The adrenal medulla secretes catecholamines (epinephrine, norepinephrine, and dopamine). The catecholamines help prepare the individual to deal with emergency situations. The major disorder of the adrenal medulla is pheochromocytoma, a neoplasm characterized by excessive catecholamine secretion.

Anatomy

The adrenal medulla is the reddish-brown central portion of the adrenal gland. Accessory medullary tissue is sometimes located in the retroperitoneum near the sympathetic ganglia or along the abdominal aorta (paraganglia) (Figure 12–1).

The adrenal medulla is made up of polyhedral cells arranged in cords or clumps. Embryologically, the adrenal medullary cells derive from neural crest cells. Medullary cells are innervated by cholinergic preganglionic nerve fibers that reach the gland via the splanchnic nerves. The adrenal medulla can be regarded as a specialized sympathetic ganglion, where preganglionic sympathetic nerve fibers (using acetylcholine as a neurotransmitter) directly make contact with postganglionic cells, which secrete catecholamines (mainly epinephrine) directly into the circulation. This relationship is analogous to the other sympathetic paraganglions, which connect preganglionic cholinergic sympathetic nerve fibers with postganglionic fibers using catecholamines (mainly norepinephrine) as neurotransmitters. Medullary parenchymal cells accumulate and store their hormone products in prominent, dense secretory granules, 150–350 nm in diameter. Histologically, these cells and granules have a high affinity for chromium salts (chromaffin reaction) and thus are called chromaffin cells and contain chromaffin granules. The granules contain the catecholamines epinephrine and norepinephrine. Morphologically, two types of medullary cells can be distinguished: epinephrine-secreting cells, which have larger, less dense granules, and norepinephrine-secreting cells, which have smaller, very dense granules. Separate dopamine-secreting cells have not been identified. Ninety percent of medullary cells are the epinephrine-secreting type and 10% are the norepinephrine-secreting type.

The catecholamines help to regulate metabolism, contractility of cardiac and smooth muscle, and neurotransmission.

Formation, Secretion, & Metabolism of Catecholamines

The adrenal medulla secretes three catecholamines: epinephrine, norepinephrine, and dopamine. Secretion occurs after release of acetylcholine from the preganglionic neurons that innervate the medullary cells. The major biosynthetic pathways and hormonal intermediates for the catecholamines are shown in Figure 12–2. In humans, most (80%) of the catecholamine output of the adrenal medulla is epinephrine. Norepinephrine is principally found in paraganglionic nerve endings of the sympathetic nervous system and in the CNS, where it functions as a major neurotransmitter.

Approximately 70% of the epinephrine and norepinephrine and 95% of the dopamine found in plasma are conjugated to sulfate and inactive. In the supine state, the normal plasma level of free epinephrine is about 30 pg/mL (0.16 nmol/L); there is a 50–100% increase on standing. The normal plasma level of free norepinephrine is about 300 pg/mL (1.8 nmol/L), and the plasma free dopamine level is about 35 pg/mL (0.23 nmol/L).

Most catecholamine metabolism takes place within the same cells where they are synthesized, mainly because of leakage of catecholamines from vesicular stores into the cytoplasm. These vesicular stores exist in a dynamic equilibrium, with outward passive leakage counterbalanced by inward active transport that is controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase in the cytoplasm leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes is dependent on the dynamics of the vesicular-axoplasmic monoamine exchange and an enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol. Subsequent extraneuronal O-methylation leads to production of 3-methoxy-4-hydroxyphenylglycol, and its oxidation in the liver catalyzed by alcohol and aldehyde dehydrogenases leads to formation of vanillylmandelic acid (VMA). Compared with intraneuronal deamination, extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represents minor pathways of metabolism.

The single largest source of metanephrine is the adrenal medulla. In the circulation, the catecholamines have a short half-life of about 2 min. Normally, only very small quantities of free epinephrine (about 6 μg/d) and norepinephrine (about 30 μg/d) are excreted, but about 700 μg of VMA is excreted daily.

Regulation of Catecholamine Secretion

Physiologic stimuli affect medullary secretion through the nervous system. Medullary cells secrete catecholamines after release of acetylcholine from the preganglionic neurons that innervate them. Catecholamine secretion is low in the basal state and is reduced even further during sleep. In emergency situations, there is increased adrenal catecholamine secretion as part of a generalized sympathetic discharge that serves to prepare the individual for stress (“fight-or-flight” response). Physiological stress such as psychological, physical (eg, mechanical, thermal), and metabolic (eg, hypoglycemia, exercise) stress leads to catecholamine secretion.

Mechanism of Action of Catecholamines

The effects of epinephrine and norepinephrine are mediated by their actions on two classes of receptors: α- and β-adrenergic receptors (Table 12–1). Alpha receptors are subdivided into α₁ and α₂ receptors and β receptors into β₁, β₂, and β₃ receptors. Alpha₁ receptors mediate smooth muscle contraction in blood vessels and the genitourinary (GU) tract and increase glycogenolysis. Alpha₂ receptors mediate smooth muscle relaxation in the GI tract and vasoconstriction of some blood vessels. Alpha₂ receptors also decrease insulin secretion. Beta₁ receptors mediate an increased rate and force of myocardial contraction and stimulate lipolysis and renin release. Beta₂ receptors mediate smooth muscle relaxation in the bronchi, blood vessels, GU tract, and GI tract and increase hepatic gluconeogenesis and glycogenolysis, muscle glycogenolysis, and release of insulin and glucagon.

Intracellular post-receptor signaling is different for each subclass of adrenergic receptor. Stimulation of α₁-adrenergic receptors results in an increase in intracellular Ca²⁺ concentrations. First, there is activation of phospholipase C by the guanine nucleotide binding stimulatory protein, G_s. Phospholipase C hydrolyzes the membrane-bound phospholipid, phosphatidylinositol-4,5-bisphosphate, to generate two second messengers: diacylglycerol and inositol-1,4,5-trisphosphate. Diacylglycerol in turn activates protein kinase C, which phosphorylates various cellular substrates. Inositol-1,4,5-trisphosphate stimulates release of intracellular Ca²⁺, which then initiates various cellular responses.

Activation of α₂-adrenergic receptors results in a decrease in intracellular cyclic adenosine 3′,5′-monophosphate (cAMP). The mechanism involves receptor interaction with an inhibitory G protein, G_i, leading to inhibition of adenylyl cyclase. The fall in cAMP level leads to a decrease in activity of the cAMP-dependent protein kinase A. The G_i protein also stimulates K⁺ channels and inhibits voltage-sensitive calcium channels.

On the other hand, β-adrenergic receptors stimulate adenylyl cyclase through the mediation of G_s. Activation of β-adrenergic receptors thus leads to an increase in cAMP, activation of the cAMP-dependent protein kinase A, and consequent phosphorylation of various cellular proteins. The G_s protein can also directly activate voltage-sensitive Ca²⁺ channels in the plasma membrane of cardiac and skeletal muscle.

The α₁– and β₁-adrenergic receptors are generally found in organs and tissues (eg, heart and gut) that are heavily innervated by—and situated so as to be readily activated by stimulation of—the sympathetic nerves. The α₁– and β₁-adrenergic receptors are preferentially stimulated by norepinephrine, especially that released by nerve endings. In contrast, the α₂– and β₂-adrenergic receptors are generally situated in postjunctional sites in organs and tissues (eg, uterine and bronchial skeletal muscle) remote from sites of norepinephrine release. The α₂– and β₂-adrenergic receptors are preferentially stimulated by circulating catecholamines, especially epinephrine.

Differences in tissue distribution, accessibility by nerve fibers, preferences for epinephrine versus norepinephrine, and differences in postreceptor signaling are thus responsible for the diverse effects of catecholamines in an organ- and cell-specific manner.

Effects of Catecholamines

The catecholamines have been termed fight-or-flight hormones because their effects on the heart, blood vessels, smooth muscle, and metabolism assist the organism in responding to stress. The principal physiologic effects of the catecholamines are shown in Table 12–1.

In the peripheral circulation, norepinephrine produces vasoconstriction in most organs (via α₁ receptors). Epinephrine produces vasodilation via β₂ receptors in skeletal muscle and liver and vasoconstriction elsewhere. The former usually outweighs the latter, and for that reason epinephrine usually lowers total peripheral resistance.

Norepinephrine causes both systolic and diastolic blood pressures to rise. The rise in blood pressure stimulates the carotid and aortic baroreceptors, resulting in reflex bradycardia and a fall in cardiac output. Epinephrine causes a widening of pulse pressure but does not stimulate the baroreceptors to the same degree, so the pulse rises and cardiac output increases.

Hence, pheochromocytomas or other tumors of the adrenal medulla, which usually secrete norepinephrine, lead to vasoconstriction and an increase in blood pressure.

The effects of catecholamines on metabolism include effects on glycogenolysis, lipolysis, and insulin secretion, mediated by both α- and β-adrenergic receptors. These metabolic effects result primarily from the action of epinephrine on four target tissues: liver, muscle, pancreas, and adipose tissue (see Table 12–1). The result is an increase in the levels of circulating glucose and free fatty acids. The increased supply of these two substances helps provide an adequate supply of metabolic fuel to the nervous system and muscle during physiologic stress.

The amount of circulating plasma epinephrine and norepinephrine needed to produce these various effects has been determined by infusing the catecholamines into resting subjects. For norepinephrine, the threshold for the cardiovascular and metabolic effects is a plasma level of about 1500 pg/mL, or about five times the basal level. In normal individuals, the plasma norepinephrine level rarely exceeds this threshold. However, for epinephrine, the threshold for tachycardia occurs at a plasma level of about 50 pg/mL, or about twice the basal level. The threshold for increasing systolic blood pressure and lipolysis is at about 75 pg/mL; for increasing glucose and lactate, about 150 pg/mL; and for increasing insulin secretion, about 40 pg/mL. In healthy individuals, plasma epinephrine levels often exceed these thresholds.

The physiologic effect of circulating dopamine is unknown. Centrally, dopamine acts to inhibit prolactin secretion. Peripherally, in small doses, injected dopamine produces renal vasodilation, probably by binding to a specific dopaminergic receptor. In moderate doses, it also produces vasodilation of the mesenteric and coronary circulation and vasoconstriction peripherally. It has a positive inotropic effect on the heart, mediated by action on the β₁-adrenergic receptors. Moderate to large doses of dopamine increase the systolic blood pressure without affecting diastolic pressure.

Overview of Adrenal Medullary Disorders

Pheochromocytoma

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