Synthesis of Epinephrine

The enzymatic steps in the synthesis of epinephrine are shown in Figure 42-4. Synthesis begins with transport of the amino acid tyrosine into the chromaffin cell cytoplasm and the 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, 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 phenylethanolamine-N-methyltransferase (PNMT) to form epinephrine. Epinephrine is then transported back into the granule.

Figure 42-4 Steps in the synthesis of catecholamines.

Secretion of epinephrine and norepinephrine from the adrenal medulla is regulated primarily by descending sympathetic signals in response to various forms of stress, including exercise, hypoglycemia, and hemorrhagic hypovolemia (Fig. 42-5). The primary autonomic centers that initiate sympathetic responses reside in the hypothalamus and brainstem, and they receive input from the cerebral cortex, the limbic system, and other regions of the hypothalamus and brainstem.

Figure 42-5 Stimuli that enhance the secretion of catecholamines.

AT THE CELLULAR LEVEL

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 (i.e., the inferior, middle, and superior suprarenal arteries; Fig. 42-1). These give rise to two types of blood vessels that carry blood from the cortex to the medulla (Fig. 42-3): (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 phenylethanolamine-N-methyltransferase (PNMT), which converts norepinephrine to epinephrine (Fig. 42-4). Glucocorticoid receptor (see later) knockout mice have an enlarged cortex, but the size of the medulla is decreased and PNMT activity is undetectable.

Figure 42-3 Blood flow through the adrenal gland. Capsular arteries give rise to sinusoidal vessels that carry blood centripetally through the cortex to the medulla.

(Modified from Young B et al: Wheater’s Functional Histology, 5th ed. Philadelphia, Churchill Livingstone, 2006.)

The chemical signal for secretion of catecholamine from the adrenal medulla is acetylcholine (ACh), which is secreted from preganglionic sympathetic neurons and binds to nicotinic receptors on chromaffin cells (Fig. 42-5). ACh increases the activity of the rate-limiting enzyme tyrosine hydroxylase in chromaffin cells (Fig. 42-4). It also increases the activity of dopamine β-hydroxylase and stimulates exocytosis of the chromaffin granules. Synthesis of epinephrine and norepinephrine is closely coupled to secretion so that levels of intracellular catecholamines do not change significantly, even in the face of changing sympathetic activity.

Mechanism of Action of Catecholamines

Adrenergic receptors are generally classified as α- and β -adrenergic receptors, with the α-adrenergic receptors further divided into α₁ and α₂ receptors and the β-adrenergic receptors divided into β₁, β₂, and β₃ receptors (Table 42-1). These receptors can be characterized according to (1) Relative potency of endogenous and pharmacological agonists and antagonists. Epinephrine and norepinephrine are potent agonists for α receptors and for β₁ and β₃ receptors, whereas epinephrine is more potent than norepinephrine for β₂ receptors. A large number of synthetic selective and nonselective adrenergic agonists and antagonists now exist. (2) Downstream signaling pathways. Table 42-1 shows the primary pathways that are coupled to the different adrenergic receptors. This is an oversimplification because differences in signaling pathways for a given receptor have been linked to the duration of agonist exposure and cell type. (3) Location and relative density of receptors. Importantly, different receptor types predominate in different tissues. For example, although both α and β receptors are expressed by pancreatic islet beta cells, the predominant response to a sympathetic discharge is mediated by α₂ receptors.

Table 42-1 Adrenergic Receptors

Physiological Actions of Adrenomedullary Catecholamines

Because the adrenal medulla is directly innervated by the autonomic nervous system, adrenomedullary responses are very rapid. Furthermore, because of the involvement of several centers in the central nervous system (CNS), most notably the cerebral cortex, adrenomedullary responses can precede onset of the actual stress (i.e., they can be anticipated) (Fig. 42-5). In many cases, the adrenomedullary output, which is primarily epinephrine, is coordinated with sympathetic nervous activity, as determined by the release of norepinephrine from postganglionic sympathetic neurons. However, some stimuli (e.g., hypoglycemia) evoke a stronger adrenomedullary than sympathetic nervous response, and vice versa.

Many organs and tissues are affected by a sympathoadrenal response (Table 42-2). An informative example of the major physiological roles of catecholamines is the sympathoadrenal response to exercise. Exercise is similar to the “fight or flight” response, but without the subjective element of fear, and involves a greater adrenomedullary response (i.e., endocrine role of epinephrine) than a sympathetic nervous response (i.e., neurotransmitter role of norepinephrine). The overall goal of the sympathoadrenal system during exercise is to meet the increased energy demands of skeletal and cardiac muscle while maintaining sufficient oxygen and glucose supply to the brain. The response to exercise includes the following major physiological actions of epinephrine (Fig. 42-6):

Table 42-2 Some Actions of Catecholamine Hormones

Figure 42-6 Some of the individual actions of catecholamines that contribute to the integrated sympathoadrenal response to exercise.

(Modified from Porterfield SP, White BA: Endocrine Physiology, 3rd ed. Philadelphia, Mosby, 2007.)

Metabolism of Catecholamines

Two primary enzymes are involved in the degradation of catecholamines: monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) (Fig. 42-7). The neurotransmitter norepinephrine is degraded by MAO and COMT after uptake into the presynaptic terminal. This mechanism is also involved in the catabolism of circulating adrenal catecholamines. However, the predominant fate of adrenal catecholamines is methylation by COMT in nonneuronal tissues such as the liver and kidney. Urinary vanillylmandelic acid (VMA) and metanephrine are sometimes used clinically to assess the level of catecholamine production in a patient. Much of the urinary VMA and metanephrine is derived from neuronal rather than adrenal catecholamines.

Figure 42-7 Degradative metabolism of catecholamines. MAO stimulates deamination; COMT stimulates methylation.

Zona Fasciculata

The zona fasciculata produces the glucocorticoid hormone cortisol. This zone is an actively steroidogenic tissue composed of straight cords of large cells. These cells have a “foamy” cytoplasm because they are filled with lipid droplets that represent stored cholesterol esters. These cells make some cholesterol de novo but also import cholesterol from blood in the form of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. Free cholesterol is then esterified and stored in lipid droplets (Fig. 42-8). The stored cholesterol is continually turned back into free cholesterol by a cholesterol ester hydrolyase, a process that is increased in response to the stimulus of cortisol synthesis (e.g., adrenocorticotropic hormone [ACTH]’see later). In the zona fasciculata, cholesterol is converted sequentially to pregnenolone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol (Figs. 42-9 and 42-10). A parallel pathway in the zona fasciculata involves the conversion of progesterone to 11-deoxycorticosterone (DOC) and then to corticosterone (Fig. 42-10, C). This pathway is minor in humans, but in the absence of active CYP11B1 (11-hydroxylase activity), the production of DOC is significant. Because DOC acts as a weak mineralocorticoid (Table 42-3), elevated levels of DOC cause hypertension.

Figure 42-8 Events involved in the first reaction in the steroidogenic pathway (conversion of cholesterol to pregnenolone) in zona fasciculata cells. ACAT, acyl CoA : cholesterol acyltransferase; CE, cholesterol esters; FC, free cholesterol; HDLR, high-density lipoprotein receptor (also called the scavenger receptor BI [SR-BI]); IMM, inner mitochondrial membrane; LDLR, low-density lipoprotein receptor; OMM, outer mitochondrial membrane; StAR, steroidogenic acute regulatory protein.

(Modified from Porterfield SP, White BA: Endocrine Physiology, 3rd ed. Philadelphia, Mosby, 2007.)

Figure 42-9 Summary of the steroidogenic pathways for each of the three zones of the adrenal cortex. The enzymatic reactions are color-coded across zones. sER, smooth endoplasmic reticulum.

(Modified from Porterfield SP, White BA: Endocrine Physiology, 3rd ed. Philadelphia, Mosby, 2007.)

Figure 42-10 A, Reaction 1, catalyzed by CYP11A1, in making cortisol. B, Reactions 2a/b and reactions 3a/b, involving CYP17 (17-hydroxylase function) and 3β-hydroxysteroid dehydrogenase (3β-HSD), in making cortisol. This figure shows the Δ5 versus Δ4 pathway. C, Reactions 4 and 5, involving CYP21B and CYP11B1, in which the last two steps in the synthesis of cortisol are carried out. Also shown is the minor pathway leading to the synthesis of corticosterone in the zona fasciculata.

(Modified from Porterfield SP, White BA: Endocrine Physiology, 3rd ed. Philadelphia, Mosby, 2007.)

Table 42-3 Relative Glucocorticoid and Mineralocorticoid Potency of Natural Corticosteroids and Some Synthetic Analogues in Clinical Use^*

* All values are relative to the glucocorticoid and mineralocorticoid potencies of cortisol, which have each been set at 1.0 arbitrarily. Cortisol actually has only 1/500 the potency of the natural mineralocorticoid aldosterone.