Ch

chromaffin granule

FIGURE 21 Biosynthetic sequence for epinephrine (E) and norepinephrine (N) in adrenal medullary cells. TH, tyrosine hydroxylase; AAD, aromatic L-amino acid decarboxylase (also called DOPA decarboxylase); DBH, dopamine beta-hydroxylase; PNMT, phenyletha-nolamine-N-methyltransferase.

Biosynthesis of the Medullary Hormones

The biosynthetic pathway for epinephrine and nore-pinephrine is shown in Fig. 21. Hydroxylation of tyrosine to form dihydroxyphenylalanine (DOPA) is the rate-determining reaction and is catalyzed by the enzyme tyrosine hydroxylase. Activity of this enzyme is inhibited by catecholamines (product inhibition) and stimulated by phosphorylation. In this way, regulatory adjustments are made rapidly and are closely tied to bursts of secretion. A protracted increase in secretory activity induces synthesis of additional enzyme after a lag time of about 12 hr.

Tyrosine hydroxylase and DOPA decarboxylase are cytosolic enzymes, but the enzyme that catalyzes the ft-hydroxylation of dopamine to form norepinephrine resides within the secretory granule. Dopamine is pumped into the granule by an energy-dependent, stereospecific process. For sympathetic nerve endings and those adreno-medullary cells that produce norepinephrine, synthesis is complete with the formation of norepinephrine, and the hormone remains in the granule until it is secreted. Synthesis of epinephrine, however, requires that norepi-nephrine reenter the cytosol for the final methylation reaction. The enzyme required for this reaction, phenylethanolamine-N-methyltransferase (PNMT), is at least partly inducible by glucocorticoids. Induction requires concentrations of cortisol that are considerably higher than those found in peripheral blood. The vascular arrangement in the adrenals is such that interstitial fluid surrounding cells of the medulla can equilibrate with venous blood that drains the cortex and therefore has a much higher content of glucocorticoids than arterial blood. Glucocorticoids may thus determine the ratio of epinephrine to norepinephrine production. Once methylated, epinephrine is pumped back into the storage granule, whose membrane protects stored catechola-mines from oxidation by cytosolic enzymes.

Storage, Release, and Metabolism

Catecholamines are stored in secretory granules in close association with ATP and at a molar ratio of 4:1, suggesting some hydrostatic interaction between the positively charged amines and the four negative charges on ATP. Some opioid peptides, including the enkepha-lins, ft endorphin, and their precursors, are also found in these granules. Acetylcholine released during neuronal stimulation increases sodium conductance of the chromaffin cell membrane. The resulting influx of sodium ions depolarizes the plasma membrane, leading to an influx of calcium through voltage-sensitive channels. Calcium is required for catecholamine secretion. Increased cytosolic concentrations of calcium promote phosphorylation of microtubules and the consequent translocation of secretory granules to the cell surface. Secretion occurs when membranes of the chromaffin granules fuse with plasma membranes and the granular contents are extruded into the extracellular space. Fusion of the granular membrane with the cell membrane may also require calcium. ATP, opioid peptides, and other contents of the granules are released along with epinephrine and norepinephrine. As yet, the physiologic significance of opioid secretion by the adrenals is not known, but it has been suggested that the analgesic effects of these compounds may be of importance in the stress response.

All of the epinephrine in blood originates in the adrenal glands. However, norepinephrine may reach the blood by either adrenal secretion or diffusion from sympathetic synapses. The half-lives of medullary hormones in the peripheral circulation have been estimated to be less than 10 sec for epinephrine and less than 15 sec for norepinephrine. Up to 90% of the catechola-mines are removed in a single passage through most capillary beds. Clearance from the blood requires uptake by both neuronal and non-neuronal tissues. Significant amounts of norepinephrine are taken up by sympathetic nerve endings and incorporated into secretory granules for release at a later time. Epinephrine and norepinephr-ine that are taken up in excess of storage capacity are degraded in neuronal cytosol principally by the enzyme monoamine oxidase (MAO). This enzyme catalyzes oxidative deamination of epinephrine, norepinephrine, and other biologically important amines (Fig. 22). Cate-cholamines taken up by endothelium, heart, liver, and other tissues are also inactivated enzymatically, principally by catecholamine-O-methyl-transferase (COMT), which catalyzes transfer of a methyl group from S-adenosyl methionine to one of the hydroxyl groups. Both of these enzymes are widely distributed and can act sequentially in either order on both epinephrine and norepinephrine. A number of pharmaceutical agents have been developed to modify the actions of these enzymes and thus modify sympathetic responses. Inactivated catecholamines, chiefly vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), are conjugated with sulfate or glucuronide and excreted in urine. As with steroid hormones, measurement of urinary metabolites of catecholamines is a useful, nonin-vasive source of diagnostic information.

Physiologic Actions of Medullary Hormones

The sympathetic nervous system and adrenal medullary hormones, like the cortical hormones, act on a wide norepinephrine

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