Adrenal Medulla

Chromaffin Cells

The adrenal medulla constitutes about 15% of the adrenal and is surrounded by the cortex. The major constituent of the medulla, the catecholamine-containing cells, are of two types: the norepinephrine and the epinephrine cells. These cells are often called chromaffin cells because they stain with chromium salts, and this was an early method used to detect these cells.5 Chromaffin cells in adults are primarily confined to the adrenal medulla, although they also occur in extra-adrenal locations. They may give rise to extra-adrenal paraganglioma in the organ of Zuckerkandl (distal aorta), in the bladder, in the neck and, more rarely, at other sites.10 In addition, the adrenal medulla contains sympathetic ganglion cells, connective tissue, and blood vessels. The adrenal medulla has an arterial supply via several small arteries and a venous outflow to the central adrenal vein.

The epinephrine cells in the medulla are localized close to the cortex, where they are exposed to high Cortisol levels of portal venous effluent. Cortisol is required for the induction of phenylethanolamine AT-methyltransferase (PNMT), the methylating enzyme that converts norepinephrine to epinephrine (Fig. 65-3). Chromaffin cells in extra-adrenal locations usually do not produce epinephrine, probably because of a lack of Cortisol to activate PNMT.11 The preganglionic cell bodies are located in the intermediolateral cell column in the spinal cord. Their axons pass the sympathetic ganglia and reach the adrenal gland via the splanchnic nerves and innervate the chromaffin cells.

Transmitter Mechanisms

SYNTHESIS

The catecholamines are synthesized from tyrosine, which is converted to dihydroxyphenylalaline by the cytosolic enzyme tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis (see Fig. 65-3),12 and further converted to dopamine by dopa decarboxylase. Dopamine is taken up into granular vesicles and converted to norepinephrine via dopamine fj-hydroxylase (DBH). This uptake is an adenosine triphosphate (ATP)-requiring process, in which the uptake of dopamine prevents its degradation by cytoplasmic monoamine oxidase. Norepinephrine is stored in the granular vesicles in a complex where one catecholamine molecule is coupled to four ATP molecules. Certain chromaffin cells contain the enzyme PNMT, which converts norepinephrine to epinephrine. Neuropeptide Y (NPY), enkephalins, somatostatin, and chromogranins are also stored in the granular vesicles.

Tyrosine

>

r

DOPA

r

Dopamine

1

r

Norepinephrine

1

f

Epinephrine

Norepinephrine

Epinephrine

FIGURE 65-3. Synthesis of catecholamines in the adrenal medulla. DOPA = dihydroxyphenylalaline.

SECRETION

When the adrenal medulla is stimulated, the chromaffin cell membrane depolarizes, secretory vesicles fuse with the cell membrane, and the vesicular content is released via exocytosis.13 All components of the granular vesicles are released: catecholamines, DBH, NPY, enkephalins, and chromogranins. Because of a rich vascular supply, most released substances are transported away from the medulla and direct reuptake back into the chromaffin cells only plays a minor role compared to sympathetic nerves. The physiologic importance of the released substances in addition to catecholamines is not clear. NPY has been shown to have vasoconstrictive effects, although it is much weaker than the catecholamines.14 Enkephalins may function as analgesics during stress.15 The chromogranins may be of importance for storage of neurotransmitters and may also serve as peptide precursors.16

DEGRADATION

The degradation of norepinephrine and epinephrine is shown in Figure 65-4. Monoamine oxidase is present in mitochondria of most cells and catalyzes the deamination of catecholamines. Catechol O-methyltransferase induces methylation of catecholamines or their deaminated metabolites to the major final product, vanillylmandelic acid. In the liver and gut, conjugation with sulfuric or glucuronic acid takes place, and these substances are then excreted in the urine. Only a small amount is excreted as free dopamine, norepinephrine, and epinephrine in the urine.

Determination of Release from the Adrenal Medulla

Free urinary catecholamines most likely reflect an estimation of the sympathoadrenal activity during the sampling period. In urine, vanillylmandelic acid and metanephrine levels also give a good indication of adrenal medulla catecholamine secretion. Plasma catecholamines are usually determined as unconjugated free and protein-bound levels. Under basal conditions, only a small amount of plasma norepinephrine

COMT I Dlhydroxymandelic acid | COMT

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