The organization of autonomic cardiovascular control systems within the central nervous system (CNS) is summarized in Figure 19-2. The final common (preganglionic) output neurons for cardiovascular control by the parasympathetic nervous system are located principally in the nucleus ambiguus of the brainstem. The preganglionic neurons of the sympathetic nervous system are located in the intermediolateral columns of the thoracolumbar region of the spinal cord. Antecedent to these final output neurons, much of the integration of neural signals contributing to autonomic regulation of cardiovascular function occurs at other sites in the brainstem. These neurons, in turn, receive input from all levels of the CNS, some of the more important of which are diagrammed in Figure 19-2.

FIGURE 19–2 Organization of autonomic cardiovascular control systems. Major inputs are in boxes. Many reciprocal connections are not illustrated. AP, Area postrema; CPA, caudal pressor area; CVLM, caudal ventrolateral medulla; CVO, circumventricular organs; DRG, dorsal root ganglia; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla; VMM, ventromedial medulla.

Origin and Regulation of Autonomic Activity

One of the principal roles of the ANS is to provide adaptive regulation and coordination of blood pressure and flow to various organs of the body in the face of an ever-changing internal environment. This is accomplished by neural circuits intrinsic to the CNS and as a response to mechanical and humoral signals originating in the periphery. Integration of these signals by the CNS produces patterns of autonomic activity that ensure adequate organ perfusion appropriate to such diverse demands as changes in posture, hemorrhage, digestion, and exercise.

Parasympathetic preganglionic neurons that project to the heart via the vagus nerves have low levels of spontaneous firing, and their discharge rate is driven mostly by inputs from various afferents, particularly arterial baroreceptors. Inputs to spinal sympathetic preganglionic neurons originate in the brainstem, pons, and hypothalamus and can be either excitatory or inhibitory. However, the activity of spinal sympathetic preganglionic neurons regulating cardiovascular function is driven primarily by excitatory neurons located in the rostral ventrolateral medulla.

In addition to intrinsic CNS control, the efferent activity of autonomic nerves is powerfully regulated by neural signals arising from the periphery. Activation of visceral sensory afferents projecting to the brain via the vagus nerves generally reduces sympathetic activity and increases parasympathetic activity. These afferents include stretch receptors located in the cardiovascular system, which provide information about arterial pressure (arterial baroreceptors) and cardiac filling (cardiac baroreceptors) as well as stretch receptors and chemosensory receptors in the lungs, which provide information about respiratory mechanics and lung irritants, respectively. Afferents with chemosensory terminals located in the carotid sinus encode blood gas O₂ concentration, send projections to the brain via the glossopharyngeal nerve, and when activated by hypoxia, hypercapnia, or acidic pH, increase efferent sympathetic nerve activity. All of these afferents make their first central synapse within the nucleus of the tractus solitarius located in the dorsomedial brainstem. Vagal afferents producing sympathoinhibition project primarily to the lateral aspects of the solitary tract nucleus, whereas glossopharyngeal afferents that produce sympathoexcitation project to more medial aspects of this nucleus.

Other visceral mechanosensitive and chemosensitive nerve terminals are located throughout the body. Some of these bipolar neurons, with cell bodies in the dorsal root ganglia, may initially commingle their axons within various sympathetic nerve trunks (sympathetic afferents) before synapsing on cells located in the dorsal horns of the spinal cord. Other sensory afferents do not travel with the sympathetic nerves and, instead, associate with various sensory-motor nerve trunks (somatic afferents) before synapsing in the spinal dorsal horns. All of these afferents typically encode noxious or painful chemical or mechanical stimuli, such as those associated with cardiac or visceral ischemia, visceral organ distension, or injury, and detect the metabolic products produced by exercising skeletal muscle. Activation of these afferents typically produces sympathoexcitation.

In addition to neural signals from the periphery, the brain also detects chemical signals (including drugs, such as digitalis) that circulate in the blood. A wide variety of circulating humoral substances, including catecholamines, indoleamines, and peptides, directly contact neurons within the CNS by diffusing through the fenestrated capillaries of circumventricular organs that lack a blood-brain barrier (see Fig. 19-2). Activation of circumventricular organ neurons produces integrated autonomic, endocrine, and behavioral responses that can regulate salt and H₂O balance and nutrient homeostasis, in addition to cardiovascular function. The most important of the circumventricular organs for central autonomic control are the area postrema, subfornical organ, and organum vasculosum of the lamina terminalis.

Baroreceptor Reflex

The most rapidly acting autonomic control system for regulating blood pressure is the baroreceptor reflex. The principal role of this reflex is to ensure adequate organ perfusion, particularly to the brain and heart, and to promote return of blood to the heart in the face of conditions that lower arterial blood pressure. These might include gravitational pooling of blood, when assuming an upright posture, and instances where blood volume is lost, such as during severe dehydration or hemorrhage. The baroreceptor reflex is also activated when drugs are used to lower blood pressure in patients with cardiovascular disease, and this reflex may profoundly affect both the therapeutic effects and potential side effects that accompany drug therapy.

Minute-to-minute control of arterial blood pressure is achieved when small pressure changes are linked to reflex alterations in autonomic nerve activity. Sensory nerve endings embedded in the wall of the carotid sinus and aortic arch (baroreceptors) are activated by wall stretch when arterial pressure increases. This leads within a few seconds to an increase in vagal (parasympathetic) activity and a reduction in sympathetic activity. Parasympathetic activation slows heart rate, and sympathetic inhibition results in passive vasodilation, thus tending to return arterial pressure toward the original level. Conversely, a decrease in arterial pressure is rapidly countered by increased sympathetic and decreased parasympathetic activity. This results in vasoconstriction and an elevated cardiac rate and force of cardiac contraction. Organization of the baroreceptor reflex is illustrated in Figure 19-3.

FIGURE 19–3 Brainstem organization of the baroreceptor reflex and associated neurotransmitters. Primary pathways only are shown. Other afferents and interneurons are omitted. CVLM, caudal ventrolateral medulla; GABA, γ-aminobutyric acid; GLU, 1-glutamate; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; RVLM, rostral ventrolateral medulla; +, excitatory pathway; –, inhibitory pathway.

The baroreceptor reflex is important primarily in short-term control of blood pressure. When changes in blood pressure persist beyond a few minutes, reflex autonomic responses diminish. This is called baroreflex adaptation and involves both peripheral and CNS components. Varying degrees of baroreflex impairment occur with normal aging and in patients with heart failure or hypertension. This impairment may help to explain why some antihypertensive drugs are more effective in hypertensive than in normotensive patients, because lowering of blood pressure by antihypertensive drugs may be less effectively counteracted by baroreflex-mediated sympathetic vasoconstriction in these individuals.

The influence of baroreceptors on sympathetic nerve activity can vary greatly in different vascular beds. Some beds, such as the cutaneous vasculature, are largely independent of arterial baroreceptor influence and contribute little to total peripheral vascular resistance. In contrast, the baroreceptor reflex predominates in controlling sympathetic regulation of vascular caliber in many organs that receive a significant fraction of the cardiac output, such as skeletal muscle and kidney. For this reason baroreflex regulation of sympathetic vasoconstriction plays an important role in determining total peripheral resistance. In fact, except under some special circumstances (exercise, sleep, and certain behavioral states), baroreceptors are able to override all other inputs affecting autonomic regulation of arterial blood pressure. This may reflect the importance of maintaining a stable systemic blood pressure to ensure adequate organ perfusion under diverse environmental conditions.

REGULATION OF SYMPATHETIC ACTIVITY

One of the causes of hypertension is a relative increase in the balance between sympathetic and parasympathetic control over the heart and blood vessels. Increased sympathetic effects can be produced by increased neural firing rate, increased catecholamine concentration at the neuroeffector junction, and alterations at postjunctional receptors and signal transduction pathways. Although there is support for each of these mechanisms, the first two are probably most important, and drugs that inhibit sympathetically mediated cardiovascular effects are useful for treating hypertension.

Under physiological conditions, the amount of NE released is influenced by various chemicals, some of which are coreleased, such as neuropeptide Y and adenosine triphosphate, whereas others are released from postjunctional tissues, including angiotensin II, or are present in the circulation such as Epi (Table 19-2). Endogenous compounds that alter Ca⁺⁺, Na⁺, or K⁺ channel activity lead to alterations in vesicular NE release. In addition, the released transmitter itself, acting at prejunctional autoreceptors, and other transmitters or hormones acting at prejunctional heteroreceptors can affect NE release. Activation of prejunctional receptors modulates the probability that individual vesicles will discharge their contents by exocytosis congruent with depolarization; it does not affect the amount of transmitter released by individual vesicles. Activation of inhibitory autoreceptors by NE may function as a physiological brake on transmitter secretion during periods of high-frequency nerve discharge, thus limiting postjunctional responses. Agonists at heteroreceptors facilitating transmitter release such as angiotensin II amplify the effects of sympathetic nerve depolarization. In contrast, activation of inhibitory heteroreceptors, such as occurs with adenosine, reduces the probability of vesicular exocytosis and transmitter release. Some of these mechanisms are illustrated in Figure 19-4. It is important to remember that because local mechanisms regulating NE release differ in different tissues, similar rates of sympathetic nerve firing may produce different effects in different tissues.

TABLE 19–2 Prejunctional Modulators of Sympathetic Neurotransmitter Release