Pure central ANS versus somatic centers are not known. Integration of ANS activity occurs at all levels of the cerebrospinal axis. Efferent ANS activity can be initiated locally and by centers located in the spinal cord, brain stem, and hypothalamus. The cerebral cortex is the highest level of ANS integration. Fainting at the sight of blood is an example of this higher level of somatic and ANS integration. ANS function has also been successfully modulated through conscious, intentional efforts demonstrating that somatic responses are always accompanied by visceral responses and vice versa.

The principal site of ANS organization is the hypothalamus. SNS functions are controlled by nuclei in the posterolateral hypothalamus. Stimulation of these nuclei results in a massive discharge of the sympathoadrenal system. PNS functions are governed by nuclei in the midline and some anterior nuclei of the hypothalamus. The anterior hypothalamus is involved with regulation of temperature. The supraoptic hypothalamic nuclei regulate water metabolism and are anatomically and functionally associated with the posterior lobe of the pituitary (see Interaction of Autonomic Nervous System Receptors). This hypothalamic–neurohypophyseal connection represents a central ANS mechanism that affects the kidney by means of antidiuretic hormone. Long-term blood pressure control, reactions to physical and emotional stress, sleep, and sexual reflexes are regulated through the hypothalamus.

The medulla oblongata and pons are vital centers of acute ANS organization. Together, they integrate momentary hemodynamic adjustments and maintain the sequence and automaticity of ventilation. Integration of afferent and efferent ANS impulses at this central nervous system (CNS) level is responsible for the tonic activity exhibited by the ANS. Tonicity holds visceral organs in a state of intermediate activity that can either be diminished or augmented by altering the rate of nerve firing. The nucleus tractus solitarius, located within the medulla, is the primary area for relay of afferent chemoreceptor and baroreceptor information from the glossopharyngeal and vagus nerves. Increased afferent impulses from these two nerves inhibits peripheral SNS vascular tone, producing vasodilation; it also increases vagal tone, producing bradycardia. Studies of patients with high spinal cord lesions show that a number of reflex changes are mediated at the spinal or segmental level. ANS hyperreflexia is an example of spinal cord mediation of ANS reflexes without integration of function from higher inhibitory centers.¹

The peripheral ANS is the efferent (motor) component of the ANS and consists of the same two complementary parts: The SNS and the PNS. Most organs receive fibers from both divisions (Fig. 15-1). In general, activities of the two systems produce opposite but complementary effects (see Table 15-1). A few tissues, such as sweat glands and spleen, are innervated by only SNS fibers. Although the anatomy of the somatic and ANS sensory pathways is identical, the motor pathways are characteristically different. The efferent somatic motor system, like somatic afferents, is composed of a single (unipolar) neuron with its cell body in the ventral gray matter of the spinal cord. Its myelinated axon extends directly to the voluntary striated muscle unit. In contrast, the efferent (motor) ANS is a two-neuron (bipolar) chain from the CNS to the effector organ. The first neuron of both the SNS and PNS originates within the CNS but does not make direct contact with the effector organ. Instead, it relays the impulse to a second station known as an ANS ganglion, which contains the cell body of the second ANS (postganglionic) neuron. Its axon contacts the effector organ. Thus, the motor pathways of both divisions of the ANS are schematically a serial two-neuron chain consisting of a preganglionic neuron and a postganglionic effector neuron (Fig. 15-2).

Preganglionic fibers of both subdivisions are myelinated with diameters of less than 3 mm.¹ Impulses are conducted at a speed of 3 to 15 m/s. The postganglionic fibers are unmyelinated and conduct impulses at slower speeds of less than 2 m/s. They are similar to unmyelinated visceral and somatic afferent C fibers (Table 15-2). Compared with the myelinated somatic nerves, the ANS conducts impulses at speeds that preclude its participation in the immediate phase of a somatic response.

ACh is the neurotransmitter for three distinct classes of receptors. These receptors can be differentiated by their anatomic location and their affinity for various agonists and antagonists. ACh mediates the “first messenger” function of transmitting impulses within the PNS, the ganglia of the SNS, and the neuroeffector junction of striated, voluntary muscle (see Fig. 15-2). Cholinergic receptors are further subdivided into muscarinic and nicotinic receptors because muscarine and nicotine stimulate them selectively. However, both muscarinic and nicotinic receptors respond to ACh (see below Cholinergic Drugs). Muscarine activates cholinergic receptors at the postganglionic PNS junctions of cardiac and smooth muscle. Muscarinic stimulation is characterized by bradycardia, decreased inotropism, bronchoconstriction, miosis, salivation, gastrointestinal hypermotility, and increased gastric acid secretion (see Table 15-1). Muscarinic receptors can be blocked by atropine without effect on nicotinic receptors (see below Cholinergic Drugs). Muscarinic receptors are known to exist in sites other than PNS postganglionic junctions. They are found on the presynaptic membrane of sympathetic nerve terminals in the myocardium, coronary vessels, and peripheral vasculature (Fig. 15-9). These are referred to as adrenergic muscarinic receptors because of their location; however, ACh stimulates them also. Stimulation of these receptors inhibits release of NE in a manner similar to α₂-receptor stimulation. Muscarinic blockade removes the inhibition of NE release, augmenting SNS activity. Atropine, the prototypical muscarinic blocker, may produce sympathomimetic activity in this manner as well as vagal blockade. Neuromuscular blocking drugs that cause tachycardia are thought to have a similar mechanism of action. ACh acting on presynaptic adrenergic muscarinic receptors is a potent inhibitor of NE release.¹¹ The prejunctional muscarinic receptor may play an important physiologic role because several autonomically innervated tissues (e.g., the heart) possess ANS plexuses in which the SNS and PNS nerve terminals are closely associated. In these plexuses, ACh, released from the nearby PNS nerve terminals (vagus nerve), can inhibit NE release by activation of presynaptic adrenergic muscarinic receptors (Fig. 15-9).

Nicotinic receptors are found at the synaptic junctions of both SNS and PNS ganglia. Because both junctions are cholinergic, ACh or ACh-like substances such as nicotine will excite
postganglionic fibers of both systems (see Fig. 15-2). Low doses of nicotine produce stimulation of ANS ganglia whereas high doses produce blockade. This dualism is referred to as the nicotinic effect (see below Ganglionic Drugs). Nicotinic stimulation of the SNS ganglia produces hypertension and tachycardia by causing the release of EPI and NE from the adrenal medulla. Adrenal hormone release is mediated by ACh in the chromaffin cells, which are analogous to postganglionic neurons (see Fig. 15-2). A further increase in nicotine concentration produces hypotension and neuromuscular weakness, as it becomes a ganglionic blocker. The cholinergic neuroeffector junction of skeletal muscle also contains nicotinic receptors, although they are not identical to the nicotinic receptors in ANS ganglia.

The adrenergic receptors are termed adrenergic or noradrenergic, depending on their responsiveness to EPI or NE. The dissimilarities of these two drugs led Ahlquist in 1948 to propose two types of opposing adrenergic receptors, termed alpha (α) and beta (β). The development of new agonists and antagonists with relatively selective activity allowed subdivision the β-receptors into β₁ and β₂. α-receptors were subsequently divided into α₁ and α₂. These were later further subdivided using molecular cloning. The sympathomimetic adrenergic drugs in current use differ from one another in their effects largely because of differences in substitution on the amine group, which influences the relative α or β effect (see Fig. 15-6).

Another major peripheral adrenergic receptor specific for dopamine is termed the dopaminergic (DA) receptor. Further studies have revealed not only subsets of the α and β receptors but also the DA receptor. These DA receptors have been identified in the CNS and in renal, mesenteric, and coronary vessels. The physiologic importance of these receptors is a matter of controversy because there are no identifiable peripheral DA neurons. Dopamine measured in the circulation is assumed to result from spillover from the brain.

The function of dopamine in the CNS has long been known, but the peripheral dopamine receptor has been elucidated only within the past 25 years. The presence of the peripheral DA receptor was obscured because dopamine does not affect the DA receptor exclusively. It also stimulates α and β receptors in a dose-related manner. However, DA receptors function independently of α or β blockade and are modified by DA antagonists such as haloperidol, droperidol, and phenothiazines. Thus, there is a necessity for the addition of the DA receptor and its subsets (DA₁ and DA₂).

The distribution of adrenergic receptors in organs and tissues is not uniform and their function differs not only by their location but also in their numbers and/or distribution. Adrenergic receptors are found in two loci in the sympathetic neuroeffector junction. They are found in both the presynaptic (prejunctional) and postsynaptic (postjunctional) sites as well as extrasynaptic sites (Fig. 15-10). Table 15-3 is a review of the function and synaptic location of some of the clinically important receptors and their subtypes.

Several reflexes in the cardiovascular system help govern arterial blood pressure control cardiac output (CO), and heart rate (HR). The aim of the circulation is to provide blood flow to all the body organs (see Chapter 10 Cardiac Anatomy and Physiology). Yet, the most important controlled variable to which the sensors are attuned is blood pressure, a product of the blood flow and vascular resistance. Étienne Marey noted in 1859 that the pulse rate is inversely proportional to the blood pressure, and this is known as Marey’s law. Subsequently, Hering, Koch, and others demonstrated that the alterations in HR evoked by changes in blood pressure are dependent on baroreceptors located in the aortic arch and the carotid sinuses. These pressure sensors react to alterations in stretch caused by blood pressure. Impulses from the carotid sinus and aortic arch reach the medullary vasomotor center by the glossopharyngeal and vagus nerves, respectively. Increased sensory traffic from the baroreceptors, caused by increased blood pressure, inhibits SNS effector traffic. The relative increase in vagal tone produces vasodilation, slowing of the HR, and a lowering of blood pressure. Real increases in vagal tone occur when blood pressure exceeds normal limits. The Valsalva maneuver can best demonstrate the arterial baroreceptor reflex (Fig. 15-11). The Valsalva maneuver raises the intrathoracic pressure by forced expiration against a closed glottis. The arterial blood pressure rises momentarily as the intrathoracic blood is forced into the heart (increased preload). Sustained intrathoracic pressure diminishes venous return, reduces the CO, and drops the blood pressure. Reflex vasoconstriction and tachycardia ensue. Blood pressure returns to normal with release of the forced expiration, but then briefly “overshoots” because of the vasoconstriction and increased venous return. A slowing of the HR accompanies the overshoot in pressure. The cardiovascular responses to the Valsalva maneuver require an intact ANS circuit from peripheral sensor to peripheral adrenergic receptors. The Valsalva maneuver has been used to identify patients at risk for anesthesia due to ANS instability (Fig. 15-11). This was once a major concern in patients receiving drugs that depleted catecholamines, such as reserpine. Dysfunction of the SNS is implicated if exaggerated and prolonged hypotension develops during the forced expiration phase (50% from resting mean arterial pressure). In addition, the overshoot at the end of the Valsalva maneuver is absent. Dysfunction of the PNS can be assumed if the HR does not respond appropriately to the blood pressure changes.

Venous baroreceptors may be more dominant in the moment-to-moment regulation of CO. Baroreceptors in the right atrium and great veins produce an increase in HR when stretched by increased right atrial pressure. Reduced venous pressure decreases HR. Unlike the arterial baroreceptors, venous sensors are not thought to alter vascular tone; however, venoconstriction is postulated to occur when atrial pressures decline. Stretch of the venous receptors produces changes in HR opposite to those produced when the arterial pressure sensors are stimulated. The
arterial and venous pressure receptors are separately monitoring two of the four major determinants of CO: Afterload and preload, respectively. Venous baroreceptors sample preload by stretch of the atrium. Arterial baroreceptors survey resistance, or afterload, as reflected in the mean arterial pressure. Afterload and preload produce opposite effects on CO; thus, one should not be surprised that the venous and arterial baroreceptors produce opposing effects after a similar stretch stimulus, pressure.

Bainbridge described the venous baroreceptor reflex and demonstrated that it can be abolished by vagal resection. Numerous investigators have confirmed the acceleration of the HR in response to volume. However, the magnitude and direction of the HR response are dependent on the prevailing HR at the time of stimulation. The denervated, transplanted mammalian heart also accelerates in response to volume loading. HR, like CO, can apparently be adjusted to the quantity of blood entering the heart. The Bainbridge reflex relates to the characteristic but paradoxical slowing of the heart seen with spinal anesthesia. Blockade of the SNS levels of T1–4 ablates the efferent limb of the cardiac accelerator nerves. This source of cardiac deceleration is obvious, as the vagus nerve is unopposed. However, bradycardia during spinal anesthesia is more related to the development of arterial hypotension than to the height of the block. The primary defect in the development of spinal hypotension is a decrease in venous return. Theoretically, the arterial hypotension should reflexly produce a tachycardia through the arterial baroreceptors. Instead, bradycardia is more common. Greene suggests that in the unmedicated person, the venous baroreceptors are dominant over the arterial. A reduced venous pressure, therefore, slows HR.²⁴ In contrast, humorally mediated tachycardia is the usual response to hypotension or acidosis from other causes. In patients with difficult to control blood pressure, decreasing the sympathetic outflow seems to be beneficial in better regulating the blood pressure. Therefore, surgical interuption of renal efferent sympathetic outflow with radiofrequency ablation through femoral artery catheterization increases natriuresis and diuresis, and reduces renin production. Also, baroreflex sensitization through an implantable carotid sinus stimulator seems to be extremely promising in patients with refractory hypertension, with more research underway.²⁵

Reflex modulation of the adrenergic agonists is best seen in the denervated transplant heart, which retains the recipient’s innervated sinoatrial node and the donor’s denervated sinoatrial node²⁶ (see Chapter 51 Transplant Anesthesia). NE infusion in the transplanted heart produces a slowing of the recipient’s atrial rate through vagal feedback as the blood pressure rises. In the unmodulated donor heart, atrial rate increases. The baroreceptors are therefore not operant in the transplanted heart. Isoproterenol, a pure β agonist, increases the discharge rate of both the recipient and donor node by direct action, with the donor rate near doubling that of the recipient node. Atropine accelerates the recipient’s atrial rate, whereas no effect is seen on the donor rate, which now controls HR.

β blockade produces comparable slowing of the sinoatrial node of both recipient and donor. The exercise capability of the denervated heart is conspicuously reduced by β blockade, presumably because of its reliance on circulating catecholamines. Propranolol has also been demonstrated to reduce the β response to chronotropic effects of NE and isoproterenol in the transplanted heart. The CO of the transplanted heart varies appropriately with changes in preload and afterload.

Strong interactions have been noted between SNS and PNS nerves in organs that receive dual, antagonistic innervation. Release of NE at the presynaptic terminal is modified by the PNS. For example, vagal inhibition of left ventricular contractility is accentuated as the level of SNS activity is raised. This interaction is termed accentuated antagonism and is mediated by a combination of presynaptic and postsynaptic mechanisms. The coronary arteries present an example of this phenomenon and deserve special attention.

The myocardium and coronary vessels are abundantly supplied with adrenergic and cholinergic fibers. Strong activity of both α and β receptors has been demonstrated in the coronary vascular bed. Selective stimulation of both the α₁ and postsynaptic α₂ receptors increases coronary vascular resistance, whereas selective α blockade eliminates this effect. Therefore, both β₁ and α₁ adrenoreceptors are present on coronary arteries and accessible to NE released by sympathetic nerves.⁶,¹⁵

The presynaptic adrenergic terminals of the myocardium and coronary vessels, like all blood vessels studied, contain muscarinic receptors.¹¹ Recent observations confirm that muscarinic agents and vagal stimulation, acting on the presynaptic, SNS muscarinic receptor, inhibit the release of NE in a manner similar to that of the presynaptic α₂ and DA₂ receptors (Fig. 15-9). Conversely, blockade of the muscarinic receptors with atropine markedly augments the positive inotropic responses to catecholamines.⁶ Suppression of NE release explains, in part, vagal-induced attenuation of the inotropic response to strong SNS stimulation (accentuated antagonism) and only a weak negative inotropic effect of vagal stimulation when there is low background SNS activity. This may also explain why vagal activity reduces the vulnerability of the myocardium to fibrillation during infusions of NE.

ACh may cause coronary spasm during periods of high SNS tone.⁶ Inhibition of NE release by presynaptic adrenergic muscarinic receptors of the smooth muscle of coronary vessels would lessen the coronary relaxation normally produced by NE on the β₁ receptor (Fig. 15-9). In anesthetized dogs, the rate of NE outflow into the coronary sinus blood, evoked by cardiac SNS stimulation, is markedly diminished by simultaneous vagal efferent stimulation.²⁷ This action is known to be prevented by atropine, which also causes coronary vasodilation.

The ANS is integrally related to several endocrine systems that ultimately summate to control blood pressure and regulate homeostasis. These include the renin–angiotensin system, ADH, glucocorticoids, and insulin (see Chapter 46 Endocrine Function). Both α and β receptors have been found in the endocrine pancreas and modulate insulin release (see Table 15-4). β stimulation increases insulin release, whereas α stimulation decreases it. The overall importance of this interaction is not entirely clear, but decreased tolerance to glucose and potassium has been noted in subjects taking β-blocking drugs. The renin–angiotensin system is a complex endocrine system that modulates both blood pressure and water–electrolyte homeostasis (Fig. 15-12). Renin is a proteolytic enzyme released by the cells of the juxtaglomerular apparatus of the renal cortex. Renin acts on plasma angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by a converting enzyme in the lung. Angiotensin II is a powerful direct arterial vasoconstrictor. It also acts
on the adrenal cortex to release aldosterone and on the adrenal medulla to release EPI. In addition to its direct effects on vascular smooth muscle, angiotensin II augments NE release via presynaptic receptors, thus enhancing peripheral SNS tone. Captopril, enalapril, and lisinopril inhibit the action of converting enzyme, thus preventing the conversion of angiotensin I to angiotensin II. Renin is released in response to hyponatremia, decreased renal perfusion pressure, and ANS stimulation via β receptors on juxtaglomerular cells. Changes in sympathetic tone may thus alter renin release and affect homeostasis in a variety of ways. The ANS is also intimately related to adrenocortical function. As outlined above, glucocorticoid release modulates phenylethanolamine-N-methyltransferase formation and thus synthesis of EPI. Glucocorticoids are also important in regulating the response of peripheral tissues to changes in SNS tone. Thus, the ANS is intimately related to other homeostatic mechanisms.

ANS drugs may be broadly classified by mode of action according to their mimetic or lytic actions. This may also be termed agonist or antagonist. A sympathomimetic, such as ephedrine, mimics SNS sympathetic activity by stimulation of adrenergic receptor sites both directly and indirectly. Sympatholytic drugs cause dissolution of SNS activity at these same receptor sites. β receptor blockers are examples of sympatholytic drugs. Several modes of ANS drug action become evident when one follows the cascade of neurotransmission. Drugs that act on prejunctional membranes may therefore (1) interfere with transmitter synthesis (α-methyl paratyrosine), (2) interfere with transmitter storage (reserpine), (3) interfere with transmitter release (clonidine), (4) stimulate transmitter release (ephedrine), or (5) interfere with reuptake of transmitter (cocaine). Drugs may also (6) modify metabolism of the neurotransmitter in the synaptic cleft (anticholinesterase). Drugs acting at postjunctional sites may (7) directly stimulate postjunctional receptors and (8) interfere with transmitter agonist at the postjunctional receptor.

The ultimate response of an effector organ to an agonist or antagonist depends on (1) the drug, (2) its plasma concentration, (3) the number of receptors in the effector organ, (4) binding by the receptor, (5) the concurrent activities of other drugs and hormones, (6) the cellular metabolic status, and (7) reflex adjustments by the organism.

SNS and PNS ganglia are pharmacologically similar in that the transmission through these ANS ganglia is effected by ACh (see Fig. 15-2). Most ganglionic agonists and antagonists are not selective and affect SNS and PNS ganglia equally. This nonselective property creates many undesirable and unpredictable side effects, which have limited the clinical usefulness of this category of drug.