The Role of the Sympathoadrenal System in Physiologic Adaptation and the Pathophysiology of Disease States

The SA system is essential for adaptation to external and internal threats that challenge the constancy of the internal environment. The SA effects are manifold combining direct effects on adrenergic receptors with coordinated changes in blood flow and hormone secretion.

Cold Exposure

Survival in the cold was a critical development in the evolution of mammals. The integrated response to cold exposure includes heat generation and heat conservation dependent upon SA regulation of metabolism and the cardiovascular system. Both the SNS and the adrenal medulla are involved with the SNS playing the dominant role. Temperature-sensing neurons in the hypothalamus, brainstem and spinal cord, as well as in the skin, initiate the SA response to a fall in temperature. SNS activation in the cold is shown in Figure 1.15 in laboratory rodents for heart; similar changes occur in BAT.

Heat conservation

Peripheral arterial and superficial venous constriction limits blood flow to the skin diminishing heat loss and improving the insulating capacity of the subcutaneous tissues. Venoconstriction is most marked in the superficial veins of the extremities which are endowed with more α₂ adrenergic receptors than the deep veins where α₁ receptors predominate. As external cooling decreases the affinity of the venous α₁ receptors (deep veins) to NE while, conversely, increasing the affinity for NE on the α₂ receptors (superficial veins), cold exposure shifts blood to the deep venous system. Increased blood flow to the deep veins of the limbs, which forms a plexus around the arteries, increases the efficiency of the countercurrent mechanism that removes heat from the arterial circulation and returns it to the central venous system. The circulation to the limbs thus plays a significant role in both heat conservation and heat loss.

Heat generation: nonshivering thermogenesis and cold acclimation

Shivering thermogenesis refers to the heat produced by muscular contractions induced by cold exposure. Shivering is mediated by the somatic nervous system but is apparently facilitated by catecholamines. In fur-bearing mammals, piloerection provides insulation; in humans, this has little effect on heat conservation but produces well-recognized “goose pimples” or “goose bumps.” Piloerection is mediated by the α₁ receptor.

Nonshivering thermogenesis (NST) refers to metabolic heat production in response to cold exposure. It has been studied extensively in laboratory rodents. BAT is the origin of the heat produced. The SNS turns on heat production via the β₃ adrenergic receptor as described in the previous section. The SNS also drives the hypertrophy of BAT that accompanies cold acclimation. Cold acclimation, which occurs after prolonged exposure to cold, greatly potentiates heat production in BAT (Fig. 3.1), a consequence of the enlarged mass of BAT and the important fact that tachyphylaxis does not occur with prolonged stimulation as the β₃ receptor, unlike other β receptors, does not undergo desensitization. Cold acclimation in fact is defined by an enhanced thermogenic response to NE.

Although generally recognized as a significant physiologic process in humans at present, the concept of regulated production of metabolic heat in large adult mammals has had a checkered history and was commonly regarded with skepticism until the 1970s. The issue was settled by experiments on army recruits who, after prolonged cold exposure, stopped shivering and increased metabolic rate, thus demonstrating that cold acclimation and NST had occurred. The site of origin of NST in humans remained controversial until the last decade when functioning BAT was unequivocally demonstrated by positon emission tomography scans, biopsy, and the demonstration of UCP 1 in fat depots identified in imaging studies.

The anatomic location of BAT, adjacent to the great vessels, and the vascularity of BAT maximize distribution of the heat throughout the body.

FIGURE 3.1. NE-stimulated thermogenesis in the rat: effect of cold acclimation. NE increases oxygen consumption (and rectal temperature), in both cold-acclimated (closed circle) and warm-acclimated (open circle) curarized rats. The effect is markedly enhanced in cold-acclimated animals; it is the hallmark of cold acclimation. NE, norepinephrine. (From Hseih ACL, Carlson LD, Gray G. Role of the sympathetic nervous system in the control of chemical regulation of heat production. Am J Physiol. 1957;190:247-251.)

Cardiovascular changes in cold exposure

In addition to the vasoconstrictive changed induced by the SNS during heat conservation as described above, cardiac stimulation driven by the SNS increases cardiac output. This serves the function of distributing heat generated by NST and delivering substrates for metabolizing tissues throughout the body. In acute cold exposure, blood pressure is elevated but the rise in BP is not sustained.

Substrate mobilization in cold exposure

The SA system stimulates lipolysis and glycogenolysis during cold exposure both directly and by suppressing the release of insulin and stimulating the release of glucagon. SA activation of hormone-sensitive lipase, lipoprotein lipase, and stimulation of hepatic glucose output are involved in the response to cold exposure.

Exercise and Physical Training

As a critical component of the “fight or flight” response, it is no surprise that exercise is associated with significant SA activation (Fig. 3.2). The enhanced activity of the SNS and adrenal medulla originates in the conscious and autonomic portions of the CNS. SA outflow during exercise is further modulated by changes in circulating levels of hormones and substrates and by the physical and chemical properties of the blood such as temperature, tonicity, pH, and oxygen and carbon dioxide tension. The SA system response is designed to address three major requirements of strenuous exertion: (1) the provision of oxygen and metabolic substrates to contracting muscle; (2) the need to dissipate excess heat generated by muscle contraction; and (3) maintenance of an adequate plasma volume. Training decreases SNS activity both during exercise and at rest (Figs. 3.2 and 3.3).

FIGURE 3.2. Plasma concentrations before and after training are compared at rest, at 40 minutes of exercise, and just before exhaustion. (From Hartley LH, Mason JW, Hogan RP, et al. Multiple hormonal responses to prolonged exercise in relation to physical training. J Appl Physiol. 1972;33:607-610.)

FIGURE 3.3. Bar graph shows the mean arterial plasma concentration of NE and epinephrine (E) for the sedentary and training phases. Plasma NE concentration was reduced by 48.3 pg per mL or 21% with training, whereas plasma E concentration remained unchanged. SED, standard error of the difference. NE, norepinephrine. (From Meredith IT, Friberg P, Jennings GL, et al. Exercise training lowers resting renal but not cardiac sympathetic activity in humans. Hypertension. 1991;18:575-582.)

Cardiovascular effects of the sympathoadrenal system in exercise

Cardiac output is increased by the inotropic and chronotropic effects of catecholamines on the heart and the increase in venous return that occurs with venoconstriction and with the increase in blood flow from exercising muscle. The splanchnic and renal circulations are constricted whereas flow to the heart and skeletal muscle is increased due in large measure to the buildup of vasodilator metabolites such as lactate (from glycogenolysis) and purine metabolites (derived from ATP). The BP rises, often substantially, assuring perfusion of muscle and heart. Plasma volume is defended in the presence of sweating and evaporative fluid loss by enhanced renal sodium reabsorption, a direct effect of the SNS and the stimulation of renin release with the consequent production of angiotensin II (A II) and aldosterone. Heat is dissipated by cutaneous vasodilation and eccrine sweating, the later mediated by cholinergic sympathetic nerves to the sweat glands.

Substrate mobilization

Activation of the SA system provides substrate to support the increased metabolism in skeletal and cardiac muscle. Both circulating epinephrine (E) and SNS activity participate in the increased production of free fatty acids (FFA) and glucose that occurs during exercise. Suppression of insulin release by the SNS plays an important role and reinforces the direct effects of catecholamines on mobilization of substrates from energy stores in adipose tissue, skeletal muscle, and liver. Stimulation of hormone-sensitive lipase in adipocytes results in the liberation of FFA and glycerol; activation of phosphorylase in liver provides glucose from glycogen while muscle phosphorylase produces glucose for local consumption in muscle and provides lactate which is added to the general circulation. Gluconeogenesis in liver utilizes the glycerol and lactate produced in adipose tissue and glycogen, respectively.

Dietary Intake: Fasting and Overfeeding

Dietary intake exerts important effects on SA activity. The underlying physiologic mechanisms have been well worked out. The activity of the adrenal medulla and the SNS, although coordinated, is not congruent during fasting.

Fasting results in suppressed sympathetic nervous system activity and slightly stimulated adrenal medullary activity

As fasting is associated with the mobilization of substrates from energy stored as triglycerides and glycogen, and from increased gluconeogenesis, all processes stimulated by catecholamines, it had been widely assumed that fasting was associated with increased SNS activity. This supposition was dispelled in the 1970s when experiments employing NE turnover techniques demonstrated unequivocally that fasting suppresses the SNS (Fig. 3.4), as shown by the line of lesser scope. This decrease in SNS activity occurs in humans as well as in laboratory rodents (Fig. 3.5). Although well established, this effect of fasting on the SNS is insufficiently appreciated. As shown in Fig. 3.5, in distinction to the stimulation of the SNS, adrenal medullary activity is mildly increased during a fast. The increase in E is small but significant and much different from the huge increase in E secretion that occurs during hypoglycemia.

Three questions immediately arise in light of these facts: (1) How are substrates mobilized during fasting? (2) What physiologic function is subserved by SNS suppression? (3) What are the signals that link the SNS and dietary intake?

Substrate mobilization depends heavily on the fall in insulin secretion that accompanies fasting. This decrease in circulating insulin in conjunction with the small rise in E stimulates lipolysis and hepatic glucose output. Fibroblast growth factor 21 has also been proposed to stimulate lipolysis during fasting but this effect is controversial.
Suppression of the SNS during fasting subserves the useful function of diminishing energy expenditure, a conservative mechanism that would prolong survival during fasting.
The physiologic mechanisms linking dietary intake with SNS activity have been well worked out: decreased insulin-mediated glucose uptake and metabolism in neurons of the ventromedial hypothalamus stimulates an inhibitory pathway to tonically active SNS neurons in the brainstem (Fig. 3.6). During fasting, the small fall in glucose and the larger fall in insulin decrease insulin-mediated glucose metabolism in the insulin-sensitive neurons of the ventromedial hypothalamus. This decrease in glucose metabolism stimulates an inhibitory pathway from the hypothalamus to the tonically active SNS neurons in the brainstem resulting in suppression of central sympathetic outflow. This is an example of regulation by descending inhibition, a fundamental principal elaborated by the famous British neurophysiologist Sir Charles Sherrington. Evidence for this sequence is summarized in Table 3.1.

FIGURE 3.4. Fasting decreases NE turnover in heart. (Modified From Young JB, Landsberg L. Suppression of sympathetic nervous system during fasting. Science. 1977;196:1473-1475.)

FIGURE 3.5. Effect of fasting on urinary catecholamine excretion in young, normal weight men. ^**P < .001. NE, norepinephrine; E, epinephrine. (From Young JB, Rosa RM, Landsberg L. Dissociation of sympathetic nervous system and adrenal medullary responses. Am J Physiol. 1984;247:E35-E40.)

FIGURE 3.6. Model of dietary effects on SNS activity. (Modified From Young JB, Landsberg L. Impaired suppression of sympathetic activity during fasting in the gold thioglucose-treated mouse. J Clin Invest. 1980;65:1086-1094.)

TABLE 3.1 Insulin-Mediated Glucose Uptake in the VMH Regulates SNS Activity in Response to Diet

Fasting suppresses the SNS
Glucose stimulates the SNS
Hypoglycemia suppresses the SNS
2-Deoxyglucose suppresses the SNS

– Blocks intracellular glucose metabolism
Insulin stimulates the SNS
Gold thioglucose treatment (ablates the insulin glucose-sensitive VMH neurons) blocks the suppressive effect of fasting

– SNS suppression with fasting is secondary to descending inhibition

VMH, ventromedial hypothalamus; SNS, sympathetic nervous system.

Feeding carbohydrates and fat, and overfeeding a mixed diet stimulates the sympathetic nervous system

In laboratory rodents, carbohydrates and fat added to the usual chow diet stimulates the SNS (Figs. 3.7 and 3.8). Dietary protein, in contrast, is without effect even when added as excess calories (Fig. 3.9). Overfeeding a mixed (“cafeteria”) diet also activates the SNS (Fig. 3.10). The link between diet and the SNS involves insulin and glucose and is the converse of that described above for fasting (Fig. 3.6). During feeding or overfeeding, the small rise in glucose and the large rise in insulin increases insulin-mediated glucose metabolism in the hypothalamic neurons thereby decreasing activity in the inhibitory pathway to the brainstem with release of the tonically active SNS neurons and an increase in central sympathetic outflow. These dietary effects occur in humans as well as in small mammals. The stimulatory effect of euglycemic insulin infusions on SNS activity in humans is shown in Figure 3.11.

FIGURE 3.7. Effect of sucrose on cardiac NE turnover. (From Young JB, Landsberg L. Stimulation of the sympathetic nervous system during sucrose feeding. Nature. 1977;269:615-617.)

FIGURE 3.8. Effect of a fat-enriched diet on NE turnover in rat heart. Data are plotted as the means ± SEM for specific activity of hearts from four to six animals from each group at each time point. Open circles denote chow-fed rats (control), whereas closed circles represent fat-fed rats (control). The slope k, of each turnover line is significant at P < 0.0001. (From Schwartz JH, Young JB, Landsberg L. Effect of dietary fat on the sympathetic nervous system activity in the rat. J Clin Invest. 1983;72:361-370.)

Although the survival value of SNS suppression in the face of limits imposed on dietary intake is obvious in terms of decreased metabolic rate and conservation of fuel stores, the stimulatory effect of dietary excess on the SNS is less clear but is likely related to the metabolic adaptation to a low protein diet.

During the course of mammalian evolution, protein has been the limiting nutrient for growth and development, as pointed out by Harvard Professor George Cahill. The capacity to increase sympathetically mediated thermogenesis in the face of excess fat and carbohydrate would permit an organism on a subsistence diet deficient in essential nutrients to overeat the deficient diet, thereby fulfilling the requirements for the limiting nutrient (protein) while dissipating the excess calories as heat. The capacity to dissipate excess calories known as dietary thermogenesis, a mechanism entirely analogous to NST, would allow an organism to overeat and burn the extra calories rather than store them as fat. In this manner, dietary requirements for growth and development could be met without excess calorie storage as fat. Consistent with this interpretation is the fact that protein does not stimulate the SNS (Fig. 3.9) and that low protein diets are extremely stimulatory (Fig. 3.12).

FIGURE 3.9. No effect of casein on [³H]NE turnover in heart (A) and IBAT (B). Animals were fed either a 2:1 mixture of chow and casein or chow alone for 5 days before the study. At the start of the turnover measurement, all rats received an intravenous injection of [³H]NE (100 µCi/kg) and were killed at various times over the ensuing 24 hours. In the figure, data are plotted as means for specific activity of NE in heart and IBAT from four to six animals in each group at each time point. Closed circles and the solid line represent rats given chow + casein; open triangles and the broken line represent animals given chow alone. The numbers in parentheses refer to the half-time disappearance of tracer (t_1/2). (From Kaufman LN, Young JB, Landsberg L. Effect of protein on sympathetic nervous system activity in the rat. Evidence for nutrient-specific responses. J Clin Invest. 1986;77:551-558.)

FIGURE 3.10. Effect of overfeeding on NE turnover in heart and BAT. (Modified data from Young JB, Saville E, Rothwell NJ, et al. Effect of diet and cold exposure on norepinephrine turnover in brown adipose tissue of the rat. J Clin Invest. 1982;69:1061-1071.)

FIGURE 3.11. Effect of insulin on SNS activity. A: (From Rowe JW, Young JB, Minaker KL, et al. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes. 1981;30(3):219-225.) B: (From Hausberg M, Mark AL, Hoffman RP, et al. Dissociation of sympathoexcitatory and vasodilator actions of modestly elevated plasma insulin levels. J Hypertension. 1995;13:1015-1021.)

FIGURE 3.11. (continued)

Hypoglycemia

In terms of cerebral metabolism, low glucose is equivalent to hypoxia; both oxygen and glucose are needed for normal brain function. When the plasma glucose falls below normal fasting levels, a series of hormonal (counter-regulatory) responses ensue in order to raise the blood sugar level toward normal.

FIGURE 3.12. Effect of 12 days of 7% protein feeding on [3H]NE turnover in rats. Open circles, rats fed 22% protein; closed circles, rats fed 7% protein. Feeding 7% protein increased NE turnover in heart and IBAT compared with 22% protein. (From Young JB, Kaufman LN, Saville ME, et al. Increased sympathetic nervous system activity in rats fed a low-protein diet. Am J Physiol. 1985;248:R627-R637.)

Glucose counter-regulation

E and glucagon are the principal counter-regulatory hormones. They both increase hepatic glucose output. In addition (Table 3.2), E stimulates lipolysis which provides alternative substrates (FFA) for use in tissues such as muscle, thereby sparing glucose for the brain, which requires glucose. E also suppresses endogenous insulin release by an α adrenergic effect on the pancreatic β cells, and inhibits insulin-mediated glucose uptake in muscle, thereby increasing glucose availability for the brain (Table 3.2).

Hypoglycemia is sensed in the ventromedial hypothalamus as well as in other areas of the brainstem. These glucose-sensitive neurons stimulate E secretion from the adrenal medulla (Fig. 3.13). Hypoglycemia, as noted above, suppresses the SNS; the rise in plasma NE, that accompanies the much larger rise in E, originates from the adrenal medulla (Fig. 3.13). E levels gradually increase as the blood sugar falls within the normal range (90 to 65 mg per dL). At levels below 50 mg per dL, the increase in adrenal medullary E is particularly intense, increasing 25 to 50 times baseline.

TABLE 3.2 Counter-Regulatory Effects of Epinephrine

Increases glucose production

– Glycogenolysis and gluconeogenesis in liver

– Stimulation of glucose production from lactate derived from skeletal muscle (Cori cycle)
Increases in lipolysis

– Provision of alternative substrates (free fatty acids) for tissues outside the brain
Inhibits insulin-mediated glucose uptake in skeletal muscle

– Increases glucose availability for the brain
Suppresses endogenous insulin release

– Direct effect on pancreatic β cells
Hypoglycemia awareness

– Tremor, palpitations, anxiety → food-seeking behavior

FIGURE 3.13. Effect of insulin-induced hypoglycemia on plasma epinephrine and norepinephrine levels. After an intravenous injection of 0.15 units per kg of regular insulin at time 0, plasma levels of epinephrine rise 50-fold in normal human subjects. (Reproduced from Garber AJ, et al. The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man. J Clin Invest. 1976;58:7-15, by copyright permission of The American Society for Clinical Investigation.)

FIGURE 3.14. Effect of 2 DG on rectal temperature. (From Freinkel N, Metzger BE, Harris E, et al. The hypothermia of hypoglycemia. Studies with 2-deoxy-D-glucose in normal human subjects and mice. N Engl J Med. 1972;287:841.)

In addition to the provision of glucose, E secretion during hypoglycemia provokes tachycardia, increased pulse pressure, tremor, and anxiety. These adrenergic symptoms constitute an early warning system that alerts the subject to the development of hypoglycemia. Profuse sweating (eccrine rather than adrenergic) also occurs mediated not by E but rather by cholinergic sympathetic nerves. The sweating is induced by the fall in temperature set point that accompanies acute hypoglycemia (Fig. 3.14); the sweating is the mechanism that induces the fall in temperature to meet the new temperature set point.

Hypoglycemia unawareness in diabetics

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