic terminal fires, the released transmitter substance opens the membrane channels for at most a millisecond or so. But the changed postsynaptic potential lasts up to 15 milliseconds after the synaptic membrane channels have already closed. Therefore, a second opening of the same channels can increase the postsynaptic potential to a still greater level, and the more rapid the rate of stimulation, the greater the postsynaptic potential becomes. Thus, successive discharges from a single presynaptic terminal, if they occur rapidly enough, can add to one another; that is, they can “summate.” This type of summation is called temporal summation. Simultaneous Summation of Inhibitory and Excitatory Postsynaptic Potentials. If an IPSP is tending to decrease the Most Dendrites Cannot Transmit Action Potentials—But They Can Transmit Signals Within the Same Neuron by Electrotonic Conduction. Most dendrites fail to transmit action potentials because their membranes have relatively few voltage-gated sodium channels, and their thresholds for excitation are too high for action potentials to occur. Yet they do transmit electrotonic current down the dendrites to the soma. Transmission of electrotonic current means direct spread of electrical current by ion conduction in the fluids of the dendrites but without generation of action potentials. Stimulation (or inhibition) of the neuron by this current has special characteristics, as follows. Decrement of Electrotonic Conduction in the Dendrites—Greater Excitatory (or Inhibitory) Effect by Synapses Located Near the Soma. In Figure 45–11, multiple excitatory and inhibitory synapses are shown stimulating the dendrites of a neuron. On the two dendrites to the left, there are excitatory effects near the tip ends; note the high levels of excitatory postsynaptic potentials at these ends—that is, note the less negative membrane potentials at these points. However, a -2 E E 0 Large Spatial Field of Excitation of the Dendrites. The dendrites of the anterior motor neurons often extend 500 to 1000 micrometers in all directions from the neu- E E -1 Special Functions of Dendrites for Exciting Neurons E E “Facilitation” of Neurons Often the summated postsynaptic potential is excitatory but has not risen high enough to reach the threshold for firing by the postsynaptic neuron. When this happens, the neuron is said to be facilitated. That is, its membrane potential is nearer the threshold for firing than normal, but not yet at the firing level. Consequently, another excitatory signal entering the neuron from some other source can then excite the neuron very easily. Diffuse signals in the nervous system often do facilitate large groups of neurons so that they can respond quickly and easily to signals arriving from other sources. E 0 membrane potential to a more negative value while an EPSP is tending to increase the potential at the same time, these two effects can either completely or partially nullify each other. Thus, if a neuron is being excited by an EPSP, an inhibitory signal from another source can often reduce the postsynaptic potential to less than threshold value for excitation, thus turning off the activity of the neuron. ronal soma. And these dendrites can receive signals from a large spatial area around the motor neuron. This provides a vast opportunity for summation of signals from many separate presynaptic nerve fibers. It is also important that between 80 and 95 per cent of all the presynaptic terminals of the anterior motor neuron terminate on dendrites, in contrast to only 5 to 20 per cent terminating on the neuronal soma. Therefore, the preponderant share of the excitation is provided by signals transmitted by way of the dendrites. 0 Unit IX -2 568 E -3 -2 E 0 I -3 5 -5 0 -40 -50 -60 -30 -40 E 0- -40 -50 I -75 -70 -60 60 -60 mV I I -70 -75 I I Figure 45–11 Stimulation of a neuron by presynaptic terminals located on dendrites, showing, especially, decremental conduction of excitatory (E) electrotonic potentials in the two dendrites to the left and inhibition (I) of dendritic excitation in the dendrite that is uppermost. A powerful effect of inhibitory synapses at the initial segment of the axon is also shown. Chapter 45 569 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” large share of the excitatory postsynaptic potential is lost before it reaches the soma. The reason is that the dendrites are long, and their membranes are thin and at least partially permeable to potassium and chloride ions, making them “leaky” to electric current. Therefore, before the excitatory potentials can reach the soma, a large share of the potential is lost by leakage through the membrane. This decrease in membrane potential as it spreads electrotonically along dendrites toward the soma is called decremental conduction. The farther the excitatory synapse is from the soma of the neuron, the greater will be the decrement, and the less will be excitatory signal reaching the soma. Therefore, those synapses that lie near the soma have far more effect in causing neuron excitation or inhibition than those that lie far away from the soma. Summation of Excitation and Inhibition in Dendrites. The uppermost dendrite of Figure 45–11 is shown to be stimulated by both excitatory and inhibitory synapses. At the tip of the dendrite is a strong excitatory postsynaptic potential, but nearer the soma are two inhibitory synapses acting on the same dendrite. These inhibitory synapses provide a hyperpolarizing voltage that completely nullifies the excitatory effect and indeed transmits a small amount of inhibition by electrotonic conduction toward the soma. Thus, dendrites can summate excitatory and inhibitory postsynaptic potentials in the same way that the soma can. Also shown in the figure are several inhibitory synapses located directly on the axon hillock and initial axon segment. This location provides especially powerful inhibition because it has the direct effect of increasing the threshold for excitation at the very point where the action potential is normally generated. Frequency of discharge per second 600 Relation of State of Excitation of the Neuron to Rate of Firing “Excitatory State.” The “excitatory state” of a neuron is defined as the summated degree of excitatory drive to the neuron. If there is a higher degree of excitation than inhibition of the neuron at any given instant, then it is said that there is an excitatory state. Conversely, if there is more inhibition than excitation, then it is said that there is an inhibitory state. When the excitatory state of a neuron rises above the threshold for excitation, the neuron will fire repetitively as long as the excitatory state remains at that level. Figure 45–12 shows responses of three types of neurons to varying levels of excitatory state. Note that neuron 1 has a low threshold for excitation, whereas neuron 3 has a high threshold. But note also that neuron 2 has the lowest maximum frequency of discharge, whereas neuron 3 has the highest maximum frequency. Some neurons in the central nervous system fire continuously because even the normal excitatory state is above the threshold level. Their frequency of firing can usually be increased still more by further increasing their excitatory state. The frequency can be decreased, or firing can even be stopped, by superimposing an inhibitory state on the neuron. Thus, different neurons respond differently, have different thresholds for excitation, and have widely differing maximum frequencies of discharge. With a little imagination, one can readily understand the importance of having different neurons with these many types of response characteristics to perform the widely varying functions of the nervous system. Neuron 1 Neuron 2 Neuron 3 500 400 300 200 Threshold 100 0 Figure 45–12 Response characteristics of different types of neurons to different levels of excitatory state. 0 5 10 15 20 25 Excitatory state (arbitrary units) 30 35 570 Unit IX The Nervous System: A. General Principles and Sensory Physiology Some Special Characteristics of Synaptic Transmission of Synaptic Transmission. When excitatory synapses are repetitively stimulated at a rapid rate, the number of discharges by the postsynaptic neuron is at first very great, but the firing rate becomes progressively less in succeeding milliseconds or seconds. This is called fatigue of synaptic transmission. Fatigue is an exceedingly important characteristic of synaptic function because when areas of the nervous system become overexcited, fatigue causes them to lose this excess excitability after awhile. For example, fatigue is probably the most important means by which the excess excitability of the brain during an epileptic seizure is finally subdued so that the seizure ceases. Thus, the development of fatigue is a protective mechanism against excess neuronal activity. This is discussed further in the description of reverberating neuronal circuits in Chapter 46. The mechanism of fatigue is mainly exhaustion or partial exhaustion of the stores of transmitter substance in the presynaptic terminals. The excitatory terminals on many neurons can store enough excitatory transmitter to cause only about 10,000 action potentials, and the transmitter can be exhausted in only a few seconds to a few minutes of rapid stimulation. Part of the fatigue process probably results from two other factors as well: (1) progressive inactivation of many of the postsynaptic membrane receptors and (2) slow development of abnormal concentrations of ions inside the postsynaptic neuronal cell. Fatigue Effect of Acidosis or Alkalosis on Synaptic Transmission. Most neurons are highly responsive to changes in pH of the surrounding interstitial fluids. Normally, alkalosis greatly increases neuronal excitability. For instance, a rise in arterial blood pH from the 7.4 norm to 7.8 to 8.0 often causes cerebral epileptic seizures because of increased excitability of some or all of the cerebral neurons. This can be demonstrated especially well by asking a person who is predisposed to epileptic seizures to overbreathe. The overbreathing blows off carbon dioxide and therefore elevates the pH of the blood momentarily, but even this short time can often precipitate an epileptic attack. Conversely, acidosis greatly depresses neuronal activity; a fall in pH from 7.4 to below 7.0 usually causes a comatose state. For instance, in very severe diabetic or uremic acidosis, coma virtually always develops. of Hypoxia on Synaptic Transmission. Neuronal excitability is also highly dependent on an adequate supply of oxygen. Cessation of oxygen for only a few seconds can cause complete inexcitability of some neurons. This is observed when the brain’s blood flow is temporarily interrupted, because within 3 to 7 seconds, the person becomes unconscious. Effect Effect of Drugs on Synaptic Transmission. Many drugs are known to increase the excitability of neurons, and others are known to decrease excitability. For instance, caffeine, theophylline, and theobromine, which are found in coffee, tea, and cocoa, respectively, all increase neuronal excitability, presumably by reducing the threshold for excitation of neurons. Strychnine is one of the best known of all agents that increase excitability of neurons. However, it does not do this by reducing the threshold for excitation of the neurons; instead, it inhibits the action of some normally inhibitory transmitter substances, especially the inhibitory effect of glycine in the spinal cord. Therefore, the effects of the excitatory transmitters become overwhelming, and the neurons become so excited that they go into rapidly repetitive discharge, resulting in severe tonic muscle spasms. Most anesthetics increase the neuronal membrane threshold for excitation and thereby decrease synaptic transmission at many points in the nervous system. Because many of the anesthetics are especially lipidsoluble, it has been reasoned that some of them might change the physical characteristics of the neuronal membranes, making them less responsive to excitatory agents. Synaptic Delay. During transmission of a neuronal signal from a presynaptic neuron to a postsynaptic neuron, a certain amount of time is consumed in the process of (1) discharge of the transmitter substance by the presynaptic terminal, (2) diffusion of the transmitter to the postsynaptic neuronal membrane, (3) action of the transmitter on the membrane receptor, (4) action of the receptor to increase the membrane permeability, and (5) inward diffusion of sodium to raise the excitatory postsynaptic potential to a high enough level to elicit an action potential. The minimal period of time required for all these events to take place, even when large numbers of excitatory synapses are stimulated simultaneously, is about 0.5 millisecond. This is called the synaptic delay. Neurophysiologists can measure the minimal delay time between an input volley of impulses into a pool of neurons and the consequent output volley. From the measure of delay time, one can then estimate the number of series neurons in the circuit. References Albright TD, Jessell TM, Kandell ER, Posner MI: Progress in the neural sciences in the century after Cajal (and the mysteries that remain). Ann N Y Acad Sci 929:11, 2001. Boehning D, Snyder SH: Novel neural modulators. Annu Rev Neurosci 26:105, 2003. Brasnjo G, Otis TS: Glycine transporters not only take out the garbage, they recycle. Neuron 40:667, 2003. Cowley MA, Cone RD, Enriori P, et al: Electrophysiological actions of peripheral hormones on melanocortin neurons. Ann N Y Acad Sci 994:175, 2003. Engelman HS, MacDermott AB: Presynaptic inotropic receptors and control of transmitter release. Nat Rev Neurosci 5:135, 2004. Girault JA, Greengard P: The neurobiology of dopamine signaling. Arch Neurol 61:641, 2004. Haines DE: Fundamental Neuroscience. New York: Churchill Livingstone, 1997. Haines DE, Lancon JA: Review of Neuroscience. New York: Churchill Livingstone, 2003. Kandel ER: The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030, 2001. Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2000. Chapter 45 Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances” Magee JC: Dendritic integration of excitatory synaptic input. Nat Rev Neurosci 1:181, 2000. Migliore M, Shepherd GM: Emerging rules for the distributions of active dendritic conductances. Nat Rev Neurosci 3:362, 2002. Muller D, Nikonenko I: Dynamic presynaptic varicosities: a role in activity-dependent synaptogenesis. Trends Neurosci 26:573, 2003. Nicholls DG, Budd SL: Mitochondria and neuronal survival. Physiol Rev 80:315, 2000. Nimchinsky EA, Sabatin BL, Svoboda K: Structure and function of dendritic spines. Annu Rev Physiol 64:313, 2002. Prast H, Philippu A: Nitric oxide as modulator of neuronal function. Prog Neurobiol 64:51, 2001. Reid CA, Bekkers JM, Clements JD: Presynaptic Ca2+ channels: a functional patchwork.Trends Neurosci 26:683, 2003. Robinson RB, Siegelbaum SA: Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 65:453, 2003. Ruff RL: Neurophysiology of the neuromuscular junction: overview. Ann N Y Acad Sci 998:1, 2003. 571 Schmolesky MT, Weber JT, De Zeeuw CI, Hansel C: The making of a complex spike: ionic composition and plasticity. Ann N Y Acad Sci 978:359, 2002. Semyanov A, Walker MC, Kullmann DM, Silver RA: Tonically active GABA A receptors: modulating gain and maintaining the tone. Trends Neurosci 27:262, 2004. Stern JE: Nitric oxide and homeostatic control: an intercellular signaling molecule contributing to autonomic and neuroendocrine integration? Prog Biophys Mol Biol 84: 197, 2004. Timofeev I, Steriade M: Neocortical seizures: initiation, development and cessation. Neuroscience 123:299, 2004. Tsay D, Yuste RL: On the electrical function of dendritic spines. Trends Neurosci 27:77, 2004. West AR, Floresco SB, Charara A, et al: Electrophysiological interactions between striatal glutamatergic and dopaminergic systems. Ann N Y Acad Sci 1003:53, 2003. Williams SR, Stuart GJ: Role of dendritic synapse location in the control of action potential output. Trends Neurosci 26:147, 2003. Zucker RS, Regehr WG: Short-term synaptic plasticity. Annu Rev Physiol 64:355, 2002. C H A P T E R 4 6 Sensory Receptors, Neuronal Circuits for Processing Information Input to the nervous system is provided by sensory receptors that detect such sensory stimuli as touch, sound, light, pain, cold, and warmth. The purpose of this chapter is to discuss the basic mechanisms by which these receptors change sensory stimuli into nerve signals that are then conveyed to and processed in the central nervous system. Types of Sensory Receptors and the Sensory Stimuli They Detect Table 46–1 lists and classifies most of the body’s sensory receptors. This table shows that there are five basic types of sensory receptors: (1) mechanoreceptors, which detect mechanical compression or stretching of the receptor or of tissues adjacent to the receptor; (2) thermoreceptors, which detect changes in temperature, some receptors detecting cold and others warmth; (3) nociceptors (pain receptors), which detect damage occurring in the tissues, whether physical damage or chemical damage; (4) electromagnetic receptors, which detect light on the retina of the eye; and (5) chemoreceptors, which detect taste in the mouth, smell in the nose, oxygen level in the arterial blood, osmolality of the body fluids, carbon dioxide concentration, and perhaps other factors that make up the chemistry of the body. In this chapter, we discuss the function of a few specific types of receptors, primarily peripheral mechanoreceptors, to illustrate some of the principles by which receptors operate. Other receptors are discussed in other chapters in relation to the sensory systems that they subserve. Figure 46–1 shows some of the types of mechanoreceptors found in the skin or in deep tissues of the body. Differential Sensitivity of Receptors The first question that must be answered is, how do two types of sensory receptors detect different types of sensory stimuli? The answer is, by “differential sensitivities.”That is, each type of receptor is highly sensitive to one type of stimulus for which it is designed and yet is almost nonresponsive to other types of sensory stimuli. Thus, the rods and cones of the eyes are highly responsive to light but are almost completely nonresponsive to normal ranges of heat, cold, pressure on the eyeballs, or chemical changes in the blood. The osmoreceptors of the supraoptic nuclei in the hypothalamus detect minute changes in the osmolality of the body fluids but have never been known to respond to sound. Finally, pain receptors in the skin are almost never stimulated by usual touch or pressure stimuli but do become highly active the moment tactile stimuli become severe enough to damage the tissues. Modality of Sensation—The “Labeled Line” Principle Each of the principal types of sensation that we can experience—pain, touch, sight, sound, and so forth—is called a modality of sensation. Yet despite the fact that we experience these different modalities of sensation, nerve fibers 572 Chapter 46 Sensory Receptors, Neuronal Circuits for Processing Information 573 Table 46–1 Classification of Sensory Receptors Free nerve endings Expanded tip receptor Tactile hair Pacinian corpuscle Meissner’s corpuscle Krause’s corpuscle Ruffini’s end-organ Golgi tendon apparatus Muscle spindle Figure 46–1 Several types of somatic sensory nerve endings. transmit only impulses. Therefore, how is it that different nerve fibers transmit different modalities of sensation? The answer is that each nerve tract terminates at a specific point in the central nervous system, and the type of sensation felt when a nerve fiber is stimulated is determined by the point in the nervous system to which the fiber leads. For instance, if a pain fiber is stimulated, the person perceives pain regardless of what type of stimulus excites the fiber. The stimulus can be electricity, overheating of the fiber, crushing of the fiber, or stimulation of the pain nerve ending by damage to the tissue cells. In all these instances, the person perceives pain. Likewise, if a touch fiber is stimulated by electrical excitation of a touch receptor or in any other way, the person perceives touch because touch fibers lead to specific touch areas in the brain. Similarly, fibers from the retina of the eye terminate in the vision areas of the brain, fibers from the ear terminate in the auditory areas of the brain, and temperature fibers terminate in the temperature areas. This specificity of nerve fibers for transmitting only one modality of sensation is called the labeled line principle. I. Mechanoreceptors Skin tactile sensibilities (epidermis and dermis) Free nerve endings Expanded tip endings Merkel’s discs Plus several other variants Spray endings Ruffini’s endings Encapsulated endings Meissner’s corpuscles Krause’s corpuscles Hair end-organs Deep tissue sensibilities Free nerve endings Expanded tip endings Spray endings Ruffini’s endings Encapsulated endings Pacinian corpuscles Plus a few other variants Muscle endings Muscle spindles Golgi tendon receptors Hearing Sound receptors of cochlea Equilibrium Vestibular receptors Arterial pressure Baroreceptors of carotid sinuses and aorta II. Thermoreceptors Cold Cold receptors Warmth Warm receptors III. Nociceptors Pain Free nerve endings IV. Electromagnetic receptors Vision Rods Cones V. Chemoreceptors Taste Receptors of taste buds Smell Receptors of olfactory epithelium Arterial oxygen Receptors of aortic and carotid bodies Osmolality Neurons in or near supraoptic nuclei Blood CO2 Receptors in or on surface of medulla and in aortic and carotid bodies Blood glucose, amino acids, fatty acids Receptors in hypothalamus Transduction of Sensory Stimuli into Nerve Impulses Local Electrical Currents at Nerve Endings—Receptor Potentials All sensory receptors have one feature in common. Whatever the type of stimulus that excites the receptor, its immediate effect is to change the membrane 574 Unit IX The Nervous System: A. General Principles and Sensory Physiology electrical potential of the receptor. This change in potential is called a receptor potential. receptor potential rises above the threshold level, the greater becomes the action potential frequency. Mechanisms of Receptor Potentials. Different receptors can be excited in one of several ways to cause receptor potentials: (1) by mechanical deformation of the receptor, which stretches the receptor membrane and opens ion channels; (2) by application of a chemical to the membrane, which also opens ion channels; (3) by change of the temperature of the membrane, which alters the permeability of the membrane; or (4) by the effects of electromagnetic radiation, such as light on a retinal visual receptor, which either directly or indirectly changes the receptor membrane characteristics and allows ions to flow through membrane channels. It will be recognized that these four means of exciting receptors correspond in general with the different types of known sensory receptors. In all instances, the basic cause of the change in membrane potential is a change in membrane permeability of the receptor, which allows ions to diffuse more or less readily through the membrane and thereby to change the transmembrane potential. Receptor Potential of the Pacinian Corpuscle— An Example of Receptor Function Maximum Receptor Potential Amplitude. The maximum amplitude of most sensory receptor potentials is about 100 millivolts, but this level occurs only at an extremely high intensity of sensory stimulus. This is about the same maximum voltage recorded in action potentials and is also the change in voltage when the membrane becomes maximally permeable to sodium ions. Relation of the Receptor Potential to Action Potentials. When the receptor potential rises above the threshold for eliciting action potentials in the nerve fiber attached to the receptor, then action potentials occur, as illustrated in Figure 46–2. Note also that the more the The student should at this point restudy the anatomical structure of the pacinian corpuscle shown in Figure 46–1. Note that the corpuscle has a central nerve fiber extending through its core. Surrounding this are multiple concentric capsule layers, so that compression anywhere on the outside of the corpuscle will elongate, indent, or otherwise deform the central fiber. Now study Figure 46–3, which shows only the central fiber of the pacinian corpuscle after all capsule layers but one have been removed. The tip of the central fiber inside the capsule is unmyelinated, but the fiber does become myelinated (the blue sheath shown in the figure) shortly before leaving the corpuscle to enter a peripheral sensory nerve. The figure also shows the mechanism by which a receptor potential is produced in the pacinian corpuscle. Observe the small area of the terminal fiber that has been deformed by compression of the corpuscle, and note that ion channels have opened in the membrane, allowing positively charged sodium ions to diffuse to the interior of the fiber. This creates increased positivity inside the fiber, which is the “receptor potential.” The receptor potential in turn induces a local circuit of current flow, shown by the arrows, that spreads along the nerve fiber. At the first node of Ranvier, which itself lies inside the capsule of the pacinian corpuscle, the local current flow depolarizes the fiber membrane at this node, which then sets off typical action potentials that are transmitted along the nerve fiber toward the central nervous system. Relation Between Stimulus Intensity and the Receptor Potential. Figure 46–4 shows the changing amplitude of the Membrane potential (millivolts) receptor potential caused by progressively stronger mechanical compression (increasing “stimulus strength”) applied experimentally to the central core of a pacinian corpuscle. Note that the amplitude Action potentials +30 0 Receptor potential -30 Receptor potential Threshold -60 Deformed area + + + +++ + + + + + + + ++- Resting membrane potential -90 0 10 20 + + - + + - Action potential - + + + + ++ + + + + + + + + + + + + + + + + - + + + + ++ + + + + + + + + + + + + + + Node of Ranvier 30 40 60 80 100 120 140 Milliseconds Figure 46–3 Figure 46–2 Typical relation between receptor potential and action potentials when the receptor potential rises above threshold level. Excitation of a sensory nerve fiber by a receptor potential produced in a pacinian corpuscle. (Modified from Loëwenstein WR: Excitation and inactivation in a receptor membrane. Ann N Y Acad Sci 94:510, 1961.) Chapter 46 Joint capsule receptors Muscle spindle Hair receptor Pacinian corpuscle 100 250 Impulses per second 90 Amplitude of observed receptor potential (per cent) 575 Sensory Receptors, Neuronal Circuits for Processing Information 80 70 60 50 40 200 150 100 50 30 0 20 0 10 1 2 3 4 5 Seconds 6 7 8 0 0 20 40 60 80 Stimulus strength (per cent) 100 Figure 46–4 Relation of amplitude of receptor potential to strength of a mechanical stimulus applied to a pacinian corpuscle. (Data from Loëwenstein WR: Excitation and inactivation in a receptor membrane. Ann N Y Acad Sci 94:510, 1961.) increases rapidly at first but then progressively less rapidly at high stimulus strength. In turn, the frequency of repetitive action potentials transmitted from sensory receptors increases approximately in proportion to the increase in receptor potential. Putting this principle together with the data in Figure 46–4, one can see that very intense stimulation of the receptor causes progressively less and less additional increase in numbers of action potentials. This is an exceedingly important principle that is applicable to almost all sensory receptors. It allows the receptor to be sensitive to very weak sensory experience and yet not reach a maximum firing rate until the sensory experience is extreme. This allows the receptor to have an extreme range of response, from very weak to very intense. Adaptation of Receptors Another characteristic of all sensory receptors is that they adapt either partially or completely to any constant stimulus after a period of time. That is, when a continuous sensory stimulus is applied, the receptor responds at a high impulse rate at first and then at a progressively slower rate until finally the rate of action potentials decreases to very few or often to none at all. Figure 46–5 shows typical adaptation of certain types of receptors. Note that the pacinian corpuscle adapts extremely rapidly and hair receptors adapt Figure 46–5 Adaptation of different types of receptors, showing rapid adaptation of some receptors and slow adaptation of others. within a second or so, whereas some joint capsule and muscle spindle receptors adapt slowly. Furthermore, some sensory receptors adapt to a far greater extent than others. For example, the pacinian corpuscles adapt to “extinction” within a few hundredths of a second, and the receptors at the bases of the hairs adapt to extinction within a second or more. It is probable that all other mechanoreceptors eventually adapt almost completely, but some require hours or days to do so, for which reason they are called “nonadapting” receptors. The longest measured time for complete adaptation of a mechanoreceptor is about 2 days, which is the adaptation time for many carotid and aortic baroreceptors. Conversely, some of the nonmechanoreceptors—the chemoreceptors and pain receptors, for instance—probably never adapt completely. Mechanisms by Which Receptors Adapt. The mechanism of receptor adaptation is different for each type of receptor, in much the same way that development of a receptor potential is an individual property. For instance, in the eye, the rods and cones adapt by changing the concentrations of their light-sensitive chemicals (which is discussed in Chapter 50). In the case of the mechanoreceptors, the receptor that has been studied in greatest detail is the pacinian corpuscle. Adaptation occurs in this receptor in two ways. First, the pacinian corpuscle is a viscoelastic structure so that when a distorting force is suddenly applied to one side of the corpuscle, this force is instantly transmitted by the viscous component of the corpuscle directly to the same side of the central nerve fiber, thus eliciting a receptor potential. However, within a few hundredths of a second, the fluid within the corpuscle redistributes, so that the receptor potential is no longer elicited. Thus, the receptor potential 576 Unit IX The Nervous System: A. General Principles and Sensory Physiology appears at the onset of compression but disappears within a small fraction of a second even though the compression continues. The second mechanism of adaptation of the pacinian corpuscle, but a much slower one, results from a process called accommodation, which occurs in the nerve fiber itself. That is, even if by chance the central core fiber should continue to be distorted, the tip of the nerve fiber itself gradually becomes “accommodated” to the stimulus. This probably results from progressive “inactivation” of the sodium channels in the nerve fiber membrane, which means that sodium current flow through the channels causes them gradually to close, an effect that seems to occur for all or most cell membrane sodium channels, as was explained in Chapter 5. Presumably, these same two general mechanisms of adaptation apply also to the other types of mechanoreceptors. That is, part of the adaptation results from readjustments in the structure of the receptor itself, and part from an electrical type of accommodation in the terminal nerve fibril. Slowly Adapting Receptors Detect Continuous Stimulus Strength—The “Tonic” Receptors. Slowly adapting recep- tors continue to transmit impulses to the brain as long as the stimulus is present (or at least for many minutes or hours). Therefore, they keep the brain constantly apprised of the status of the body and its relation to its surroundings. For instance, impulses from the muscle spindles and Golgi tendon apparatuses allow the nervous system to know the status of muscle contraction and load on the muscle tendon at each instant. Other slowly adapting receptors include (1) receptors of the macula in the vestibular apparatus, (2) pain receptors, (3) baroreceptors of the arterial tree, and (4) chemoreceptors of the carotid and aortic bodies. Because the slowly adapting receptors can continue to transmit information for many hours, they are called tonic receptors. Rapidly Adapting Receptors Detect Change in Stimulus Strength—The “Rate Receptors,” “Movement Receptors,” or “Phasic Receptors.” Receptors that adapt rapidly cannot be used to transmit a continuous signal because these receptors are stimulated only when the stimulus strength changes. Yet they react strongly while a change is actually taking place. Therefore, these receptors are called rate receptors, movement receptors, or phasic receptors. Thus, in the case of the pacinian corpuscle, sudden pressure applied to the tissue excites this receptor for a few milliseconds, and then its excitation is over even though the pressure continues. But later, it transmits a signal again when the pressure is released. In other words, the pacinian corpuscle is exceedingly important in apprising the nervous system of rapid tissue deformations, but it is useless for transmitting information about constant conditions in the body. status is taking place, one can predict in one’s mind the state of the body a few seconds or even a few minutes later. For instance, the receptors of the semicircular canals in the vestibular apparatus of the ear detect the rate at which the head begins to turn when one runs around a curve. Using this information, a person can predict how much he or she will turn within the next 2 seconds and can adjust the motion of the legs ahead of time to keep from losing balance. Likewise, receptors located in or near the joints help detect the rates of movement of the different parts of the body. For instance, when one is running, information from the joint rate receptors allows the nervous system to predict where the feet will be during any precise fraction of the next second. Therefore, appropriate motor signals can be transmitted to the muscles of the legs to make any necessary anticipatory corrections in position so that the person will not fall. Loss of this predictive function makes it impossible for the person to run. Nerve Fibers That Transmit Different Types of Signals, and Their Physiologic Classification Some signals need to be transmitted to or from the central nervous system extremely rapidly; otherwise, the information would be useless. An example of this is the sensory signals that apprise the brain of the momentary positions of the legs at each fraction of a second during running. At the other extreme, some types of sensory information, such as that depicting prolonged, aching pain, do not need to be transmitted rapidly, so that slowly conducting fibers will suffice. As shown in Figure 46–6, nerve fibers come in all sizes between 0.5 and 20 micrometers in diameter—the larger the diameter, the greater the conducting velocity. The range of conducting velocities is between 0.5 and 120 m/sec. General Classification of Nerve Fibers. Shown in Figure 46–6 is a “general classification” and a “sensory nerve classification” of the different types of nerve fibers. In the general classification, the fibers are divided into types A and C, and the type A fibers are further subdivided into a, b, g, and d fibers. Type A fibers are the typical large and medium-sized myelinated fibers of spinal nerves. Type C fibers are the small unmyelinated nerve fibers that conduct impulses at low velocities. The C fibers constitute more than one half of the sensory fibers in most peripheral nerves as well as all the postganglionic autonomic fibers. The sizes, velocities of conduction, and functions of the different nerve fiber types are also given in Figure 46–6. Note that a few large myelinated fibers can transmit impulses at velocities as great as 120 m/sec, a distance in 1 second that is longer than a football field. Conversely, the smallest fibers transmit impulses as slowly as 0.5 m/sec, requiring about 2 seconds to go from the big toe to the spinal cord. Alternative Classification Used by Sensory Physiologists. Importance of the Rate Receptors—Their Predictive Function. If one knows the rate at which some change in bodily Certain recording techniques have made it possible to separate the type Aa fibers into two subgroups; yet Chapter 46 577 Sensory Receptors, Neuronal Circuits for Processing Information Myelinated Unmyelinated Diameter (micrometers) 20 15 120 80 1 2.0 0.5 Conduction velocity (m/sec.) 60 30 6 2.0 0.5 10 5 General classification A C a b g d Sensory nerve classification I II III IV IA IB Sensory functions Muscle spindle (primary ending) Muscle spindle (secondary ending) Muscle tendon (Golgi tendon organ) Hair receptors Vibration (pacinian corpuscle) High discrimination touch (Meissner's expanded tips) Crude touch and pressure Deep pressure and touch Tickle Pricking pain Aching pain Cold Warmth Motor function Skeletal muscle (type Aa) Figure 46–6 20 15 Muscle spindle (type Ag) Sympathetic (type C) 10 5 1 2.0 Nerve fiber diameter (micrometers) 0.5 Physiologic classifications and functions of nerve fibers. these same recording techniques cannot distinguish easily between Ab and Ag fibers. Therefore, the following classification is frequently used by sensory physiologists: Group Ia Fibers from the annulospiral endings of muscle spindles (average about 17 microns in diameter; these are a-type A fibers in the general classification). Group Ib Group III Fibers carrying temperature, crude touch, and pricking pain sensations (average about 3 micrometers in diameter; they are d-type A fibers in the general classification). Group IV Unmyelinated fibers carrying pain, itch, temperature, and crude touch sensations (0.5 to 2 micrometers in diameter; they are type C fibers in the general classification). Group II Transmission of Signals of Different Intensity in Nerve Tracts—Spatial and Temporal Summation Fibers from most discrete cutaneous tactile receptors and from the flower-spray endings of the muscle spindles (average about 8 micrometers in diameter; these are b- and g-type A fibers in the general classification). One of the characteristics of each signal that always must be conveyed is signal intensity—for instance, the intensity of pain. The different gradations of intensity Fibers from the Golgi tendon organs (average about 16 micrometers in diameter; these also are a-type A fibers). 578 Unit IX The Nervous System: A. General Principles and Sensory Physiology can be transmitted either by using increasing numbers of parallel fibers or by sending more action potentials along a single fiber. These two mechanisms are called, respectively, spatial summation and temporal summation. Spatial Summation. Figure 46–7 shows the phenomenon of spatial summation, whereby increasing signal strength is transmitted by using progressively greater numbers of fibers. This figure shows a section of skin innervated by a large number of parallel pain fibers. Each of these arborizes into hundreds of minute free nerve endings that serve as pain receptors. The entire cluster of fibers from one pain fiber frequently covers an area of skin as large as 5 centimeters in diameter. This area is called the receptor field of that fiber. The number of endings is large in the center of the field but diminishes toward the periphery. One can also see from the figure that the arborizing fibrils overlap those from other pain fibers. Therefore, a pinprick of the skin usually stimulates endings from many different pain fibers simultaneously. When the pinprick is in the center of the receptive field of a particular pain fiber, the degree of stimulation of that fiber is far greater than when it is in the periphery of the field, because the number of free nerve endings in the middle of the field is much greater than at the periphery. Thus, the lower part of Figure 46–7 shows three views of the cross section of the nerve bundle leading from the skin area. To the left is the effect of a weak stimulus, with only a single nerve fiber in the middle of the bundle stimulated strongly (represented by the red-colored fiber), whereas several adjacent fibers are stimulated weakly (half-red fibers). The other two views of the nerve cross section show the effect of a moderate stimulus and a strong stimulus, with progressively more fibers being stimulated. Thus, the stronger signals spread to more and more fibers. This is the phenomenon of spatial summation. Temporal Summation. A second means for transmitting signals of increasing strength is by increasing the frequency of nerve impulses in each fiber, which is called temporal summation. Figure 46–8 demonstrates this, showing in the upper part a changing strength of signal and in the lower part the actual impulses transmitted by the nerve fiber. Transmission and Processing of Signals in Neuronal Pools The central nervous system is composed of thousands to millions of neuronal pools; some of these contain few neurons, while others have vast numbers. For instance, the entire cerebral cortex could be considered to be a single large neuronal pool. Other neuronal pools include the different basal ganglia and the specific nuclei in the thalamus, cerebellum, mesencephalon, pons, and medulla. Also, the entire dorsal gray matter of the spinal cord could be considered one long pool of neurons. Each neuronal pool has its own special organization that causes it to process signals in its own unique way, Pin Strength of signal (impulses per second) 80 Nerve Skin 60 40 20 Impulses 0 Weak stimulus Moderate stimulus Strong stimulus Figure 46–7 Pattern of stimulation of pain fibers in a nerve leading from an area of skin pricked by a pin. This is an example of spatial summation. Time Figure 46–8 Translation of signal strength into a frequency-modulated series of nerve impulses, showing the strength of signal (above) and the separate nerve impulses (below). This is an example of temporal summation. Chapter 46 579 Sensory Receptors, Neuronal Circuits for Processing Information thus allowing the total consortium of pools to achieve the multitude of functions of the nervous system. Yet despite their differences in function, the pools also have many similar principles of function, described in the following pages. Relaying of Signals Through Neuronal Pools Organization of Neurons for Relaying Signals. Figure 46–9 is a schematic diagram of several neurons in a neuronal pool, showing “input” fibers to the left and “output” fibers to the right. Each input fiber divides hundreds to thousands of times, providing a thousand or more terminal fibrils that spread into a large area in the pool to synapse with dendrites or cell bodies of the neurons in the pool. The dendrites usually also arborize and spread hundreds to thousands of micrometers in the pool. The neuronal area stimulated by each incoming nerve fiber is called its stimulatory field. Note in Figure 46–9 that large numbers of the terminals from each input fiber lie on the nearest neuron in its “field,” but progressively fewer terminals lie on the neurons farther away. Threshold and Subthreshold Stimuli—Excitation or Facilitation. From the discussion of synaptic function in Chapter 45, it will be recalled that discharge of a single 1 a excitatory presynaptic terminal almost never causes an action potential in a postsynaptic neuron. Instead, large numbers of input terminals must discharge on the same neuron either simultaneously or in rapid succession to cause excitation. For instance, in Figure 46–9, let us assume that six terminals must discharge almost simultaneously to excite any one of the neurons. If the student counts the number of terminals on each one of the neurons from each input fiber, he or she will see that input fiber 1 has more than enough terminals to cause neuron a to discharge. The stimulus from input fiber 1 to this neuron is said to be an excitatory stimulus; it is also called a suprathreshold stimulus because it is above the threshold required for excitation. Input fiber 1 also contributes terminals to neurons b and c, but not enough to cause excitation. Nevertheless, discharge of these terminals makes both these neurons more likely to be excited by signals arriving through other incoming nerve fibers. Therefore, the stimuli to these neurons are said to be subthreshold, and the neurons are said to be facilitated. Similarly, for input fiber 2, the stimulus to neuron d is a suprathreshold stimulus, and the stimuli to neurons b and c are subthreshold, but facilitating, stimuli. Figure 46–9 represents a highly condensed version of a neuronal pool because each input nerve fiber usually provides massive numbers of branching terminals to hundreds or thousands of neurons in its distribution “field,” as shown in Figure 46–10. In the central portion of the field in this figure, designated by the circled area, all the neurons are stimulated by the incoming fiber. Therefore, this is said to be the discharge zone of the incoming fiber, also called the excited zone or liminal zone. To each side, the neurons are facilitated but not excited, and these areas are called the facilitated zone, also called the subthreshold zone or subliminal zone. Inhibition of a Neuronal Pool. We must also remember b c that some incoming fibers inhibit neurons, rather than exciting them. This is the opposite of facilitation, and the entire field of the inhibitory branches is called the inhibitory zone. The degree of inhibition in the center of this zone is great because of large numbers of endings in the center; it becomes progressively less toward its edges. d 2 Facilitated zone Input nerve fiber Discharge zone Facilitated zone Figure 46–9 Basic organization of a neuronal pool. Figure 46–10 “Discharge” and “facilitated” zones of a neuronal pool. 580 Unit IX The Nervous System: A. General Principles and Sensory Physiology Source Source #1 Source #2 Convergence from single source Divergence in same tract A Divergence in multiple tracts B Figure 46–11 “Divergence” in neuronal pathways. A, Divergence within a pathway to cause “amplification” of the signal. B, Divergence into multiple tracts to transmit the signal to separate areas. Divergence of Signals Passing Through Neuronal Pools Often it is important for weak signals entering a neuronal pool to excite far greater numbers of nerve fibers leaving the pool. This phenomenon is called divergence. Two major types of divergence occur and have entirely different purposes. An amplifying type of divergence is shown in Figure 46–11A. This means simply that an input signal spreads to an increasing number of neurons as it passes through successive orders of neurons in its path. This type of divergence is characteristic of the corticospinal pathway in its control of skeletal muscles, with a single large pyramidal cell in the motor cortex capable, under highly facilitated conditions, of exciting as many as 10,000 muscle fibers. The second type of divergence, shown in Figure 46–11B, is divergence into multiple tracts. In this case, the signal is transmitted in two directions from the pool. For instance, information transmitted up the dorsal columns of the spinal cord takes two courses in the lower part of the brain: (1) into the cerebellum and (2) on through the lower regions of the brain to the thalamus and cerebral cortex. Likewise, in the thalamus, almost all sensory information is relayed both into still deeper structures of the thalamus and at the same time to discrete regions of the cerebral cortex. Convergence of Signals Convergence means signals from multiple inputs uniting to excite a single neuron. Figure 46–12A shows convergence from a single source. That is, multiple terminals from a single incoming fiber tract terminate on the same neuron. The importance of this is that neurons are almost never excited by an action potential from a single input terminal. But action potentials converging on the neuron from multiple terminals provide enough spatial summation to bring the neuron to the threshold required for discharge. A B Source #3 Convergence from multiple sources Figure 46–12 “Convergence” of multiple input fibers onto a single neuron. A, Multiple input fibers from a single source. B, Input fibers from multiple separate sources. Convergence can also result from input signals (excitatory or inhibitory) from multiple sources, as shown in Figure 46–12B. For instance, the interneurons of the spinal cord receive converging signals from (1) peripheral nerve fibers entering the cord, (2) propriospinal fibers passing from one segment of the cord to another, (3) corticospinal fibers from the cerebral cortex, and (4) several other long pathways descending from the brain into the spinal cord.Then the signals from the interneurons converge on the anterior motor neurons to control muscle function. Such convergence allows summation of information from different sources, and the resulting response is a summated effect of all the different types of information. Convergence is one of the important means by which the central nervous system correlates, summates, and sorts different types of information. Neuronal Circuit with Both Excitatory and Inhibitory Output Signals Sometimes an incoming signal to a neuronal pool causes an output excitatory signal going in one direction and at the same time an inhibitory signal going elsewhere. For instance, at the same time that an excitatory signal is transmitted by one set of neurons in the spinal cord to cause forward movement of a leg, an inhibitory signal is transmitted through a separate set of neurons to inhibit the muscles on the back of the leg so that they will not oppose the forward movement. This type of circuit is characteristic for controlling all antagonistic pairs of muscles, and it is called the reciprocal inhibition circuit. Figure 46–13 shows the means by which the inhibition is achieved. The input fiber directly excites the excitatory output pathway, but it stimulates an intermediate inhibitory neuron (neuron 2), which secretes a different type of transmitter substance to inhibit the second output pathway from the pool. This type of circuit is also important in preventing overactivity in many parts of the brain. Chapter 46 Sensory Receptors, Neuronal Circuits for Processing Information Input Excitatory synapse #1 Input fiber #2 #3 Excitation A Inhibition Input 581 Output Output Inhibitory synapse Figure 46–13 B Facilitation Inhibitory circuit. Neuron 2 is an inhibitory neuron. Input Output Prolongation of a Signal by a Neuronal Pool—“Afterdischarge” Thus far, we have considered signals that are merely relayed through neuronal pools. However, in many instances, a signal entering a pool causes a prolonged output discharge, called afterdischarge, lasting a few milliseconds to as long as many minutes after the incoming signal is over. The most important mechanisms by which afterdischarge occurs are the following. C Inhibition Input Output Synaptic Afterdischarge. When excitatory synapses dis- charge on the surfaces of dendrites or soma of a neuron, a postsynaptic electrical potential develops in the neuron and lasts for many milliseconds, especially when some of the long-acting synaptic transmitter substances are involved. As long as this potential lasts, it can continue to excite the neuron, causing it to transmit a continuous train of output impulses, as was explained in Chapter 45. Thus, as a result of this synaptic “afterdischarge” mechanism alone, it is possible for a single instantaneous input signal to cause a sustained signal output (a series of repetitive discharges) lasting for many milliseconds. Reverberatory (Oscillatory) Circuit as a Cause of Signal Prolongation. One of the most important of all circuits in the entire nervous system is the reverberatory, or oscillatory, circuit. Such circuits are caused by positive feedback within the neuronal circuit that feeds back to re-excite the input of the same circuit. Consequently, once stimulated, the circuit may discharge repetitively for a long time. Several possible varieties of reverberatory circuits are shown in Figure 46–14. The simplest, shown in Figure 46–14A, involves only a single neuron. In this case, the output neuron simply sends a collateral nerve fiber back to its own dendrites or soma to restimulate itself. Although this type of circuit probably is not an important one, theoretically, once the neuron discharges, the feedback stimuli could keep the neuron discharging for a protracted time thereafter. Figure 46–14B shows a few additional neurons in the feedback circuit, which causes a longer delay between initial discharge and the feedback signal. Figure 46–14C shows a still more complex system in which both facilitatory and inhibitory fibers impinge on the reverberating circuit.A facilitatory signal enhances the D Figure 46–14 Reverberatory circuits of increasing complexity. intensity and frequency of reverberation, whereas an inhibitory signal depresses or stops the reverberation. Figure 46–14D shows that most reverberating pathways are constituted of many parallel fibers. At each cell station, the terminal fibrils spread widely. In such a system, the total reverberating signal can be either weak or strong, depending on how many parallel nerve fibers are momentarily involved in the reverberation. Characteristics of Signal Prolongation from a Reverberatory Circuit. Figure 46–15 shows output signals from a typical reverberatory circuit. The input stimulus may last only 1 millisecond or so, and yet the output can last for many milliseconds or even minutes. The figure demonstrates that the intensity of the output signal usually increases to a high value early in reverberation and then decreases to a critical point, at which it suddenly ceases entirely. The cause of this sudden cessation of reverberation is fatigue of synaptic junctions in the circuit. Fatigue beyond a certain critical level lowers the stimulation of the next neuron in the circuit below threshold level so that the circuit feedback is suddenly broken. The Nervous System: A. General Principles and Sensory Physiology Inhibited Normal Facilitated Input stimulus Output pulse rate Unit IX Output Excitation Inhibition Impulses per second 582 Time Time Figure 46–15 Typical pattern of the output signal from a reverberatory circuit after a single input stimulus, showing the effects of facilitation and inhibition. The duration of the total signal before cessation can also be controlled by signals from other parts of the brain that inhibit or facilitate the circuit. Almost these exact patterns of output signals are recorded from the motor nerves exciting a muscle involved in a flexor reflex after pain stimulation of the foot (as shown later in Figure 46–18). Continuous Signal Output from Some Neuronal Circuits Some neuronal circuits emit output signals continuously, even without excitatory input signals. At least two mechanisms can cause this effect: (1) continuous intrinsic neuronal discharge and (2) continuous reverberatory signals. Continuous Discharge Caused by Intrinsic Neuronal Excitability. Neurons, like other excitable tissues, discharge repetitively if their level of excitatory membrane potential rises above a certain threshold level. The membrane potentials of many neurons even normally are high enough to cause them to emit impulses continually. This occurs especially in many of the neurons of the cerebellum, as well as in most of the interneurons of the spinal cord. The rates at which these cells emit impulses can be increased by excitatory signals or decreased by inhibitory signals; inhibitory signals often can decrease the rate of firing to zero. Continuous Signals Emitted from Reverberating Circuits as a Means for Transmitting Information. A reverberating circuit that does not fatigue enough to stop reverberation is a source of continuous impulses. And excitatory impulses entering the reverberating pool can increase the output signal, whereas inhibition can decrease or even extinguish the signal. Figure 46–16 shows a continuous output signal from a pool of neurons. The pool may be emitting impulses because of intrinsic neuronal excitability or as a result Figure 46–16 Continuous output from either a reverberating circuit or a pool of intrinsically discharging neurons. This figure also shows the effect of excitatory or inhibitory input signals. of reverberation. Note that an excitatory input signal greatly increases the output signal, whereas an inhibitory input signal greatly decreases the output. Those students who are familiar with radio transmitters will recognize this to be a carrier wave type of information transmission. That is, the excitatory and inhibitory control signals are not the cause of the output signal, but they do control its changing level of intensity. Note that this carrier wave system allows a decrease in signal intensity as well as an increase, whereas up to this point, the types of information transmission we have discussed have been mainly positive information rather than negative information. This type of information transmission is used by the autonomic nervous system to control such functions as vascular tone, gut tone, degree of constriction of the iris in the eye, and heart rate. That is, the nerve excitatory signal to each of these can be either increased or decreased by accessory input signals into the reverberating neuronal pathway. Rhythmical Signal Output Many neuronal circuits emit rhythmical output signals—for instance, a rhythmical respiratory signal originates in the respiratory centers of the medulla and pons. This respiratory rhythmical signal continues throughout life. Other rhythmical signals, such as those that cause scratching movements by the hind leg of a dog or the walking movements of any animal, require input stimuli into the respective circuits to initiate the rhythmical signals. All or almost all rhythmical signals that have been studied experimentally have been found to result from reverberating circuits or a succession of sequential reverberating circuits that feed excitatory or inhibitory signals in a circular pathway from one neuronal pool to the next. 583 Sensory Receptors, Neuronal Circuits for Processing Information Phrenic nerve output Flexor muscle contraction force (g) Chapter 46 Flexor reflexes–decremental responses Stimulus 50 40 30 20 10 0 0 Increasing carotid body stimulation 15 30 Seconds 45 60 Figure 46–18 Figure 46–17 The rhythmical output of summated nerve impulses from the respiratory center, showing that progressively increasing stimulation of the carotid body increases both the intensity and the frequency of the phrenic nerve signal to the diaphragm to increase respiration. Excitatory or inhibitory signals can also increase or decrease the amplitude of the rhythmical signal output. Figure 46–17, for instance, shows changes in the respiratory signal output in the phrenic nerve. When the carotid body is stimulated by arterial oxygen deficiency, both the frequency and the amplitude of the respiratory rhythmical output signal increase progressively. Instability and Stability of Neuronal Circuits Almost every part of the brain connects either directly or indirectly with every other part, and this creates a serious problem. If the first part excites the second, the second the third, the third the fourth, and so on until finally the signal re-excites the first part, it is clear that an excitatory signal entering any part of the brain would set off a continuous cycle of re-excitation of all parts. If this should occur, the brain would be inundated by a mass of uncontrolled reverberating signals—signals that would be transmitting no information but, nevertheless, would be consuming the circuits of the brain so that none of the informational signals could be transmitted. Such an effect occurs in widespread areas of the brain during epileptic seizures. How does the central nervous system prevent this from happening all the time? The answer lies mainly in two basic mechanisms that function throughout the central nervous system: (1) inhibitory circuits and (2) fatigue of synapses. Successive flexor reflexes showing fatigue of conduction through the reflex pathway. Inhibitory Circuits as a Mechanism for Stabilizing Nervous System Function Two types of inhibitory circuits in widespread areas of the brain help prevent excessive spread of signals: (1) inhibitory feedback circuits that return from the termini of pathways back to the initial excitatory neurons of the same pathways—these circuits occur in virtually all sensory nervous pathways and inhibit either the input neurons or the intermediate neurons in the sensory pathway when the termini become overly excited; and (2) some neuronal pools that exert gross inhibitory control over widespread areas of the brain—for instance, many of the basal ganglia exert inhibitory influences throughout the muscle control system. Synaptic Fatigue as a Means for Stabilizing the Nervous System Synaptic fatigue means simply that synaptic transmission becomes progressively weaker the more prolonged and more intense the period of excitation. Figure 46–18 shows three successive records of a flexor reflex elicited in an animal caused by inflicting pain in the footpad of the paw. Note in each record that the strength of contraction progressively “decrements”— that is, its strength diminishes; much of this effect is caused by fatigue of synapses in the flexor reflex circuit. Furthermore, the shorter the interval between successive flexor reflexes, the less the intensity of the subsequent reflex response. Automatic Short-Term Adjustment of Pathway Sensitivity by the Fatigue Mechanism. Now let us apply this phenomenon of fatigue to other pathways in the brain. Those that 584 Unit IX The Nervous System: A. General Principles and Sensory Physiology are overused usually become fatigued, so that their sensitivities decrease. Conversely, those that are underused become rested, and their sensitivities increase. Thus, fatigue and recovery from fatigue constitute an important short-term means of moderating the sensitivities of the different nervous system circuits. These help to keep the circuits operating in a range of sensitivity that allows effective function. Long-Term Changes in Synaptic Sensitivity Caused by Automatic Downregulation or Upregulation of Synaptic Receptors. The long-term sensitivities of synapses can be changed tremendously by upregulating the number of receptor proteins at the synaptic sites when there is underactivity, and downregulating the receptors when there is overactivity. The mechanism for this is the following: Receptor proteins are being formed constantly by the endoplasmic reticular–Golgi apparatus system and are constantly being inserted into the receptor neuron synaptic membrane. However, when the synapses are overused so that excesses of transmitter substance combine with the receptor proteins, many of these receptors are inactivated and removed from the synaptic membrane. It is indeed fortunate that upregulation and downregulation of receptors, as well as other control mechanisms for adjusting synaptic sensitivity, continually adjust the sensitivity in each circuit to almost the exact level required for proper function. Think for a moment how serious it would be if the sensitivities of only a few of these circuits were abnormally high; one might then expect almost continual muscle cramps, seizures, psychotic disturbances, hallucinations, mental tension, or other nervous disorders. But fortunately, the automatic controls normally readjust the sensitivities of the circuits back to controllable ranges of reactivity any time the circuits begin to be too active or too depressed. References Buzsaki G: Large-scale recording of neuronal ensembles. 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Mombaerts P: Genes and ligands for odorant, vomeronasal and taste receptors. Nat Rev Neurosci 5:263, 2004. Palmer MJ, von Gersdorff H: Phasic transmitter release from tonic neurons. Neuron 35:600, 2002. Pearson KG: Neural adaptation in the generation of rhythmic behavior. Annu Rev Physiol 62:723, 2000. Renteria RC, Johnson J, Copenhagen DR: Need rods? Get glycine receptors and taurine. Neuron 41:839, 2004. Richerson GB, Wu Y: Dynamic equilibrium of neurotransmitter transporters: not just for reuptake anymore. J Neurophysiol 90:1363, 2003. Schwartz EA: Transport-mediated synapses in the retina. Physiol Rev 82:875, 2002. Shen K: Molecular mechanisms of target specificity during synapse formation. Curr Opin Neurobiol 14:83, 2004. Williams JT, Christie MJ, Manzoni O: Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 81:299, 2001. C H A P T E R 4 7 Somatic Sensations: I. General Organization, the Tactile and Position Senses The somatic senses are the nervous mechanisms that collect sensory information from all over the body. These senses are in contradistinction to the special senses, which mean specifically vision, hearing, smell, taste, and equilibrium. CLASSIFICATION OF SOMATIC SENSES The somatic senses can be classified into three physiologic types: (1) the mechanoreceptive somatic senses, which include both tactile and position sensations that are stimulated by mechanical displacement of some tissue of the body; (2) the thermoreceptive senses, which detect heat and cold; and (3) the pain sense, which is activated by any factor that damages the tissues. This chapter deals with the mechanoreceptive tactile and position senses. Chapter 48 discusses the thermoreceptive and pain senses. The tactile senses include touch, pressure, vibration, and tickle senses, and the position senses include static position and rate of movement senses. Other Classifications of Somatic Sensations. Somatic sensations are also often grouped together in other classes, as follows. Exteroreceptive sensations are those from the surface of the body. Proprioceptive sensations are those having to do with the physical state of the body, including position sensations, tendon and muscle sensations, pressure sensations from the bottom of the feet, and even the sensation of equilibrium (which is often considered a “special” sensation rather than a somatic sensation). Visceral sensations are those from the viscera of the body; in using this term, one usually refers specifically to sensations from the internal organs. Deep sensations are those that come from deep tissues, such as from fasciae, muscles, and bone. These include mainly “deep” pressure, pain, and vibration. Detection and Transmission of Tactile Sensations Interrelations Among the Tactile Sensations of Touch, Pressure, and Vibration. Although touch, pressure, and vibration are frequently classified as separate sensations, they are all detected by the same types of receptors. There are three principal differences among them: (1) touch sensation generally results from stimulation of tactile receptors in the skin or in tissues immediately beneath the skin; (2) pressure sensation generally results from deformation of deeper tissues; and (3) vibration sensation results from rapidly repetitive sensory signals, but some of the same types of receptors as those for touch and pressure are used. Tactile Receptors. There are at least six entirely different types of tactile receptors, but many more similar to these also exist. Some were shown in Figure 46–1 of the previous chapter; their special characteristics are the following. 585 586 Unit IX The Nervous System: A. General Principles and Sensory Physiology First, some free nerve endings, which are found everywhere in the skin and in many other tissues, can detect touch and pressure. For instance, even light contact with the cornea of the eye, which contains no other type of nerve ending besides free nerve endings, can nevertheless elicit touch and pressure sensations. Second, a touch receptor with great sensitivity is the Meissner’s corpuscle (illustrated in Figure 46–1), an elongated encapsulated nerve ending of a large (type Ab) myelinated sensory nerve fiber. Inside the capsulation are many branching terminal nerve filaments. These corpuscles are present in the nonhairy parts of the skin and are particularly abundant in the fingertips, lips, and other areas of the skin where one’s ability to discern spatial locations of touch sensations is highly developed. Meissner’s corpuscles adapt in a fraction of a second after they are stimulated, which means that they are particularly sensitive to movement of objects over the surface of the skin as well as to lowfrequency vibration. Third, the fingertips and other areas that contain large numbers of Meissner’s corpuscles usually also contain large numbers of expanded tip tactile receptors, one type of which is Merkel’s discs, shown in Figure 47–1. The hairy parts of the skin also contain moderate numbers of expanded tip receptors, even though they have almost no Meissner’s corpuscles. These receptors differ from Meissner’s corpuscles in that they transmit an initially strong but partially adapting signal and then a continuing weaker signal that adapts only slowly. Therefore, they are responsible for giving steady-state signals that allow one to determine continuous touch of objects against the skin. Merkel’s discs are often grouped together in a receptor organ called the Iggo dome receptor, which projects upward against the underside of the epithelium of the skin, as also shown in Figure 47–1. This causes the epithelium at this point to protrude outward, thus creating a dome and constituting an extremely sensitive receptor. Also note that the entire group of Merkel’s discs is innervated by a single large myelinated nerve fiber (type Ab). These receptors, along with the Meissner’s corpuscles discussed earlier, play extremely important roles in localizing touch sensations to specific surface areas of the body and in determining the texture of what is felt. Fourth, slight movement of any hair on the body stimulates a nerve fiber entwining its base. Thus, each hair and its basal nerve fiber, called the hair end-organ, are also a touch receptor. This receptor adapts readily and, like Meissner’s corpuscles, detects mainly (a) movement of objects on the surface of the body or (b) initial contact with the body. Fifth, located in the deeper layers of the skin and also in still deeper internal tissues are many Ruffini’s end-organs, which are multibranched, encapsulated endings, as shown in Figure 46–1. These endings adapt very slowly and, therefore, are important for signaling continuous states of deformation of the tissues, such as heavy prolonged touch and pressure signals. They are also found in joint capsules and help to signal the degree of joint rotation. Sixth, pacinian corpuscles, which were discussed in detail in Chapter 46, lie both immediately beneath the skin and deep in the fascial tissues of the body. They are stimulated only by rapid local compression of the tissues because they adapt in a few hundredths of a second. Therefore, they are particularly important for detecting tissue vibration or other rapid changes in the mechanical state of the tissues. Transmission of Tactile Signals in Peripheral Nerve Fibers. Almost all specialized sensory receptors, such as Meissner’s corpuscles, Iggo dome receptors, hair E FF C Figure 47–1 CF A AA 10 mm Iggo dome receptor. Note the multiple numbers of Merkel’s discs connecting to a single large myelinated fiber and abutting tightly the undersurface of the epithelium. (From Iggo A, Muir AR: The structure and function of a slowly adapting touch corpuscle in hairy skin. J Physiol 200: 763, 1969.) Chapter 47 Somatic Sensations: I. General Organization, the Tactile and Position Senses receptors, pacinian corpuscles, and Ruffini’s endings, transmit their signals in type Ab nerve fibers that have transmission velocities ranging from 30 to 70 m/sec. Conversely, free nerve ending tactile receptors transmit signals mainly by way of the small type Ad myelinated fibers that conduct at velocities of only 5 to 30 m/sec. Some tactile free nerve endings transmit by way of type C unmyelinated fibers at velocities from a fraction of a meter up to 2 m/sec; these send signals into the spinal cord and lower brain stem, probably subserving mainly the sensation of tickle. Thus, the more critical types of sensory signals— those that help to determine precise localization on the skin, minute gradations of intensity, or rapid changes in sensory signal intensity—are all transmitted in more rapidly conducting types of sensory nerve fibers. Conversely, the cruder types of signals, such as crude pressure, poorly localized touch, and especially tickle, are transmitted by way of much slower, very small nerve fibers that require much less space in the nerve bundle than the fast fibers. Detection of Vibration All tactile receptors are involved in detection of vibration, although different receptors detect different frequencies of vibration. Pacinian corpuscles can detect signal vibrations from 30 to 800 cycles per second because they respond extremely rapidly to minute and rapid deformations of the tissues, and they also transmit their signals over type Ab nerve fibers, which can transmit as many as 1000 impulses per second. Lowfrequency vibrations from 2 up to 80 cycles per second, in contrast, stimulate other tactile receptors, especially Meissner’s corpuscles, which are less rapidly adapting than pacinian corpuscles. TICKLE AND ITCH Neurophysiologic studies have demonstrated the existence of very sensitive, rapidly adapting mechanoreceptive free nerve endings that elicit only the tickle and itch sensations. Furthermore, these endings are found almost exclusively in superficial layers of the skin, which is also the only tissue from which the tickle and itch sensations usually can be elicited. These sensations are transmitted by very small type C, unmyelinated fibers similar to those that transmit the aching, slow type of pain. The purpose of the itch sensation is presumably to call attention to mild surface stimuli such as a flea crawling on the skin or a fly about to bite, and the elicited signals then activate the scratch reflex or other maneuvers that rid the host of the irritant. Itch can be relieved by scratching if this removes the irritant or if the scratch is strong enough to elicit pain. The pain signals are believed to suppress the itch signals in the cord by lateral inhibition, as described in Chapter 48. 587 Sensory Pathways for Transmitting Somatic Signals into the Central Nervous System Almost all sensory information from the somatic segments of the body enters the spinal cord through the dorsal roots of the spinal nerves. However, from the entry point into the cord and then to the brain, the sensory signals are carried through one of two alternative sensory pathways: (1) the dorsal column–medial lemniscal system or (2) the anterolateral system. These two systems come back together partially at the level of the thalamus. The dorsal column–medial lemniscal system, as its name implies, carries signals upward to the medulla of the brain mainly in the dorsal columns of the cord. Then, after the signals synapse and cross to the opposite side in the medulla, they continue upward through the brain stem to the thalamus by way of the medial lemniscus. Conversely, signals in the anterolateral system, immediately after entering the spinal cord from the dorsal spinal nerve roots, synapse in the dorsal horns of the spinal gray matter, then cross to the opposite side of the cord and ascend through the anterior and lateral white columns of the cord. They terminate at all levels of the lower brain stem and in the thalamus. The dorsal column–medial lemniscal system is composed of large, myelinated nerve fibers that transmit signals to the brain at velocities of 30 to 110 m/sec, whereas the anterolateral system is composed of smaller myelinated fibers that transmit signals at velocities ranging from a few meters per second up to 40 m/sec. Another difference between the two systems is that the dorsal column–medial lemniscal system has a high degree of spatial orientation of the nerve fibers with respect to their origin, while the anterolateral system has much less spatial orientation. These differences immediately characterize the types of sensory information that can be transmitted by the two systems. That is, sensory information that must be transmitted rapidly and with temporal and spatial fidelity is transmitted mainly in the dorsal column–medial lemniscal system; that which does not need to be transmitted rapidly or with great spatial fidelity is transmitted mainly in the anterolateral system. The anterolateral system has a special capability that the dorsal system does not have: the ability to transmit a broad spectrum of sensory modalities— pain, warmth, cold, and crude tactile sensations; most of these are discussed in detail in Chapter 48. The dorsal system is limited to discrete types of mechanoreceptive sensations. With this differentiation in mind, we can now list the types of sensations transmitted in the two systems. 588 Unit IX The Nervous System: A. General Principles and Sensory Physiology Dorsal Column–Medial Lemniscal System 1. Touch sensations requiring a high degree of localization of the stimulus 2. Touch sensations requiring transmission of fine gradations of intensity 3. Phasic sensations, such as vibratory sensations 4. Sensations that signal movement against the skin 5. Position sensations from the joints 6. Pressure sensations having to do with fine degrees of judgment of pressure intensity Anterolateral System 1. Pain 2. Thermal sensations, including both warmth and cold sensations 3. Crude touch and pressure sensations capable only of crude localizing ability on the surface of the body 4. Tickle and itch sensations 5. Sexual sensations then upward in the dorsal column, proceeding by way of the dorsal column pathway all the way to the brain. The lateral branch enters the dorsal horn of the cord gray matter, then divides many times to provide terminals that synapse with local neurons in the intermediate and anterior portions of the cord gray matter. These local neurons in turn serve three functions: (1) A major share of them give off fibers that enter the dorsal columns of the cord and then travel upward to the brain. (2) Many of the fibers are very short and terminate locally in the spinal cord gray matter to elicit local spinal cord reflexes, which are discussed in Chapter 54. (3) Others give rise to the spinocerebellar tracts, which we will discuss in Chapter 56 in relation to the function of the cerebellum. The Dorsal Column–Medial Lemniscal Pathway. Note in Figure 47–3 that nerve fibers entering the dorsal columns pass uninterrupted up to the dorsal medulla, where they synapse in the dorsal column nuclei (the cuneate and gracile nuclei). From there, second-order neurons Cortex Transmission in the Dorsal Column–Medial Lemniscal System Anatomy of the Dorsal Column–Medial Lemniscal System On entering the spinal cord through the spinal nerve dorsal roots, the large myelinated fibers from the specialized mechanoreceptors divide almost immediately to form a medial branch and a lateral branch, shown by the right-hand fiber entering through the spinal root in Figure 47–2. The medial branch turns medially first and Internal capsule Ventrobasal complex of thalamus Spinal nerve Lamina marginalis Substantia gelatinosa Tract of Lissauer Spinocervical tract Dorsal spinocerebellar tract Medulla oblongata Dorsal column Medial lemniscus Dorsal column nuclei I II III Ascending branches of dorsal root fibers IV V VI Spinal cord VII Ventral spinocerebellar tract Spinocervical tract IX VIII Dorsal root and spinal ganglion Anterolateral spinothalamic pathway Figure 47–3 Figure 47–2 Cross section of the spinal cord, showing the anatomy of the cord gray matter and of ascending sensory tracts in the white columns of the spinal cord. The dorsal column–medial lemniscal pathway for transmitting critical types of tactile signals. (Modified from Ranson SW, Clark SL: Anatomy of the Nervous System. Philadelphia: WB Saunders Co, 1959.) Chapter 47 589 Somatic Sensations: I. General Organization, the Tactile and Position Senses decussate immediately to the opposite side of the brain stem and continue upward through the medial lemnisci to the thalamus. In this pathway through the brain stem, each medial lemniscus is joined by additional fibers from the sensory nuclei of the trigeminal nerve; these fibers subserve the same sensory functions for the head that the dorsal column fibers subserve for the body. In the thalamus, the medial lemniscal fibers terminate in the thalamic sensory relay area, called the ventrobasal complex. From the ventrobasal complex, third-order nerve fibers project, as shown in Figure 47–4, mainly to the postcentral gyrus of the cerebral cortex, which is called somatic sensory area I (as shown in Figure 47–6, these fibers also project to a smaller area in the lateral parietal cortex called somatic sensory area II). Spatial Orientation of the Nerve Fibers in the Dorsal Column-Medial Lemniscal System One of the distinguishing features of the dorsal column–medial lemniscal system is a distinct spatial orientation of nerve fibers from the individual parts of the body that is maintained throughout. For instance, in the dorsal columns of the spinal cord, the fibers from the lower parts of the body lie toward the center of the cord, whereas those that enter the cord at progressively higher segmental levels form successive layers laterally. In the thalamus, distinct spatial orientation is still maintained, with the tail end of the body represented by the most lateral portions of the ventrobasal complex and the head and face represented by the POSTCENTRAL GYRUS Lower extremity Trunk medial areas of the complex. Because of the crossing of the medial lemnisci in the medulla, the left side of the body is represented in the right side of the thalamus, and the right side of the body in the left side of the thalamus. Somatosensory Cortex Before discussing the role of the cerebral cortex in somatic sensation, we need to give an orientation to the various areas of the cortex. Figure 47–5 is a map of the human cerebral cortex, showing that it is divided into about 50 distinct areas called Brodmann’s areas based on histological structural differences. This map is important because virtually all neurophysiologists and neurologists use it to refer by number to many of the different functional areas of the human cortex. Note in the figure the large central fissure (also called central sulcus) that extends horizontally across the brain. In general, sensory signals from all modalities of sensation terminate in the cerebral cortex immediately posterior to the central fissure. And, generally, the anterior half of the parietal lobe is concerned almost entirely with reception and interpretation of somatosensory signals. But the posterior half of the parietal lobe provides still higher levels of interpretation. Visual signals terminate in the occipital lobe, and auditory signals in the temporal lobe. Conversely, that portion of the cerebral cortex anterior to the central fissure and constituting the posterior half of the frontal lobe is called the motor cortex and is devoted almost entirely to control of muscle contractions and body movements. A major share of this motor control is in response to somatosensory Upper extremity Central fissure 3 2 4 Face 7a 8 5 6 9 7a 1 Ventrobasal complex of thalamus 40 46 39 10 45 MESENCEPHALON Spinothalamic tract Medial lemniscus 47 11 44 43 41 19 42 22 37 38 21 18 17 Lateral fissure 20 Figure 47–4 Figure 47–5 Projection of the dorsal column–medial lemniscal system through the thalamus to the somatosensory cortex. (Modified from Brodal A: Neurological Anatomy in Relation to Clinical Medicine. New York: Oxford University Press, 1969, by permission of Oxford University Press.) Structurally distinct areas, called Brodmann’s areas, of the human cerebral cortex. Note specifically areas 1, 2, and 3, which constitute primary somatosensory area I, and areas 5 and 7, which constitute the somatosensory association area. Unit IX The Nervous System: A. General Principles and Sensory Physiology Trunk Neck Head Shoulder Arm Elbow rm a Fore st W ri d g e r n in er Ha e f ng ttl f i Li ing R Somatosensory area I Thigh Somatosensory Thorax area II Neck Shoulder Hand Fingers Tongue Abdomen Leg Arm Face M In id Th dex dle Ey umb fin fing e ge e Nos r r e Face Upper lip Hip Leg 590 ot Fo s Toe l a t i s Gen Lips Lower lip Teeth, gums, and jaw Tongue Figure 47–6 Pharynx Intra-abdominal Two somatosensory cortical areas, somatosensory areas I and II. signals received from the sensory portions of the cortex, which keep the motor cortex informed at each instant about the positions and motions of the different body parts. Figure 47–7 Representation of the different areas of the body in somatosensory area I of the cortex. (From Penfield W, Rasmussen T: Cerebral Cortex of Man: A Clinical Study of Localization of Function. New York: Hafner, 1968.) Somatosensory Areas I and II. Figure 47–6 shows two sep- arate sensory areas in the anterior parietal lobe called somatosensory area I and somatosensory area II. The reason for this division into two areas is that a distinct and separate spatial orientation of the different parts of the body is found in each of these two areas. However, somatosensory area I is so much more extensive and so much more important than somatosensory area II that in popular usage, the term “somatosensory cortex” almost always means area I. Somatosensory area I has a high degree of localization of the different parts of the body, as shown by the names of virtually all parts of the body in Figure 47–6. By contrast, localization is poor in somatosensory area II, although roughly, the face is represented anteriorly, the arms centrally, and the legs posteriorly. Little is known about the function of somatosensory area II. It is known that signals enter this area from the brain stem, transmitted upward from both sides of the body. In addition, many signals come secondarily from somatosensory area I as well as from other sensory areas of the brain, even from the visual and auditory areas. Projections from somatosensory area I are required for function of somatosensory area II. However, removal of parts of somatosensory area II has no apparent effect on the response of neurons in somatosensory area I. Thus, much of what we know about somatic sensation appears to be explained by the functions of somatosensory area I. Spatial Orientation of Signals from Different Parts of the Body in Somatosensory Area I. Somatosensory area I lies immediately behind the central fissure, located in the postcentral gyrus of the human cerebral cortex (in Brodmann’s areas 3, 1, and 2). Figure 47–7 shows a cross section through the brain at the level of the postcentral gyrus, demonstrating representations of the different parts of the body in separate regions of somatosensory area I. Note, however, that each lateral side of the cortex receives sensory information almost exclusively from the opposite side of the body. Some areas of the body are represented by large areas in the somatic cortex—the lips the greatest of all, followed by the face and thumb—whereas the trunk and lower part of the body are represented by relatively small areas. The sizes of these areas are directly proportional to the number of specialized sensory receptors in each respective peripheral area of the body. For instance, a great number of specialized nerve endings are found in the lips and thumb, whereas only a few are present in the skin of the body trunk. Note also that the head is represented in the most lateral portion of somatosensory area I, and the lower part of the body is represented medially. Layers of the Somatosensory Cortex and Their Function The cerebral cortex contains six layers of neurons, beginning with layer I next to the brain surface and extending progressively deeper to layer VI, shown in Figure 47–8. As would be expected, the neurons in each layer perform functions different from those in other layers. Some of these functions are: Chapter 47 Somatic Sensations: I. General Organization, the Tactile and Position Senses I II III IV V VIa VIb Figure 47–8 Structure of the cerebral cortex, showing I, molecular layer; II, external granular layer; III, layer of small pyramidal cells; IV, internal granular layer; V, large pyramidal cell layer; and VI, layer of fusiform or polymorphic cells. (From Ranson SW, Clark SL [after Brodmann]: Anatomy of the Nervous System. Philadelphia: WB Saunders, 1959.) 1. The incoming sensory signal excites neuronal layer IV first; then the signal spreads toward the surface of the cortex and also toward deeper layers. 2. Layers I and II receive diffuse, nonspecific input signals from lower brain centers that facilitate specific regions of the cortex; this system is described in Chapter 57. This input mainly controls the overall level of excitability of the respective regions stimulated. 3. The neurons in layers II and III send axons to related portions of the cerebral cortex on the opposite side of the brain through the corpus callosum. 4. The neurons in layers V and VI send axons to the deeper parts of the nervous system. Those in layer V are generally larger and project to more distant areas, such as to the basal ganglia, brain stem, and spinal cord where they control signal transmission. From layer VI, especially large numbers of axons extend to the thalamus, providing signals from the cerebral cortex that interact with and help to control the excitatory levels of incoming sensory signals entering the thalamus. 591 The Sensory Cortex Is Organized in Vertical Columns of Neurons; Each Column Detects a Different Sensory Spot on the Body with a Specific Sensory Modality Functionally, the neurons of the somatosensory cortex are arranged in vertical columns extending all the way through the six layers of the cortex, each column having a diameter of 0.3 to 0.5 millimeter and containing perhaps 10,000 neuronal cell bodies. Each of these columns serves a single specific sensory modality, some columns responding to stretch receptors around joints, some to stimulation of tactile hairs, others to discrete localized pressure points on the skin, and so forth. At layer IV, where the input sensory signals first enter the cortex, the columns of neurons function almost entirely separately from one another. At other levels of the columns, interactions occur that initiate analysis of the meanings of the sensory signals. In the most anterior 5 to 10 millimeters of the postcentral gyrus, located deep in the central fissure in Brodmann’s area 3a, an especially large share of the vertical columns respond to muscle, tendon, and joint stretch receptors. Many of the signals from these sensory columns then spread anteriorly, directly to the motor cortex located immediately forward of the central fissure. These signals play a major role in controlling the effluent motor signals that activate sequences of muscle contraction. As one moves posteriorly in somatosensory area I, more and more of the vertical columns respond to slowly adapting cutaneous receptors, and then still farther posteriorly, greater numbers of the columns are sensitive to deep pressure. In the most posterior portion of somatosensory area I, about 6 per cent of the vertical columns respond only when a stimulus moves across the skin in a particular direction. Thus, this is a still higher order of interpretation of sensory signals; the process becomes even more complex as the signals spread farther backward from somatosensory area I into the parietal cortex, an area called the somatosensory association area, as we discuss subsequently. Functions of Somatosensory Area I Widespread bilateral excision of somatosensory area I causes loss of the following types of sensory judgment: 1. The person is unable to localize discretely the different sensations in the different parts of the body. However, he or she can localize these sensations crudely, such as to a particular hand, to a major level of the body trunk, or to one of the legs. Thus, it is clear that the brain stem, thalamus, or parts of the cerebral cortex not normally considered to be concerned with somatic sensations can perform some degree of localization. 2. The person is unable to judge critical degrees of pressure against the body. 3. The person is unable to judge the weights of objects. 4. The person is unable to judge shapes or forms of objects. This is called astereognosis. Unit IX The Nervous System: A. General Principles and Sensory Physiology 5. The person is unable to judge texture of materials because this type of judgment depends on highly critical sensations caused by movement of the fingers over the surface to be judged. Note that in the list nothing has been said about loss of pain and temperature sense. In specific absence of only somatosensory area I, appreciation of these sensory modalities is still preserved both in quality and intensity. But the sensations are poorly localized, indicating that pain and temperature localization depend greatly on the topographical map of the body in somatosensory area I to localize the source. Strong stimulus Discharges per second 592 Moderate stimulus Weak stimulus Somatosensory Association Areas Brodmann’s areas 5 and 7 of the cerebral cortex, located in the parietal cortex behind somatosensory area I (see Figure 47–5), play important roles in deciphering deeper meanings of the sensory information in the somatosensory areas. Therefore, these areas are called somatosensory association areas. Electrical stimulation in a somatosensory association area can occasionally cause an awake person to experience a complex body sensation, sometimes even the “feeling” of an object such as a knife or a ball. Therefore, it seems clear that the somatosensory association area combines information arriving from multiple points in the primary somatosensory area to decipher its meaning. This also fits with the anatomical arrangement of the neuronal tracts that enter the somatosensory association area because it receives signals from (1) somatosensory area I, (2) the ventrobasal nuclei of the thalamus, (3) other areas of the thalamus, (4) the visual cortex, and (5) the auditory cortex. Effect of Removing the Somatosensory Association Area— Amorphosynthesis. When the somatosensory association area is removed on one side of the brain, the person loses ability to recognize complex objects and complex forms felt on the opposite side of the body. In addition, he or she loses most of the sense of form of his or her own body or body parts on the opposite side. In fact, the person is mainly oblivious to the opposite side of the body—that is, forgets that it is there. Therefore, he or she also often forgets to use the other side for motor functions as well. Likewise, when feeling objects, the person tends to recognize only one side of the object and forgets that the other side even exists. This complex sensory deficit is called amorphosynthesis. Overall Characteristics of Signal Transmission and Analysis in the Dorsal Column–Medial Lemniscal System Basic Neuronal Circuit in the Dorsal Column–Medial Lemniscal System. The lower part of Figure 47–9 shows the basic Cortex Thalamus Dorsal column nuclei Single-point stimulus on skin Figure 47–9 Transmission of a pinpoint stimulus signal to the cerebral cortex. organization of the neuronal circuit of the spinal cord dorsal column pathway, demonstrating that at each synaptic stage, divergence occurs. The upper curves of the figure show that the cortical neurons that discharge to the greatest extent are those in a central part of the cortical “field” for each respective receptor. Thus, a weak stimulus causes only the centralmost neurons to fire. A stronger stimulus causes still more neurons to fire, but those in the center discharge at a considerably more rapid rate than do those farther away from the center. Two-Point Discrimination. A method frequently used to test tactile discrimination is to determine a person’s so-called “two-point” discriminatory ability. In this test, two needles are pressed lightly against the skin at the same time, and the person determines whether two points of stimulus are felt or one point. On the tips of the fingers, a person can distinguish two separate points even when the needles are as close together as 1 to 2 millimeters. However, on the person’s back, the needles must usually be as far apart as 30 to 70 Somatic Sensations: I. General Organization, the Tactile and Position Senses Discharges per second Chapter 47 Cortex Two adjacent points strongly stimulated Figure 47–10 Transmission of signals to the cortex from two adjacent pinpoint stimuli. The blue curve represents the pattern of cortical stimulation without “surround” inhibition, and the two red curves represent the pattern when “surround” inhibition does occur. millimeters before two separate points can be detected. The reason for this difference is the different numbers of specialized tactile receptors in the two areas. Figure 47–10 shows the mechanism by which the dorsal column pathway (as well as all other sensory pathways) transmits two-point discriminatory information. This figure shows two adjacent points on the skin that are strongly stimulated as well as the areas of the somatosensory cortex (greatly enlarged) that are excited by signals from the two stimulated points. The blue curve shows the spatial pattern of cortical excitation when both skin points are stimulated simultaneously. Note that the resultant zone of excitation has two separate peaks. These two peaks, separated by a valley, allow the sensory cortex to detect the presence of two stimulatory points, rather than a single point. The capability of the sensorium to distinguish this presence of two points of stimulation is strongly influenced by another mechanism, lateral inhibition, as explained in the next section. Effect of Lateral Inhibition (Also Called Surround Inhibition) to Increase the Degree of Contrast in the Perceived Spatial Pattern. As pointed out in Chapter 46, virtually every sensory pathway, when excited, gives rise simultaneously to lateral inhibitory signals; these spread to the sides of the excitatory signal and inhibit adjacent neurons. For instance, consider an excited neuron in a dorsal column nucleus. Aside from the central 593 excitatory signal, short lateral pathways transmit inhibitory signals to the surrounding neurons. That is, these signals pass through additional interneurons that secrete an inhibitory transmitter. The importance of lateral inhibition is that it blocks lateral spread of the excitatory signals and, therefore, increases the degree of contrast in the sensory pattern perceived in the cerebral cortex. In the case of the dorsal column system, lateral inhibitory signals occur at each synaptic level—for instance, in (1) the dorsal column nuclei of the medulla, (2) the ventrobasal nuclei of the thalamus, and (3) the cortex itself. At each of these levels, the lateral inhibition helps to block lateral spread of the excitatory signal. As a result, the peaks of excitation stand out, and much of the surrounding diffuse stimulation is blocked. This effect is demonstrated by the two red curves in Figure 47–10, showing complete separation of the peaks when the intensity of lateral inhibition is great. Transmission of Rapidly Changing and Repetitive Sensations. The dorsal column system also is of particular importance in apprising the sensorium of rapidly changing peripheral conditions. Based on recorded action potentials, this system can recognize changing stimuli that occur in as little as 1/400 of a second. Vibratory Sensation. Vibratory signals are rapidly repetitive and can be detected as vibration up to 700 cycles per second. The higher-frequency vibratory signals originate from the pacinian corpuscles in the skin and deeper tissues, but lower-frequency signals (below about 200 per second) can originate from Meissner’s corpuscles as well. These signals are transmitted only in the dorsal column pathway. For this reason, application of vibration (e.g., from a “tuning fork”) to different peripheral parts of the body is an important tool used by neurologists for testing functional integrity of the dorsal columns. Interpretation of Sensory Stimulus Intensity The ultimate goal of most sensory stimulation is to apprise the psyche of the state of the body and its surroundings. Therefore, it is important that we discuss briefly some of the principles related to transmission of sensory stimulus intensity to the higher levels of the nervous system. The first question that comes to mind is, how is it possible for the sensory system to transmit sensory experiences of tremendously varying intensities? For instance, the auditory system can detect the weakest possible whisper but can also discern the meanings of an explosive sound, even though the sound intensities of these two experiences can vary more than 10 billion times; the eyes can see visual images with light intensities that vary as much as a half million times; and the skin can detect pressure differences of 10,000 to 100,000 times. As a partial explanation of these effects, Figure 46–4 in the previous chapter shows the relation of the receptor potential produced by the pacinian corpuscle to the Unit IX The Nervous System: A. General Principles and Sensory Physiology intensity of the sensory stimulus. At low stimulus intensity, slight changes in intensity increase the potential markedly, whereas at high levels of stimulus intensity, further increases in receptor potential are slight. Thus, the pacinian corpuscle is capable of accurately measuring extremely minute changes in stimulus at lowintensity levels, but at high-intensity levels, the change in stimulus must be much greater to cause the same amount of change in receptor potential. The transduction mechanism for detecting sound by the cochlea of the ear demonstrates still another method for separating gradations of stimulus intensity. When sound stimulates a specific point on the basilar membrane, weak sound stimulates only those hair cells at the point of maximum sound vibration. But as the sound intensity increases, many more hair cells in each direction farther away from the maximum vibratory point also become stimulated. Thus, signals are transmitted over progressively increasing numbers of nerve fibers, which is another mechanism by which stimulus intensity is transmitted to the central nervous system. This mechanism, plus the direct effect of stimulus intensity on impulse rate in each nerve fiber, as well as several other mechanisms, makes it possible for some sensory systems to operate reasonably faithfully at stimulus intensity levels changing as much as millions of times. Importance of the Tremendous Intensity Range of Sensory Reception. Were it not for the tremendous intensity range of sensory reception that we can experience, the various sensory systems would more often than not be operating in the wrong range. This is demonstrated by the attempts of most people, when taking photographs with a camera, to adjust the light exposure without using a light meter. Left to intuitive judgment of light intensity, a person almost always overexposes the film on bright days and greatly underexposes the film at twilight. Yet, that person’s own eyes are capable of discriminating with great detail visual objects in bright sunlight or at twilight; the camera cannot do this without very special manipulation because of the narrow critical range of light intensity required for proper exposure of film. Judgment of Stimulus Intensity Weber-Fechner Principle—Detection of “Ratio” of Stimulus Strength. In the mid-1800s, Weber first and Fechner later proposed the principle that gradations of stimulus strength are discriminated approximately in proportion to the logarithm of stimulus strength. That is, a person already holding 30 grams weight in his or her hand can barely detect an additional 1-gram increase in weight. And, when already holding 300 grams, he or she can barely detect a 10-gram increase in weight. Thus, in this instance, the ratio of the change in stimulus strength required for detection remains essentially constant, about 1 to 30, which is what the logarithmic principle means. To express this mathematically. Fechner principle is still a good one to remember, because it emphasizes that the greater the background sensory intensity, the greater an additional change must be for the psyche to detect the change. Power Law. Another attempt by physiopsychologists to find a good mathematical relation is the following formula, known as the power law. Interpreted signal strength = K • (Stimulus - k)y In this formula, the exponent y and the constants K and k are different for each type of sensation. When this power law relation is plotted on a graph using double logarithmic coordinates, as shown in Figure 47–11, and when appropriate quantitative values for the constants y, K, and k are found, a linear relation can be attained between interpreted stimulus strength and actual stimulus strength over a large range for almost any type of sensory perception. Position Senses The position senses are frequently also called proprioceptive senses. They can be divided into two subtypes: (1) static position sense, which means conscious perception of the orientation of the different parts of the body with respect to one another, and (2) rate of movement sense, also called kinesthesia or dynamic proprioception. Position Sensory Receptors. Knowledge of position, both static and dynamic, depends on knowing the degrees of angulation of all joints in all planes and their rates of change. Therefore, multiple different types of receptors help to determine joint angulation and are used 500 Interpreted stimulus strength (arbitrary units) 594 200 100 50 20 10 0 0 10 100 1000 10,000 Stimulus strength (arbitrary units) Interpreted signal strength = Log (Stimulus) + Constant More recently, it has become evident that the WeberFechner principle is quantitatively accurate only for higher intensities of visual, auditory, and cutaneous sensory experience and applies only poorly to most other types of sensory experience. Yet the Weber- Figure 47–11 Graphical demonstration of the “power law” relation between actual stimulus strength and strength that the psyche interprets it to be. Note that the power law does not hold at either very weak or very strong stimulus strengths. Chapter 47 Somatic Sensations: I. General Organization, the Tactile and Position Senses together for position sense. Both skin tactile receptors and deep receptors near the joints are used. In the case of the fingers, where skin receptors are in great abundance, as much as half of position recognition is believed to be detected through the skin receptors. Conversely, for most of the larger joints of the body, deep receptors are more important. For determining joint angulation in mid ranges of motion, among the most important receptors are the muscle spindles. They are also exceedingly important in helping to control muscle movement, as we shall see in Chapter 54. When the angle of a joint is changing, some muscles are being stretched while others are loosened, and the net stretch information from the spindles is transmitted into the computational system of the spinal cord and higher regions of the dorsal column system for deciphering joint angulations. At the extremes of joint angulation, stretch of the ligaments and deep tissues around the joints is an additional important factor in determining position. Types of sensory endings used for this are the pacinian corpuscles, Ruffini’s endings, and receptors similar to the Golgi tendon receptors found in muscle tendons. The pacinian corpuscles and muscle spindles are especially adapted for detecting rapid rates of change. It is likely that these are the receptors most responsible for detecting rate of movement. Processing of Position Sense Information in the Dorsal Column–Medial Lemniscal Pathway. Referring to Figure 47–12, one sees that thalamic neurons responding to joint rotation are of two categories: (1) those Impulses per second 100 80 60 #1 #4 #5 #2 40 #3 20 595 maximally stimulated when the joint is at full rotation and (2) those maximally stimulated when the joint is at minimal rotation. Thus, the signals from the individual joint receptors are used to tell the psyche how much each joint is rotated. Transmission of Less Critical Sensory Signals in the Anterolateral Pathway The anterolateral pathway for transmitting sensory signals up the spinal cord and into the brain, in contrast to the dorsal column pathway, transmits sensory signals that do not require highly discrete localization of the signal source and do not require discrimination of fine gradations of intensity. These types of signals include pain, heat, cold, crude tactile, tickle, itch, and sexual sensations. In Chapter 48, pain and temperature sensations will be discussed specifically. Anatomy of the Anterolateral Pathway The spinal cord anterolateral fibers originate mainly in dorsal horn laminae I, IV, V, and VI (see Figure 47–2). These laminae are where many of the dorsal root sensory nerve fibers terminate after entering the cord. As shown in Figure 47–13, the anterolateral fibers cross immediately in the anterior commissure of the cord to the opposite anterior and lateral white columns, where they turn upward toward the brain by way of the anterior spinothalamic and lateral spinothalamic tracts. The upper terminus of the two spinothalamic tracts is mainly twofold: (1) throughout the reticular nuclei of the brain stem and (2) in two different nuclear complexes of the thalamus, the ventrobasal complex and the intralaminar nuclei. In general, the tactile signals are transmitted mainly into the ventrobasal complex, terminating in some of the same thalamic nuclei where the dorsal column tactile signals terminate. From here, the signals are transmitted to the somatosensory cortex along with the signals from the dorsal columns. Conversely, only a small fraction of the pain signals project directly to the ventrobasal complex of the thalamus. Instead, most pain signals terminate in the reticular nuclei of the brain stem and from there are relayed to the intralaminar nuclei of the thalamus where the pain signals are further processed, as discussed in greater detail in Chapter 48. Characteristics of Transmission in the Anterolateral Pathway. 0 0 60 80 100 120 140 Degrees 160 180 Figure 47–12 Typical responses of five different thalamic neurons in the thalamic ventrobasal complex when the knee joint is moved through its range of motion. (Data from Mountcastle VB, Poggie GF, Werner G: The relation of thalamic cell response to peripheral stimuli varied over an intensive continuum. J Neurophysiol 26:807, 1963.) In general, the same principles apply to transmission in the anterolateral pathway as in the dorsal column–medial lemniscal system, except for the following differences: (1) the velocities of transmission are only one third to one half those in the dorsal column–medial lemniscal system, ranging between 8 and 40 m/sec; (2) the degree of spatial localization of signals is poor; (3) the gradations of intensities are also far less accurate, most of the sensations being recognized in 10 to 20 gradations of strength, rather than as many as 100 gradations for the dorsal column system; 596 Unit IX The Nervous System: A. General Principles and Sensory Physiology Cortex C2 C2 C3 C3 C5 C4 C4 C5 T3 T5 Internal capsule Ventrobasal and intralaminar nuclei of the thalamus T7 T2 T2 T4 T8 T10 T12 L3 L5 T11 T12 Medial lemniscus L1 C6 Medulla oblongata C7 L2 C8 T6 T7 T8 T9 T6 T9 T10 Mesencephalon T2 T4 T5 T4 T5 T11 S2 L1 S4&5 L2 S3 L3 L3 Lateral division of the anterolateral pathway L4 L4 Spinal cord Anterior division of the anterolateral pathway Dorsal root and spinal ganglion L5 S1 L5 S1 L5 L4 Figure 47–13 Anterior and lateral divisions of the anterolateral sensory pathway. S2 Figure 47–14 Dermatomes. (Modified from Grinker RR, Sahs AL: Neurology, 6th ed. Springfield, IL: Charles C Thomas, 1966. Courtesy of Charles C Thomas, Publisher, Ltd., Springfield, Illinois.) and (4) the ability to transmit rapidly changing or rapidly repetitive signals is poor. Thus, it is evident that the anterolateral system is a cruder type of transmission system than the dorsal column–medial lemniscal system. Even so, certain modalities of sensation are transmitted only in this system and not at all in the dorsal column–medial lemniscal system. They are pain, temperature, tickle, itch, and sexual sensations, in addition to crude touch and pressure. Some Special Aspects of Somatosensory Function Function of the Thalamus in Somatic Sensation When the somatosensory cortex of a human being is destroyed, that person loses most critical tactile sensibilities, but a slight degree of crude tactile sensibility does return. Therefore, it must be assumed that the thalamus (as well as other lower centers) has a slight ability to discriminate tactile sensation, even though the thalamus normally functions mainly to relay this type of information to the cortex. Conversely, loss of the somatosensory cortex has little effect on one’s perception of pain sensation and only a moderate effect on the perception of temperature. Therefore, there is much reason to believe that the lower brain stem, the thalamus, and other associated basal regions of the brain play dominant roles in discrimination of these sensibilities. It is interesting that these sensibilities appeared very early in the phylogenetic development of animals, whereas the critical tactile sensibilities and the somatosensory cortex were late developments. Chapter 47 Somatic Sensations: I. General Organization, the Tactile and Position Senses Cortical Control of Sensory Sensitivity—“Corticofugal” Signals In addition to somatosensory signals transmitted from the periphery to the brain, corticofugal signals are transmitted in the backward direction from the cerebral cortex to the lower sensory relay stations of the thalamus, medulla, and spinal cord; they control the intensity of sensitivity of the sensory input. Corticofugal signals are almost entirely inhibitory, so that when sensory input intensity becomes too great, the corticofugal signals automatically decrease transmission in the relay nuclei. This does two things: First, it decreases lateral spread of the sensory signals into adjacent neurons and, therefore, increases the degree of sharpness in the signal pattern. Second, it keeps the sensory system operating in a range of sensitivity that is not so low that the signals are ineffectual nor so high that the system is swamped beyond its capacity to differentiate sensory patterns. This principle of corticofugal sensory control is used by all sensory systems, not only the somatic system, as explained in subsequent chapters. Segmental Fields of Sensation— The Dermatomes Each spinal nerve innervates a “segmental field” of the skin called a dermatome. The different dermatomes are shown in Figure 47–14. They are shown in the figure as if there were distinct borders between the adjacent dermatomes, which is far from true because much overlap exists from segment to segment. The figure shows that the anal region of the body lies in the dermatome of the most distal cord segment, dermatome S5. In the embryo, this is the tail region and the most distal portion of the body. The legs originate embryologically from the lumbar and upper sacral segments (L2 to S3), rather than from the distal sacral segments, which is evident from the dermatomal map. One can use a dermatomal map as shown in Figure 47–14 to determine the level in the spinal cord at which a cord injury has occurred when the peripheral sensations are disturbed by the injury. References Bosco G, Poppele RE: Proprioception from a spinocerebellar perspective. Physiol Rev 81:539, 2001. 597 Chen R, Cohen LG, Hallett M: Nervous system reorganization following injury. Neuroscience 111(4):761, 2002. Cohen YE, Andersen RA: A common reference frame for movement plans in the posterior parietal cortex. Nat Rev Neurosci 3:553, 2002. Craig AD: Pain mechanisms: labeled lines versus convergence in central processing.Annu Rev Neurosci 26:1, 2003. Foeller E, Feldman DE: Synaptic basis for developmental plasticity in somatosensory cortex. Curr Opin Neurobiol 14:89, 2004. Haines DE: Fundamental Neuroscience. New York: Churchill Livingstone, 1997. Haines DE, Lancon JA: Review of Neuroscience. New York: Churchill Livingstone, 2003. Ivry RB, Spencer RM: The neural representation of time. Curr Opin Neurobiol 14:225, 2004. Janig W, Baron R: Complex regional pain syndrome: mystery explained? Lancet Neurol 2:687, 2003. Jeannerod M: The mechanism of self-recognition in humans. Behav Brain Res 142:1, 2003. Johnson KO: The roles and functions of cutaneous mechanoreceptors. Curr Opin Neurobiol 11:455, 2001. Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2000. Lumb BM: Hypothalamic and midbrain circuitry that distinguishes between escapable and inescapable pain. News Physiol Sci 19:22, 2004. Maravita A, Spence C, Driver J: Multisensory integration and the body schema: close to hand and within reach. Curr Biol 13:R531, 2003. Pears S, Jackson SR: Cognitive neuroscience: vision and touch are constant companions. Curr Biol 14:R349, 2004. Petersen CC: The barrel cortex—integrating molecular, cellular and systems physiology. Pflugers Arch 447:126, 2003. Pouget A, Deneve S, Duhamel JR: A computational perspective on the neural basis of multisensory spatial representations. Nat Rev Neurosci 3:741, 2002. Sommer MA: The role of the thalamus in motor control. Curr Opin Neurobiol 13:663, 2003. Suga N, Ma X: Multiparametric corticofugal modulation and plasticity in the auditory system. Nat Rev Neurosci 4:783, 2003. Thaut MH: Neural basis of rhythmic timing networks in the human brain. Ann N Y Acad Sci 999:364, 2003. C H A P T E R 4 Somatic Sensations: II. Pain, Headache, and Thermal Sensations Many, if not most, ailments of the body cause pain. Furthermore, the ability to diagnose different diseases depends to a great extent on a physician’s knowledge of the different qualities of pain. For these reasons, the first part of this chapter is devoted mainly to pain and to the physiologic bases of some associated clinical phenomena. Pain Is a Protective Mechanism. Pain occurs whenever any tissues are being damaged, and it causes the individual to react to remove the pain stimulus. Even such simple activities as sitting for a long time on the ischia can cause tissue destruction because of lack of blood flow to the skin where it is compressed by the weight of the body. When the skin becomes painful as a result of the ischemia, the person normally shifts weight subconsciously. But a person who has lost the pain sense, as after spinal cord injury, fails to feel the pain and, therefore, fails to shift. This soon results in total breakdown and desquamation of the skin at the areas of pressure. Types of Pain and Their Qualities—Fast Pain and Slow Pain Pain has been classified into two major types: fast pain and slow pain. Fast pain is felt within about 0.1 second after a pain stimulus is applied, whereas slow pain begins only after 1 second or more and then increases slowly over many seconds and sometimes even minutes. During the course of this chapter, we shall see that the conduction pathways for these two types of pain are different and that each of them has specific qualities. Fast pain is also described by many alternative names, such as sharp pain, pricking pain, acute pain, and electric pain. This type of pain is felt when a needle is stuck into the skin, when the skin is cut with a knife, or when the skin is acutely burned. It is also felt when the skin is subjected to electric shock. Fast-sharp pain is not felt in most deeper tissues of the body. Slow pain also goes by many names, such as slow burning pain, aching pain, throbbing pain, nauseous pain, and chronic pain. This type of pain is usually associated with tissue destruction. It can lead to prolonged, unbearable suffering. It can occur both in the skin and in almost any deep tissue or organ. Pain Receptors and Their Stimulation Pain Receptors Are Free Nerve Endings. The pain receptors in the skin and other tissues are all free nerve endings. They are widespread in the superficial layers of the skin as well as in certain internal tissues, such as the periosteum, the arterial walls, the joint surfaces, and the falx and tentorium in the cranial vault. Most other deep tissues are only sparsely supplied with pain endings; nevertheless, any widespread tissue damage can summate to cause the slow-chronic-aching type of pain in most of these areas. 598 8 Chapter 48 599 Somatic Sensations: II. Pain, Headache, and Thermal Sensations types of stimuli. They are classified as mechanical, thermal, and chemical pain stimuli. In general, fast pain is elicited by the mechanical and thermal types of stimuli, whereas slow pain can be elicited by all three types. Some of the chemicals that excite the chemical type of pain are bradykinin, serotonin, histamine, potassium ions, acids, acetylcholine, and proteolytic enzymes. In addition, prostaglandins and substance P enhance the sensitivity of pain endings but do not directly excite them. The chemical substances are especially important in stimulating the slow, suffering type of pain that occurs after tissue injury. Number of subjects Three Types of Stimuli Excite Pain Receptors—Mechanical, Thermal, and Chemical. Pain can be elicited by multiple Nonadapting Nature of Pain Receptors. In contrast to most other sensory receptors of the body, pain receptors adapt very little and sometimes not at all. In fact, under some conditions, excitation of pain fibers becomes progressively greater, especially so for slow-aching-nauseous pain, as the pain stimulus continues. This increase in sensitivity of the pain receptors is called hyperalgesia. One can readily understand the importance of this failure of pain receptors to adapt, because it allows the pain to keep the person apprised of a tissue-damaging stimulus as long as it persists. Rate of Tissue Damage as a Stimulus for Pain The average person begins to perceive pain when the skin is heated above 45°C, as shown in Figure 48–1. This is also the temperature at which the tissues begin to be damaged by heat; indeed, the tissues are eventually destroyed if the temperature remains above this level indefinitely. Therefore, it is immediately apparent that pain resulting from heat is closely correlated with the rate at which damage to the tissues is occurring and not with the total damage that has already occurred. The intensity of pain is also closely correlated with the rate of tissue damage from causes other than heat, such as bacterial infection, tissue ischemia, tissue contusion, and so forth. Special Importance of Chemical Pain Stimuli During Tissue Damage. Extracts from damaged tissue cause intense pain when injected beneath the normal skin. Most of the chemicals listed earlier that excite the chemical pain receptors can be found in these extracts. One chemical that seems to be more painful than others is bradykinin. Many researchers have suggested that bradykinin might be the agent most responsible for causing pain following tissue damage. Also, the intensity of the pain felt correlates with the local increase in potassium ion concentration or the increase in proteolytic enzymes that directly attack the nerve endings and excite pain by making the nerve membranes more permeable to ions. 43 44 45 46 Temperature (∞C) 47 Figure 48–1 Distribution curve obtained from a large number of persons showing the minimal skin temperature that will cause pain. (Modified from Hardy DJ: Nature of pain. J Clin Epidemiol 4:22, 1956.) Tissue Ischemia as a Cause of Pain. When blood flow to a tissue is blocked, the tissue often becomes very painful within a few minutes. The greater the rate of metabolism of the tissue, the more rapidly the pain appears. For instance, if a blood pressure cuff is placed around the upper arm and inflated until the arterial blood flow ceases, exercise of the forearm muscles sometimes can cause muscle pain within 15 to 20 seconds. In the absence of muscle exercise, the pain may not appear for 3 to 4 minutes even though the muscle blood flow remains zero. One of the suggested causes of pain during ischemia is accumulation of large amounts of lactic acid in the tissues, formed as a consequence of anaerobic metabolism (metabolism without oxygen). It is also probable that other chemical agents, such as bradykinin and proteolytic enzymes, are formed in the tissues because of cell damage and that these, in addition to lactic acid, stimulate the pain nerve endings. Muscle Spasm as a Cause of Pain. Muscle spasm is also a common cause of pain, and it is the basis of many clinical pain syndromes. This pain probably results partially from the direct effect of muscle spasm in stimulating mechanosensitive pain receptors, but it might also result from the indirect effect of muscle spasm to compress the blood vessels and cause ischemia. Also, the spasm increases the rate of metabolism in the muscle tissue, thus making the relative ischemia even greater, creating ideal conditions for the release of chemical pain-inducing substances. 600 Unit IX The Nervous System: A. General Principles and Sensory Physiology Dual Pathways for Transmission of Pain Signals into the Central Nervous System Even though all pain receptors are free nerve endings, these endings use two separate pathways for transmitting pain signals into the central nervous system. The two pathways mainly correspond to the two types of pain—a fast-sharp pain pathway and a slow-chronic pain pathway. Peripheral Pain Fibers—“Fast” and “Slow” Fibers. The fast- sharp pain signals are elicited by either mechanical or thermal pain stimuli; they are transmitted in the peripheral nerves to the spinal cord by small type Ad fibers at velocities between 6 and 30 m/sec. Conversely, the slow-chronic type of pain is elicited mostly by chemical types of pain stimuli but sometimes by persisting mechanical or thermal stimuli. This slowchronic pain is transmitted to the spinal cord by type C fibers at velocities between 0.5 and 2 m/sec. Because of this double system of pain innervation, a sudden painful stimulus often gives a “double” pain sensation: a fast-sharp pain that is transmitted to the brain by the Ad fiber pathway, followed a second or so later by a slow pain that is transmitted by the C fiber pathway. The sharp pain apprises the person rapidly of a damaging influence and, therefore, plays an important role in making the person react immediately to remove himself or herself from the stimulus. The slow pain tends to become greater over time. This sensation eventually produces the intolerable suffering of longcontinued pain and makes the person keep trying to relieve the cause of the pain. On entering the spinal cord from the dorsal spinal roots, the pain fibers terminate on relay neurons in the dorsal horns. Here again, there are two systems for processing the pain signals on their way to the brain, as shown in Figures 48–2 and 48–3. Dual Pain Pathways in the Cord and Brain Stem—The Neospinothalamic Tract and the Paleospinothalamic Tract On entering the spinal cord, the pain signals take two pathways to the brain, through (1) the neospinothalamic tract and (2) the paleospinothalamic tract. Neospinothalamic Tract for Fast Pain. The fast type Ad pain fibers transmit mainly mechanical and acute thermal pain. They terminate mainly in lamina I (lamina marginalis) of the dorsal horns, as shown in Figure 48–2, and there excite second-order neurons of the neospinothalamic tract. These give rise to long fibers that cross immediately to the opposite side of the cord through the anterior commissure and then turn upward, passing to the brain in the anterolateral columns. C Ad Fast-sharp pain fibers Spinal nerve Tract of Lissauer III III IV V VI VII IX VIII Lamina marginalis Substantia gelatinosa Anterolateral pathway Slow-chronic pain fibers Figure 48–2 Transmission of both “fast-sharp” and “slow-chronic” pain signals into and through the spinal cord on their way to the brain. To: Somatosensory areas Thalamus Intralaminar nuclei Ventrobasal complex and posterior nuclear group "Slow" Pain Fibers "Fast" Pain Fibers Reticular formation Pain tracts Figure 48–3 Transmission of pain signals into the brain stem, thalamus, and cerebral cortex by way of the fast pricking pain pathway and the slow burning pain pathway. Termination of the Neospinothalamic Tract in the Brain Stem and Thalamus. A few fibers of the neospinothal- amic tract terminate in the reticular areas of the brain stem, but most pass all the way to the thalamus without interruption, terminating in the ventrobasal complex along with the dorsal column–medial lemniscal tract for tactile sensations, as was discussed in Chapter 47. A few fibers also terminate in the posterior nuclear Chapter 48 Somatic Sensations: II. Pain, Headache, and Thermal Sensations group of the thalamus. From these thalamic areas, the signals are transmitted to other basal areas of the brain as well as to the somatosensory cortex. Capability of the Nervous System to Localize Fast Pain in the Body. The fast-sharp type of pain can be local- ized much more exactly in the different parts of the body than can slow-chronic pain. However, when only pain receptors are stimulated, without the simultaneous stimulation of tactile receptors, even fast pain may be poorly localized, often only within 10 centimeters or so of the stimulated area. Yet when tactile receptors that excite the dorsal column–medial lemniscal system are simultaneously stimulated, the localization can be nearly exact. Glutamate, the Probable Neurotransmitter of the Type Ad Fast Pain Fibers. It is believed that glutamate is the neurotransmitter substance secreted in the spinal cord at the type Ad pain nerve fiber endings. This is one of the most widely used excitatory transmitters in the central nervous system, usually having a duration of action lasting for only a few milliseconds. Paleospinothalamic Pathway for Transmitting Slow-Chronic Pain. The paleospinothalamic pathway is a much older system and transmits pain mainly from the peripheral slow-chronic type C pain fibers, although it does transmit some signals from type Ad fibers as well. In this pathway, the peripheral fibers terminate in the spinal cord almost entirely in laminae II and III of the dorsal horns, which together are called the substantia gelatinosa, as shown by the lateral most dorsal root type C fiber in Figure 48–2. Most of the signals then pass through one or more additional short fiber neurons within the dorsal horns themselves before entering mainly lamina V, also in the dorsal horn. Here the last neurons in the series give rise to long axons that mostly join the fibers from the fast pain pathway, passing first through the anterior commissure to the opposite side of the cord, then upward to the brain in the anterolateral pathway. Substance P, the Probable Slow-Chronic Neurotransmitter of Type C Nerve Endings. Research experi- ments suggest that type C pain fiber terminals entering the spinal cord secrete both glutamate transmitter and substance P transmitter. The glutamate transmitter acts instantaneously and lasts for only a few milliseconds. Substance P is released much more slowly, building up in concentration over a period of seconds or even minutes. In fact, it has been suggested that the “double” pain sensation one feels after a pinprick might result partly from the fact that the glutamate transmitter gives a faster pain sensation, whereas the substance P transmitter gives a more lagging sensation. Regardless of the yet unknown details, it seems clear that glutamate is the neurotransmitter most involved in transmitting fast pain into the central nervous system, and substance P is concerned with slow-chronic pain. 601 Projection of the Paleospinothalamic Pathway (SlowChronic Pain Signals) into the Brain Stem and Thalamus. The slow-chronic paleospinothalamic pathway terminates widely in the brain stem, in the large shaded area shown in Figure 48–3. Only one tenth to one fourth of the fibers pass all the way to the thalamus. Instead, most terminate in one of three areas: (1) the reticular nuclei of the medulla, pons, and mesencephalon; (2) the tectal area of the mesencephalon deep to the superior and inferior colliculi; or (3) the periaqueductal gray region surrounding the aqueduct of Sylvius. These lower regions of the brain appear to be important for feeling the suffering types of pain, because animals whose brains have been sectioned above the mesencephalon to block pain signals from reaching the cerebrum still evince undeniable evidence of suffering when any part of the body is traumatized. From the brain stem pain areas, multiple short-fiber neurons relay the pain signals upward into the intralaminar and ventrolateral nuclei of the thalamus and into certain portions of the hypothalamus and other basal regions of the brain. Very Poor Capability of the Nervous System to Localize Precisely the Source of Pain Transmitted in the Slow-Chronic Pathway. Localization of pain transmit- ted by way of the paleospinothalamic pathway is poor. For instance, slow-chronic pain can usually be localized only to a major part of the body, such as to one arm or leg but not to a specific point on the arm or leg. This is in keeping with the multisynaptic, diffuse connectivity of this pathway. It explains why patients often have serious difficulty in localizing the source of some chronic types of pain. Function of the Reticular Formation, Thalamus, and Cerebral Cortex in the Appreciation of Pain. Complete removal of the somatic sensory areas of the cerebral cortex does not destroy an animal’s ability to perceive pain. Therefore, it is likely that pain impulses entering the brain stem reticular formation, the thalamus, and other lower brain centers cause conscious perception of pain. This does not mean that the cerebral cortex has nothing to do with normal pain appreciation; electrical stimulation of cortical somatosensory areas does cause a human being to perceive mild pain from about 3 per cent of the points stimulated. However, it is believed that the cortex plays an especially important role in interpreting pain quality, even though pain perception might be principally the function of lower centers. Special Capability of Pain Signals to Arouse Overall Brain Excitability. Electrical stimulation in the reticular areas of the brain stem and in the intralaminar nuclei of the thalamus, the areas where the slow-suffering type of pain terminates, has a strong arousal effect on nervous activity throughout the entire brain. In fact, these two areas constitute part of the brain’s principal “arousal system,” which is discussed in Chapter 59.This explains why it is almost impossible for a person to sleep when he or she is in severe pain. 602 Unit IX The Nervous System: A. General Principles and Sensory Physiology Surgical Interruption of Pain Pathways. When a person has severe and intractable pain (sometimes resulting from rapidly spreading cancer), it is necessary to relieve the pain. To do this, the pain nervous pathways can be cut at any one of several points. If the pain is in the lower part of the body, a cordotomy in the thoracic region of the spinal cord often relieves the pain for a few weeks to a few months. To do this, the spinal cord on the side opposite to the pain is partially cut in its anterolateral quadrant to interrupt the anterolateral sensory pathway. A cordotomy, however, is not always successful in relieving pain, for two reasons. First, many pain fibers from the upper part of the body do not cross to the opposite side of the spinal cord until they have reached the brain, so that the cordotomy does not transect these fibers. Second, pain frequently returns several months later, partly as a result of sensitization of other pathways that normally are too weak to be effectual (e.g., sparse pathways in the dorsolateral cord). Another experimental operative procedure to relieve pain has been to cauterize specific pain areas in the intralaminar nuclei in the thalamus, which often relieves suffering types of pain while leaving intact one’s appreciation of “acute” pain, an important protective mechanism. Pain Suppression (“Analgesia”) System in the Brain and Spinal Cord The degree to which a person reacts to pain varies tremendously. This results partly from a capability of the brain itself to suppress input of pain signals to the nervous system by activating a pain control system, called an analgesia system. The analgesia system is shown in Figure 48–4. It consists of three major components: (1) The periaqueductal gray and periventricular areas of the mesencephalon and upper pons surround the aqueduct of Sylvius and portions of the third and fourth ventricles. Neurons from these areas send signals to (2) the raphe magnus nucleus, a thin midline nucleus located in the lower pons and upper medulla, and the nucleus reticularis paragigantocellularis, located laterally in the medulla. From these nuclei, second-order signals are transmitted down the dorsolateral columns in the spinal cord to (3) a pain inhibitory complex located in the dorsal horns of the spinal cord. At this point, the analgesia signals can block the pain before it is relayed to the brain. Electrical stimulation either in the periaqueductal gray area or in the raphe magnus nucleus can suppress many strong pain signals entering by way of the dorsal spinal roots. Also, stimulation of areas at still higher levels of the brain that excite the periaqueductal gray area can also suppress pain. Some of these areas are (1) the periventricular nuclei in the hypothalamus, lying adjacent to the third ventricle, and (2) to a lesser extent, the medial forebrain bundle, also in the hypothalamus. Several transmitter substances are involved in the analgesia system; especially involved are enkephalin and serotonin. Many nerve fibers derived from the Third ventricle Aqueduct Mesencephalon Periventricular nuclei Periaqueductal gray Enkephalin neurons Fourth ventricle Pons Raphe magnus nucleus Medulla Serotonergic neurons Pain fibers Enkephalin neurons Presynaptic pain inhibition Anterolateral somatosensory tract Figure 48–4 Analgesia system of the brain and spinal cord, showing (1) inhibition of incoming pain signals at the cord level and (2) presence of enkephalin-secreting neurons that suppress pain signals in both the cord and the brain stem. periventricular nuclei and from the periaqueductal gray area secrete enkephalin at their endings. Thus, as shown in Figure 48–4, the endings of many fibers in the raphe magnus nucleus release enkephalin when stimulated. Fibers originating in this area send signals to the dorsal horns of the spinal cord to secrete serotonin at their endings. The serotonin causes local cord neurons to secrete enkephalin as well. The enkephalin is believed to cause both presynaptic and postsynaptic inhibition of incoming type C and type Ad pain fibers where they synapse in the dorsal horns. Thus, the analgesia system can block pain signals at the initial entry point to the spinal cord. In fact, it can also block many local cord reflexes that result from pain signals, especially withdrawal reflexes described in Chapter 54. Brain’s Opiate System—Endorphins and Enkephalins More than 35 years ago it was discovered that injection of minute quantities of morphine either into the periventricular nucleus around the third ventricle or Chapter 48 Somatic Sensations: II. Pain, Headache, and Thermal Sensations into the periaqueductal gray area of the brain stem causes an extreme degree of analgesia. In subsequent studies, it has been found that morphine-like agents, mainly the opiates, also act at many other points in the analgesia system, including the dorsal horns of the spinal cord. Because most drugs that alter excitability of neurons do so by acting on synaptic receptors, it was assumed that the “morphine receptors” of the analgesia system must be receptors for some morphine-like neurotransmitter that is naturally secreted in the brain. Therefore, an extensive search was undertaken for the natural opiate of the brain. About a dozen such opiate-like substances have now been found at different points of the nervous system; all are breakdown products of three large protein molecules: proopiomelanocortin, proenkephalin, and prodynorphin. Among the more important of these opiate-like substances are b-endorphin, met-enkephalin, leuenkephalin, and dynorphin. The two enkephalins are found in the brain stem and spinal cord, in the portions of the analgesia system described earlier, and b-endorphin is present in both the hypothalamus and the pituitary gland. Dynorphin is found mainly in the same areas as the enkephalins, but in much lower quantities. Thus, although the fine details of the brain’s opiate system are not understood, activation of the analgesia system by nervous signals entering the periaqueductal gray and periventricular areas, or inactivation of pain pathways by morphine-like drugs, can almost totally suppress many pain signals entering through the peripheral nerves. Inhibition of Pain Transmission by Simultaneous Tactile Sensory Signals Another important event in the saga of pain control was the discovery that stimulation of large type Ab sensory fibers from peripheral tactile receptors can depress transmission of pain signals from the same body area. This presumably results from local lateral inhibition in the spinal cord. It explains why such simple maneuvers as rubbing the skin near painful areas is often effective in relieving pain. And it probably also explains why liniments are often useful for pain relief. This mechanism and the simultaneous psychogenic excitation of the central analgesia system are probably also the basis of pain relief by acupuncture. been reported in some instances. Also, pain relief has been reported to last for as long as 24 hours after only a few minutes of stimulation. Referred Pain Often a person feels pain in a part of the body that is fairly remote from the tissue causing the pain. This is called referred pain. For instance, pain in one of the visceral organs often is referred to an area on the body surface. Knowledge of the different types of referred pain is important in clinical diagnosis because in many visceral ailments the only clinical sign is referred pain. Mechanism of Referred Pain. Figure 48–5 shows the prob- able mechanism by which most pain is referred. In the figure, branches of visceral pain fibers are shown to synapse in the spinal cord on the same second-order neurons (1 and 2) that receive pain signals from the skin. When the visceral pain fibers are stimulated, pain signals from the viscera are conducted through at least some of the same neurons that conduct pain signals from the skin, and the person has the feeling that the sensations originate in the skin itself. Visceral Pain In clinical diagnosis, pain from the different viscera of the abdomen and chest is one of the few criteria that can be used for diagnosing visceral inflammation, visceral infectious disease, and other visceral ailments. Often, the viscera have sensory receptors for no other modalities of sensation besides pain. Also, visceral pain differs from surface pain in several important aspects. One of the most important differences between surface pain and visceral pain is that highly localized types of damage to the viscera seldom cause severe pain. For instance, a surgeon can cut the gut entirely in two in a patient who is awake without causing significant pain. Conversely, any stimulus that causes diffuse stimulation of pain nerve endings throughout a viscus causes pain that can be severe. For instance, ischemia 1 2 Treatment of Pain by Electrical Stimulation Several clinical procedures have been developed for suppressing pain by electrical stimulation. Stimulating electrodes are placed on selected areas of the skin or, on occasion, implanted over the spinal cord, supposedly to stimulate the dorsal sensory columns. In some patients, electrodes have been placed stereotaxically in appropriate intralaminar nuclei of the thalamus or in the periventricular or periaqueductal area of the diencephalon. The patient can then personally control the degree of stimulation. Dramatic relief has 603 Visceral nerve fibers Skin nerve fibers Figure 48–5 Mechanism of referred pain and referred hyperalgesia. 604 Unit IX The Nervous System: A. General Principles and Sensory Physiology caused by occluding the blood supply to a large area of gut stimulates many diffuse pain fibers at the same time and can result in extreme pain. Causes of True Visceral Pain Any stimulus that excites pain nerve endings in diffuse areas of the viscera can cause visceral pain. Such stimuli include ischemia of visceral tissue, chemical damage to the surfaces of the viscera, spasm of the smooth muscle of a hollow viscus, excess distention of a hollow viscus, and stretching of the connective tissue surrounding or within the viscus. Essentially all visceral pain that originates in the thoracic and abdominal cavities is transmitted through small type C pain fibers and, therefore, can transmit only the chronic-aching-suffering type of pain. Ischemia. Ischemia causes visceral pain in the same way that it does in other tissues, presumably because of the formation of acidic metabolic end products or tissuedegenerative products such as bradykinin, proteolytic enzymes, or others that stimulate pain nerve endings. Chemical Stimuli. On occasion, damaging substances leak from the gastrointestinal tract into the peritoneal cavity. For instance, proteolytic acidic gastric juice often leaks through a ruptured gastric or duodenal ulcer. This juice causes widespread digestion of the visceral peritoneum, thus stimulating broad areas of pain fibers. The pain is usually excruciatingly severe. Spasm of a Hollow Viscus. Spasm of a portion of the gut, the gallbladder, a bile duct, a ureter, or any other hollow viscus can cause pain, possibly by mechanical stimulation of the pain nerve endings. Or the spasm might cause diminished blood flow to the muscle, combined with the muscle’s increased metabolic need for nutrients, thus causing severe pain. Often pain from a spastic viscus occurs in the form of cramps, with the pain increasing to a high degree of severity and then subsiding. This process continues intermittently, once every few minutes. The intermittent cycles result from periods of contraction of smooth muscle. For instance, each time a peristaltic wave travels along an overly excitable spastic gut, a cramp occurs. The cramping type of pain frequently occurs in appendicitis, gastroenteritis, constipation, menstruation, parturition, gallbladder disease, or ureteral obstruction. Overdistention of a Hollow Viscus. Extreme overfilling of a hollow viscus also can result in pain, presumably because of overstretch of the tissues themselves. Overdistention can also collapse the blood vessels that encircle the viscus or that pass into its wall, thus perhaps promoting ischemic pain. Insensitive Viscera. A few visceral areas are almost completely insensitive to pain of any type. These include the parenchyma of the liver and the alveoli of the lungs. Yet the liver capsule is extremely sensitive to both direct trauma and stretch, and the bile ducts are also sensitive to pain. In the lungs, even though the alveoli are insensitive, both the bronchi and the parietal pleura are very sensitive to pain. “Parietal Pain” Caused by Visceral Disease When a disease affects a viscus, the disease process often spreads to the parietal peritoneum, pleura, or pericardium. These parietal surfaces, like the skin, are supplied with extensive pain innervation from the peripheral spinal nerves. Therefore, pain from the parietal wall overlying a viscus is frequently sharp. An example can emphasize the difference between this pain and true visceral pain: a knife incision through the parietal peritoneum is very painful, whereas a similar cut through the visceral peritoneum or through a gut wall is not very painful, if painful at all. Localization of Visceral Pain— “Visceral” and the “Parietal” Pain Transmission Pathways Pain from the different viscera is frequently difficult to localize, for a number of reasons. First, the patient’s brain does not know from firsthand experience that the different internal organs exist; therefore, any pain that originates internally can be localized only generally. Second, sensations from the abdomen and thorax are transmitted through two pathways to the central nervous system—the true visceral pathway and the parietal pathway. True visceral pain is transmitted via pain sensory fibers within the autonomic nerve bundles, and the sensations are referred to surface areas of the body often far from the painful organ. Conversely, parietal sensations are conducted directly into local spinal nerves from the parietal peritoneum, pleura, or pericardium, and these sensations are usually localized directly over the painful area. Localization of Referred Pain Transmitted via Visceral Pathways. When visceral pain is referred to the surface of the body, the person generally localizes it in the dermatomal segment from which the visceral organ originated in the embryo, not necessarily where the visceral organ now lies. For instance, the heart originated in the neck and upper thorax, so that the heart’s visceral pain fibers pass upward along the sympathetic sensory nerves and enter the spinal cord between segments C-3 and T-5. Therefore, as shown in Figure 48–6, pain from the heart is referred to the side of the neck, over the shoulder, over the pectoral muscles, down the arm, and into the substernal area of the upper chest. These are the areas of the body surface that send their own somatosensory nerve fibers into the C-3 to T-5 cord segments. Most frequently, the pain is on the left side rather than on the right because the left side of the heart is much more frequently involved in coronary disease than the right. The stomach originated approximately from the seventh to ninth thoracic segments of the embryo. Therefore, stomach pain is referred to the anterior epigastrium above the umbilicus, which is the surface area of the body subserved by the seventh through ninth thoracic segments. Figure 48–6 shows several other surface areas to which visceral pain is referred from other organs, representing in general the areas in the embryo from which the respective organs originated. Parietal Pathway for Transmission of Abdominal and Thoracic Pain. Pain from the viscera is frequently localized to two surface areas of the body at the same time because of Chapter 48 605 Somatic Sensations: II. Pain, Headache, and Thermal Sensations Hear t T-10 Es ophagus L-1 Stomach Liver and gallbladder Pylorus Umbilicus Appendix and small intestine Right kidney Visceral pain Left kidney Parietal pain Colon Ureter Figure 48–6 Surface areas of referred pain from different visceral organs. Figure 48–7 Visceral and parietal transmission of pain signals from the appendix. Herpes Zoster (Shingles) the dual transmission of pain through the referred visceral pathway and the direct parietal pathway. Thus, Figure 48–7 shows dual transmission from an inflamed appendix. Pain impulses pass first from the appendix through visceral pain fibers located within sympathetic nerve bundles, and then into the spinal cord at about T-10 or T-11; this pain is referred to an area around the umbilicus and is of the aching, cramping type. Pain impulses also often originate in the parietal peritoneum where the inflamed appendix touches or is adherent to the abdominal wall. These cause pain of the sharp type directly over the irritated peritoneum in the right lower quadrant of the abdomen. Some Clinical Abnormalities of Pain and Other Somatic Sensations Hyperalgesia A pain nervous pathway sometimes becomes excessively excitable; this gives rise to hyperalgesia, which means hypersensitivity to pain. Possible causes of hyperalgesia are (1) excessive sensitivity of the pain receptors themselves, which is called primary hyperalgesia, and (2) facilitation of sensory transmission, which is called secondary hyperalgesia. An example of primary hyperalgesia is the extreme sensitivity of sunburned skin, which results from sensitization of the skin pain endings by local tissue products from the burn—perhaps histamine, perhaps prostaglandins, perhaps others. Secondary hyperalgesia frequently results from lesions in the spinal cord or the thalamus. Several of these lesions are discussed in subsequent sections. Occasionally herpesvirus infects a dorsal root ganglion. This causes severe pain in the dermatomal segment subserved by the ganglion, thus eliciting a segmental type of pain that circles halfway around the body.The disease is called herpes zoster, or “shingles,” because of a skin eruption that often ensues. The cause of the pain is presumably infection of the pain neuronal cells in the dorsal root ganglion by the virus. In addition to causing pain, the virus is carried by neuronal cytoplasmic flow outward through the neuronal peripheral axons to their cutaneous origins. Here the virus causes a rash that vesiculates within a few days and then crusts over within another few days, all of this occurring within the dermatomal area served by the infected dorsal root. Tic Douloureux Lancinating pain occasionally occurs in some people over one side of the face in the sensory distribution area (or part of the area) of the fifth or ninth nerves; this phenomenon is called tic douloureux (or trigeminal neuralgia or glossopharyngeal neuralgia). The pain feels like sudden electrical shocks, and it may appear for only a few seconds at a time or may be almost continuous. Often it is set off by exceedingly sensitive trigger areas on the surface of the face, in the mouth, or inside the throat—almost always by a mechanoreceptive stimulus rather than a pain stimulus. For instance, when the patient swallows a bolus of food, as the food touches a tonsil, it might set off a severe lancinating pain in the mandibular portion of the fifth nerve. The pain of tic douloureux can usually be blocked by surgically cutting the peripheral nerve from the hypersensitive area. The sensory portion of the fifth nerve is 606 Unit IX The Nervous System: A. General Principles and Sensory Physiology often sectioned immediately inside the cranium, where the motor and sensory roots of the fifth nerve separate from each other, so that the motor portions, which are needed for many jaw movements, can be spared while the sensory elements are destroyed. This operation leaves the side of the face anesthetic, which in itself may be annoying. Furthermore, sometimes the operation is unsuccessful, indicating that the lesion that causes the pain might be in the sensory nucleus in the brain stem and not in the peripheral nerves. Brown-Séquard Syndrome If the spinal cord is transected entirely, all sensations and motor functions distal to the segment of transection are blocked, but if the spinal cord is transected on only one side, the Brown-Séquard syndrome occurs. The effects of such transection can be predicted from a knowledge of the cord fiber tracts shown in Figure 48–8. All motor functions are blocked on the side of the transection in all segments below the level of the transection. Yet only some of the modalities of sensation are lost on the transected side, and others are lost on the opposite side. The sensations of pain, heat, and cold— sensations served by the spinothalamic pathway—are lost on the opposite side of the body in all dermatomes two to six segments below the level of the transection. By contrast, the sensations that are transmitted only in the dorsal and dorsolateral columns—kinesthetic and position sensations, vibration sensation, discrete localization, and two-point discrimination—are lost on the side of the transection in all dermatomes below the level of the transection. Discrete “light touch” is impaired on the side of the transection because the principal pathway for the transmission of light touch, the dorsal column, is transected. That is, the fibers in this column do not cross to the opposite side until they reach the medulla of the brain. “Crude touch,” which is poorly localized, still persists because of partial transmission in the opposite spinothalamic tract. result from pain stimuli arising inside the cranium, but others result from pain arising outside the cranium, such as from the nasal sinuses. Headache of Intracranial Origin Pain-Sensitive Areas in Cranial Vault. The brain tissues themselves are almost totally insensitive to pain. Even cutting or electrically stimulating the sensory areas of the cerebral cortex only occasionally causes pain; instead, it causes prickly types of paresthesias on the area of the body represented by the portion of the sensory cortex stimulated. Therefore, it is likely that much or most of the pain of headache is not caused by damage within the brain itself. Conversely, tugging on the venous sinuses around the brain, damaging the tentorium, or stretching the dura at the base of the brain can cause intense pain that is recognized as headache. Also, almost any type of traumatizing, crushing, or stretching stimulus to the blood vessels of the meninges can cause headache. An especially sensitive structure is the middle meningeal artery, and neurosurgeons are careful to anesthetize this artery specifically when performing brain operations under local anesthesia. Areas of the Head to Which Intracranial Headache Is Referred. Stimulation of pain receptors in the cerebral vault above the tentorium, including the upper surface of the tentorium itself, initiates pain impulses in the cerebral portion of the fifth nerve and, therefore, causes referred headache to the front half of the head in the surface areas supplied by this somatosensory portion of the fifth cranial nerve, as shown in Figure 48–9. Conversely, pain impulses from beneath the tentorium enter the central nervous system mainly through the glossopharyngeal, vagal, and second cervical nerves, which also supply the scalp above, behind, and slightly below the ear. Subtentorial pain stimuli cause “occipital headache” referred to the posterior part of the head. Headache Headaches are a type of pain referred to the surface of the head from deep head structures. Some headaches Cerebral vault headaches Brain stem and cerebellar vault headaches Fasciculus gracilis Fasciculus cuneatus Lateral corticospinal Rubrospinal Olivospinal Tectospinal Ventral corticospinal Vestibulospinal Descending Tracts Dorsal spinocerebellar Lateral spinothalamic Nasal sinus and eye headaches Ventral spinocerebellar Spinotectal Ventral spinothalamic Ascending Tracts Figure 48–8 Figure 48–9 Cross section of the spinal cord, showing principal ascending tracts on the right and principal descending tracts on the left. Areas of headache resulting from different causes. Chapter 48 Somatic Sensations: II. Pain, Headache, and Thermal Sensations Types of Intracranial Headache Headache of Meningitis. One of the most severe headaches of all is that resulting from meningitis, which causes inflammation of all the meninges, including the sensitive areas of the dura and the sensitive areas around the venous sinuses. Such intense damage can cause extreme headache pain referred over the entire head. Headache Caused by Low Cerebrospinal Fluid Pressure. Removing as little as 20 milliliters of fluid from the spinal canal, particularly if the person remains in an upright position, often causes intense intracranial headache. Removing this quantity of fluid removes part of the flotation for the brain that is normally provided by the cerebrospinal fluid. The weight of the brain stretches and otherwise distorts the various dural surfaces and thereby elicits the pain that causes the headache. Migraine Headache. Migraine headache is a special type of headache that is thought to result from abnormal vascular phenomena, although the exact mechanism is unknown. Migraine headaches often begin with various prodromal sensations, such as nausea, loss of vision in part of the field of vision, visual aura, and other types of sensory hallucinations. Ordinarily, the prodromal symptoms begin 30 minutes to 1 hour before the beginning of the headache. Any theory that explains migraine headache must also explain the prodromal symptoms. One of the theories of the cause of migraine headaches is that prolonged emotion or tension causes reflex vasospasm of some of the arteries of the head, including arteries that supply the brain. The vasospasm theoretically produces ischemia of portions of the brain, and this is responsible for the prodromal symptoms. Then, as a result of the intense ischemia, something happens to the vascular walls, perhaps exhaustion of smooth muscle contraction, to allow the blood vessels to become flaccid and incapable of maintaining vascular tone for 24 to 48 hours. The blood pressure in the vessels causes them to dilate and pulsate intensely, and it is postulated that the excessive stretching of the walls of the arteries—including some extracranial arteries, such as the temporal artery—causes the actual pain of migraine headaches. Other theories of the cause of migraine headaches include spreading cortical depression, psychological abnormalities, and vasospasm caused by excess local potassium in the cerebral extracellular fluid. There may be a genetic predisposition to migraine headaches, because a positive family history for migraine has been reported in 65 to 90 per cent of cases. Migraine headaches also occur about twice as frequently in women as in men. Alcoholic Headache. As many people have experi- enced, a headache usually follows an alcoholic binge. It is most likely that alcohol, because it is toxic to tissues, directly irritates the meninges and causes the intracranial pain. Headache Caused by Constipation. Constipation causes headache in many people. Because it has been shown that constipation headache can occur in people whose pain sensory tracts in the spinal cord have been cut, we know that this headache is not caused by nervous impulses from the colon. Therefore, it may result from 607 absorbed toxic products or from changes in the circulatory system resulting from loss of fluid into the gut. Extracranial Types of Headache Headache Resulting from Muscle Spasm. Emotional tension often causes many of the muscles of the head, especially those muscles attached to the scalp and the neck muscles attached to the occiput, to become spastic, and it is postulated that this is one of the common causes of headache. The pain of the spastic head muscles supposedly is referred to the overlying areas of the head and gives one the same type of headache as intracranial lesions do. Headache Caused by Irritation of Nasal and Accessory Nasal Structures. The mucous membranes of the nose and nasal sinuses are sensitive to pain, but not intensely so. Nevertheless, infection or other irritative processes in widespread areas of the nasal structures often summate and cause headache that is referred behind the eyes or, in the case of frontal sinus infection, to the frontal surfaces of the forehead and scalp, as shown in Figure 48–9. Also, pain from the lower sinuses, such as from the maxillary sinuses, can be felt in the face. Headache Caused by Eye Disorders. Difficulty in focusing one’s eyes clearly may cause excessive contraction of the eye ciliary muscles in an attempt to gain clear vision. Even though these muscles are extremely small, it is believed that tonic contraction of them can cause retroorbital headache. Also, excessive attempts to focus the eyes can result in reflex spasm in various facial and extraocular muscles, which is a possible cause of headache. A second type of headache that originates in the eyes occurs when the eyes are exposed to excessive irradiation by light rays, especially ultraviolet light. Looking at the sun or the arc of an arc-welder for even a few seconds may result in headache that lasts from 24 to 48 hours. The headache sometimes results from “actinic” irritation of the conjunctivae, and the pain is referred to the surface of the head or retro-orbitally. However, focusing intense light from an arc or the sun on the retina can also burn the retina, and this could be the cause of the headache. Thermal Sensations Thermal Receptors and Their Excitation The human being can perceive different gradations of cold and heat, from freezing cold to cold to cool to indifferent to warm to hot to burning hot. Thermal gradations are discriminated by at least three types of sensory receptors: cold receptors, warmth receptors, and pain receptors. The pain receptors are stimulated only by extreme degrees of heat or cold and, therefore, are responsible, along with the cold and warmth receptors, for “freezing cold” and “burning hot” sensations. The cold and warmth receptors are located immediately under the skin at discrete separated spots. In 608 Unit IX The Nervous System: A. General Principles and Sensory Physiology out slightly above 40°C. Above about 30°C, the warmth receptors begin to be stimulated, but these also fade out at about 49°C. Finally, at around 45°C, the heat-pain fibers begin to be stimulated by heat and, paradoxically, some of the cold fibers begin to be stimulated again, possibly because of damage to the cold endings caused by the excessive heat. One can understand from Figure 48–10 that a person determines the different gradations of thermal sensations by the relative degrees of stimulation of the different types of endings. One can also understand why extreme degrees of both cold and heat can be painful and why both these sensations, when intense enough, may give almost the same quality of sensation—that is, freezing cold and burning hot sensations feel almost alike. most areas of the body, there are 3 to 10 times as many cold spots as warmth spots, and the number in different areas of the body varies from 15 to 25 cold spots per square centimeter in the lips to 3 to 5 cold spots per square centimeter in the finger to less than 1 cold spot per square centimeter in some broad surface areas of the trunk. Although the existence of distinctive warmth nerve endings is quite certain, based on psychological tests, they have not been identified histologically. They are presumed to be free nerve endings, because warmth signals are transmitted mainly over type C nerve fibers at transmission velocities of only 0.4 to 2 m/sec. Conversely, a definitive cold receptor has been identified. It is a special, small type Ad myelinated nerve ending that branches a number of times, the tips of which protrude into the bottom surfaces of basal epidermal cells. Signals are transmitted from these receptors via type Ad nerve fibers at velocities of about 20 m/sec. Some cold sensations are believed to be transmitted in type C nerve fibers as well, which suggests that some free nerve endings also might function as cold receptors. Stimulatory Effects of Rising and Falling Temperature—Adaptation of Thermal Receptors. When a cold receptor is sud- denly subjected to an abrupt fall in temperature, it becomes strongly stimulated at first, but this stimulation fades rapidly during the first few seconds and progressively more slowly during the next 30 minutes or more. In other words, the receptor “adapts” to a great extent, but never 100 per cent. Thus, it is evident that the thermal senses respond markedly to changes in temperature, in addition to being able to respond to steady states of temperature. This means that when the temperature of the skin is actively falling, a person feels much colder than when the temperature remains cold at the same level. Conversely, if the temperature is actively rising, the person feels much warmer than he or she would at the same temperature if it were constant. The response to changes in temperature explains the extreme degree of heat one feels on first entering a tub of hot water and the extreme degree of cold felt on going from a heated room to the out-of-doors on a cold day. Stimulation of Thermal Receptors—Sensations of Cold, Cool, Indifferent, Warm, and Hot. Figure 48–10 shows the effects of different temperatures on the responses of four types of nerve fibers: (1) a pain fiber stimulated by cold, (2) a cold fiber, (3) a warmth fiber, and (4) a pain fiber stimulated by heat. Note especially that these fibers respond differently at different levels of temperature. For instance, in the very cold region, only the cold-pain fibers are stimulated (if the skin becomes even colder, so that it nearly freezes or actually does freeze, these fibers cannot be stimulated). As the temperature rises to +10° to 15°C, the cold-pain impulses cease, but the cold receptors begin to be stimulated, reaching peak stimulation at about 24°C and fading Freezing cold Cool IndifferWarm Hot ent Burning hot Cold-pain Cold-receptors Warmth receptors Heat-pain 10 Impulses per second Cold 8 6 4 2 5 10 15 20 25 30 35 40 Temperature (∞C) 45 50 55 60 Figure 48–10 Discharge frequencies at different skin temperatures of a cold-pain fiber, a cold fiber, a warmth fiber, and a heat-pain fiber. Chapter 48 Somatic Sensations: II. Pain, Headache, and Thermal Sensations Mechanism of Stimulation of Thermal Receptors It is believed that the cold and warmth receptors are stimulated by changes in their metabolic rates, and that these changes result from the fact that temperature alters the rate of intracellular chemical reactions more than twofold for each 10°C change. In other words, thermal detection probably results not from direct physical effects of heat or cold on the nerve endings but from chemical stimulation of the endings as modified by temperature. Spatial Summation of Thermal Sensations. Because the number of cold or warm endings in any one surface area of the body is slight, it is difficult to judge gradations of temperature when small skin areas are stimulated. However, when a large skin area is stimulated all at once, the thermal signals from the entire area summate. For instance, rapid changes in temperature as little as 0.01°C can be detected if this change affects the entire surface of the body simultaneously. Conversely, temperature changes 100 times as great often will not be detected when the affected skin area is only 1 square centimeter in size. Transmission of Thermal Signals in the Nervous System In general, thermal signals are transmitted in pathways parallel to those for pain signals. On entering the spinal cord, the signals travel for a few segments upward or downward in the tract of Lissauer and then terminate mainly in laminae I, II, and III of the dorsal horns—the same as for pain. After a small amount of processing by one or more cord neurons, the signals enter long, ascending thermal fibers that cross to the opposite anterolateral sensory tract and terminate in both (1) the reticular areas of the brain stem and (2) the ventrobasal complex of the thalamus. A few thermal signals are also relayed to the cerebral somatic sensory cortex from the ventrobasal complex. Occasionally a neuron in cortical somatic sensory area I has been found by microelectrode studies to be directly responsive to either cold or warm stimuli on a specific area of the skin. However, removal of the entire cortical postcentral gyrus in the human 609 being reduces but does not abolish the ability to distinguish gradations of temperature. References Almeida TF, Roizenblatt S, Tufik S: Afferent pain pathways: a neuroanatomical review. Brain Res 1000:40, 2004. Ballantyne JC, Mao J: Opioid therapy for chronic pain. N Engl J Med 349:1943, 2003. Borsook D, Becerra L: Pain imaging: future applications to integrative clinical and basic neurobiology. Adv Drug Deliv Rev 55:967, 2003. Bromm B: Brain images of pain. News Physiol Sci 16:244, 2001. Bruera E, Kim HN: Cancer pain. JAMA 290:2476, 2003. Cervero F, Laird JM: Role of ion channels in mechanisms controlling gastrointestinal pain pathways. Curr Opin Pharmacol 3:608, 2003. Costigan M, Woolf CJ: No DREAM, no pain: closing the spinal gate. Cell 108:297, 2002. Gebhart GF: Descending modulation of pain. Neurosci Biobehav Rev 27:729, 2004. Haines DE: Fundamental Neuroscience. New York: Churchill Livingstone, 1997. Haines DE, Lancon JA: Review of Neuroscience. New York: Churchill Livingstone, 2003. Jordt SE, McKemy DD, Julius D: Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr Opin Neurobiol 13:487, 2003. Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2000. Kors EE, Vanmolkot KR, Haan J, et al: Recent findings in headache genetics. Curr Opin Neurol 17:283, 2004. Mendell JR, Sahenk Z: Clinical practice: painful sensory neuropathy. N Engl J Med 348:1243, 2003. Montell C: Thermosensation: hot findings make TRPNs very cool. Curr Biol 13:R476, 2003. Sanchez-del-Rio M, Reuter U: Migraine aura: new information on underlying mechanisms. Curr Opin Neurol 17:289, 2004. Schaible HG, Ebersberger A, Von Banchet GS: Mechanisms of pain in arthritis. Ann N Y Acad Sci 966:343, 2002. Silberstein SD: Migraine. Lancet 363:381, 2004. Vogt BA: Knocking out the DREAM to study pain. N Engl J Med 347:362, 2002. Watkins LR, Maier SF: Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82:981, 2002. Zubrzycka M, Janecka A: Substance P: transmitter of nociception (minireview). Endocr Regul 34:195, 2000. U N The Nervous System: B. The Special Senses 49. The Eye: I. Optics of Vision 50. The Eye: II. Receptor and Neural Function of the Retina 51. The Eye: III. Central Neurophysiology of Vision 52. The Sense of Hearing 53. The Chemical Senses—Taste and Smell I T X C H A P T E R 4 9 The Eye: I. Optics of Vision Physical Principles of Optics Before it is possible to understand the optical system of the eye, the student must first be thoroughly familiar with the basic principles of optics, including the physics of light refraction, focusing, depth of focus, and so forth. A brief review of these physical principles is presented; then the optics of the eye is discussed. Refraction of Light Refractive Index of a Transparent Substance. Light rays travel through air at a velocity of about 300,000 km/sec, but they travel much slower through transparent solids and liquids. The refractive index of a transparent substance is the ratio of the velocity of light in air to the velocity in the substance. The refractive index of air itself is 1.00. Thus, if light travels through a particular type of glass at a velocity of 200,000 km/sec, the refractive index of this glass is 300,000 divided by 200,000, or 1.50. Refraction of Light Rays at an Interface Between Two Media with Different Refractive Indices. When light rays traveling forward in a beam (as shown in Figure 49–1A) strike an interface that is perpendicular to the beam, the rays enter the second medium without deviating from their course. The only effect that occurs is decreased velocity of transmission and shorter wavelength, as shown in the figure by the shorter distances between wave fronts. If the light rays pass through an angulated interface as shown in Figure 49–1B, the rays bend if the refractive indices of the two media are different from each other. In this particular figure, the light rays are leaving air, which has a refractive index of 1.00, and are entering a block of glass having a refractive index of 1.50. When the beam first strikes the angulated interface, the lower edge of the beam enters the glass ahead of the upper edge. The wave front in the upper portion of the beam continues to travel at a velocity of 300,000 km/sec, while that which entered the glass travels at a velocity of 200,000 km/sec. This causes the upper portion of the wave front to move ahead of the lower portion, so that the wave front is no longer vertical but angulated to the right. Because the direction in which light travels is always perpendicular to the plane of the wave front, the direction of travel of the light beam bends downward. This bending of light rays at an angulated interface is known as refraction. Note particularly that the degree of refraction increases as a function of (1) the ratio of the two refractive indices of the two transparent media and (2) the degree of angulation between the interface and the entering wave front. Application of Refractive Principles to Lenses Convex Lens Focuses Light Rays. Figure 49–2 shows parallel light rays entering a convex lens. The light rays passing through the center of the lens strike the lens exactly perpendicular to the lens surface and, therefore, pass through the lens without being refracted. Toward either edge of the lens, however, the light rays strike a progressively more angulated interface. The outer rays bend more and more toward the center, which is called convergence of the rays. Half the bending occurs when the rays enter the lens, and half as they exit from the opposite side. (At this time, the student should pause and analyze why the rays bend toward the center on leaving the lens.) Finally, if the lens has exactly the proper curvature, parallel light 613 614 A Unit X Wave fronts The Nervous System: B. The Special Senses Glass Light from distant source B Figure 49–3 Figure 49–1 Light rays entering a glass surface perpendicular to the light rays (A) and a glass surface angulated to the light rays (B). This figure demonstrates that the distance between waves after they enter the glass is shortened to about two thirds that in air. It also shows that light rays striking an angulated glass surface are bent. Light from distant source Bending of light rays at each surface of a concave spherical lens, showing that parallel light rays are diverged. Focal length Figure 49–2 Bending of light rays at each surface of a convex spherical lens, showing that parallel light rays are focused to a focal point. A rays passing through each part of the lens will be bent exactly enough so that all the rays will pass through a single point, which is called the focal point. Concave Lens Diverges Light Rays. Figure 49–3 shows the effect of a concave lens on parallel light rays. The rays that enter the center of the lens strike an interface that is perpendicular to the beam and, therefore, do not refract. The rays at the edge of the lens enter the lens ahead of the rays in the center. This is opposite to the effect in the convex lens, and it causes the peripheral light rays to diverge from the light rays that pass through the center of the lens. Thus, the concave lens diverges light rays, but the convex lens converges light rays. Cylindrical Lens Bends Light Rays in Only One Plane—Comparison with Spherical Lenses. Figure 49–4 shows both a convex spherical lens and a convex cylindrical lens. Note that the cylindrical lens bends light rays from the two sides of the lens but not from the top or the bottom. That is, bending occurs in one plane but not the other. Thus, parallel light rays are bent to a focal line. Conversely, light rays that pass through the spherical lens are refracted B Figure 49–4 A, Point focus of parallel light rays by a spherical convex lens. B, Line focus of parallel light rays by a cylindrical convex lens. Chapter 49 615 The Eye: I. Optics of Vision at all edges of the lens (in both planes) toward the central ray, and all the rays come to a focal point. The cylindrical lens is well demonstrated by a test tube full of water. If the test tube is placed in a beam of sunlight and a piece of paper is brought progressively closer to the opposite side of the tube, a certain distance will be found at which the light rays come to a focal line. The spherical lens is demonstrated by an ordinary magnifying glass. If such a lens is placed in a beam of sunlight and a piece of paper is brought progressively closer to the lens, the light rays will impinge on a common focal point at an appropriate distance. Concave cylindrical lenses diverge light rays in only one plane in the same manner that convex cylindrical lenses converge light rays in one plane. Combination of Two Cylindrical Lenses at Right Angles Equals a Spherical Lens. Figure 49–5B shows two convex cylindrical lenses at right angles to each other. The vertical cylindrical lens converges the light rays that pass through the two sides of the lens, and the horizontal lens converges the top and bottom rays. Thus, all the light rays come to a single-point focus. In other words, two cylindrical lenses crossed at right angles to each other perform the same function as one spherical lens of the same refractive power. Focal Length of a Lens The distance beyond a convex lens at which parallel rays converge to a common focal point is called the focal length of the lens. The diagram at the top of Figure 49–6 demonstrates this focusing of parallel light rays. In the middle diagram, the light rays that enter the convex lens are not parallel but are diverging because the origin of the light is a point source not far away from the lens itself. Because these rays are diverging outward from the point source, it can be seen from the diagram that they do not focus at the same distance away from the lens as do parallel rays. In other words, when rays of light that are already diverging enter a convex lens, the distance of focus on the other side of the lens is farther from the lens than is the focal length of the lens for parallel rays. The bottom diagram of Figure 49–6 shows light rays that are diverging toward a convex lens that has far greater curvature than that of the other two lenses in the figure. In this diagram, the distance from the lens at which the light rays come to focus is exactly the same as that from the lens in the first diagram, in which the lens is less convex but the rays entering it are parallel. This demonstrates that both para