Bertram G. Katzung, MD, phD
A 49-year-old man with a history of congenital heart disease had a successful cardiac transplant 6 months ago. He is now admitted to the hospital in severe agitation. He is found to have a blood pressure of 170/110 mm Hg, heart rate 130, respirations 35, sweating, and cutaneous vasoconstriction. He admits to self-injecting methamphetamine 4 hours previously. How does methamphetamine increase blood pressure? Normally, heart rate would be greatly reduced with this degree of drug-induced hypertension. Why is this patient’s heart rate elevated?
The nervous system is conventionally divided into the central nervous system (CNS; the brain and spinal cord) and the peripheral nervous system (PNS; neuronal tissues outside the CNS). The motor (efferent) portion of 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 visceral functions such as cardiac output, blood flow distribution, and digestion, which are necessary for life. Evidence is accumulating that the ANS, especially the vagus nerve, also influences immune function and some CNS functions such as seizure discharge. Remarkably, recent evidence indicates that autonomic nerves also influence prostate cancer development and progression. The somatic subdivision is largely concerned with consciously controlled functions such as movement, respiration, and posture. Both systems have important afferent (sensory) inputs that provide information regarding the internal and external environments and modify motor output through reflex arcs of varying size and complexity.
The nervous system has several properties in common with the endocrine system. These include high-level 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. 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 have unwanted effects on autonomic function (see Case Study).
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 (craniosacral) division (Figure 6–1). 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 and lumbar spinal nerves. The parasympathetic preganglionic fibers leave the CNS through the cranial nerves (especially the third, seventh, ninth, and tenth) and the third and fourth sacral spinal nerve roots.
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. ACh, acetylcholine; D, dopamine; Epi, epinephrine; M, muscarinic receptors; N, nicotinic receptors; NE, norepinephrine.
Most sympathetic preganglionic fibers are short and terminate in ganglia located in the paravertebral chains that lie on either side of the spinal column. 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, otic, and several pelvic ganglia. However, the majority of para-sympathetic preganglionic fibers terminate on ganglion cells distributed diffusely or in networks in the walls of the innervated organs. 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). 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 critical in the 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. 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 gene-related 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, utilizing input from the motor outflow of the ANS for modulation of GI activity and sending sensory information back to 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 neuron-neuron 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.
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 terminal boutons 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 (non-autonomic) motor fibers to skeletal muscle as well. Thus, almost all efferent fibers leaving the CNS are cholinergic. In addition, most parasympathetic postganglionic and a few sympathetic post-ganglionic fibers are cholinergic. A significant number of para-sympathetic postganglionic neurons utilize nitric oxide or peptides as the primary transmitter or 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 text that follows), 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.
The terminals and varicosities of cholinergic neurons contain large numbers of small membrane-bound vesicles concentrated near the synaptic portion of the cell membrane (Figure 6–3) as well as a smaller number of large dense-cored 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 are initially synthesized in the neuron cell body and carried to the terminal by axonal transport. They may also be recycled several times within the terminal. Vesicles are provided with vesicle-associated 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 nerve-associated proteins (SNAPs), which interact with VAMPs. VAMPs and SNAPs are collectively called fusion proteins.
Acetylcholine is synthesized in the cytoplasm from acetyl-CoA and choline through the catalytic action of the enzyme choline acetyltransferase (ChAT). Acetyl-CoA 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 sodium-dependent 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 vesicle-associated 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 to 50,000 molecules in each vesicle). Most of the vesicular acetylcholine (ACh) is bound to negatively charged vesicular proteoglycan (VPG).
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 acetyl-CoA (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine (ACh) is then transported into the storage vesicle by a vesicle-associated 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 voltage-sensitive 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 nerve-associated proteins; VAMPs, vesicle-associated membrane proteins.
Vesicles are concentrated on the inner surface of the nerve terminal facing the synapse through the interaction of so-called SNARE proteins on the vesicle (a subgroup of VAMPs called v-SNAREs, especially synaptobrevin) and on the inside of the terminal cell membrane (SNAPs called t-SNAREs, especially syntaxin and SNAP-25). 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 N-type 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 through the enzymatic removal of two amino acids from one or more of the fusion proteins.
TABLE 6–1 Some of the transmitter substances found in autonomic nervous system, enteric nervous system, and nonadrenergic, noncholinergic neurons.1
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 acetylcho-line 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 half-life 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 acetylcho-line, including butyrylcholinesterase [pseudocholinesterase], are found in blood plasma, liver, glia, and many other tissues.)
Adrenergic neurons (Figure 6–4) transport a precursor amino acid (tyrosine) into the nerve ending, then synthesize the catecholamine transmitter (Figure 6–5), and store it in membrane-bound 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 rate-limiting step in catecholamine transmitter synthesis. It can be inhibited by the tyrosine analog metyrosine. A high-affinity antiporter for catecholamines located in the wall of the storage vesicle (vesicular monoamine transporter, VMAT) can be inhibited by the reserpine alkaloids. Reserpine causes 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 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 ending or varicosity by a sodium-dependent 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. The same carrier transports norepinephrine (NE) and several related amines into these vesicles. Dopamine is converted to NE in the vesicle by dopamine-β-hydroxylase. Physiologic release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine, cotransmitters, and dopamine-β-hydroxylase. 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, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins.
FIGURE 6–5 Biosynthesis of catecholamines. The rate-limiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (α-methyltyrosine). 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 [editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.)
Release of the vesicular transmitter store from noradrenergic nerve endings is similar to the calcium-dependent process previously described for cholinergic terminals. In addition to the primary transmitter (norepinephrine), adenosine triphosphate (ATP), dopamine-β-hydroxylase, and peptide cotransmitters are also released into the synaptic cleft. Indirectly acting and mixed sympathomimetics, eg, tyramine, amphetamines, and ephedrine, are capable of releasing stored transmitter from noradrenergic nerve endings by a calcium-independent 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.
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 24-hour 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 catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). (Reproduced, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.)
Neurotransmitter Uptake Carriers
As noted in Chapter 1, 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 utilize 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 sodium-independent fashion.
NET, SLC6A2, the norepinephrine transporter, is a member of the SLC family, as are similar transporters responsible for the reuptake of dopamine (DAT, SLC6A3) and 5-HT (serotonin, SERT, SLC6A4) into the neurons that release these transmitters. These transport proteins are found in peripheral tissues and in the CNS wherever neurons utilizing 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, γ-aminobutyric 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.
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 light-dark cycle.
Historically, structure-activity 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 isotope-labeled 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.
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 acetylcho-line. 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 α-adrenoceptor, β-adrenoceptor, and dopamine-receptor 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 α-adrenoceptor 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. 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 neurotoxin 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 gene-related peptide, cholecystokinin, dynorphin, enkephalins, gastrin-releasing peptide, 5-hydroxytryptamine (5-HT, 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 “sensory-efferent” or “sensory-local 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.
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 tropho-tropic 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 energy-conserving and storing 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 nerve activity on some organ systems. Autonomic drug effects are similar but not identical (see text).
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).
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. Changes in any variable contributing to mean arterial pressure (eg, a drug-induced 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 parasym-pathetic (vagus nerve) discharge at the cardiac pacemaker. This response is mediated by increased firing by the baroreceptor nerves of the carotid sinus and the aortic arch. Increased baroreceptor activity causes the changes mentioned in central sympathetic and 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 a consistent 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 parasym-pathetic (vagal) outflow.
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 well-documented 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
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 in all nerve fibers.
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 receptor-effector systems. Up-regulation and down-regulation are known to occur in response to decreased or increased activation, respectively, of the receptors. An extreme form of up-regulation 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 transmitter-receptor 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 longer-lasting 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 M1cholinoceptors. 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, M1-dependent EPSP, and this is sometimes followed by a still slower peptide-induced excitatory postsynaptic potential.
PHARMACOLOGIC MODIFICATION OF AUTONOMIC FUNCTION
Because transmission involves different mechanisms in different segments of the ANS, some drugs produce highly specific effects, whereas others are much less selective 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 the Box: Pharmacology of the Eye. Even greater selectivity may be attainable in the future using drugs that target post-receptor processes, eg, receptors for second messengers.
TABLE 6–5 Steps in autonomic transmission: Effects of drugs.
Pharmacology of the Eye
The eye is a good example of 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 α-agonist 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 β-blocking 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 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.
The next four chapters provide many more examples of this useful diversity of autonomic control processes.
Andersson K-E: Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev 2011;63:811.
Birdsall NJM: Class A GPCR heterodimers: Evidence from binding studies. Trends Pharmacol Sci 2010;31:499.
Broten TP et al: Role of endothelium-derived relaxing factor in parasympathetic coronary vasodilation. Am J Physiol 1992;262:H1579.
Burnstock G: Non-synaptic transmission at autonomic neuroeffector junctions. Neurochem Int 2008;52:14.
Burnstock G: Purinergic signalling: Its unpopular beginning, its acceptance and its exciting future. Bioessays 2012;34:218.
Dulcis D et al: Neurotransmitter switching in the adult brain regulates behaviour. Science 2013;340:449.
Fagerlund MJ, Eriksson LI: Current concepts in neuromuscular transmission. Br J Anaesthesia 2009;103:108.
Furchgott RF: Role of endothelium in responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol 1984;24:175.
Galligan JJ: Ligand-gated ion channels in the enteric nervous system. Neurogastroenterol Motil 2002;14:611.
Goldstein DS et al: Dysautonomias: Clinical disorders of the autonomic nervous system. Ann Intern Med 2002;137:753.
Hills JM, Jessen KR: Transmission: γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and dopamine. In: Burnstock G, Hoyle CHV (editors): Autonomic Neuroeffector Mechanisms. Harwood Academic, 1992.
Holzer P, Reichmann F, Farzi A: Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 2012;46:261.
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.
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.
Magnon C: Autonomic nerve development contributes to prostate cancer progression. Science 2013;341:1236361.
Mikoshiba K: IP3 receptor/Ca2+ channel: From discovery to new signaling concepts. J Neurochem 2007;102:1426.
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.
Rizo J: Staging membrane fusion. Science 2012;337:1300.
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.
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.
Vernino S, Hopkins S, Wang Z: Autonomic ganglia, acetylcholine antibodies, and autoimmune gangliopathy. Auton Neurosci 2009;146:3.
Verrier RL, Tan A: Heart rate, autonomic markers, and cardiac mortality. Heart Rhythm 2009;6 (Suppl 11):S68.
Westfall DP, Todorov LD, Mihaylova-Todorova ST: ATP as a cotransmitter in sympathetic nerves and its inactivation by releasable enzymes. J Pharmacol Exp Ther 2002;303:439.
Whittaker VP: Some currently neglected aspects of cholinergic function. J Mol Neurosci 2010;40:7
CASE STUDY ANSWER
Methamphetamine is transported into adrenergic nerve endings and causes release of norepinephrine stores. It thus causes dose-dependent vasoconstriction in addition to the central nervous system effects for which it is abused. It may also cause tachycardia, depending on the amount of norepinephrine released in the heart or reaching it in the circulation. Vasoconstriction-induced hypertension normally causes bradycardia, mediated by the vagus nerve (see Figure 6–7). In a patient with a heart transplant, cardiac innervation may be completely severed so that vagal impulses do not reach the pacemaker. In such patients, the heart rate remains at the intrinsic sinoatrial node frequency, usually about 100–110 bpm, under most conditions. If the vasoconstrictor also has β-agonist activity (as does norepinephrine), the heart rate may increase further. Reinnervation of transplanted hearts takes months to years and may never be complete.