PHYSIOLOGY Angelo Mikhael V. Luna, MDPTRP SMOOTH MUSCLE VS SKELETAL MUSCLE SMOOTH MS SKELETAL MS Troponin No troponin, (+) calmodulin Greater length of actin & myosin A:M 1:15 (+) Dense bodies No NMJ (+) Diffuse junction & varicosities (+) T-tubules Shortens 2/3 of length Prolonged contraction (less ATPase) 4-6 kg/cm2 Location of T-tubules in Skeletal Ms: Z-disk Location of T-tubules in Cardiac Ms: B ends of myosin (2) Curare – competes with Ach on receptors Botulinum – decreases releases of Ach at nerve terminal RMPs Skeletal Muscle: -90 mV Large Nerve: -90 mV Small Nerve: -40 - -60 mV Smooth Muscle: -40 - -60 mV Cardiac Muscle(ventricles): -80 - -90 mV Sinus node: -55 - -60 mV (reduced negativity due to leakiness to Na) F-actin – Backbone of actin filament G-actin – Active sites, (+) ADP Positive Afterpotential More negative than RMP due to slow closing K channels Hypertrophy – inc number of myofibrils Hyperplasia – inc number of ms fibers Maximal efficiency of muscle contraction 20-25% occurring at velocity of 30% of max Staircase Effect (Treppe) Strength of Ms contraction from long rest is minimal, strength increases to a plateau 10-50 muscle contractions later 3000 : 1500 (+) Z-disk (+) NMJ (+) Caveoli Shortens to 1/3 of length Rapid contraction 3-4 kg/cm2 CARDIOVASCULAR SYSTEM Heart muscles A syncytium – interconnection of individual muscle cells Intercalated discs – cell membrane that separate individual myocytes Gap junctions – communicating junctions formed by cell membrane fusion RMP: -85- -95mV (N cardiocytes) -90 - -100 mV Purkinje fibers Plateau in depolarization of cardiac muscle: 1. opening of fast sodium channels 2. opening of slow calcium channels Strength of contraction of cardiac muscle depends on: ECF Ca++ Strength of contraction of skeletal muscles: Ca++ on sarcoplasmic reticulum Duration of contraction: Atrial muscle: 0.2 s Ventricular muscle: 0.3s Skeletal muscle: 1-5msec ATRIA Function as pump: increase ventricular pumping effectiveness by 25% Pressure changes in atria: A wave: atrial contraction C wave: bulging of AV valves during ventricular contraction (with slight backflow) V –wave: build-up of blood due to closed AV valves during ventricular contraction 1 VENTRICLES Period of rapid filling – 1st 1/3 of diastole Atrial contraction - last 1/3 of diastole Period of isovolumic or isometric contraction (+) ventricular contraction (-) emptying Period of ejection 1st 1/3 – period of rapid ejection; 70% of emptying last 2/3 – period of slow ejection; 30 % Period of isovolumic or isometric relaxation End Diastolic volume ventricular filling during diastole; 110-120ml Strove volume output – systole; 70ml End-systolic volume remaining volume in ventricles; 40-50ml Ejection fraction fraction of end-diastolic volume that is ejected; 60% Heart sounds: S1 – A-V valve closure S2 – semilunar valve closure S3 – rumbling into almost filled ventricle S4 – atrial contraction Preload – volume of blood remaining in ventricle at end of diastole Afterload – pressure in artery leading from ventricle Main energy source for cardiac contraction: Fatty acids Substances with (+) Inotropic effect 1. caffeine – increases formation of cAMP 2. xanthene – same 3. Digitalis – inhibits Na-K ATPase 4. Glucagon – inhibits breakdown of cAMP (-) Inotropic Effect Hypoxia Acidosis Hypercapnea B – blockers (blocks NE) Cause of self-excitation of Sinus nodal fibers: Inherent leakiness to sodium ions Location of RBB and LBB - endocardium Location of Purkinje fibers - 1/3 myocardium Stokes Adam Syndrome – Complete AV block causing faintness or death - AV block causes development of new pacemaker within the purkinje fibers of the ventricle, with a delay by 5-30 sec. during this time, the ventricle does not contract and blood flow to brain becomes insufficient Control of heart rhythmicity and conduction by ANS Parasympathetic – Acetylcholine – increases permeability to POTASSIUM Sympathetic – Norepinephrine – increase permeability to Na++ & Ca++ Efficiency of cardiac contraction – 20 -25% Effect of POTTASIUM in cardiac function Excess K – dilated, flaccid, slow heart rate Effect of Calcium Ions: Excess Ca++ - spastic contraction Deficiency Ca++ - flaccidity Inc Temp: Inc HR Dec Temp: Dec HR Laplace law Myocardial tension = intracavitary pressure x ventricular radius Frank-Starling mechanism strerch on heart muscles by increased venous return causes increased force of contraction by bringing the actin and myosin to optimal degree of interdigitation - stretch of atria increases heart rate by 10-20% Parasympathetic – decreases rate of rhythm of sinus node - decreases excitability of AV junctional fibers - (main control of SA node during rest) Sympathetic – increases sinus rate - increase rate of conduction and excitability - increase force of contraction ECG PHYSIO P wave – immediately before the beginning of contraction of atria QRS wave – immediately before the beginning of ventricular contraction T wave – ventricular repolarization 2 P-Q Interval (P-R interval) beginning of contraction of atrium and beginning of contraction of ventricle Q-T Interval duration of ventricular contraction (0.35s) Einthoven’s Triangle – 2 arms and the LEFT leg Einthoven’s Law – electrical potentials of any 2 of the 3 bipolar limb is known, the 3rd one can be determined mathematically by summing up the 2. Most common cause of high voltage QRS complexes Hypetrophy of cardiac muscle Conditions causing DECREASED voltage Old myocardial infarction (cardiomyopathies) Fluid in the pericardium Pleural effusion Pulmonary emphysema Current of injury Damage or injury to heart muscle itself, charge is always negative Conditions causing current of injury Mechanical trauma Infectious process Ischemia (most common) CIRCULATION Systemic circulation – supplies all the tissues of the body except LUNGS Arterioles – act as control valves Veins - major reservoir of blood; most distensible Capillaries – largest cross-sectional area Volumes of blood in different parts of circulation Systemic veins – 84% of entire blood volume Heart – 7% Pulmonary vessels – 9% Characteristic of blood flow in blood vessels streamline or laminar flow – each layer of blood remains in the same distance away from the wall; central part of blood stays in the center of the vessel Conditions causing Turbulent flow (blood flows crosswise, forming whorls or eddy currents) Blood flow is great Obstruction Sharp turn Rough surface Reynolds number – measures the tendency for turbulence to occur Resistance – impediment to blood flow in a vessel Conductance – a measure of blood flow thru a vessel for a given pressure difference - reciprocal of resistance - increases in proportion to 4th power of the diameter Poiseuille’s law – rate of blood flow is directly proportional to the pressure difference & 4th power of the radius; inversely proportional to length & viscosity of blood Major determinant of blood flow = diameter Factors affecting blood viscosity in blood vessels: 1. Hematocrit 2. Plasma proteins 3. Fahraeus-Lindqvist effect (smaller blood vessels causes less viscosity because blood cells line up and move singly) 4. Decreased velocity 5. Constrictions in blood vessels Windkessel Effect: recoil of arteries during diastole Ohm’s Law Blood is directly proportional to pressure difference, inversely proportional to resistance Q= ∆P/R Vascular distensibility: fractional increase in volume for each mmHg rise in pressure Vascular compliance(capacitance) – quantity of blood that can be stored for each mmHg rise Compliance = Distensibility x volume Greater the compliance, slower velocity of pulse pressure transmission Blood flow Quantity of blood that passes in a certain point in a given time 2 major factors affecting pulse pressure 1. stroke volume 2. compliance (total distensibility) Main control of Cardiac Output – Local tissue flow 3 Pulsus Paradoxus Decreased stroke volume and pulse strength during INSPIRATION Increase dunring EXPIRATION LYMPHATICS Ausculatatory BP determination: Accuracy is within 10% of values obtained by direct arterial measurement Areas in the body without lymphatic drainage 1. superficial portion of skin 2. CNS 3. deeper portion peripheral nerves 4. endomysium (muscle) 5. bones Mean Arterial Pressure Average of all pressures measured over time Nearer to diastolic pressure ( 60%DBP + 40% SBP) SBP + 2DBP/3 or DBP + 1/3 PP Histologic characteristic of Lymphatics: 1. No basement membrane 2. No smooth muscle Endothelial layer only Pressure Reference level for Pressure Measurement At the level of TRICUSPID valve Area where hydrostatic pressure changes due to body positional changes does not affect pressure measurement Rate of lymph flow: 120 mL/hr Sites of blood reservoirs 1. spleen (100 mL) 2. liver (several hundred mL) 3. large abdominal veins (300 mL) 4. venous plexus beneath the skin (several hundred mL) 5. heart and lungs Pores in the Capillary Membranes = Intercellular clefts 1. Brain – (+) tight junction (BBB) 2. Liver – wide open 3. Glomerular tufts of kidney – (+) oval windows or fenestrae Vasomotion Intermittent contraction of metarterioles and precapillary sphincters Most important regulator of opening or closure: Oxygen in tissues Capillary pressure – Moves fluid outward thru capillaries Interstitial fluid pressure – Inward Plasma colloid osmotic pressure – inward Interstitial fluid colloid osmotic pressure – outward Arterial end of capillaries – 13 mmHg filtration pressure (outward) Venous end of capillaries – 7 mmHg reabsorptive pressure Local Blood Flow Regulation Vasodilator Theory (release of vasodilator substance in response to O2 deficiency) Oxygen Demand Theory (inc utilization of O2 due to inc metabolism) Vasodilator Substances Carbon dioxide Hydrogen Histamine Lactic Acid Adenosine (most important) Adenosine PO4 cmpds Potassium ions Examples of Metabolic control of local blood flow Reactive Hyperemia – increased blood flow to tissues after short periods of vascular occlusion to repay accrued oxygen deficit Active Hyperemia – increase blood flow to tissues during inc activity due to release of vasodilator substances Maintenance of blood flow in response to arterial pressure changes Metabolic Theory – increases pressure FLUSHES vasodilator substances, causes blood vessels to constrict Myogenic Theory – STRETCH of small blood vessels causes smooth ms to conract - proposed mechanism which protects capillaries vs excessively high blood pressures 4 Mechanism of Long term regulation of Blood Flow Change in degree of Vascularity - Inc in pressure: increase size and number of blood vessel - Dec in pressure: decrease in size & number of blood vessel Humoral regulation of the circulation Vasoconstrictors: 1. Vasopressin – most potent vasoconstrictor substance 2. Angiotensin 3. NE 4. Epi 5. Serotonin (both vasodilator and vasoconstrictor, which depends on site of action) Vasodilators 1. Bradykinin – both arteriolar dilation & increased capillary permeability 2. Prostaglandin 3. Histamine 4. Serotonin Ions: Vasoconstrictor: Calcium Vasodilator: Potassium Magnesium Sodium Glucose Acetate Citrate Hydrogen Carbon dioxide Nervous Regulation Of Circulation Vasomotor Center Reticular substance of medulla & lower 1/3 of pons Lateral portions: inc HR & contractility Medial portions: decrease HR Vaoconstrictor area (C1) Anterolateral upper medulla Secretes NE- the sympathetic VC transmitter substance Vasodilator area (A1) Anterolateral lower medulla MOA: inhibits vasoconstrictor area Sensory area (A2) Tractus Solitarius (posterolateral medulla & lower pons) CN 9 & 10 Reflex control of circulation (both constrict & dilate) Vasomotor tone continues firing of sympathetic Vonstrictor fibers Sympathetic Vasodilator System Anterior hypothalamus Allows an anticipatory increase in blood flow even before muscle activity (exercise) Vasovagal syncope Intense emotion Activation of vasodilator system in anterior hypothalamus Vagal cardioinhibitory center in medulla HR slows, BP falls Reduced blood flow to brain Most rapid mechanism of pressure control - Nervous control of arterial pressure Baroreceptor relexes Carotid sinus – CN 9 via hering N; stimulate by pressures >60 mmhg Aortic arch – CN 10; stimulated by pressures >30mmHg Baroreceptor signals enter tractus solitarius of medulla, where secondary signals inhibit vasoconstrictor center & stimulate vagal center Effects: 1. vasodilation of veins & arterioles 2. Dec HR & contractility (decreasing arterial pressure, TPR, CO) Chemoreceptors Sensitive to O2 deficiency; CO2 & H excess Hering N & Vagus Excites vasomotor center, elevating arterial pressure Baroreceptor reflex – Inc blood volume to LV, Inc HR on EXP Bainbridge Reflex – Inc venous return to RA, Inc HR on INSP; mediated by vagus N stimulated by atrial stretch; prevents damming of veins in atria, veins, pulmo circulation CNS Ischemic response Insufficient blood flow to brain causes rise in CO2, stimulating SNS, elevating arterial pressure One of the MOST powerful activator of sympathetic vasoconstrictor system “Last Ditch Stand” of pressure control mechanism 5 Cushing’s Reaction Special type of CNS ischemic response, a reaction to increased ICP Inc BP, Dec HR, Dec RR Protective response to maintain nutrition on brain vital centers Kidney’s dominant role in Long term regulation of Arterial Pressure Main determinant of ECF volume - salt in the body 3. Hyperthyroid (inc metabolism, increasing vasodilator products) 4. Anemia (reduced viscosity, dec O2 causing vasodilation) Conditions with DEC CO Heart conditions (MI, myocarditis, cardiac tamponade, valvular dse) Dec. venous return (dec blood volume, venous dilatation, obstruction of large arteries) CORONARY CIRCULATION RAA system Renin – “enzyme” from JG cells in AFFerent arterioles - converts rennin substrate (angiotensinogen) to angiotensin I AI – AII – converted in endothelium of lung vessels Primary controller of coronary flow Myocardial oxygen demand (mvO2) [Metabolic Factors] AII Coronary sinus – where most of LV blood drain into Anterior cardiac veins – where most of RV drain Thebesian veins – minute blood vessels where drains directly in the chambers 1. acts directly on kidneys (H2O & Na retention) 2. stim adrenals- aldosterone (H20 & Na rebsorption) Goldblatt Hypertension “one kidney” HPN 1st phase: vasoconstrictor type of HPN ( renninangiotensin sys) 2nd phase: volume-loading HPN (fluid retention) HPN in coarctation of aorta Blood in lower body is carried by collateral lood vessels in body wall with increased vascular resistance Higher BP in upper part of body Mechanism of higher BP similar with Goldblatt HPN Left coronary A – supplies Ant & Lat LV Right coronary A – most of RV & post LV Sympathetics – NE, inc HR & contractility, DILATES coronary arteries Parasympathetics – Ach, dec HR & contractility, CONSTRICTS coronaries Epicardial coronary vessels – mostly ALPHA receptors (constrictors) Intramuscular coronary vessels – mostly BETA receptors (dilators) Coronary Ischemia > 30 minutes - duration where relief of ischemia may be too late to save lives of cardiac cells CO AND VR AND REGULATION BP = CO x TPR CO = SV x HR SV = PL x MC x AL Primary controller of CO - Venous Return (Frank-Starling Mech) Conditions with INC CO MC cause of elevated CO - DEC. TPR Other causes: 1. Beriberi (thiamine deficiency with resultant peripheral vasodilation) 2. AV fistula 3 known causes of reduced renal output of urine during cardiac failure 1. Dec GFR (due to dec arterial pressure & sympathetic constriction of afferent arterioles) 2. Activation of rennin-angiotensin sys (inc reabsorption of H2O & Na) 3. Inc Aldosterone secretion Excess POTASSIUM – most powerful stimulus for aldosterone secretion Atrial Natriuretic Factor (ANF) Hormone released by stretch of atrial walls Direct effect on kidneys to increase EXCRETION of Na & H2O Help prevent extreme congestive symptoms of HF 6 Type of shock with increased viscosity - Hypovolemic shock caused by plasma loss (intestinal obstruction & severe burns) Type of shock with increased temperature - Septic shock BLOOD Amount of Hgb / 100 mL of blood - 15mg/100mL of blood Binding capacity of Hgb - 1.34mL O2 / 1g of Hgb ( 1.39 if pure Hgb) Amount of O2 released from hemoglobin in the tissues 5mL O2 / 1 dL of blood is transported into tissues Also 4 mL CO2 / dL of blood Heme – mitochondria (kreb’s cycle) Globin – ribosomes Immediate precursor of Heme Acetic acid (+) glycine Acetic acid forms succinyl-coA thru kreb’s cycle Succinyl coA (+) Glycine = Pyrrole 4 Pyrrole à Protoporphyrin IX Protoporphyrin IX (+) Fe = Heme 1gm Hgb = 4 Fe = 4 O2 molecule = 8 O2 atoms Heme (+) a polypeptide forms Hgb Chain 2 alpha chain (+) 2 Beta chain = Hgb A Sickle cell Valine substituted for glutamic acid (+) Hgb S, (+) AbN B-globin Pernicious Anemia – Vit B12 deficiency Sprue – Pteroylglutamic acid deficiency (Folate deficiency) Proerythroblast à Basophilic erythrocyte à polychroatophilic à Orthochromatophilic à Reticulocyte à Erythrocyte Possible sources of Erythropoietin Mesangial cells Tubular epithelial cells Stim by NE, Epi & PG Life span of Reticulocytes 1-2 days Half-lives: Granulocytes (B, E, N) 4-8 hrs in blood; 4-5 days in tissues Monocytes 10-20 hrs in blood; mos – years in tissues as macrophages Lymphocytes (+) Recirculation; mos – years Platelets 10 days Lipases – seen only in macrophages Pseudopodia – commonly seen only in Neutrophils 1st Line of Defense Tissue macrophages 2nd Line of Defense Neutrophils 3rd Line of Defense Monocyte – macrophage th 4 Line of Defense Granulocyte – monocyte by bone marrow Larvicidal agent of eosinophils Major Basic Protein Substance secreted by macrophages to promote growth & reproduction of Lymphocyte - IL – 1 Promotes growth & reproduction of virtually all types of stem cells - IL – 3 Activation of a clone of Lymphocyte B-Lymphocyte – by Antigens T- Lymphocytes – by surface receptor proteins (Tcell markers) Mechanism by which Antibodies inactivate invading agents Precipitation – insoluble (tetanus toxin) Lysis – rupture Agglutination – clump (large particles : bacteria or RBC) Neutralization – cover active site of toxin IgG – Bivalent (2), most abundant (75%) IgM – 10 binding sites, (+) primary response IgE – 10 binding sites, allergic rxn 7 COMPLEMENT SYSTEM Chemotaxis – C5a Opsonization – C3b Lysis – C5b 6789 Anaphylaxis – C3a, C4a, C5a Classical Complement Ag- Ab complex – activates C1 Alternative Complement response to large polysaccharide of microorganism Reacts with complement factors B & D, which activates factor C3 Major stimulant of cytotoxic & suppressor T-cells - IL – 2 Major stimulant of B-cell, plasma cells - IL -4,5,6 Major stimulant of T-helper cells - IL-2 Mechanism of action of cytotoxic (killer)T-cells - forms perforins Major regulator of all immune functions - T – helper cells Madiator of Immune tolerance - Suppressor T-cells Erythroblastosis Fetalis Mother – Rh (-) Father – Rh (+) Baby – Rh(+) In mismatch transfusion rection The donor blood is the one hemolyzed, clumped & agglutinized Most Important antigens causing graft rejection Class I HLA antigens Class I HLA – all cells Class II HLA – Lymphocyte Class III HLA – Complement BLOOD COAGULATION Rate-limiting factor in coagulation of blood - Prtothrombin activator Difference between serum & plasma - Serum has NO fibrinogen or clotting factors Actual Protease that split Prothrombin to thrombin Activated Factor X (stuart factor) CLOTTING FACTORS I - Fibrinogen II – Prothrombin III – Tissue thromboplastin, tissue factor IV – Calcium V – Proaccelerin, Labile factor, Ac-globulin VII – Proconvertin, stable factor, serum prothrombin conversion accelerator VIII – antihemophilic factor A, AHF, AHG IX – Antihemophilic factor B, Christmas factor, PTC X – Stuart Factor XI – Antihemophilic factor C, PTA XII – Hageman Factor XIII – Fibrin-stabilizing factor Prekalikrein – Fletcher HMWK – Fletzgerald EXTRINSIC PATHWAY Tissue trauma à Tissue thromboplastin (Lipoprotein + phospholipids) à Thromboplastin (+) Factor 7 à F10 – F10a à F10 + F5 + phospholipid of thromboplastin à Prothrombin activation INTRINSIC PATHWAY Blood Trauma à F12 – F12a (+) PF3 à F11 – F11a (HMWK & prekalikrein) à F9 – F9a à F9a (+) F8 (+) PF3 (+) platelet phospholipids à F10 – F10a à F10 (+) F5 à Prothrombin activation ALL reactions in Both Extrinsic & Intrinsic Pathway requires Calcium EXCEPT F12 activation F11 activation Factors that prevent clotting in Normal Blood vessels Smooth blood vessels Glycocalyx in endothelium Thrombomodulin Inactivators of coagulation factors (Anticoagulants) Protein C - F5, F8 Heparin & Antithrombin III – F9,10,11,12 Plasmin – F1,2,5,8,12 8 Heparin – activates antithrombin III Warfarin – blocks Vit K Basement membrane – mesangial cells (increases surface area for filtration by inc slit pores Functions similarly with antithrombin III but not accelerated by heparin - Alpha2 macroglobulin Electronegativity of glomerular BM - due to proteoglycans & protein - repulses protein molecules larger than 69,000 MW PT – Extrinsic (N: 12 mins) aPTT – Intrinsic BT – No. of platelets (N: 1-6 mins) CT – Function of platelets (N: 6-10mins) KIDNEYS AND BODY FLUIDS Total body water: Adult: 57% (40L) NB: 75% Daily Loss of Body Water Sensible: 1. sweat – 100 mL 2. feces – 100 mL 3. urine – 1400 mL Insensible: 1. skin – 300-400 mL 2. lungs – 300-400 mL Cold weather: cold temp decreases atmospheric vapor pressure, causing GREATER water loss Major Ions ECF: 1. chloride 2. bicarbonate 3. sodium ICF: 1. Potassium 2. Phosphate 3. Moderate Mg & Sulfate No Calcium ions Greatest amount of anion in ECF – Cl Greatest amount of anion in ICF – Protein Characteristic of Nephrons Cortical Nephrons – short loops of Henle Juxtamedullary Nephrons – Long loops of Henle Peritubular Capillaries – cortex – reabsorbs most fluid Vasa Recta – branch of pertubular capillaries that extend to Medulla – concentrates urine Glomerular filtrate Same composition with plasma except: No glucose No protein No RBC Higher Cl & HCO3 Lower (+) ions GFR – 125 L/min 180 L/day Filtration fraction Fraction of renal plasma flow that becomes glomerular filtrate 1/5 or 19% Renal fraction Portion of cardiac output that passes to kidneys 21% Dynamics of Filtration (glomerular membrane) Glomerular Pressure (promotes filtration) Bowman’s capsule P – opposes Colloid osmotic pressure of plasma proteins – opposes Colloid osmotic pressure in Bowman’s capsule – promotes Juxtaglomerular complex Macula Densa – epithelial cells of distal tubules Juxtaglomerular cells – smooth muscle cells of both afferent & efferent arterioles, (+) renin Autoregulation of GFR AFFerent arteriolar vasoDILATION low Na & Cl conc due to low GFR stimulates macula densa to dilate afferents Most important mechanism for autoregulation EFFerent arteriolar vasoCONSTRICTION Low Na & Cl at macula densa cause JG cells to release rennin, constrictor the more sensitive efferents Glomerular membrane Endothelium – fenestrae Epithelium – slit pores 9 URINE FORMATION 3 primary processes involved in urine formation Filtration Secretion Reabsorption PRIMARY ACTIVE TRANSPORT OF SODIUM Basolateral side of tubular epithelium (+) Na-K ATPase (3Na/2K) Brush Border (+) Na-carrier proteins that provide facilitated-diffusion of Na SECONDARY ACTIVE REABSORPTION FROM TUBULES (CO-TRANSPORT) Substances co-transported with Na: Proximal Tubules- glucose, amino acids, organic subst (acetoacetate, H20-sol vit) Thick ascending Loop of H – chloride Others- PO4, Mg, Ca, H SECONDARY ACTIVE SECRETION INTO TUBULES (COUNTERTRANSPORT) (Proximal Tubules) Hydrogen K Urate PASSIVE ABSORPTION OF H2O – Osmosis PASSIVE ABSORPTION OF Cl& UREA – Diffusion ABSORPTIVE CAPABILITIES OF DIFFERENT TUBULE SEGMENTS Proximal Tubule Co-Transport & Countertransport, Majority of reabsorption (65%) Thin Loop H2O permeable only Thick Loop H20 & Urea IMpermeable Concentrating function Early half of Distal Tubule “Diluting Segment” H20 & Urea IMpermeable Late Distal Tubule & Cortical Collecting Duct IMpermeable to Urea Aldosterone Fxns (Na, K) ADH Fxns (H20) (+)Brown cells aka intercalated cells – secretes H by 1o active secretion (+) Acidification fxn Collecting Duct ADH fxns H secretion (+) Acidification fxn Late Distal Tubule (+) intercalated cells – H secretion (+) Principal cells – Na reabsorption & K secretion Special Mechanism of Absorption of Protein in Proximal Tubules Pinocytosis Inulin Neither secreted nor reabsorbed Measures GFR (125 mL/min) Para-aminohippuric acid (PAH) Secreted but not reabsorbed Measures plasma flow thru kidneys (650mL) Countercurrent multiplier Repetitive reabsorption of NaCl by THICK ascending limb Contercurrent exchanger Occurs in vasa recta Mechanism of increasing permeability of Na & H20 ADH – at basolateral memb of epithelium – Inc adenylyl cyclase (inc. cAMP) Aldosterone – at luminal border of epithelium – Nuclear transcription (steroid) Aldosterone 3 known factors that stimulate secretion from zona glomerulosa 1. Inc AII 2. Inc K+ (most potent) 3. Dec Na+ ANF vs Aldosterone ANF – H2O & Na secretion Aldosterone – H2O & Na reabsorption Both Aldosterone and principal cells act on Na-K ATPase Parathyroid Hormone sites of action Kidney Bone GIT MOA: Increase ECF Ca, Dec ECF PO4 Calcium Reabsorption Late Distal Tubule – primary active transport in basolateral memb Proximal Tubule – Co-transport with Na 10 Phosphate concentration regulation - mainly by “overflow” mechanism ACID – BASE BALANCE Bases: Proteins, Hgb, HCO3, HPO4, NaHCO3, NaPO4 Metabolic acidosis – INC RR Metabolic alkalosis – DEC RR Acidosis – depress CNS Alkalosis – excite CNS PULMONARY VENTILATION Defenses vs changes in H ion conc 1. buffer systems a. bicarbonate buffer b. PO4 buffer c. Protein buffer – most abundant, most powerful 2. Respiratory 3. Renal Henderson-Hesselbach equation pH = 6.1 + log HCO3/CO2 An increase in HCO3 increases pH Isohydric principle Hydrogen ion is common to chemical rxns of all systems, any condition that changes H concentration affects the balance of all buffer systems H secretion Early tubules – countertransport Distal tubules – intercalated discs (H+ATPase) Conditions causing Respi Alkalosis (a rare condition) Psychoneurosis (overbreathing) High Altitude Duration of inspiration = 2 sec Duration of expirarion = 2-3sec Accessory muscles of Inspiration (muscles that raise rib cage) SCM Serratus anterior Scalene Accessosry muscles of Expiration Rectus abdominis Internal intercostals Pleural Pressure Pressure in the space bet pleura and chest wall -5 cmH2O at beginning of insp; 7.5 cmH2O during inspiration Alveolar Pressure Pressure inside the alveoli Equal to atmospheric pressure if glottis is closed (0 cmH20) -1 cmH20 during inspiration Respiratory acidosis Any condition that impairs gas exchange bet blood & alveolar air Transpulmonary Pressure Pressure difference bet alveolar P & pleural P Measure ELASTIC forces that tends to collapse the lung (recoil pressure) Compliance of Lungs Extent by which lungs EXPAND for each unit of increase in transpulmonary pressure 200mL/cm of H20 Metabolic acidosis Diarrhea – lose NaHCO3 Vomiting – If from UGI – alkalosis; ifrom LGI – acidosis Uremia DM –fats split into acetoacetic acid Surfactant Type II pneumocytes Dipaylmitoyl Lecithin – decreases surface tension; Surfactant apoproteins & Lecithin – increases the rate by which Lecithin spreads Metabolic Alkalosis Any condition that INC Na reabsorption increases H secretion Diuretics (except carbonic anhydrase inhibitors) Alkaline Drugs (drugs containg NaHCO3) Pyloric stenosis Excess Aldosterone Interdependence Phenomenon Large Alveolus cannot exist adjacent to a small alveolus because they share common septal walls & the presence of surfactant First Generation Respiratory Passageway - Trachea 11 Greatest amount of Resistance to airflow - Bronchi (near trachea) Histology of Bronchioles No cartilage Only smooth Ms Volumes TV – 500 mL IRV - 3000 mL ERV – 1100 mL RV – 1200 mL Capacities IC = From beginning of N expiration then inhale maximally; TV + IRV = 3500mL FRC = Air remaining in lungs after N expiration; ERV + RV 2300mL VC = Max inhalation followed by Max Expiration; IRV +ERV + TV 4600 mL TLC = IRV + ERV + TV +RV = 5800 mL Volumes and Capacities 20 -25% lower in WOMEN Minute Respiratory Volume RR x TV 6L/min Normal dead space volume 150mL Anatomic dead space Part of respiratory system besides gas exchange areas Physiologic dead space Alveolar dead space Hering-Breuer Inflation Reflex When lungs become overly inflated, stretch receptors in bronchial & bronchiolar walls are activated, this switches off the inspiratory ramp & stops further inspiration Activated only when TV >1.5L BOHR EFFECT Effect of CO2 & H on O2-Hgb dissociation curve Lungs: CO2 diffuses from blood to alveoli, decreasing PCO2 & H Shifts the curve LEFTward & Upward Tissues: CO2 enters blood from tissues Shifts the curve RIGHTward Inc CO2 in blood promotes Hgb release of O2 into tissues Dec CO2 in blood promotes Hgb binding of O2 from lungs Chloride Shift Venous blood has higher Cl- than arterial blood HALDANE EFFECT Lungs: Increased release of CO2 because of O2 pick-up by Hgb - More important for CO2 transport than Bohr Tissues: Inc pick-up of CO2 because of O2 removal from hemoglobin Afferents of cough reflex – Vagus Afferents of sneeze reflex – CN 5 - (+) Uvular depression so air passes to nose (not in the mouth as in coughing) RLD – Dec FVC, N FEV1, ratio of FVC/FEV1 decreases OLD – N FVC, Dec FEV1, ratio of FVC/FEV1 increase Phonators – Larynx Articulators – Mouth (lips, tongue, soft palate) Resonators – Mouth, Nose with nasal sinuses, pharynx & chest cavity O2-Hgb Dissociation curve Shift to the Right (release) Inc CO2 Inc Temp Inc 2,3 DPG Inc Hydrogen Dec pH Pulmonary SBP – 25mmHg Pulmonary DBP – 8 mmHg Mean pulmonary arterial p – 15mmHg Measures LEFT ATRIAL pressure Pulmonary Wedge Pressure ( 5mmHg) Shift to the Left Inc fetal Hgb 12 RESPIRATORY CENTER DORSAL RESPIRATORY GROUP Nucleus of Tractus Solitarius on reticular subst of Medulla Control of INSP & RHYTHM (+) Ramp signal PNEUMOTAXIC CENTER Nuleus Parabrachialis on dorsal upper pons Limit duration of Inspiration (thereby increasing RR) “Switch-off” for inspiratory ramp VENTRAL RESPIRATOR GROUP Nucleus Ambiguus & Retroambisguus Both INSP & EXP “Overdrive” mechanism for high levels of pulmo venti Powerful EXP signals to abdominal muscles APNEUSTIC CENTER Lower pons Prevent switch-off of Inspiratory ramp Control RATE & PATTERN of breathing Controls DEPTH of respi (like pneumotaxic) Inspiratory “RAMP” signal Nerous signals begins very weakly then increases steadily for 2 sec then abruptly stops for 3 sec, then begin again Not instantaneous burst of signals which would produce inspiratory gaps Chemical Control of Respiration The only important direct stimulus for chemosensitive neurons - Hydrogen Hydrogen ions are impermeable to BBB & Blood-CSF barrier Major controller of respiration - Carbon dioxide Carbon dioxide Very permeable to barriers has an indirect effect by first combining with H20 Forms Carbonic Acid (H2CO3) which then dissociates into H & HCO3 upon passing the barriers Respiratory Centers affected MORE by changes in CO2 level then hydrogen Chemosensitive area - 1mm beneath ventral surface of medulla Chemoreceptors Carotid bodies – Hering’s Nerve (CN9) Aortic bodies – CN10 During Strenous Exercise PO2, PCO2 & pH are WNL The 2 factors causing inc RR during exercise: 1. stimulatory signals to CNS 2. Proprioceptors J – receptors Stimulated by irritant chemicals in pulmo blood In juxtaposition to pulmo capillaries FCN: gives the person a feeling of DYSPNEA Cheyne-Stokes Periodic respiration seen in: Heart failure Brain damage HIGHT ALTITUDE PHYSIOLOGY Level of Arterial O2 saturation causing LOC 40-50% 12,000 ft = (+) HA, dizziness 18,000ft = (+) twitching, convulsions 23,000ft = (+) coma Physiologic changes in ACCLIMITIZATION Inc pulmo ventilation Inc RBC Inc Diffusing capacity of Lung Inc Vascularity Inc O2 utilization ability Inc Hct (60-65) Inc Hgb (22) Inc blood volume (20-30%) Inc cardiac output (30%) Inc mitochondria Physical changes seen in natives of high Altitudes Inc chest size Inc right side of heart Dec body size Factors decreased in high altitude Dec Body size Dec Work capacity Accelerations = mv2/r 4-6G : (+) LOC 20G : (+) vertebral fracture Negative 4-5G : (+) hyperemia of head (+) psychosis (+) brain edema (+) redout eye 13 Function of nitrogen in sealed aircrafts - prevent atelectasis DEEP SEA 120ft : (+) joviality (lose many of his cares) 150 – 200ft : drowsy 200-250ft : strength wanes; clumsy Observed effects of prolonged stay in space 1. decrease in blood volume 2. dec RBC mass 3. dec strength & ork capacity 4. dec cardiac output 5. loss of Ca & PO4 Effects are NOT progressive after a few weeks EXCEPT for BONE LOSS (continues for many months) Oxygen toxicity manifestation (+) visual disturbance & disorientation Chronic O2 poisoning (exposure to 100% O2 > 12hrs) Pulmo congestion Pulmo edema Atelectasis Mechanism of Nitrogen narcosis Dec excitability of membranes due to high fat affinity PCO2 toxicity level for respiratory depression >80mmHg Effect of EXERCISE on decompression sickness Hastens formation of nitrogen bubbles due to increased agitation of tissues and fluids Inc susceptibility to O2 toxicity Gas used in deep-sea diving as a gas mixture HELIUM (instead of nitrogen as in high altitudes) - has only 1/5 narcotic effect than N2 - only ½ dissolves in body fluids than N2 - low density, less airway resistance for breathing To prevent EMBOLISM during ascend Exhale continually Uses of Hyperbaric O2 Therapy Gas gangrene Leprosy MI Osteomyelitis Arterial gas embolism CO poisoning WEIGHTLESSNESS Physiologic problems of weightlessness is related to 3 known effects: 1. motion sickness 2. translocation of fluid 3. dec physical activity GIT PHSYIOLOGY Myeneteric (Auerbach’s Plexus) – bet longitudinal & circular muscle layers Fcns 1. Inc tone of gut wall 2. inc intensity of rhythmical contraction 3. inc rate of rhythm 4. inc velocity of conduction for rapid peristalsis - Inhibits contracted intestinal sphincter that impedes food mov’t thru VIP Submucosal (Meissner’s Plexus) – submucosa Fcns 1. intestinal secretion 2. local absorption 3. contraction of submucosal muscle causing infolding of stomach muosa Law of the gut Peristaltic reflex plus the analward direction of movement of peristalsis Usual stimulus for peristalsis - Distention Storage capacity of stomach 1.5L Promoters of stomach emptying 1. gastric distention 2. gastrin Both increase pyloric pumping force & inhibit pylorus Most potent inhibitor of Gastric Emptying CCK (stimulated by FATS) Movements of small intestine 1. Mixing or segmentation contractions 2. Propulsive movements (peristalsis) Movements of the Colon 1. haustral contraction 2. mass movements 14 Tubular glands in stomach mucosa Oxyntic (or gastric) glands (body or fundus) Secretes: HCl, Intrinsic factor, mucus, pepsinogen Pyloric glands (antrum) Secretes: gastrin, mucus, pepsinogen Stimulators of gastric gland secretion: Histamine Ach Gastrin H2O absorption Diffusion (Osmosis) at tight junctions of apical epithelial cells Na absorption Active transport at basolateral walls of epithelial cells Chloride Passively Co-transported with Na Active absorption of HCO3 Indirectly absorbed by Na-H countertransport H binds with HCO3 forming carbonic acid, which then dissociates to form CO2 & H2O Gastrin - stimulates parietal cell to increase HCl secretion released by G-cells G17 – more abundant, longer t ½ G34 – more active, shorter t ½ Stimulus of Pepsinogen secretion 1. Ach released from vagus 2. acid in stomach Stimulators of Pancreatic Enzyme secretion 1. Ach 2. Gastrin 3. CCK 4. Secretin Secretin - stimulated by acids from stomach released by S-cells of duodenum & jejunum stimulates the pancreas to secrete large quantities of HCO3 bicarbonate secretion lower duodenal pH to optimal activity of pancreatic enzymes CCK - stimulated by fats & AA released by I-cells in duodenum ABSORPTION Absorption by Na-cotransport Glucose Galactose (most rapidly transported monosaccharide) Amino acids Absorption by facilitated diffusion Fructose (only monosaccharide with this mech of absorption) 15