Adrenal Medulla, Catecholamines, and Pheochromocytoma

Adrenal Medulla and Catecholamines

The adrenal medulla occupies the central portion of the adrenal gland. Adrenomedullary cells are called chromaffin cells because they stain brown with chromium salts. Chromaffin cells differentiate in the center of the adrenal gland in response to cortisol; some chromaffin cells also migrate to form paraganglia. The largest cluster of chromaffin cells outside the adrenal medulla is near the level of the inferior mesenteric artery and is referred to as the organ of Zuckerkandl.

Catecholamines are substances that contain catechol ( o -dihydroxybenzene) and a side chain with an amino group—the catechol nucleus ( E-Fig. 209-1 ). Epinephrine, which is synthesized and stored in the adrenal medulla, is released into the systemic circulation. Norepinephrine is synthesized and stored not only in the adrenal medulla but also in the peripheral sympathetic nerves. Dopamine, the precursor of norepinephrine, is found in the adrenal medulla and peripheral sympathetic nerves.

Catecholamines have many cardiovascular and metabolic actions, including increasing the heart rate, blood pressure, myocardial contractility, and velocity of cardiac conduction. Three types of specific adrenergic receptors mediate their biologic actions: α, β, and DA. Their receptor subtypes are α ₁ , α ₂ , β ₁ , β ₂ , β ₃ , DA ₁ , and DA ₂ . The α ₁ subtype is a postsynaptic receptor that mediates vascular and smooth muscle contraction; stimulation causes vasoconstriction and increased blood pressure. The α ₂ -receptors are located on presynaptic sympathetic nerve endings and, when activated, inhibit the release of norepinephrine; stimulation causes suppression in central sympathetic outflow and decreased blood pressure. Stimulation of the β ₁ -receptor causes positive inotropic and chronotropic effects on the heart, increased renin secretion in the kidney, and lipolysis in adipocytes, as well as bronchodilation, vasodilation in skeletal muscle, glycogenolysis, and increased release of norepinephrine from sympathetic nerve terminals. The β ₃ -receptor regulates energy expenditure and lipolysis. DA ₁ receptors are localized to the cerebral, renal, mesenteric, and coronary vasculature; stimulation causes vasodilation in these vascular beds. DA ₂ receptors are presynaptic and localized to sympathetic nerve endings, sympathetic ganglia, and brain; their stimulation inhibits the release of norepinephrine, inhibits ganglionic transmission, and inhibits the release of prolactin.

Catecholamines are synthesized from tyrosine by a process of hydroxylation and decarboxylation (see E-Fig. 209-1 ). Tyrosine, which is derived from the diet or synthesized from phenylalanine in the liver, enters neurons and chromaffin cells by active transport. The conversion of tyrosine to 3,4-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase is the rate-limiting step in the synthesis of catecholamines. α-Methyl- p -tyrosine (metyrosine) is a tyrosine hydroxylase inhibitor that may be used therapeutically in patients with catecholamine-secreting tumors. Aromatic l -amino acid decarboxylase catalyzes the decarboxylation of dopa to dopamine. Dopamine is actively transported into granulated vesicles where it is hydroxylated to norepinephrine by the dopamine β-hydroxylase. These reactions occur in the synaptic vesicle of adrenergic neurons and the chromaffin cells of the adrenal medulla. In the adrenal medulla, norepinephrine is released from the granule into the cytoplasm, where phenylethanolamine N -methyltransferase converts it to epinephrine. Expression of phenylethanolamine N -methyltransferase is positively regulated by glucocorticoids. Catecholamine-secreting tumors that secrete primarily epinephrine are localized to the adrenal medulla. In normal adrenal medullary tissue, approximately 80% of the catecholamine released is epinephrine.

The biologic half-life of circulating catecholamines is between 10 and 100 seconds, so plasma concentrations of catecholamines can fluctuate widely. Catecholamines are removed from the circulation by either reuptake by sympathetic nerve terminals or metabolism through two enzyme pathways (see E-Fig. 209-1 ), followed by sulfate conjugation and renal excretion. Almost 90% of catecholamines released at sympathetic synapses are taken up locally by the nerve endings (i.e., uptake 1). Uptake 1 can be blocked by cocaine, tricyclic antidepressants, and phenothiazine. Extraneuronal tissues also take up catecholamines (i.e., uptake 2). Most of these catecholamines are metabolized by catechol- O -methyltransferase. Metanephrine and normetanephrine are oxidized by monoamine oxidase to vanillylmandelic acid by oxidative deamination. Monoamine oxidase may also oxidize epinephrine and norepinephrine to 3,4-dihydroxymandelic acid, which is then converted by catechol- O -methyltransferase to vanillylmandelic acid. In the storage vesicle, norepinephrine is protected from metabolism by monoamine oxidase. Monoamine oxidase and catechol- O -methyltransferase metabolize dopamine to homovanillic acid (see E-Fig. 209-1 ).

Pheochromocytoma and Paraganglioma