The hypothalamus receives neural afferents from blood vessels and viscera and samples the blood for hormones, substrates, ions, tonicity, and the like. SA outflow is adjusted to maintain the adequacy of the circulation, the provision of substrates for metabolizing tissues, and the appropriate level of visceral function. An example of hypothalamic integration may be illustrated in the response elicited by volume depletion. A fall in venous return triggers an increase in SNS outflow to the venous capacitance vessels, with the resultant venoconstriction increasing central blood volume. If the decrease in venous return is sufficiently great to cause a fall in blood pressure, the arterial baroreceptors trigger an increase in outflow to the resistance portion of the circulation, resulting in arteriolar vasoconstriction. At the same time, an increase in renin secretion is stimulated by the SNS, resulting in enhanced aldosterone secretion and the consequent increase in renal sodium reabsorption. Also at the level of the hypothalamus, the decrease in venous return
changes the relationship between vasopressin release and plasma tonicity so that more vasopressin is secreted at lower tonicity of the body fluids. The vasopressin response maintains the circulating plasma volume (albeit at a lower serum sodium) and supports arteriolar vasoconstriction. Thus, the integration within the hypothalamus results in coordinated changes in SNS outflow along with appropriate endocrine adaptation that supports the circulation. These changes reflect the redundancy and the hierarchy that characterize sympathetic responses.

Generalized SA discharge is most dramatic in the classic “fight or flight” response. These striking cardiovascular and metabolic changes first described by Walter Cannon permit rapid adaptation to abrupt environmental challenges. This should not, however, obscure the fact that the SA system is tonically active regulating blood flow distribution, cardiac output, substrate supply, and energy expenditure, to highlight but a few of the many functions that reflect the continuous discriminating outflow from the SA system.

As an efferent limb of the CNS, sympathetic responses are rapid in comparison with the slower effects induced by circulating hormones. Connections between the integrative centers in the hypothalamus, the tonically active brainstem centers, and the cerebral cortex provide the anatomic and neurophysiologic basis for conscious influence on autonomic functions. Among other things, these connections enable anticipation a role in physiologic regulation. It has been shown, for example, that in runners competing in a race, plasma renin rises before the race actually begins. This change, mediated by the SNS, defends against volume depletion in anticipation of strenuous exertion, thereby lessening the impact of the upcoming activity on the circulation and protecting the integrity of the internal environment.

It is well established, although not sufficiently appreciated, that the adrenal medulla and the SNS are regulated independently. Although these two limbs of the SA system always function in a coordinated manner, the activation is not always congruent. The classic view, best enunciated by Walter Cannon, is that the adrenal medulla supports the functions of the SNS with circulating E under conditions of “fight or flight.” Activation of both the adrenal medulla and the SNS is noted with exertion and cold exposure. There are, however, many situations in which the SNS is suppressed and the adrenal medulla is stimulated, such as hypoglycemia and severe trauma. The physiologic significance of this dissociation is discussed in subsequent sections.

In addition to the direct effect exerted by catecholamines on adrenergic receptors, several indirect effects also contribute to the physiologic responses regulated by the SA
system. These indirect effects include changes in blood flow, catecholamine-mediated changes in the secretion of other hormones, and the provision of substrate for metabolizing tissues. For example, during physical exercise, SA stimulation not only increases cardiac output directly but also distributes blood flow to the musculature; mobilizes substrates by stimulating glycogenolysis and lipolysis; suppresses insulin that aids in substrate mobilization; and stimulates renin that helps maintain plasma volume. The indirect effects reinforce the direct ones.

Well-developed mechanisms, in the form of mechanoreceptors, assess changes in pressure and relay these changes to the nucleus of the solitary tract (NTS) via the IXth and Xth cranial nerves. There are, however, no mechanisms that permit direct assessment of plasma volume. A surrogate, therefore, is utilized to determine volume status, namely changes in pressure in the capacitance (low-pressure) portion of the circulation. Mechanoreceptors in the great veins, pulmonary veins, and right atrium transmit impulses in cranial nerve X; an increase in pressure stimulates an increase in impulse traffic, which registers as adequate filling pressure and diminishes SNS outflow to the veins; a decrease in pressure indicates a fall in venous return and initiates an increase in SNS-mediated venoconstriction, which returns blood from the low-pressure portion of the circulation to the central pool, thereby restoring venous return.

The arterial baroreceptors, located principally in the aorta and carotid arteries, respond directly to changes in arterial pressure; mechanoreceptors in the adventitia of the arteries transmit impulses via the IXth and Xth cranial nerves to the NTS. Increases in BP suppress SNS outflow, whereas decreases stimulate SNS, resulting in arteriolar vasoconstriction and increased heart rate.

With standing, the fall in venous return decreases impulse traffic from the receptors in the great veins; at the level of the NTS, this decrease releases the tonic inhibition on the lower SNS centers, thereby increasing SNS outflow, causing venoconstriction that maintains venous return and prevents a fall in BP. If the arterial pressure dips, the arterial (high-pressure) mechanoreceptors come into play. Decreased impulse traffic, transmitted to the NTS, disinhibits the lower brainstem centers, resulting in enhanced SNS outflow, consequent arteriolar vasoconstriction, and an increase in heart rate. The smooth functioning of this system, operating continuously, prevents significant postural changes in blood pressure. The changes in SNS outflow are, of course, more pronounced in exigent situations such as severe volume depletion or hemorrhage.

The operation of this system demonstrates an important additional feature of SNS regulation: control by descending inhibition. Tonically active lower centers are under constant restraint from above, and regulation is achieved by modulating that restraint. This is an important principle of SNS regulation, presaged by the experiments of Sir Charles Sherrington in the late 19th century.

Changes in the partial pressure of oxygen, carbon dioxide, pH, insulin, glucose, leptin, angiotensin II, among others, all affect SNS outflow from the brainstem (RVLM) to the circulatory system. These are described in the appropriate sections that follow.

The predominant direct effect of catecholamines on the heart is postjunctional β₁-mediated cardiac stimulation (Fig. 2.1). Heart rate is increased (+ chronotropic effect), as is contractility (+ inotropic effect) and conduction velocity. The net effect is to increase cardiac output at the expense of increased myocardial oxygen consumption, which depends importantly on rate and contractile state (Table 2.1).

Vasoconstriction involving arteries and veins is the major effect of catecholamines on the vasculature. Both the α₁ and α₂ receptors mediate vascular smooth muscle contraction, but significant heterogeneity in the disposition of receptor subtypes exists depending on the vascular bed, size of artery, and location of veins. Large arteries, in general, possess α₁ receptors, deep veins favor α₁ receptors, and both receptor subtypes mediate constriction in the arteriolar resistance vessels. There appears to be a regulatory component to the disposition of α receptor subtypes in veins: α₁ receptors predominate in deep veins, and these are associated with diminished responsiveness to NE in the cold; α₂ receptors are more prevalent in the superficial veins, and cold enhances α₂ responses in the superficial venous system. The net result of these changes is shunting of blood to the deep system during cold exposure, thus conserving heat, rather than dissipating it to the environment.

SNS stimulation enhances venous return by venoconstriction, by a direct effect to enhance renal tubular sodium reabsorption, and by stimulation of renin release with the generation of angiotensin II and an increase in aldosterone.

Although controversy has existed about the role, if any, of sympathetically mediated vasodilation, it is clear that in humans that role is inconsequential at best. Evidence for cholinergic vasodilatory neurons within the sympathetic outflow in humans is scant to nonexistent. β₂-mediated vasodilation is demonstrable in
the presence of α blockade, but in unblocked subjects it occurs only at very low circulating levels of E. The local release of nitrous oxide in stimulated tissues may account for some of the vasodilatory effects attributed to catecholamines. Taken together, the effects of catecholamines on the cardiovascular system increase cardiac output, increase blood pressure, and increase myocardial oxygen consumption (Table 2.1).