The adrenal medulla bridges the endocrine and sympathetic nervous systems
On page 978, we describe cells of the hypothalamus as neuroendocrine because they are part of the CNS and appear anatomically as neural tissue, yet they release peptide hormones (e.g., CRH) into the blood that act downstream on the pituitary—a classic endocrine function. The adrenal medulla is similar in many ways. The cells of the medulla, termed chromaffin cells because the catecholamines that they contain stain avidly with chromium salts, derive from neural crest cells (see p. 261) and migrate into the center of the adrenal cortex, which is derived from the mesoderm. The adrenomedullary cells synthesize and secrete epinephrine and—to a lesser extent—norepinephrine. Norepinephrine is the neurotransmitter of the sympathetic division of the autonomic nervous system (see pp. 342–343). Both the norepinephrine and epinephrine made in the adrenal medulla enter the circulation and act on distal tissues just like other hormones.
Chromaffin cells are the structural and functional equivalents of the postganglionic neurons in the sympathetic nervous system (see p. 343). The preganglionic sympathetic fibers of the splanchnic nerves, which release acetylcholine (ACh), are the principal regulators of adrenomedullary hormone secretion.
The vascular supply to the adrenal medulla is also unusual. The medulla receives vascular input from vessels that begin in a subcapsular plexus of the adrenal cortex. The vessels then branch into a capillary network in the cortex only to merge into small venous vessels that branch into a second capillary network within the medulla. This portal blood supply (originating at the entrance to the adrenal) exposes the adrenal medulla to the highest concentrations of glucocorticoids and mineralocorticoids of all somatic tissues.
Only chromaffin cells of the adrenal medulla have the enzyme for epinephrine synthesis
It was first appreciated nearly a century ago that extracts of the adrenal medulla have a powerful pressor effect. Subsequent work showed that catecholamines (Fig. 50-8A)—L-dopa, dopamine, norepinephrine, and epinephrine—are all made in the adrenal medulla. Norepinephrine is found in many other somatic tissues in amounts that roughly parallel the extent of sympathetic innervation of the tissue. In other words, the norepinephrine in these other tissues is not made there but is derived from the sympathetic nerve endings in them. Virtually all the circulating epinephrine, the principal product of the adrenal medulla, comes from the adrenal medulla.
FIGURE 50-8 Synthesis and degradation of catecholamines. In A, the horizontal arrows indicate enhancement of the reaction. MAO, monoamine oxidase.
Dopamine, norepinephrine, and epinephrine are all synthesized from the amino acid tyrosine. Figure 50-8A summarizes the reactions involved in the synthesis of epinephrine. Figure 50-9 illustrates the cellular localization of the four enzymatic reactions, as well as the three critical transport steps that shuttle the reactants and products to their proper location.
1. The activity of the first enzyme in the pathway, tyrosine hydroxylase, which converts tyrosine to L-dopa, is rate limiting for overall synthesis. This enzyme is located within the cytosol of adrenal medullary cells as well as in sympathetic nerve terminals and in specific cells within the CNS.
2. The cytosolic enzyme amino-acid decarboxylase converts L-dopa to dopamine in numerous tissues, including the adrenal medulla.
3. A catecholamine-H+ exchanger (vesicular monoamine transporter 1, or VMAT1) moves the dopamine into membrane-enclosed dense-core vesicles called chromaffin granules.
4. Dopamine β-hydroxylase converts dopamine to norepinephrine by hydroxylating the β carbon. This β-hydroxylase is localized to the inner surface of the membrane of granules within the adrenal medulla and sympathetic nerves. In the nerve terminals of postganglionic sympathetic neurons, the synthetic pathway terminates at this step, and the granules store the norepinephrine for later secretion. However, the cells of the adrenal medulla convert the norepinephrine to epinephrine in three final steps.
5. Norepinephrine formed in the secretory granules moves out into the cytosol.
6. The cytosolic enzyme phenylethanolamine-N-methyltransferase (PNMT) transfers a methyl group from S-adenosylmethionine to norepinephrine, thus creating epinephrine. Substantial amounts of this enzyme are present only in the cytosol of adrenal chromaffin cells. N50-5
7. The secretory granules in the adrenal medulla take up the newly synthesized epinephrine. The same VMAT1 catecholamine-H+ exchanger noted in step 3 appears to mediate this uptake of epinephrine. The proton gradient is maintained by an H pump (i.e., a vacuolar-type H-ATPase; see pp. 118–119) within the secretory vesicle membrane. Thus, in the adrenal medulla, the secretory granules store both epinephrine and norepinephrine before secretion.
FIGURE 50-9 Cellular view of catecholamine synthesis. The chromaffin cell synthesizes and stores epinephrine in a sequence of four enzymatic and three transport steps. AADC, amino-acid decarboxylase; DA, dopamine; DBH, dopamine β-hydroxylase; Epi, epinephrine; NE, norepinephrine; TH, tyrosine hydroxylase.
Contributed by Gene Barrett
PNMT is the enzyme that catalyzes the last step—the addition of a methyl group—in the synthesis of epinephrine. PNMT is also present in very small amounts in the ganglion cells within the heart and in the CNS.
In addition, the kidney also has an enzyme that is an N-methyltransferase—but this enzyme is distinct from PNMT. The renal form of N-methyltransferase is also present in liver (perhaps along with a small amount of PNMT).
Epinephrine synthesis is under the control of the CRH-ACTH-cortisol axis at two levels. First, ACTH stimulates the synthesis of L-dopa and norepinephrine. Second, cortisol transported from the adrenal cortex by the portal circulation to the medulla upregulates PNMT in chromaffin cells. The result is synergy between the CRH-ACTH-cortisol axis and the sympathetic-epinephrine axis. Thus, the stress that is sensed and propagated by the CRH-ACTH-cortisol axis sustains the epinephrine response.
Similar to the secretory granules that are present in the postganglionic sympathetic neurons, the secretory granules of the adrenal medulla contain very high concentrations of catecholamines (as high as 0.5 M). These catecholamines—along with ATP and Ca2+—bind to granular proteins called chromogranins and thus are not osmotically active in these storage vesicles. Chromogranins are what make dense-core vesicles dense. In humans, the dominant chromogranin is chromogranin B. The release of catecholamines is initiated by CNS control. ACh released from preganglionic neurons in the splanchnic nerves acts on nicotinic ACh receptors to depolarize the postganglionic chromaffin cells. This depolarization triggers the opening of voltage-gated Ca2+ channels, a process that raises [Ca2+]i and triggers the exocytotic release of epinephrine. The secretion of adrenal catecholamines is accompanied by the release of ATP and the granule proteins. The release of chromogranin A has been used as a marker of adrenal medullary activity. In the circulation, the catecholamines dissociate from the binding complex and are free to act on target tissues.
The early description of the fight-or-flight response to stress (see p. 347) exemplifies the central control of adrenomedullary function. An organism faced with a severe external threat responds with centrally driven release of adrenal hormones, as well as activation of other aspects of the sympathetic nervous system. This response includes increases in heart rate and contractility, mobilization of fuel stores from muscle and fat, piloerection, pupillary dilatation, and increased sphincter tone of the bowel and bladder. Each response is in some way adapted to deal with the perceived threat successfully. This combined neuroendocrine response is activated within seconds. The secreted catecholamines act very quickly after reaching their target tissues.
The biological actions of catecholamines are very brief, lasting only ~10 seconds in the case of epinephrine. Circulating catecholamines are degraded first by the enzyme catechol-O-methyltransferase (COMT), which is present in high concentrations in endothelial cells and the heart, liver, and kidneys (see Fig. 50-8B). COMT converts epinephrine to metanephrine, as well as norepinephrine to normetanephrine. A second enzyme, monoamine oxidase, converts these metabolites to vanillylmandelic acid (VMA). The liver and also the gut then conjugate these compounds to sulfate (see p. 955) or glucuronide (see p. 955) to form derivatives that the kidney excretes in the urine. Determination of the concentration of catecholamines, metanephrines, and VMA in the urine provides a measure of the total adrenal catecholamine production by both the adrenal medulla and the sympathetic system.
Catecholamines bind to α and β adrenoceptors on the cell surface and act through heterotrimeric G proteins
Many of the hormones already discussed have a unique receptor on the cell surface (e.g., insulin, parathyroid hormone, growth hormone, thyroid-stimulating hormone) or within the cell (e.g., thyroid hormones or cortisol). Other hormones (e.g., AVP) and neurotransmitters (e.g., ACh and glutamate) may bind to more than one type of receptor, each acting via a different signal-transduction process. The situation for the catecholamines is even more complex. Epinephrine and norepinephrine can each bind to more than one type of adrenergic receptor, or adrenoceptor, all of which are GPCRs. Conversely, individual adrenoceptors can generally bind both epinephrine and norepinephrine—albeit with different affinities. For their work on GPCRs, including adrenoceptors, Robert J. Lefkowitz and Brian K. Kobilka shared the 2012 Nobel Prize in Chemistry. N50-6
Robert J. Lefkowitz and Brian K. Kobilka
For more information about Robert Lefkowitz and Brian Kobilka and the work that led to their Nobel Prize, visit http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/ (accessed September 2014).
In the late 1940s, Raymond Ahlquist found that epinephrine and epinephrine analogs could produce both excitatory and inhibitory effects, depending on the tissue. This property led to the designation of α-adrenergic receptors (mostly associated with stimulation) and β-adrenergic receptors (mostly associated with inhibition). Moreover, certain drugs could selectively block the α and β effects. This dichotomy proved to be too simple when it was observed that the actions of some drugs that have pure α or pure β activity could be blocked in some tissues but not in others; this variability in response suggested that the tissue response is determined by a subtype of α or β receptor.
It is now clear that at least three types of β and two types of α receptors exist (see Table 14-2), as well as subtypes within these major classes. These receptors differ in primary structure and in the types of G proteins that associate with the receptor. The several β receptors are coupled to stimulatory heterotrimeric G proteins (Gαs) that stimulate adenylyl cyclase and thus increase levels of cAMP (see p. 53), the principal intracellular mediator of β activation. The α2 adrenoceptors are coupled to other G proteins (Gαi) that inhibit adenylyl cyclase and thus lower [cAMP]i in target tissues. The α1 receptors are coupled to yet another heterotrimeric G protein (Gαq) that activates PLC (see p. 58) and thereby increases [IP3]i and [Ca2+]i in target tissues.
Recognition of the diversity of adrenoceptor subtypes has led to a panoply of pharmacological agents that block or stimulate one or the other of these receptor subtypes. Some drugs are nonspecific and affect several receptor subtypes; others specifically block only a single subtype. The clinical value of a particular drug depends on its spectrum of activity. Thus, for example, an agent that selectively blocks the vasoconstrictor response to norepinephrine could be a very useful antihypertensive agent, but its utility would be compromised if it also blocked the ability of bladder smooth muscle to contract.
The CNS-epinephrine axis provides integrated control of multiple functions
The actions of the sympathetic nervous system (see Chapter 14) in the control of blood pressure (see p. 539), heart rate (see p. 539), sweating (see p. 1218), micturition (see p. 736), and airway resistance (see p. 620) are discussed in more detail in other chapters, as indicated. Here, we mention only some of the unique actions attributed to adrenal catecholamine release that integrate several bodily functions as part of the stress response. These adrenal-mediated activities do not occur in isolation but are usually accompanied by generalized noradrenergic sympathetic discharge.
In response to the stress of simple exercise (see pp. 583 and 1210), blood flow to muscle is increased; circulating epinephrine appears to be important in this response. Circulating epinephrine also relaxes bronchial smooth muscle to meet the demand for increased ventilation and, when combined with the increased blood flow, increases oxygen delivery to the exercising muscle. Similarly, to sustain muscular activity, particularly early in exercise, epinephrine acting via the β adrenoceptor activates the degradation of muscle glycogen to provide a ready fuel source for the contracting muscle (see p. 1182). Epinephrine also activates lipolysis in adipose tissue (see p. 1182) to furnish fatty acids for more sustained muscular activity if needed. In liver, as in muscle, epinephrine activates glycogenolysis, so that the supply of glucose is maintained in the blood.
In addition to enhancing blood flow and ventilation, the integrated response to exercise increases fuel availability by decreasing insulin levels. Circulating epinephrine, acting through a β adrenoceptor, stimulates the secretion of insulin (see p. 1041). However, during exercise, local autonomic innervation, acting by means of an α adrenoceptor of the pancreas, inhibits this effect so that insulin levels fall. The net effects are to promote glycogenolysis and to allow muscle to increase its work while maintaining glycemia so that brain function is not impaired. The fleeing human must not only run, but know where to run!
Unlike in other glandular tissue, no endocrine feedback loop governs the secretion of adrenal medullary hormones. Control of catecholamine secretion resides within the CNS. This principle can be illustrated by the changes in epinephrine secretion that occur with even mild hypoglycemia. Decreases in blood glucose concentration to less than ~3.5 mM (normal concentration, ~5.5 mM) are sensed by the CNS, which triggers a central sympathetic response that increases the firing of preganglionic fibers in the celiac plexus. This sympathetic outflow suppresses endogenous insulin secretion by the α-adrenergic mechanism noted above, thus promoting an increase in plasma [glucose]. This sympathetic outflow to the adrenal medulla also triggers a major release of epinephrine that, through β adrenoceptors in the liver, stimulates increased hepatic glycogenolysis. This response helps to restore plasma [glucose] to normal. Restoration of normoglycemia diminishes central sympathetic outflow (Box 50-5).
The dramatic biological effects of catecholamines are well illustrated by patients with pheochromocytoma. A pheochromocytoma is a relatively uncommon tumor caused by hyperplasia or more rarely neoplasia of either adrenal medullary tissue or extra-adrenal chromaffin tissue that failed to involute after birth. These tumors, which can be benign or malignant, make catecholamines, just like the normal medulla, except in an unregulated fashion. Patients with pheochromocytomas typically have a plethora of symptoms, as would be expected from such a wide-ranging hormonal system. Paroxysmal (sudden) hypertension, tachycardia, headache, episodes of sweating, anxiousness, tremor, and glucose intolerance usually dominate the clinical findings. The key to the diagnosis of this disorder is a careful history taking, evidence on physical examination of excessive adrenergic tone, and laboratory detection of increased amounts of serum and urinary catecholamines and their metabolites. When chemical evaluation of the metabolites confirms the presence of a pheochromocytoma, it is often possible to localize the tumor to one or the other adrenal gland and resect the tumor. Rarely, both glands are affected, necessitating bilateral adrenalectomy. Such patients must subsequently receive glucocorticoid and mineralocorticoid replacement. No therapy is routinely given to replace the adrenal medullary function. It is not clear whether these individuals react less well to external stimuli that would trigger the fight-or-flight response.