Chapter 6 - Introduction To Autonomic Pharmacology

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Basic & Clinical Pharmacology, 15e
Chapter 6: Introduction to Autonomic Pharmacology
Bertram G. Katzung
CASE STUDY
CASE STUDY
A 56yearold woman is brought to the university eye center with a complaint of “loss of vision.” Because of visual impairment, she has lost her
driver’s license and has fallen several times in her home. Examination reveals that her eyelids close involuntarily with a frequency and duration
sufficient to prevent her from seeing her surroundings for more than brief moments at a time. When she holds her eyelids open with her fingers, she
can see normally. She has no other muscle dysfunction. A diagnosis of blepharospasm is made. Using a fine needle, several injections of botulinum
toxin type A are made in the orbicularis oculi muscle of each eyelid. After observation in the waiting area, she is sent home. Two days later, she
reports by telephone that her vision has improved dramatically. How did botulinum toxin improve her vision? How long can her vision be expected
to remain normal after this single treatment?
The nervous system is anatomically divided into the central nervous system (CNS; the brain and spinal cord) and the peripheral nervous system (PNS;
neuronal tissues outside the CNS). Functionally, the nervous system can be divided into two major subdivisions: autonomic and somatic. The
autonomic nervous system (ANS) is largely independent (autonomous) in that its activities are not under direct conscious control. It is concerned
primarily with control and integration of visceral functions necessary for life such as cardiac output, blood flow distribution, and digestion. Evidence is
accumulating that the ANS, especially the vagus nerve, also influences immune function and some CNS functions such as seizure discharge.
Remarkably, some evidence indicates that autonomic nerves can also influence cancer development and progression. The efferent (motor) portion of
the somatic subdivision is largely concerned with consciously controlled functions such as movement, respiration, and posture. Both the autonomic
and the somatic systems have important afferent (sensory) inputs that provide information regarding the internal and external environments and
modify motor output through reflex arcs of varying complexity.
The nervous system has several properties in common with the endocrine system. These include highlevel integration in the brain, the ability to
influence processes in distant regions of the body, and extensive use of negative feedback. Both systems use chemicals for the transmission of
information; the nervous system also uses electrical signaling. In the nervous system, chemical transmission occurs between nerve cells and between
nerve cells and their effector cells. Chemical transmission takes place through the release of small amounts of transmitter substances from the nerve
terminals into the synaptic cleft. The transmitter crosses the cleft by diffusion and activates or inhibits the postsynaptic cell by binding to a specialized
receptor molecule. In a few cases, retrograde transmission may occur from the postsynaptic cell to the presynaptic neuron terminal and modify its
subsequent activity.
By using drugs that mimic or block the actions of chemical transmitters, we can selectively modify many autonomic functions. These functions involve a
variety of effector tissues, including cardiac muscle, smooth muscle, vascular endothelium, exocrine glands, and presynaptic nerve terminals.
Autonomic drugs are useful in many clinical conditions. Unfortunately, a very large number of drugs used for other purposes (eg, allergies, mental
illness) have unwanted effects on autonomic function.
ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM
The ANS lends itself to division on anatomic grounds into two major portions: the sympathetic (thoracolumbar) division and the
parasympathetic (traditionally craniosacral, but see Box: Sympathetic Sacral Outflow) division (Figure 6–1). Motor neurons in both divisions
originate in nuclei within the CNS and give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in motor
ganglia. The sympathetic preganglionic fibers leave the CNS through the thoracic, lumbar, and (according to new information) sacral spinal nerves.
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Chapter 6: Introduction to Autonomic Pharmacology, Bertram G. Katzung
The parasympathetic preganglionic fibers leave the CNS through the cranial nerves (especially the third, seventh, ninth, and tenth). Page 1 / 25
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FIGURE 6–1
ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM
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The ANS lends itself to division on anatomic grounds into two major portions: the sympathetic (thoracolumbar) division and the
parasympathetic (traditionally craniosacral, but see Box: Sympathetic Sacral Outflow) division (Figure 6–1). Motor neurons in both divisions
originate in nuclei within the CNS and give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in motor
ganglia. The sympathetic preganglionic fibers leave the CNS through the thoracic, lumbar, and (according to new information) sacral spinal nerves.
The parasympathetic preganglionic fibers leave the CNS through the cranial nerves (especially the third, seventh, ninth, and tenth).
FIGURE 6–1
Schematic diagram comparing some anatomic and neurotransmitter features of autonomic and somatic motor nerves. Only the primary transmitter
substances are shown. Parasympathetic ganglia are not shown because most are in or near the wall of the organ innervated. Cholinergic nerves are
shown in blue, noradrenergic in red. Note that some sympathetic postganglionic fibers release acetylcholine rather than norepinephrine. Sympathetic
nerves to the renal vasculature and kidney may release dopamine as well as norepinephrine during stress. The adrenal medulla, a modified
sympathetic ganglion, receives sympathetic preganglionic fibers and releases epinephrine and norepinephrine into the blood. Not shown are the
sacral preganglionic fibers that innervate the rectum, bladder, and genitalia. These fibers are probably sympathetic preganglionic nerves with
cholinergic postganglionic fibers (see Box: Sympathetic Sacral Outflow). ACh, acetylcholine; D, dopamine; Epi, epinephrine; M, muscarinic receptors; N,
nicotinic receptors; NE, norepinephrine.
Most thoracic and lumbar sympathetic preganglionic fibers are short and terminate in ganglia located in the paravertebral chains that lie on either
side of the spinal column. Most of the remaining sympathetic preganglionic fibers are somewhat longer and terminate in prevertebral ganglia,
which lie in front of the vertebrae, usually on the ventral surface of the aorta. From the ganglia, postganglionic sympathetic fibers run to the tissues
innervated. Some preganglionic parasympathetic fibers terminate in parasympathetic ganglia located outside the organs innervated: the ciliary,
pterygopalatine, submandibular, and otic ganglia. However, the majority of parasympathetic preganglionic fibers terminate on ganglion cells
distributed diffusely or in networks in the walls of the innervated organs. Several pelvic ganglia are innervated by sacral preganglionic nerves that
are ontogenetically similar to sympathetic preganglionic fibers (see Box: Sympathetic Sacral Outflow). Note that the terms “sympathetic” and
“parasympathetic” are anatomic designations and do not depend on the type of transmitter chemical released from the nerve endings nor on the kind
of effect—excitatory or inhibitory—evoked by nerve activity.
In addition to these clearly defined peripheral motor portions of the ANS, large numbers of afferent fibers run from the periphery to integrating
centers, including the enteric plexuses in the gut, the autonomic ganglia, and the CNS. Many of the sensory pathways that end in the CNS terminate in
the hypothalamus and medulla and evoke reflex motor activity that is carried to the effector cells by the efferent fibers described previously. There is
increasing evidence that some of these sensory fibers also have peripheral motor functions.
The enteric nervous system (ENS) is a large and highly organized collection of neurons located in the walls of the gastrointestinal (GI) system
(Figure 6–2). With more than 150 million neurons, it is sometimes considered a third division of the ANS. It is found in the wall of the GI tract from the
esophagus to the distal colon and is involved in both motor and secretory activities of the gut. It is particularly important in the control of motor activity
of the colon. The ENS includes the myenteric plexus (the plexus of Auerbach) and the submucous plexus (the plexus of Meissner). These neuronal
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networks receive preganglionic fibers from the parasympathetic system and postganglionic sympathetic axons. They also receive sensory input from
within the wall of the gut. Fibers from the neuronal cell bodies in these plexuses travel forward, backward, and in a circular direction to the smooth
centers, including the enteric plexuses in the gut, the autonomic ganglia, and the CNS. Many of the sensory pathways that end in the CNS terminate in
the hypothalamus and medulla and evoke reflex motor activity that is carried to the effector cells by the efferent fibers described previously. There is
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increasing evidence that some of these sensory fibers also have peripheral motor functions.
The enteric nervous system (ENS) is a large and highly organized collection of neurons located in the walls of the gastrointestinal (GI) system
(Figure 6–2). With more than 150 million neurons, it is sometimes considered a third division of the ANS. It is found in the wall of the GI tract from the
esophagus to the distal colon and is involved in both motor and secretory activities of the gut. It is particularly important in the control of motor activity
of the colon. The ENS includes the myenteric plexus (the plexus of Auerbach) and the submucous plexus (the plexus of Meissner). These neuronal
networks receive preganglionic fibers from the parasympathetic system and postganglionic sympathetic axons. They also receive sensory input from
within the wall of the gut. Fibers from the neuronal cell bodies in these plexuses travel forward, backward, and in a circular direction to the smooth
muscle of the gut to control motility and to secretory cells in the mucosa. Sensory fibers transmit chemical and mechanical information from the
mucosa and from stretch receptors to motor neurons in the plexuses and to postganglionic neurons in the sympathetic ganglia. For example,
enteroendocrine epithelial cells in the mucosal layer synapse with vagal and other sensory fibers to send information regarding gut content chemicals
to the CNS. This signaling appears to utilize glutamate for rapid transmission and peptides such as cholecystokinin for slower, longerlasting
transmission. The parasympathetic and sympathetic fibers that synapse on enteric plexus neurons appear to play a modulatory role, as indicated by
the observation that deprivation of input from both ANS divisions does not abolish GI activity. In fact, selective denervation may result in greatly
enhanced motor activity.
FIGURE 6–2
A highly simplified diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the
sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter
or neuromodulator substances have been identified in the ENS; see Table 6–1. ACh, acetylcholine; AC, absorptive cell; CGRP, calcitonin generelated
peptide; CM, circular muscle layer; EC, enterochromaffin cell; EN, excitatory neuron; EPAN, extrinsic primary afferent neuron; 5HT, serotonin; IN,
inhibitory neuron; IPAN, intrinsic primary afferent neuron; LM, longitudinal muscle layer; MP, myenteric plexus; NE, norepinephrine; NP,
neuropeptides; SC, secretory cell; SMP, submucosal plexus.
The ENS functions in a semiautonomous manner, using input from the motor outflow of the ANS for modulation of GI activity and sending sensory
information back to the autonomic centers in the CNS. The ENS also provides the necessary synchronization of impulses that, for example, ensures
forward, not backward, propulsion of gut contents and relaxation of sphincters when the gut wall contracts.
The anatomy of autonomic synapses and junctions determines the localization of transmitter effects around nerve endings. Classic synapses such as
the mammalian neuromuscular junction and most neuronneuron synapses are relatively “tight” in that the nerve terminates in small boutons very
close to the tissue innervated, so that the diffusion path from nerve terminal to postsynaptic receptors is very short. The effects are thus relatively
rapid and localized. In contrast, junctions between autonomic neuron terminals and effector cells (smooth muscle, cardiac muscle, glands) differ from
classic synapses in that transmitter is often released from a chain of varicosities in the postganglionic nerve fiber in the region of the smooth muscle
cells rather than from boutons, and autonomic junctional clefts are wider than somatic synaptic clefts. Effects are thus slower in onset, and discharge
of a single motor fiber often activates or inhibits many effector cells.
Sympathetic Sacral Outflow
Chapter 6: Introduction to Autonomic Pharmacology, Bertram G. Katzung Page 3 / 25
As noted in the previous editions of this book and other standard texts, it has long been believed that, like the cranial nerve cholinergic system
described earlier, the cholinergic nerves that innervate the pelvic organs (rectum, bladder, and reproductive organs) are part of the
close to the tissue innervated, so that the diffusion path from nerve terminal to postsynaptic receptors is very short. The effects are thus relatively
rapid and localized. In contrast, junctions between autonomic neuron terminals and effector cells (smooth muscle, cardiac muscle, glands) differ from
classic synapses in that transmitter is often released from a chain of varicosities in the postganglionic nerve fiber in the region of the smooth muscle
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cells rather than from boutons, and autonomic junctional clefts are wider than somatic synaptic clefts. Effects are thus slower in onset, and discharge
of a single motor fiber often activates or inhibits many effector cells.
Sympathetic Sacral Outflow
As noted in the previous editions of this book and other standard texts, it has long been believed that, like the cranial nerve cholinergic system
described earlier, the cholinergic nerves that innervate the pelvic organs (rectum, bladder, and reproductive organs) are part of the
parasympathetic nervous system. However, recent evidence (see EspinozaMedina reference at the end of this chapter) suggests that the cholinergic
preganglionic sacral fibers are actually derived from embryonic sympathetic precursor cells and that the postganglionic fibers innervated by them
are therefore members of the sympathetic cholinergic class. This claim is based on several lines of evidence, as follows: (1) Cranial parasympathetic
preganglionic neurons express the homeogene Phox2b and the transcription factors Tbx20, Tbx2, and Tbx3; thoracic sympathetic and sacral
preganglionic neurons do not. Sacral preganglionic neurons do express transcription factor Foxp1, which is not expressed by cranial neurons. (2)
Cranial parasympathetic preganglionic fibers exit the CNS via dorsolateral exit points; the sympathetic and sacral preganglionic nerves exit the
spinal cord via ventral root exits. (3) At an early stage of development, cranial preganglionic neurons express the vesicular acetylcholine transporter
(VAChT; VAT in Figure 6–3) but not nitric oxide synthase (NOS); sympathetic and sacral nerves at the same stage express NOS but not VAChT (even
though they do express VAChT later in their development). These observations require independent confirmation but constitute strong evidence in
favor of changing the traditional “craniosacral” synonym for the parasympathetic nervous system to “cranial autonomic” nervous system.
FIGURE 6–3
Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium
dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from
choline and acetylCoA (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine (ACh) is then transported into the storage vesicle by a
vesicleassociated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also
stored in the vesicle. Release of transmitters occurs when voltagesensitive calcium channels in the terminal membrane are opened, allowing an influx
of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of
acetylcholine and cotransmitters into the junctional cleft (see text). This step can be blocked by botulinum toxin. Acetylcholine’s action is terminated by
metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosomal
nerveassociated proteins; VAMPs, vesicleassociated membrane proteins.
of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of
acetylcholine and cotransmitters into the junctional cleft (see text). This step can be blocked by botulinum toxin. Acetylcholine’s action is terminated by
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metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosomal
nerveassociated proteins; VAMPs, vesicleassociated membrane proteins.
NEUROTRANSMITTER CHEMISTRY OF THE AUTONOMIC NERVOUS SYSTEM
An important traditional classification of autonomic nerves is based on the primary transmitter molecules—acetylcholine or norepinephrine—
released from their terminals and varicosities. A large number of peripheral ANS fibers synthesize and release acetylcholine; they are cholinergic
fibers; that is, they work by releasing acetylcholine. As shown in Figure 6–1, these include all preganglionic efferent autonomic fibers and the somatic
(nonautonomic) motor fibers to skeletal muscle as well. Thus, almost all efferent fibers leaving the CNS are cholinergic. In addition, most
parasympathetic postganglionic and some sympathetic postganglionic fibers are cholinergic. A significant number of parasympathetic postganglionic
neurons use nitric oxide or peptides as the primary transmitter or as cotransmitters.
Most postganglionic sympathetic fibers (Figure 6–1) release norepinephrine (also known as noradrenaline); they are noradrenergic (often called
simply “adrenergic”) fibers; that is, they work by releasing norepinephrine (noradrenaline). As noted, some sympathetic fibers release acetylcholine.
Dopamine is a very important transmitter in the CNS, and it may be released by some peripheral sympathetic fibers under certain circumstances.
Adrenal medullary cells, which are embryologically analogous to postganglionic sympathetic neurons, release a mixture of epinephrine and
norepinephrine. Finally, most autonomic nerves also release several cotransmitter substances (described in the following text), in addition to the
primary transmitters just described.
Five key features of neurotransmitter function provide potential targets for pharmacologic therapy: synthesis, storage, release, termination of
action of the transmitter, and receptor effects. These processes are discussed next.
Cholinergic Transmission
The terminals and varicosities of cholinergic neurons contain large numbers of small membranebound vesicles concentrated near the portion of the
cell membrane facing the synapse (Figure 6–3) as well as a smaller number of large densecored vesicles located farther from the synaptic membrane.
The large vesicles contain a high concentration of peptide cotransmitters (Table 6–1), whereas the smaller clear vesicles contain most of the
acetylcholine. Vesicles may be synthesized in the neuron cell body and carried to the terminal by axonal transport. They may also be recycled several
Five key features of neurotransmitter function provide potential targets for pharmacologic therapy: synthesis, storage, release, termination of
action of the transmitter, and receptor effects. These processes are discussed next. Access Provided by:
Cholinergic Transmission
The terminals and varicosities of cholinergic neurons contain large numbers of small membranebound vesicles concentrated near the portion of the
cell membrane facing the synapse (Figure 6–3) as well as a smaller number of large densecored vesicles located farther from the synaptic membrane.
The large vesicles contain a high concentration of peptide cotransmitters (Table 6–1), whereas the smaller clear vesicles contain most of the
acetylcholine. Vesicles may be synthesized in the neuron cell body and carried to the terminal by axonal transport. They may also be recycled several
times within the terminal after each exocytotic release of transmitter. Ultrafast neuronal firing appears to be supported by rapid recycling of clathrin
coated vesicles from endosomes in the nerve terminal. Vesicles are provided with vesicleassociated membrane proteins (VAMPs), which serve
to align them with release sites on the inner neuronal cell membrane and participate in triggering the release of transmitter. The release site on the
inner surface of the nerve terminal membrane contains synaptosomal nerveassociated proteins (SNAPs), which interact with VAMPs. VAMPs
and SNAPs are collectively called fusion proteins.
TABLE 6–1
Some of the transmitter substances found in autonomic nervous system, enteric nervous system, and nonadrenergic, noncholinergic
neurons.1
Substance Functions
Acetylcholine The primary transmitter at ANS ganglia, at the somatic neuromuscular junction, and at parasympathetic postganglionic nerve endings.
(ACh) A primary excitatory transmitter to smooth muscle and secretory cells in the ENS. Probably also the major neurontoneuron
(“ganglionic”) transmitter in the ENS.
Adenosine Acts as a transmitter or cotransmitter at many ANSeffector synapses.
triphosphate
(ATP)
Calcitonin gene Found with substance P in cardiovascular sensory nerve fibers. Present in some secretomotor ENS neurons and interneurons. A cardiac
related peptide stimulant.
(CGRP)
Cholecystokinin May act as a cotransmitter in some excitatory neuromuscular ENS neurons.
(CCK)
Dopamine A modulatory transmitter in some ganglia and the ENS. Possibly a postganglionic sympathetic transmitter in renal blood vessels.
Enkephalin and Present in some secretomotor and interneurons in the ENS. Appear to inhibit ACh release and thereby inhibit peristalsis. May stimulate
related opioid secretion.
peptides
Galanin Present in secretomotor neurons; may play a role in appetitesatiety mechanisms.
GABA (γ May have presynaptic effects on excitatory ENS nerve terminals. Has some relaxant effect on the gut. Probably not a major transmitter
aminobutyric in the ENS.
acid)
Gastrin Extremely potent excitatory transmitter to gastrin cells. Also known as mammalian bombesin.
releasing
peptide (GRP)
Neuropeptide Y Found in many noradrenergic neurons. Present in some secretomotor neurons in the ENS and may inhibit secretion of water and
(NPY) electrolytes by the gut. Causes longlasting vasoconstriction. It is also a cotransmitter in some parasympathetic postganglionic
neurons.
Nitric oxide (NO) A cotransmitter at inhibitory ENS and other neuromuscular junctions; may be especially important at sphincters. Cholinergic nerves
innervating blood vessels appear to activate the synthesis of NO by vascular endothelium. NO is not stored, it is synthesized on
demand by nitric oxide synthase, NOS; see Chapter 19.
peptide (GRP)
Neuropeptide Y Found in many noradrenergic neurons. Present in some secretomotor neurons in the ENS and may inhibit secretion of water and
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(NPY) electrolytes by the gut. Causes longlasting vasoconstriction. It is also a cotransmitter in some parasympathetic postganglionic
neurons.
Nitric oxide (NO) A cotransmitter at inhibitory ENS and other neuromuscular junctions; may be especially important at sphincters. Cholinergic nerves
innervating blood vessels appear to activate the synthesis of NO by vascular endothelium. NO is not stored, it is synthesized on
demand by nitric oxide synthase, NOS; see Chapter 19.
Norepinephrine The primary transmitter at most sympathetic postganglionic nerve endings.
(NE)
Serotonin (5 An important transmitter or cotransmitter at excitatory neurontoneuron junctions in the ENS.
HT)
Substance P, Substance P is an important sensory neurotransmitter in the ENS and elsewhere. Tachykinins appear to be excitatory cotransmitters
related with ACh at ENS neuromuscular junctions. Found with CGRP in cardiovascular sensory neurons. Substance P is a vasodilator (probably
tachykinins via release of nitric oxide).
Vasoactive Excitatory secretomotor transmitter in the ENS; may also be an inhibitory ENS neuromuscular cotransmitter. A probable cotransmitter
intestinal in many cholinergic neurons. A vasodilator (found in many perivascular neurons) and cardiac stimulant.
peptide (VIP)
1See Chapter 21 for transmitters found in the central nervous system.
Acetylcholine (ACh) is synthesized in the cytoplasm from acetylCoA and choline through the catalytic action of the enzyme choline
acetyltransferase (ChAT). AcetylCoA is synthesized in mitochondria, which are present in large numbers in the nerve ending. Choline is
transported from the extracellular fluid into the neuron terminal by a sodiumdependent membrane choline transporter (CHT; Figure 6–3). This
symporter can be blocked by a group of research drugs called hemicholiniums. Once synthesized, acetylcholine is transported from the cytoplasm
into the vesicles by a vesicleassociated transporter (VAT) that is driven by proton efflux (Figure 6–3). This antiporter can be blocked by the
research drug vesamicol. Acetylcholine synthesis is a rapid process capable of supporting a very high rate of transmitter release. Storage of
acetylcholine is accomplished by the packaging of “quanta” of acetylcholine molecules (usually 1000–50,000 molecules in each vesicle). Most of the
vesicular acetylcholine (a positively charged quaternary amine) is bound to negatively charged vesicular proteoglycan (VPG). (ACh is also
synthesized in lymphocytes and may play a role in immunologic reactions to viral infection.)
Vesicles are concentrated on the inner surface of the nerve terminal facing the synapse through the interaction of socalled SNARE proteins on the
vesicle (a subgroup of VAMPs called vSNAREs, especially synaptobrevin) and on the inside of the terminal cell membrane (SNAPs called tSNAREs,
especially syntaxin and SNAP25). Physiologic release of transmitter from the vesicles is dependent on extracellular calcium and occurs when an
action potential reaches the terminal and triggers sufficient influx of calcium ions via Ntype calcium channels. Calcium interacts with the VAMP
synaptotagmin on the vesicle membrane and triggers fusion of the vesicle membrane with the terminal membrane and opening of a pore into the
synapse. The opening of the pore and inrush of cations results in release of the acetylcholine from the proteoglycan and exocytotic expulsion into the
synaptic cleft. One depolarization of a somatic motor nerve may release several hundred quanta into the synaptic cleft. One depolarization of an
autonomic postganglionic nerve varicosity or terminal probably releases less and releases it over a larger area. In addition to acetylcholine, several
cotransmitters are released at the same time (Table 6–1). The acetylcholine vesicle release process is blocked by botulinum toxin (BoNT) through
the enzymatic cleavage of two amino acids from one or more of the fusion proteins. (Tetanus toxin [tetanospasmin, TeNT] blocks transmitter
release by a similar cleavage of fusion proteins, but it does so mainly in inhibitory neurons, thus resulting in spasm, rather than paralysis, of skeletal
muscle.)
After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor (cholinoceptor). Eventually
(and usually very rapidly), all of the acetylcholine released diffuses within range of an acetylcholinesterase (AChE) molecule. AChE very efficiently
splits acetylcholine into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter
(Figure 6–3). Most cholinergic synapses are richly supplied with acetylcholinesterase; the halflife of acetylcholine molecules in the synapse is therefore
very short (a fraction of a second). Acetylcholinesterase is also found in other tissues, eg, red blood cells. (Other cholinesterases with a lower specificity
for acetylcholine, including butyrylcholinesterase [pseudocholinesterase], are found in blood plasma, liver, glia, and many other tissues.)
Adrenergic Transmission
Adrenergic neurons (Figure 6–4) transport the precursor amino acid tyrosine into the nerve ending, convert it to dopa, and then synthesize a
catecholamine transmitter (dopamine, norepinephrine, or epinephrine; Figure 6–5), and store it in membranebound vesicles. In most sympathetic
(and usually very rapidly), all of the acetylcholine released diffuses within range of an acetylcholinesterase (AChE) molecule. AChE very efficiently
splits acetylcholine into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter
(Figure 6–3). Most cholinergic synapses are richly supplied with acetylcholinesterase; the halflife of acetylcholine molecules in the synapse is therefore
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very short (a fraction of a second). Acetylcholinesterase is also found in other tissues, eg, red blood cells. (Other cholinesterases with a lower specificity
for acetylcholine, including butyrylcholinesterase [pseudocholinesterase], are found in blood plasma, liver, glia, and many other tissues.)
Adrenergic Transmission
Adrenergic neurons (Figure 6–4) transport the precursor amino acid tyrosine into the nerve ending, convert it to dopa, and then synthesize a
catecholamine transmitter (dopamine, norepinephrine, or epinephrine; Figure 6–5), and store it in membranebound vesicles. In most sympathetic
postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, some norepinephrine is further
converted to epinephrine. In dopaminergic neurons, synthesis terminates with dopamine. Several processes in these nerve terminals are potential
sites of drug action. One of these, the conversion of tyrosine to dopa by tyrosine hydroxylase, is the ratelimiting step in catecholamine transmitter
synthesis. It can be inhibited by the tyrosine analog metyrosine. A highaffinity antiporter for catecholamines located in the wall of the storage vesicle
(vesicular monoamine transporter, VMAT) can be inhibited by the reserpine alkaloids. Reserpine and related drugs (tetrabenazine,
deutetrabenazine) cause depletion of transmitter stores. Another transporter (norepinephrine transporter, NET) carries norepinephrine and
similar molecules back into the cell cytoplasm from the synaptic cleft (Figure 6–4; NET). NET is also commonly called uptake 1 or reuptake 1 and is
partially responsible for the termination of synaptic activity. NET can be inhibited by cocaine, solriamfetol, and certain antidepressant drugs,
resulting in an increase of transmitter activity in the synaptic cleft (see Box: Neurotransmitter Uptake Carriers).
FIGURE 6–4
Schematic diagram of a generalized noradrenergic junction (not to scale). Tyrosine is transported into the noradrenergic nerve ending or varicosity by
a sodiumdependent carrier (A). Tyrosine is converted to dopamine (see Figure 6–5 for details), and transported into the vesicle by the vesicular
monoamine transporter (VMAT), which can be blocked by reserpine and tetrabenazine. The same carrier transports norepinephrine (NE) and several
related amines into these vesicles. Dopamine is converted to NE in the vesicle by dopamineβhydroxylase. Physiologic release of transmitter occurs
when an action potential opens voltagesensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane
results in expulsion of norepinephrine, cotransmitters, and dopamineβhydroxylase. Release can be blocked by drugs such as guanethidine and
bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter
(NET), which can be blocked by cocaine and certain antidepressants, or into postjunctional or perijunctional cells. Regulatory receptors are present on
the presynaptic terminal. SNAPs, synaptosomeassociated proteins; VAMPs, vesicleassociated membrane proteins.
FIGURE 6–5
results in expulsion of norepinephrine, cotransmitters, and dopamineβhydroxylase. Release can be blocked by drugs such as guanethidine and
bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter
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(NET), which can be blocked by cocaine and certain antidepressants, or into postjunctional or perijunctional cells. Regulatory receptors are present on
the presynaptic terminal. SNAPs, synaptosomeassociated proteins; VAMPs, vesicleassociated membrane proteins.
FIGURE 6–5
Biosynthesis of catecholamines. The ratelimiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (αmethyltyrosine). The
alternative pathway shown by the dashed arrows has not been found to be of physiologic significance in humans. However, tyramine and octopamine
may accumulate in patients treated with monoamine oxidase inhibitors. (Reproduced with permission from Gardner DG, Shoback D: Greenspan’s
Basic & Clinical Endocrinology, 9th ed. New York, NY: McGraw Hill; 2011.)
Biosynthesis of catecholamines. The ratelimiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (αmethyltyrosine). The
alternative pathway shown by the dashed arrows has not been found to be of physiologic significance in humans. However, tyramine and octopamine
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may accumulate in patients treated with monoamine oxidase inhibitors. (Reproduced with permission from Gardner DG, Shoback D: Greenspan’s
Basic & Clinical Endocrinology, 9th ed. New York, NY: McGraw Hill; 2011.)
Release of the vesicular transmitter store from noradrenergic nerve endings is similar to the calciumdependent process previously described for
cholinergic terminals. In addition to the primary transmitter (norepinephrine), adenosine triphosphate (ATP), dopamineβhydroxylase, and peptide
cotransmitters are simultaneously released from the same vesicles. Indirectly acting and mixedaction sympathomimetics, eg, tyramine,
amphetamines, and ephedrine, are capable of releasing stored transmitter from noradrenergic nerve endings by a calciumindependent process.
These drugs are poor agonists (some are inactive) at adrenoceptors, but they are excellent substrates for monoamine transporters. As a result, they
are avidly taken up into noradrenergic nerve endings by NET. In the nerve ending, they are then transported by VMAT into the vesicles, displacing
norepinephrine, which is subsequently expelled into the synaptic space by reverse transport via NET. Amphetamines also inhibit monoamine oxidase
and have other effects that result in increased norepinephrine activity in the synapse. Their action does not require vesicle exocytosis.
Neurotransmitter Uptake Carriers
As noted in Chapters 1, 4, and 5, several large families of transport proteins have been identified. The most important of these are the ABC (ATP
binding cassette) and SLC (solute carrier) transporter families. As indicated by the name, the ABC carriers use ATP for transport. The SLC proteins
are cotransporters and, in most cases, use the movement of sodium down its concentration gradient as the energy source. Under some
circumstances, they also transport transmitters in the reverse direction in a sodiumindependent fashion.
NET, SLC6A2, the norepinephrine transporter, is a member of the SLC family, as are similar transporters responsible for the reuptake of dopamine
(D A T , SLC6A3) and 5HT (serotonin, SERT, SLC6A4) into the neurons that release these transmitters. These transport proteins are found in
peripheral tissues and in the CNS wherever neurons using these transmitters are located.
NET is important in the peripheral actions of cocaine and the amphetamines. In the CNS, NET and SERT are important targets of several
antidepressant drug classes (see Chapter 30). The most important inhibitory transmitter in the CNS, γaminobutyric acid (GABA), is the substrate for
at least three SLC transporters: GAT1, GAT2, and GAT3. GAT1 is the target of an antiseizure medication (see Chapter 24). Other SLC proteins
These drugs are poor agonists (some are inactive) at adrenoceptors, but they are excellent substrates for monoamine transporters. As a result, they
are avidly taken up into noradrenergic nerve endings by NET. In the nerve ending, they are then transported by VMAT into the vesicles, displacing
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norepinephrine, which is subsequently expelled into the synaptic space by reverse transport via NET. Amphetamines also inhibit monoamine oxidase
and have other effects that result in increased norepinephrine activity in the synapse. Their action does not require vesicle exocytosis.
Neurotransmitter Uptake Carriers
As noted in Chapters 1, 4, and 5, several large families of transport proteins have been identified. The most important of these are the ABC (ATP
binding cassette) and SLC (solute carrier) transporter families. As indicated by the name, the ABC carriers use ATP for transport. The SLC proteins
are cotransporters and, in most cases, use the movement of sodium down its concentration gradient as the energy source. Under some
circumstances, they also transport transmitters in the reverse direction in a sodiumindependent fashion.
NET, SLC6A2, the norepinephrine transporter, is a member of the SLC family, as are similar transporters responsible for the reuptake of dopamine
(D A T , SLC6A3) and 5HT (serotonin, SERT, SLC6A4) into the neurons that release these transmitters. These transport proteins are found in
peripheral tissues and in the CNS wherever neurons using these transmitters are located.
NET is important in the peripheral actions of cocaine and the amphetamines. In the CNS, NET and SERT are important targets of several
antidepressant drug classes (see Chapter 30). The most important inhibitory transmitter in the CNS, γaminobutyric acid (GABA), is the substrate for
at least three SLC transporters: GAT1, GAT2, and GAT3. GAT1 is the target of an antiseizure medication (see Chapter 24). Other SLC proteins
transport glutamate, the major excitatory CNS transmitter.
Norepinephrine and epinephrine can be metabolized by several enzymes, as shown in Figure 6–6. Because of the high activity of monoamine oxidase
in the mitochondria of the nerve terminal, there is significant turnover of norepinephrine even in the resting terminal. Since the metabolic products
are excreted in the urine, an estimate of catecholamine turnover can be obtained from measurement of total metabolites (sometimes referred to as
“VMA and metanephrines”) in a 24hour urine sample. However, metabolism is not the primary mechanism for termination of action of norepinephrine
physiologically released from noradrenergic nerves. Termination of noradrenergic transmission results from two processes: simple diffusion away
from the receptor site (with eventual metabolism in the plasma or liver) and reuptake into the nerve terminal by NET (Figure 6–4) or into perisynaptic
glia or other cells.
FIGURE 6–6
Metabolism of catecholamines by catecholOmethyltransferase (COMT) and monoamine oxidase (MAO). (Reproduced with permission from Gardner
DG, Shoback D: Greenspan’s Basic & Clinical Endocrinology, 9th ed. New York, NY: McGraw Hill; 2011.)
Cotransmitters in Cholinergic & Adrenergic Nerves Page 11 / 25
As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary transmitter, sometimes
in the same vesicles and sometimes in a separate vesicle population. Some of the substances identified to date are listed in Table 6–1. Many of these
FIGURE 6–6
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Metabolism of catecholamines by catecholOmethyltransferase (COMT) and monoamine oxidase (MAO). (Reproduced with permission from Gardner
DG, Shoback D: Greenspan’s Basic & Clinical Endocrinology, 9th ed. New York, NY: McGraw Hill; 2011.)
Cotransmitters in Cholinergic & Adrenergic Nerves
As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary transmitter, sometimes
in the same vesicles and sometimes in a separate vesicle population. Some of the substances identified to date are listed in Table 6–1. Many of these
substances are also primary transmitters in the nonadrenergic, noncholinergic nerves described in the text that follows. They appear to play several
roles in the function of nerves that release acetylcholine or norepinephrine. In some cases, they provide a faster or slower action to supplement or
modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals.
Growth of neurons and transmitter expression in specific neurons is a dynamic process. For example, neurotrophic factors released from target
tissues influence growth and synapse formation by neurons. In addition, the transmitters released from a specific population of neurons can change in
response to environmental factors such as the lightdark cycle.
AUTONOMIC RECEPTORS
Historically, structureactivity analyses, with careful comparisons of the potency of series of autonomic agonist and antagonist analogs, led to the
definition of different autonomic receptor subtypes, including muscarinic and nicotinic cholinoceptors, and α, β, and dopamine adrenoceptors (Table
6–2). Subsequently, binding of isotopelabeled ligands permitted the purification and characterization of several of the receptor molecules. Molecular
biology now provides techniques for the discovery and expression of genes that code for related receptors within these groups (see Chapter 2).
TABLE 6–2
Major autonomic receptor types.
Receptor
Typical Locations Result of Ligand Binding
Name
Cholinoceptors
CNS neurons, sympathetic postganglionic neurons, some presynaptic sites Formation of IP3 and DAG, increased
Muscarinic intracellular calcium
M1
Myocardium, smooth muscle, some presynaptic sites; CNS neurons Opening of potassium channels, inhibition of
Muscarinic adenylyl cyclase
Typical Locations Result of Ligand Binding
Name
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Cholinoceptors
CNS neurons, sympathetic postganglionic neurons, some presynaptic sites Formation of IP3 and DAG, increased
Muscarinic intracellular calcium
M1
Myocardium, smooth muscle, some presynaptic sites; CNS neurons Opening of potassium channels, inhibition of
Muscarinic adenylyl cyclase
M2
Exocrine glands, vessels (smooth muscle and endothelium); CNS neurons Like M1 receptorligand binding
Muscarinic
M3
CNS neurons; possibly vagal nerve endings Like M2 receptorligand binding
Muscarinic
M4
Vascular endothelium, especially cerebral vessels; CNS neurons Like M1 receptorligand binding
Muscarinic
M5
Postganglionic neurons, some presynaptic cholinergic terminals; pentameric receptors Opening of Na+, K+ channels, depolarization
Nicotinic typically contain α and βtype subunits only (see Chapter 7)
NN
Skeletal muscle neuromuscular end plates; receptors typically contain two α1 and β1 Opening of Na+, K+ channels, depolarization
Nicotinic type subunits in addition to g and δ subunits
NM
Adrenoceptors
Alpha1 Postsynaptic effector cells, especially smooth muscle Formation of IP3 and DAG, increased

intracellular calcium
Alpha2 Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Inhibition of adenylyl cyclase, decreased cAMP
Beta1 Postsynaptic effector cells, especially heart, lipocytes, brain; presynaptic adrenergic and Stimulation of adenylyl cyclase, increased

cholinergic nerve terminals, juxtaglomerular apparatus of renal tubules, ciliary body cAMP
epithelium
Beta2 Postsynaptic effector cells, especially smooth muscle and cardiac muscle Stimulation of adenylyl cyclase and increased

cAMP. Activates cardiac Gi under some
conditions.
Beta3 Postsynaptic effector cells, especially lipocytes; heart Stimulation of adenylyl cyclase and increased

cAMP1
Dopamine receptors
D1 Brain; effector tissues, especially smooth muscle of the renal vascular bed Stimulation of adenylyl cyclase and increased

(DA1), D5 cAMP
D2 Brain; effector tissues, especially smooth muscle; presynaptic nerve terminals
Chapter 6: Introduction to Autonomic Pharmacology, Bertram G. Katzung Inhibition of adenylyl cyclase; increased
Page 13 / 25
(DA2) potassium conductance
D3 Brain Inhibition of adenylyl cyclase

Dopamine receptors International Medical University
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D1 Brain; effector tissues, especially smooth muscle of the renal vascular bed Stimulation of adenylyl cyclase and increased
(DA1), D5 cAMP
D2 Brain; effector tissues, especially smooth muscle; presynaptic nerve terminals Inhibition of adenylyl cyclase; increased

(DA2) potassium conductance
D3 Brain Inhibition of adenylyl cyclase
D4 Brain, cardiovascular system Inhibition of adenylyl cyclase
1Cardiac β receptor function is poorly understood, but activation does not appear to result in stimulation of rate or force.
3
The primary acetylcholine receptor subtypes were named after the alkaloids originally used in their identification: muscarine and nicotine, thus
muscarinic and nicotinic receptors. In the case of receptors associated with noradrenergic nerves, the use of the names of the agonists
(noradrenaline, phenylephrine, isoproterenol, and others) was not practicable. Therefore, the term adrenoceptor is widely used to describe
receptors that respond to catecholamines such as norepinephrine. By analogy, the term cholinoceptor denotes receptors (both muscarinic and
nicotinic) that respond to acetylcholine. In North America, receptors were colloquially named after the nerves that usually innervate them; thus,
adrenergic (or noradrenergic) receptors and cholinergic receptors. The general class of adrenoceptors can be further subdivided into `
adrenoceptor, aadrenoceptor, and dopaminereceptor types on the basis of both agonist and antagonist selectivity and on genomic grounds.
Development of more selective blocking drugs has led to the naming of subclasses within these major types; for example, within the αadrenoceptor
class, α1 and α2 receptors differ in both agonist and antagonist selectivity. Examples of such selective drugs are given in the chapters that follow.
NONADRENERGIC, NONCHOLINERGIC (NANC) NEURONS
It has been known for many years that autonomic effector tissues (eg, gut, airways, bladder) contain nerve fibers that do not show the histochemical
characteristics of either cholinergic or adrenergic fibers. Both motor and sensory NANC fibers are present in these tissues. Although peptides are the
most common transmitter substances found in these nerve endings, other substances, eg, nitric oxide synthase and purines, are also present in many
nerve terminals (Table 6–1). Capsaicin, a toxin derived from chili peppers, can cause the release of transmitter (especially substance P) from such
neurons and, if given in high doses, destruction of the neuron.
The enteric system in the gut wall (Figure 6–2) is the most extensively studied system containing NANC neurons in addition to cholinergic and
adrenergic fibers. In the small intestine, for example, these neurons contain one or more of the following: nitric oxide synthase (which produces nitric
oxide, NO), calcitonin generelated peptide, cholecystokinin, dynorphin, enkephalins, gastrinreleasing peptide, 5hydroxytryptamine (5HT,
serotonin), neuropeptide Y, somatostatin, substance P, and vasoactive intestinal peptide (VIP). Some neurons contain as many as five different
transmitters.
The sensory fibers in the nonadrenergic, noncholinergic systems are probably better termed “sensoryefferent” or “sensorylocal effector” fibers
because, when activated by a sensory input, they are capable of releasing transmitter peptides from the sensory ending itself, from local axon
branches, and from collaterals that terminate in the autonomic ganglia. These peptides are potent agonists in many autonomic effector tissues.
FUNCTIONAL ORGANIZATION OF AUTONOMIC ACTIVITY
Autonomic function is integrated and regulated at many levels, from the CNS to the effector cells. Most regulation uses negative feedback, but several
other mechanisms have been identified. Negative feedback is particularly important in the responses of the ANS to the administration of autonomic
drugs.
Central Integration
At the highest level—midbrain and medulla—the two divisions of the ANS and the endocrine system are integrated with each other, with sensory input,
and with information from higher CNS centers, including the cerebral cortex. These interactions are such that early investigators called the
parasympathetic system a trophotropic one (ie, leading to growth) used to “rest and digest” and the sympathetic system an ergotropic one (ie,
leading to energy expenditure), which is activated for “fight or flight.” Although such terms offer little insight into the mechanisms involved, they do
provide simple descriptions applicable to many of the actions of the systems (Table 6–3). For example, slowing of the heart and stimulation of digestive
activity are typical energyconserving and energystoring actions of the parasympathetic system. In contrast, cardiac stimulation, increased blood
sugar, and cutaneous vasoconstriction are responses produced by sympathetic discharge that are suited to fighting or surviving attack.
TABLE 6–3
Central Integration
At the highest level—midbrain and medulla—the two divisions of the ANS and the endocrine system are integrated with each other, with sensory input,
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and with information from higher CNS centers, including the cerebral cortex. These interactions are such that early investigators called the
parasympathetic system a trophotropic one (ie, leading to growth) used to “rest and digest” and the sympathetic system an ergotropic one (ie,
leading to energy expenditure), which is activated for “fight or flight.” Although such terms offer little insight into the mechanisms involved, they do
provide simple descriptions applicable to many of the actions of the systems (Table 6–3). For example, slowing of the heart and stimulation of digestive
activity are typical energyconserving and energystoring actions of the parasympathetic system. In contrast, cardiac stimulation, increased blood
sugar, and cutaneous vasoconstriction are responses produced by sympathetic discharge that are suited to fighting or surviving attack.
TABLE 6–3
Direct effects of autonomic n e r v e activity on some organ systems. Autonomic d r u g effects are similar but not identical (see text).
Effect of
Sympathetic Activity Parasympathetic Activity
Organ Action1 Receptor2 Action Receptor2
Eye
Iris radial muscle Contracts α1 — —
Iris circular muscle — — Contracts M3
Ciliary muscle [Relaxes] β Contracts M3
Heart
Sinoatrial node Accelerates β1, β2 Decelerates M2
Ectopic pacemakers Accelerates β1, β2 — —
Contractility Increases β1, β2 Decreases (atria) M2
Blood vessels
Skin, splanchnic vessels Contracts α — —
Skeletal muscle vessels Relaxes β2 — —
[Contracts] α — —
Relaxes3 M3 — —
Endothelium of vessels in heart, brain, viscera — — Synthesizes and releases EDRF4 M , M 5

3 5
Bronchiolar smooth muscle Relaxes β2 Contracts M3
Gastrointestinal tract
Smooth muscle
Walls Relaxes α2,6 β2 Contracts7 M3
Sphincters Contracts α1 Relaxes M3
Secretion [Decreases] α2 Increases M3
Gastrointestinal tract
Smooth muscle
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Walls Relaxes α2,6 β2 Contracts7 M3
Sphincters Contracts α1 Relaxes M3
Secretion [Decreases] α2 Increases M3
Genitourinary smooth muscle
Bladder wall Relaxes β2 Contracts7 M3
Sphincter Contracts α1 Relaxes M3
Uterus, pregnant Relaxes β2 — …
Contracts α Contracts M3
Penis, seminal vesicles Ejaculation α Erection M
Skin
Pilomotor smooth muscle Contracts α — —
Sweat glands — —
Eccrine Increases M — —
Apocrine (stress) Increases α — —
Metabolic functions
Liver Gluconeogenesis β2, α — —
Liver Glycogenolysis β2, α — —
Fat cells Lipolysis β3 — —
Kidney Renin release β1 — —
1Less important actions are shown in brackets.
2Specific receptor type: α, alpha; β, beta; M, muscarinic.
3Vascular smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibers.
4The endothelium of most blood vessels releases EDRF (endotheliumderived relaxing factor), which causes marked vasodilation, in response to muscarinic stimuli.
Parasympathetic fibers innervate muscarinic receptors in vessels in the viscera and brain, and sympathetic cholinergic fibers innervate skeletal muscle blood
vessels. The muscarinic receptors in the other vessels of the peripheral circulation are not innervated and respond only to circulating muscarinic agonists.
5Cerebral blood vessels dilate in response to M receptor activation.
5
6Probably through presynaptic inhibition of parasympathetic activity.
7The cholinergic innervation of the rectum and the genitourinary organs may be anatomically sympathetic; see Box: Sympathetic Sacral Outflow.
At a more subtle level of interactions in the brain stem, medulla, and spinal cord, there are important cooperative interactions between the
parasympathetic and sympathetic systems. For some organs, sensory fibers associated with the parasympathetic system exert reflex control over
motor outflow in the sympathetic system. Thus, the sensory carotid sinus baroreceptor fibers in the glossopharyngeal nerve have a major influence on
vessels. The muscarinic receptors in the other vessels of the peripheral circulation are not innervated and respond only to circulating muscarinic agonists.
5Cerebral blood vessels dilate in response to M receptor activation.
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6Probably through presynaptic inhibition of parasympathetic activity.
7The cholinergic innervation of the rectum and the genitourinary organs may be anatomically sympathetic; see Box: Sympathetic Sacral Outflow.
At a more subtle level of interactions in the brain stem, medulla, and spinal cord, there are important cooperative interactions between the
parasympathetic and sympathetic systems. For some organs, sensory fibers associated with the parasympathetic system exert reflex control over
motor outflow in the sympathetic system. Thus, the sensory carotid sinus baroreceptor fibers in the glossopharyngeal nerve have a major influence on
sympathetic outflow from the vasomotor center. This example is described in greater detail in the following text. Similarly, parasympathetic sensory
fibers in the wall of the urinary bladder significantly influence sympathetic inhibitory outflow to that organ. Within the ENS, sensory fibers from the wall
of the gut synapse on both preganglionic and postganglionic motor neurons that control intestinal smooth muscle and secretory cells (Figure 6–2).
A. Integration of Cardiovascular Function
Autonomic reflexes are particularly important in understanding cardiovascular responses to autonomic drugs. As indicated in Figure 6–7, the primary
controlled variable in cardiovascular function is mean arterial pressure. In the absence of autonomic control, heart rate takes on an intrinsic value
somewhat higher than normal resting rate—that is, resting heart rate in a transplanted human heart is 110–130 beats/min. This suggests that in the
intact resting human, heart rate is dominated by parasympathetic tone, lowering the heart rate to the range of 70–80 beats/min. Changes in any
variable contributing to mean arterial pressure (eg, a druginduced increase in peripheral vascular resistance) evoke powerful homeostatic
secondary responses that tend to compensate for the directly evoked change. The homeostatic response may be sufficient to reduce the change in
mean arterial pressure and to reverse the drug’s effects on heart rate. A slow infusion of norepinephrine provides a useful example. This agent
produces direct effects on both vascular and cardiac muscle. It is a powerful vasoconstrictor and, by increasing peripheral vascular resistance,
increases mean arterial pressure. In the absence of reflex control—in a patient who has had a heart transplant, for example—the drug’s effect on the
heart is also stimulatory; that is, it increases heart rate and contractile force. However, in a subject with intact reflexes, the negative feedback response
to increased mean arterial pressure causes decreased sympathetic outflow to the heart and a powerful increase in parasympathetic (vagus nerve)
discharge at the cardiac pacemaker (sinoatrial [SA] node). This response is mediated by increased firing by the baroreceptor nerves of the carotid
sinus and the aortic arch. Increased baroreceptor activity causes the decreased central sympathetic outflow and increased vagal outflow. As a result,
the net effect of ordinary pressor doses of norepinephrine in a normal subject is to produce a marked increase in peripheral vascular resistance, an
increase in mean arterial pressure, and often, a slowing of heart rate. Bradycardia, the reflex compensatory response elicited by this agent, is the exact
opposite of the drug’s direct action; yet it is completely predictable if the integration of cardiovascular function by the ANS is understood.
FIGURE 6–7
Autonomic and hormonal control of cardiovascular function. Note that two feedback loops are present: the autonomic nervous system loop and the
hormonal loop. The sympathetic nervous system directly influences four major variables: peripheral vascular resistance, heart rate, force, and venous
tone. It also directly modulates renin production (not shown). The parasympathetic nervous system directly influences heart rate. In addition to its role
in stimulating aldosterone secretion, angiotensin II directly increases peripheral vascular resistance and facilitates sympathetic effects (not shown).
The net feedback effect of each loop is to compensate for changes in arterial blood pressure. Thus, decreased blood pressure due to blood loss would
evoke increased sympathetic outflow and renin release. Conversely, elevated pressure due to the administration of a vasoconstrictor drug would
cause reduced sympathetic outflow, reduced renin release, and increased parasympathetic (vagal) outflow.
in stimulating aldosterone secretion, angiotensin II directly increases peripheral vascular resistance and facilitates sympathetic effects (not shown).
The net feedback effect of each loop is to compensate for changes in arterial blood pressure. Thus, decreased blood pressure due to blood loss would
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evoke increased sympathetic outflow and renin release. Conversely, elevated pressure due to the administration of a vasoconstrictor drug would
cause reduced sympathetic outflow, reduced renin release, and increased parasympathetic (vagal) outflow.
B. Presynaptic Regulation
The principle of negative feedback control is also found at the presynaptic level of autonomic function. Important presynaptic feedback inhibitory
control mechanisms have been shown to exist at most nerve endings. A welldocumented mechanism involves the α2 receptor located on
noradrenergic nerve terminals. This receptor is activated by norepinephrine and similar molecules; activation diminishes further release of
norepinephrine from these nerve endings (Table 6–4). The mechanism of this G protein–mediated effect involves inhibition of the inward calcium
current that causes vesicular fusion and transmitter release. Conversely, a presynaptic β receptor appears to facilitate the release of norepinephrine
from some adrenergic neurons. Presynaptic receptors that respond to the primary transmitter substance released by the nerve ending are called
autoreceptors. Autoreceptors are usually inhibitory, but in addition to the excitatory β receptors on noradrenergic fibers, many cholinergic fibers,
especially somatic motor fibers, have excitatory nicotinic autoreceptors.
TABLE 6–4
Autoreceptor, heteroreceptor, and modulatory effects on nerve terminals in peripheral synapses.1
Transmitter/Modulator Receptor Type Neuron Terminals Where Found
Inhibitory effects
Acetylcholine M2, M4 Adrenergic, enteric nervous system
Norepinephrine Alpha2 Adrenergic
Dopamine D2; less evidence for D1 Adrenergic
Serotonin (5HT) 5HT1, 5HT2, 5HT3 Cholinergic preganglionic
ATP, ADP P2Y Adrenergic autonomic and ENS cholinergic neurons
Adenosine A1 Adrenergic autonomic and ENS cholinergic neurons
Histamine H3, possibly H2 H3 type identified on CNS adrenergic and serotonergic neurons
Enkephalin Delta (also mu, kappa) Adrenergic, ENS cholinergic

Neuropeptide Y Y1, Y2 (NPY) Adrenergic, some cholinergic
Prostaglandin E1, E2 EP3 Adrenergic

current that causes vesicular fusion and transmitter release. Conversely, a presynaptic β receptor appears to facilitate the release of norepinephrine
from some adrenergic neurons. Presynaptic receptors that respond to the primary transmitter substance released by the nerve ending are called
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autoreceptors. Autoreceptors are usually inhibitory, but in addition to the excitatory β receptors on noradrenergic fibers, many cholinergic fibers,
especially somatic motor fibers, have excitatory nicotinic autoreceptors.
TABLE 6–4
Autoreceptor, heteroreceptor, and modulatory effects on nerve terminals in peripheral synapses.1
Transmitter/Modulator Receptor Type Neuron Terminals Where Found
Inhibitory effects
Acetylcholine M2, M4 Adrenergic, enteric nervous system
Norepinephrine Alpha2 Adrenergic
Dopamine D2; less evidence for D1 Adrenergic
Serotonin (5HT) 5HT1, 5HT2, 5HT3 Cholinergic preganglionic
ATP, ADP P2Y Adrenergic autonomic and ENS cholinergic neurons
Adenosine A1 Adrenergic autonomic and ENS cholinergic neurons
Histamine H3, possibly H2 H3 type identified on CNS adrenergic and serotonergic neurons
Enkephalin Delta (also mu, kappa) Adrenergic, ENS cholinergic
Neuropeptide Y Y1, Y2 (NPY) Adrenergic, some cholinergic
Prostaglandin E1, E2 EP3 Adrenergic
Excitatory effects
Epinephrine Beta2 Adrenergic, somatic motor cholinergic
Acetylcholine N Somatic motor cholinergic
Angiotensin II AT1 Adrenergic
1A provisional list. The number of transmitters and locations will undoubtedly increase with additional research.
Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to
many other substances. Such heteroreceptors may be activated by substances released from other nerve terminals that synapse with the nerve
ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release.
Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and
receptors identified to date are listed in Table 6–4. Presynaptic regulation by a variety of endogenous chemicals probably occurs at all synapses.
C. Postsynaptic Regulation
Postsynaptic regulation can be considered from two perspectives: modulation by previous activity at the primary receptor (which may up or down
regulate receptor number or desensitize receptors; see Chapter 2), and modulation by other simultaneous events.
The first mechanism has been well documented in several receptoreffector systems. Upregulation and downregulation are known to occur in
response to decreased or increased activation, respectively, of the receptors. An extreme form of upregulation occurs after denervation of some
tissues, resulting in denervation supersensitivity of the tissue to activators of that receptor type. In skeletal muscle, for example, nicotinic
receptors are normally restricted to the end plate regions underlying somatic motor nerve terminals. Surgical or traumatic denervation results in
marked proliferation of nicotinic cholinoceptors over all parts of the fiber, including areas not previously associated with any motor nerve junctions. A
pharmacologic supersensitivity related to denervation supersensitivity occurs in autonomic effector tissues after administration of drugs that deplete
C. Postsynaptic Regulation
Postsynaptic regulation can be considered from two perspectives: modulation by previous activity at the primary receptor (which may up or down
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regulate receptor number or desensitize receptors; see Chapter 2), and modulation by other simultaneous events.
The first mechanism has been well documented in several receptoreffector systems. Upregulation and downregulation are known to occur in
response to decreased or increased activation, respectively, of the receptors. An extreme form of upregulation occurs after denervation of some
tissues, resulting in denervation supersensitivity of the tissue to activators of that receptor type. In skeletal muscle, for example, nicotinic
receptors are normally restricted to the end plate regions underlying somatic motor nerve terminals. Surgical or traumatic denervation results in
marked proliferation of nicotinic cholinoceptors over all parts of the fiber, including areas not previously associated with any motor nerve junctions. A
pharmacologic supersensitivity related to denervation supersensitivity occurs in autonomic effector tissues after administration of drugs that deplete
transmitter stores and prevent activation of the postsynaptic receptors for a sufficient period of time. For example, prolonged administration of large
doses of reserpine, a norepinephrine depleter, can cause increased sensitivity of the smooth muscle and cardiac muscle effector cells served by the
depleted sympathetic fibers.
The second mechanism involves modulation of the primary transmitterreceptor event by events evoked by the same or other transmitters acting on
different postsynaptic receptors. Ganglionic transmission is a good example of this phenomenon (Figure 6–8). The postganglionic cells are activated
(depolarized) as a result of binding of an appropriate ligand to a neuronal nicotinic (NN) acetylcholine receptor. The resulting fast excitatory
postsynaptic potential (EPSP) evokes a propagated action potential if threshold is reached. This event is often followed by a small and slowly
developing but longerlasting hyperpolarizing afterpotential—a slow inhibitory postsynaptic potential (IPSP). This hyperpolarization involves
opening of potassium channels by M2 cholinoceptors. The IPSP is followed by a small, slow excitatory postsynaptic potential caused by closure of
potassium channels linked to M1 cholinoceptors. Finally, a late, very slow EPSP may be evoked by peptides released from other fibers. These slow
potentials serve to modulate the responsiveness of the postsynaptic cell to subsequent primary excitatory presynaptic nerve activity. (See Chapter 21
for additional examples.)
FIGURE 6–8
Excitatory and inhibitory postsynaptic potentials (EPSP and IPSP) in an autonomic ganglion cell. The postganglionic neuron shown at the left with a
recording electrode might undergo the membrane potential changes shown schematically in the recording. The response begins with two EPSP
responses to nicotinic (N) receptor activation, the first not reaching threshold. The second, suprathreshold, EPSP evokes an action potential, which is
followed by an IPSP, probably evoked by M2 receptor activation (with possible participation from dopamine receptor activation). The IPSP is, in turn,
followed by a slower, M1dependent EPSP, and this is sometimes followed by a still slower peptideinduced excitatory postsynaptic potential.
PHARMACOLOGIC MODIFICATION OF AUTONOMIC FUNCTION
Because transmission involves both similar (eg, ganglionic) and different (eg, effector cell receptor) mechanisms in different segments of the ANS,
some drugs produce less selective effects, whereas others are highly specific in their actions. A summary of the steps in transmission of impulses, from
the CNS to the autonomic effector cells, is presented in Table 6–5. Drugs that block action potential propagation (local anesthetics and some natural
toxins) are very nonselective in their action, since they act on a process that is common to all neurons. On the other hand, drugs that act on the
biochemical processes involved in transmitter synthesis and storage are more selective, since the biochemistry of each transmitter differs, eg,
norepinephrine synthesis is very different from acetylcholine synthesis. Activation or blockade of effector cell receptors offers maximum flexibility and
selectivity of effect attainable with currently available drugs: adrenoceptors are easily distinguished from cholinoceptors. Furthermore, individual
receptor subgroups can often be selectively activated or blocked within each major type. Some examples are given in Box: Pharmacology of the Eye.
Even greater selectivity may be attainable in the future using drugs that target postreceptor processes, eg, receptors for second messengers.
TABLE 6–5
Steps in autonomic transmission: Effects of some drugs.
toxins) are very nonselective in their action, since they act on a process that is common to all neurons. On the other hand, drugs that act on the
biochemical processes involved in transmitter synthesis and storage are more selective, since the biochemistry of each transmitter differs, eg,
norepinephrine synthesis is very different from acetylcholine synthesis. Activation or blockade of effector cell receptors offers maximum flexibility and
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selectivity of effect attainable with currently available drugs: adrenoceptors are easily distinguished from cholinoceptors. Furthermore, individual
receptor subgroups can often be selectively activated or blocked within each major type. Some examples are given in Box: Pharmacology of the Eye.
Even greater selectivity may be attainable in the future using drugs that target postreceptor processes, eg, receptors for second messengers.
TABLE 6–5
Steps in autonomic transmission: Effects of some drugs.
Process
Drug Example Site Action
Affected
Action potential Local anesthetics, Nerve axons Block voltagegated sodium channels; block

propagation tetrodotoxin,1 saxitoxin2 conduction
Transmitter Hemicholiniums Cholinergic nerve terminals: membrane Block uptake of choline and slow ACh synthesis

synthesis
αMethyltyrosine Adrenergic nerve terminals and adrenal Inhibits tyrosine hydroxylase and blocks

(metyrosine) medulla: cytoplasm synthesis of catecholamines
Transmitter Vesamicol Cholinergic terminals: VAT on vesicles Prevents storage, depletes

storage
Reserpine, tetrabenazine Adrenergic terminals: VMAT on vesicles Prevents storage, depletes
Transmitter Many3 Nerve terminal membrane receptors Modulate release

release
ωConotoxin GVIA4 Nerve terminal calcium channels Reduces transmitter release
Amifampridine Blocks nerve terminal K channels Increases transmitter release by prolonging

action potential and increasing calcium influx
Domoic acid Nerve terminal kainate receptors (primarily CNS; Modulates transmitter release by altering

see Chapter 21) calcium influx/release
Botulinum toxin Cholinergic vesicles Prevents ACh release
αLatrotoxin5 Cholinergic and adrenergic vesicles Causes explosive transmitter release
Tyramine, amphetamine Adrenergic nerve terminals Promote transmitter release
Transmitter Cocaine, tricyclic Adrenergic nerve terminals, NET Inhibit uptake; increase transmitter effect on

reuptake after antidepressants, SNRI postsynaptic receptors
release antidepressants6
Receptor Norepinephrine Receptors at adrenergic junctions Binds and activates a receptors; causes

activation or contraction
blockade
Phentolamine Receptors at adrenergic junctions Binds α receptors; prevents activation
Isoproterenol Receptors at adrenergic junctions Binds β receptors; activates adenylyl cyclase
Propranolol Receptors at adrenergic junctions Binds β receptors; prevents activation
Nicotine Receptors at nicotinic cholinergic junctions Binds nicotinic receptors; opens ion channel in
(autonomic ganglia, neuromuscular end plates) postsynaptic membrane
blockade
Phentolamine Receptors at adrenergic junctions Binds α receptors; prevents activation
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Isoproterenol Receptors at adrenergic junctions Binds β receptors; activates adenylyl cyclase
Propranolol Receptors at adrenergic junctions Binds β receptors; prevents activation
Nicotine Receptors at nicotinic cholinergic junctions Binds nicotinic receptors; opens ion channel in

(autonomic ganglia, neuromuscular end plates) postsynaptic membrane
Tubocurarine Neuromuscular end plates Prevents activation of nicotinic receptors
Bethanechol Receptors, parasympathetic effector cells Binds and activates muscarinic receptors

(smooth muscle, glands)
Atropine Receptors, parasympathetic effector cells Binds muscarinic receptors; prevents activation
Enzymatic Neostigmine Cholinergic synapses (acetylcholinesterase) Inhibits enzyme; prolongs and intensifies

inactivation of transmitter action after release
transmitter
Tranylcypromine Adrenergic nerve terminals (monoamine Inhibits enzyme; increases stored transmitter

oxidase) pool
1Toxin of puffer fish, California newt.
2Toxin of Gonyaulax (red tide organism).
3Norepinephrine, dopamine, acetylcholine, angiotensin II, various prostaglandins, etc.
4Toxin of marine snails of the genus Conus.
5Black widow spider venom.
6Serotonin, norepinephrine reuptake inhibitors.
NET, norepinephrine transporter; SNRI, serotoninnorepinephrine reuptake inhibitors; VAT, vesicleassociated transporter; VMAT, vesicular monoamine transporter.
The next four chapters provide many more examples of this useful diversity of autonomic control processes.
Pharmacology of the Eye
The eye is an organ with multiple autonomic functions, controlled by several autonomic receptors. As shown in Figure 6–9, the anterior chamber is
the site of several autonomic effector tissues. These tissues include three muscles (pupillary dilator and constrictor muscles in the iris and the ciliary
muscle) and the secretory epithelium of the ciliary body.
Parasympathetic nerve activity and muscarinic cholinomimetics mediate contraction of the circular pupillary constrictor muscle and of the ciliary
muscle. Contraction of the pupillary constrictor muscle causes miosis, a reduction in pupil size. Miosis is usually present in patients exposed to large
systemic or small topical doses of cholinomimetics, especially organophosphate cholinesterase inhibitors. Ciliary muscle contraction causes
accommodation of focus for near vision. Marked contraction of the ciliary muscle, which often occurs with cholinesterase inhibitor intoxication, is
called cyclospasm. Ciliary muscle contraction also puts tension on the trabecular meshwork, opening its pores and facilitating outflow of the
aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure, a very useful result in patients with glaucoma. All of
these effects are prevented or reversed by muscarinic blocking drugs such as atropine.
Alpha adrenoceptors mediate contraction of the radially oriented pupillary dilator muscle fibers in the iris and result in mydriasis. This occurs
during sympathetic discharge and when αagonist drugs such as phenylephrine are placed in the conjunctival sac. Beta adrenoceptors on the ciliary
epithelium facilitate the secretion of aqueous humor. Blocking these receptors (with βblocking drugs) reduces the secretory activity and reduces
intraocular pressure, providing another therapy for glaucoma.
FIGURE 6–9
6Serotonin, norepinephrine reuptake inhibitors.
NET, norepinephrine transporter; SNRI, serotoninnorepinephrine reuptake inhibitors; VAT, vesicleassociated transporter; VMAT, vesicular monoamine transporter.
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The next four chapters provide many more examples of this useful diversity of autonomic control processes.
Pharmacology of the Eye
The eye is an organ with multiple autonomic functions, controlled by several autonomic receptors. As shown in Figure 6–9, the anterior chamber is
the site of several autonomic effector tissues. These tissues include three muscles (pupillary dilator and constrictor muscles in the iris and the ciliary
muscle) and the secretory epithelium of the ciliary body.
Parasympathetic nerve activity and muscarinic cholinomimetics mediate contraction of the circular pupillary constrictor muscle and of the ciliary
muscle. Contraction of the pupillary constrictor muscle causes miosis, a reduction in pupil size. Miosis is usually present in patients exposed to large
systemic or small topical doses of cholinomimetics, especially organophosphate cholinesterase inhibitors. Ciliary muscle contraction causes
accommodation of focus for near vision. Marked contraction of the ciliary muscle, which often occurs with cholinesterase inhibitor intoxication, is
called cyclospasm. Ciliary muscle contraction also puts tension on the trabecular meshwork, opening its pores and facilitating outflow of the
aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure, a very useful result in patients with glaucoma. All of
these effects are prevented or reversed by muscarinic blocking drugs such as atropine.
Alpha adrenoceptors mediate contraction of the radially oriented pupillary dilator muscle fibers in the iris and result in mydriasis. This occurs
during sympathetic discharge and when αagonist drugs such as phenylephrine are placed in the conjunctival sac. Beta adrenoceptors on the ciliary
epithelium facilitate the secretion of aqueous humor. Blocking these receptors (with βblocking drugs) reduces the secretory activity and reduces
intraocular pressure, providing another therapy for glaucoma.
FIGURE 6–9
Structures of the anterior chamber of the eye. Tissues with significant autonomic functions and the associated ANS receptors (α, β, M) are shown in
this schematic diagram. Aqueous humor is secreted by the epithelium of the ciliary body, flows into the space in front of the iris, flows through the
trabecular meshwork, and exits via the canal of Schlemm (arrow). Blockade of the β adrenoceptors associated with the ciliary epithelium causes
decreased secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control and influence aqueous drainage.
CASE STUDY ANSWER
This case illustrates the overlap of autonomic pharmacology with somatic motor pharmacology through their use of a common transmitter.
Blepharospasm and other manifestations of involuntary muscle spasm can be disabling and, in the case of large muscles, painful. Contraction of
skeletal muscle is triggered by exocytotic release of acetylcholine (ACh) from motor nerves in response to calcium influx at the nerve ending. Release
of ACh can be reduced or blocked by botulinum toxin, which interferes with the fusion of nerve ending ACh vesicles with the nerve ending
membrane (see text). Depending on dosage, botulinum blockade has an average duration of 1 to 3 months after a single administration.
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CASE STUDY ANSWER
This case illustrates the overlap of autonomic pharmacology with somatic motor pharmacology through their use of a common transmitter.
Blepharospasm and other manifestations of involuntary muscle spasm can be disabling and, in the case of large muscles, painful. Contraction of
skeletal muscle is triggered by exocytotic release of acetylcholine (ACh) from motor nerves in response to calcium influx at the nerve ending. Release
of ACh can be reduced or blocked by botulinum toxin, which interferes with the fusion of nerve ending ACh vesicles with the nerve ending
membrane (see text). Depending on dosage, botulinum blockade has an average duration of 1 to 3 months after a single administration.
REFERENCES
Andersson KE: Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev 2011;63:811.
[PubMed: 21880989]
Barrenschee M et al: SNAP25 is abundantly expressed in enteric neuronal networks and upregulated by the neurotrophic factor GDNF. Histochem
Cell Biol 2015;143:611. [PubMed: 25655772]
Biaggioni I: The pharmacology of autonomic failure: from hypotension to hypertension. Pharmacol Rev 2017;69:53. [PubMed: 28011746]
Birdsall NJM: Class A GPCR heterodimers: Evidence from binding studies. Trends Pharmacol Sci 2010;31:499. [PubMed: 20870299]
Burnstock G: Nonsynaptic transmission at autonomic neuroeffector junctions. Neurochem Int 2008;52:14. [PubMed: 17493707]
Burnstock G: Purinergic signalling in the gut. Adv Exp Med Biol 2016;891:91. [PubMed: 27379638]
Centers for Disease Control and Prevention: Paralytic shellfish poisoning—Southeast Alaska, MayJune 2011. MMWR Morb Mortal Wkly Rep
2011;60:1554. [PubMed: 22089968]
Dulcis D et al: Neurotransmitter switching in the adult brain regulates behaviour. Science 2013;340:449. [PubMed: 23620046]
EspinozaMedina I et al: The sacral autonomic outflow is sympathetic. Science 2016;354:893. [PubMed: 27856909]
Fisher J: The neurotoxin domoate causes longlasting inhibition of the kainate receptor GluK5 subunit. Neuropharmacology 2014;85:9. [PubMed:
24859608]
Furchgott RF: Role of endothelium in responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol 1984;24:175. [PubMed: 6203480]
Galligan JJ: Ligandgated ion channels in the enteric nervous system. Neurogastroenterol Motil 2002;14:611. [PubMed: 12464083]
Hills JM, Jessen KR: Transmission: γaminobutyric acid (GABA), 5hydroxytryptamine (5HT) and dopamine. In: Burnstock G, Hoyle CHV (editors):
Autonomic Neuroeffector Mechanisms . Harwood Academic, 1992.
Holzer P et al: Neuropeptide Y, peptide YY and pancreatic polypeptide in the gutbrain axis. Neuropeptides 2012;46:261. [PubMed: 22979996]
Johnston GR, Webster NR: Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesthesiol 2009;102:453.
Langer SZ: Presynaptic receptors regulating transmitter release. Neurochem Int 2008;52:26. [PubMed: 17583385]
Li YC, Kavalali ET: Synaptic vesiclerecycling machinery components as potential therapeutic targets. Pharmacol Rev 2017;69:142.
Luther JA, Birren SJ: Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic
properties. Auton Neurosci 2009;151:46. [PubMed: 19748836]
Magnon C: Autonomic nerve development contributes to prostate cancer progression. Science 2013;341:1236361. [PubMed: 23846904]
2+
Langer SZ: Presynaptic receptors regulating transmitter release. Neurochem Int 2008;52:26. [PubMed: 17583385]
Access Provided by:
Li YC, Kavalali ET: Synaptic vesiclerecycling machinery components as potential therapeutic targets. Pharmacol Rev 2017;69:142.
Luther JA, Birren SJ: Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic
properties. Auton Neurosci 2009;151:46. [PubMed: 19748836]
Magnon C: Autonomic nerve development contributes to prostate cancer progression. Science 2013;341:1236361. [PubMed: 23846904]
Mikoshiba K: IP3 receptor/Ca2+ channel: From discovery to new signaling concepts. J Neurochem 2007;102:1426. [PubMed: 17697045]
Pirazzini M et al: Botulinum neurotoxins: Biology, pharmacology, and toxicology. Pharmacol Rev 2017;69:200. [PubMed: 28356439]
Raj SR, Coffin ST: Medical therapy and physical maneuvers in the treatment of the vasovagal syncope and orthostatic hypotension. Prog Cardiovasc
Dis 2013;55:425. [PubMed: 23472781]
Rizo J: Staging membrane fusion. Science 2012;337:1300. [PubMed: 22984057]
Robertson D et al: Primer on the Autonomic Nervous System , 3rd ed. Academic Press, 2012.
Shibasaki M, Crandall CG: Mechanisms and controllers of eccrine sweating in humans. Front Biosci (Schol Ed) 2011;2:685.
Symposium: Gastrointestinal reviews. Curr Opin Pharmacol 2007;7:555.
Tobin G, Giglio D, Lundgren O: Muscarinic receptor subtypes in the alimentary tract. J Physiol Pharmacol 2009;60:3. [PubMed: 19439804]
Vanderlaan RD et al: Enhanced exercise performance and survival associated with evidence of autonomic reinnervation in pediatric heart transplant
recipients. Am J Transplant 2012;12:2157. [PubMed: 22487123]
Vernino S, Hopkins S, Wang Z: Autonomic ganglia, acetylcholine antibodies, and autoimmune gangliopathy. Auton Neurosci 2009;146:3. [PubMed:
18951069]
Verrier RL, Tan A: Heart rate, autonomic markers, and cardiac mortality. Heart Rhythm 2009;6(Suppl 11):S68. [PubMed: 19880076]
Watanabe S et al: Clathrin regenerates synaptic vesicles from endosomes. Nature 2014;515:228. [PubMed: 25296249]
Westfall DP, Todorov LD, MihaylovaTodorova ST: ATP as a cotransmitter in sympathetic nerves and its inactivation by releasable enzymes. J
Pharmacol Exp Ther 2002;303:439. [PubMed: 12388622]
Whittaker VP: Some currently neglected aspects of cholinergic function. J Mol Neurosci 2010;40:7. [PubMed: 19787460]

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Alpha1 Postsynaptic effector cells, especially smooth muscle Formation of IP3 and DAG, increased

Alpha2 Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Inhibition of adenylyl cyclase, decreased cAMP

Beta1 Postsynaptic effector cells, especially heart, lipocytes, brain; presynaptic adrenergic and Stimulation of adenylyl cyclase, increased

Beta2 Postsynaptic effector cells, especially smooth muscle and cardiac muscle Stimulation of adenylyl cyclase and increased

Beta3 Postsynaptic effector cells, especially lipocytes; heart Stimulation of adenylyl cyclase and increased

D1 Brain; effector tissues, especially smooth muscle of the renal vascular bed Stimulation of adenylyl cyclase and increased

D3 Brain Inhibition of adenylyl cyclase

D2 Brain; effector tissues, especially smooth muscle; presynaptic nerve terminals Inhibition of adenylyl cyclase; increased

D3 Brain Inhibition of adenylyl cyclase

D4 Brain, cardiovascular system Inhibition of adenylyl cyclase

Organ Action1 Receptor2 Action Receptor2

Ciliary muscle [Relaxes] β Contracts M3

Sinoatrial node Accelerates β1, β2 Decelerates M2

Ectopic pacemakers Accelerates β1, β2 — —

Contractility Increases β1, β2 Decreases (atria) M2

Endothelium of vessels in heart, brain, viscera — — Synthesizes and releases EDRF4 M , M 5

Bronchiolar smooth muscle Relaxes β2 Contracts M3

Walls Relaxes α2,6 β2 Contracts7 M3

Walls Relaxes α2,6 β2 Contracts7 M3

Sphincters Contracts α1 Relaxes M3

Secretion [Decreases] α2 Increases M3

Bladder wall Relaxes β2 Contracts7 M3

Sphincter Contracts α1 Relaxes M3

Penis, seminal vesicles Ejaculation α Erection M

Liver Gluconeogenesis β2, α — —

Liver Glycogenolysis β2, α — —

Transmitter/Modulator Receptor Type Neuron Terminals Where Found

Acetylcholine M2, M4 Adrenergic, enteric nervous system

Norepinephrine Alpha2 Adrenergic

Dopamine D2; less evidence for D1 Adrenergic

Serotonin (5­HT) 5­HT1, 5­HT2, 5­HT3 Cholinergic preganglionic

ATP, ADP P2Y Adrenergic autonomic and ENS cholinergic neurons

Histamine H3, possibly H2 H3 type identified on CNS adrenergic and serotonergic neurons

Enkephalin Delta (also mu, kappa) Adrenergic, ENS cholinergic

Prostaglandin E1, E2 EP3 Adrenergic

Transmitter/Modulator Receptor Type Neuron Terminals Where Found

Acetylcholine M2, M4 Adrenergic, enteric nervous system

Norepinephrine Alpha2 Adrenergic

Dopamine D2; less evidence for D1 Adrenergic

Serotonin (5­HT) 5­HT1, 5­HT2, 5­HT3 Cholinergic preganglionic

ATP, ADP P2Y Adrenergic autonomic and ENS cholinergic neurons

Histamine H3, possibly H2 H3 type identified on CNS adrenergic and serotonergic neurons

Enkephalin Delta (also mu, kappa) Adrenergic, ENS cholinergic

Neuropeptide Y Y1, Y2 (NPY) Adrenergic, some cholinergic

Prostaglandin E1, E2 EP3 Adrenergic

Epinephrine Beta2 Adrenergic, somatic motor cholinergic

Angiotensin II AT1 Adrenergic

Action potential Local anesthetics, Nerve axons Block voltage­gated sodium channels; block

Transmitter Hemicholiniums Cholinergic nerve terminals: membrane Block uptake of choline and slow ACh synthesis

α­Methyltyrosine Adrenergic nerve terminals and adrenal Inhibits tyrosine hydroxylase and blocks

Transmitter Vesamicol Cholinergic terminals: VAT on vesicles Prevents storage, depletes

Reserpine, tetrabenazine Adrenergic terminals: VMAT on vesicles Prevents storage, depletes

Transmitter Many3 Nerve terminal membrane receptors Modulate release

ω­Conotoxin GVIA4 Nerve terminal calcium channels Reduces transmitter release

Amifampridine Blocks nerve terminal K channels Increases transmitter release by prolonging

Domoic acid Nerve terminal kainate receptors (primarily CNS; Modulates transmitter release by altering

Botulinum toxin Cholinergic vesicles Prevents ACh release

α­Latrotoxin5 Cholinergic and adrenergic vesicles Causes explosive transmitter release

Serotonin (5HT) 5HT1, 5HT2, 5HT3 Cholinergic preganglionic

Serotonin (5HT) 5HT1, 5HT2, 5HT3 Cholinergic preganglionic

Action potential Local anesthetics, Nerve axons Block voltagegated sodium channels; block

αMethyltyrosine Adrenergic nerve terminals and adrenal Inhibits tyrosine hydroxylase and blocks

ωConotoxin GVIA4 Nerve terminal calcium channels Reduces transmitter release

αLatrotoxin5 Cholinergic and adrenergic vesicles Causes explosive transmitter release