Adrenomedullary catecholamines, which are normally secreted near a target organ as neurotransmitters, behave as hormones when they are released into the bloodstream. The adrenal medulla consists of approximately 80% epinephrine-secreting cells and 20% norepinephrine-secreting cells. While all circulating epinephrine originates from the adrenal medulla, only about 30% of circulating norepinephrine is produced there. The remaining 70% is released from postganglionic sympathetic nerve terminals and diffuses into the vascular system. Therefore, the adrenal medulla is not essential for sustaining life, as it is not the sole source of catecholamine production.

Epinephrine synthesis involves several enzymatic steps. First, the amino acid tyrosine is transported into the cytoplasm of chromaffin cells and undergoes hydroxylation by the rate-limiting enzyme tyrosine hydroxylase, resulting in the formation of dihydroxyphenylalanine (DOPA). DOPA is then converted to dopamine by a cytoplasmic enzyme called aromatic amino acid decarboxylase. Subsequently, dopamine is transported into secretory vesicles (chromaffin granules), where it is completely converted to norepinephrine by the enzyme dopamine β-hydroxylase. In most adrenomedullary cells, almost all the norepinephrine diffuses out of the chromaffin granules and is methylated by the cytoplasmic enzyme PNMT to produce epinephrine.

The medulla of the adrenal gland maintains a high local concentration of cortisol due to its vascular configuration. The adrenal gland's outer connective tissue capsule is penetrated by an abundant arterial supply derived from three main arterial branches: the inferior, middle, and superior suprarenal arteries. These arteries give rise to two types of blood vessels that transport blood from the cortex to the medulla. The first type consists of relatively few medullary arterioles, which directly supply oxygen- and nutrient-rich blood to the chromaffin cells of the medulla. The second type includes numerous cortical sinusoids into which cortical cells secrete steroid hormones, including cortisol. These two vessel types fuse to form the medullary plexus of vessels, which ultimately drain into a single suprarenal vein. As a result, the secretions from the adrenal cortex pass through the chromaffin cells, exposing them to high concentrations of cortisol, before leaving the gland and entering the inferior vena cava. Cortisol inhibits the neuronal differentiation of medullary cells, preventing the formation of dendrites and axons. Additionally, cortisol induces the expression of the enzyme PNMT, which converts norepinephrine into epinephrine.
Instead of being secreted near a target organ and acting as neurotransmitters, adrenomedullary catecholamines are secreted into blood and act as hormones. About 80% of the cells of the adrenal medulla secrete epinephrine, and the remaining 20% secrete norepinephrine. Although circulating epinephrine is derived entirely from the adrenal medulla, only about 30% of the circulating norepinephrine comes from the medulla. The remaining 70% is released from postganglionic sympathetic nerve terminals and diffuses into the vascular system. Because the adrenal medulla is not the sole source of catecholamine production, this tissue is not essential for life.
Synthesis of Epinephrine
The enzymatic steps in epinephrine synthesis are shown in
Fig. 43.4 . Synthesis begins with transport of the amino acid tyrosine into the chromaffin cell cytoplasm and subsequent hydroxylation of tyrosine by the rate-limiting enzyme tyrosine hydroxylase to produce dihydroxyphenylalanine (DOPA). DOPA is converted to dopamine by a cytoplasmic enzyme, aromatic amino acid decarboxylase, and is then transported into the secretory vesicle (also called the chromaffin granule). Within the granule, all dopamine is completely converted to norepinephrine by the enzyme dopamine β-hydroxylase. In most adrenomedullary cells, essentially all of the norepinephrine diffuses out of the chromaffin granule by facilitated transport and is methylated by the cytoplasmic enzyme PNMT to form epinephrine.
The high local concentration of cortisol in the medulla is maintained by the vascular configuration within the adrenal gland. The outer connective tissue capsule of the adrenal gland is penetrated by a rich arterial supply coming from three main arterial branches: the inferior, middle, and superior suprarenal arteries (see
Fig. 43.1 ). These give rise to two types of blood vessels that carry blood from the cortex to the medulla (Fig. 43.3 ): (1) relatively few medullary arterioles, which provide high oxygen- and nutrient-laden blood directly to the medullary chromaffin cells, and (2) relatively numerous cortical sinusoids into which cortical cells secrete steroid hormones (including cortisol). Both vessel types fuse to give rise to the medullary plexus of vessels that ultimately drains into a single suprarenal vein. Thus secretions of the adrenal cortex percolate through the chromaffin cells and bathe them in high concentrations of cortisol before leaving the gland and entering the inferior vena cava. Cortisol inhibits neuronal differentiation of the medullary cells, so they fail to form dendrites and axons. Additionally, cortisol induces expression of the enzyme PNMT, which converts norepinephrine to epinephrine (