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Endocrinology G. V. (Sonny) Montgomery Veterans Affairs Medical Center and the University of Mississippi Medical Center Jackson, Mississippi 39216
Address all correspondence and requests for reprints to: Celso E. Gomez-Sanchez, M.D., G. V. (Sonny) Montgomery Veterans Affairs Medical Center, 1500 East Woodrow Wilson Drive, Jackson, Mississippi 39216. E-mail: cgomez-sanchez{at}medicine.umsmed.edu.
The assumption that the production of the adrenal steroids aldosterone and cortisol (corticosterone in rodents) is regulated solely by the interaction of humoral factors, mainly ACTH and angiotensin II, with surface receptors of steroidogenic cells has proven to be overly simplistic. It is now clear that humoral, neural, hemodynamic, paracrine, and autocrine factors contribute to the regulation of adrenal steroid production (1, 2, 3, 4).
The adrenal gland is a highly vascular tissue that receives a high blood flow for its size, about 0.14% of the cardiac output for approximately 0.02% of total body weight (5). It is supplied by multiple small arteries originating from the aorta, the renal artery, and inferior phrenic arteries (6) that enter the adrenal capsule and divide into arterioles within the capsule and flow centripetally through the adrenal cortex into the medulla. The architecture of the blood supply to the adrenal cortex is species dependent. One common general pattern is a subcapsular arteriolar plexus, as in the cat or rat (7, 8), plus a rete of capillaries linked by numerous anastomotic vessels that carry blood centripetally between and around zona glomerulosa and fasciculata cells. A second common pattern is a capsular arteriolar plexus, as in the dog or human, which then form into intraadrenal sinusoids (6, 9, 10); the cortical capillaries distribute into the thin-walled sinusoids that surround cells of the cortex and medulla. These longitudinal capillary sinusoids are closely associated with adrenal cells of the zona glomerulosa and fasciculata and drain into a plexus of larger-bore sinusoids that surround the cells of the zona reticularis, which in turn drain into the central vein of the adrenal (7). There are also sinusoids in the adrenal medulla with additional medullary arterioles that provide blood directly from the capsule to the adrenal medulla (6, 7, 8, 9, 10, 11).
There is no other significant direct arterial supply to the deeper layers of the cortex. Capsular capillaries provide substrate, oxygen, and humoral regulatory factors first to the zona glomerulosa; blood reaching the zona fasciculata-reticularis, then the medulla, in addition to having a lower oxygen content, contains zona glomerulosa steroids and other factors. Corticosteroids secreted by the zona fasciculata and thus carried to the medulla are well known to influence catecholamine synthesis (12). This arrangement of centripetal flow from the capsule through the cortex to the medulla with each deeper layer of cells being bathed in products from the outer layers is preserved even in the adrenals of large animals such as the elephant (13).
Blood flow in the adrenal gland is controlled by neural and hormonal mechanisms (1, 14). The adrenal cortex has a rich nerve supply, and there is evidence that nerve terminals directly contact steroid-secreting cells of the adrenal (4, 15). Sectioning of splanchnic nerves decreases the corticoid synthetic response to ACTH (16), and stimulation of the splanchnic nerve stimulates adrenal blood flow in both dogs and calves (8, 17). Early observations demonstrated that ACTH stimulation increases both corticosteroid biosynthesis (18, 19, 20) and adrenal blood flow and that the stimulation of cortisol and corticosterone production by ACTH is dependent upon increased blood flow to the adrenal (18, 20). A potential mechanism for the adrenal vascular effects of ACTH is its ability to stimulate the degranulation of mast cells within the walls of the adrenal arteries where they penetrate the adrenal capsule. Mast cells secrete the potent vasoactive agents histamine and serotonin upon stimulation by multiple factors, including ACTH, and cause adrenal vasodilatation. Degranulation of mast cells by other agents mimics the ACTH-induced increase in adrenal steroid production and blood flow. Disodium cromoglycate, an inhibitor of mast cell degranulation, abolishes the vascular effects of ACTH, further evidence that mast cell degranulation is an important step in the adrenal vascular response to ACTH (21, 22). Serotonin constricts isolated bovine adrenal cortical arteries (23), and histamine relaxes them through endothelium-derived nitric oxide and prostaglandins (24). Because the effect of the direct inhibition of histamine or serotonin on adrenal gland blood flow has yet to be reported, it is not known whether these are secreted mediators of ACTH increase in flow (21, 22). An additional potential mechanism is described in a paper published in this issue of Endocrinology (25).
The endothelium secretes several relaxing factors, the first identified being the prostaglandin PGI2 (26). This discovery was followed by the recognition that endothelial cells secrete a relaxing factor (27) later identified as NO (28). A third endothelial vasodilator was described that relaxed vascular smooth muscle by opening potassium channels and hyperpolarizing plasma membranes that was called endothelium-derived hyperpolarizing factor (EDHF), as recently reviewed by Campbell and Falck (29). In a series of elegant studies, Campbell incubated endothelial cells with arachidonic acid and identified four regioisomers of epoxyeicosatrienoid acids (EETs). The endothelium-derived hyperpolarizing factor proved to be the major metabolites of arachidonic acid produced by cytochrome P450s: 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET (29, 30). EETs are released from endothelial cells by agonists such as acetylcholine or bradykinin and hyperpolarize the membrane of underlying vascular smooth muscle cells (29). The acetylcholine-induced hyperpolarization is mediated by the opening of potassium channels and is inhibited by increased potassium concentration, potassium channel inhibitors, or cytochrome P450 inhibitors (31).
Functional receptors for ACTH have been demonstrated in vascular smooth muscle cells and seem to decrease the expression and activity of the enzyme 11ß-hydroxysteroid dehydrogenase 2 in these cells, which would enhance the vascular effects of glucocorticoids (32). However, ACTH-induced increase in adrenal flow is not mediated by a direct action of ACTH upon the vascular smooth muscle of the adrenal arterioles (23). Isolated beef zona glomerulosa cells added to preconstricted adrenal arteries with or without endothelium caused a relaxation in proportion to the number of cells perfused. Relaxation was not altered by prostaglandin inhibitors or NO synthase inhibitors but was blocked by iberotoxin, a potassium channel inhibitor, and by the EET antagonist 14,15-EEZE (25). The isolated beef zona glomerulosa cells were found to release transferable relaxing factors identified as EET metabolites of arachidonic acid, and this release was increased by ACTH (25).
These studies by Zhang et al. (25) beautifully demonstrate that upon stimulation by ACTH adrenal steroidogenic cells increase arachidonic acid metabolism to secrete EETs and thus increase blood flow that enhances steroid production. There are, however, several questions that remain to be addressed. The isolated adrenal arteries chosen for the studies and the cannulated adrenal cortical arterioles in adrenal slices both have to be precontracted with serotonin for vasodilation to occur. It is possible that vascular tone decreases when the gland is isolated and/or adrenal arterioles are separated and, thus, that they cannot relax any further. In situ studies with intact vascular and neural connections will have to be done to further demonstrate the physiological importance of the findings. When adrenal arteries penetrate the adrenal capsule, they immediately divide into small arterioles and capillaries either within the capsule or subcapsular space and then into sinusoids in immediate contact with adrenal cells of the zona glomerulosa and fasciculata. Because sinusoids have a limited vascular smooth muscle layer, it is not clear which vessels are dilated by arachidonic acid products of the zona glomerulosa cells. Neither is it known whether the fractional increase in glucocorticoid synthesis in the zona fasciculata that is blood flow dependent produced by the ACTH is mediated by increased supply of blood-borne oxygen and substrate or also by an increase in ACTH-induced release of mediators from zona glomerulosa cells that interact with cells of the zona fasciculata.
Stimulation of endothelial cells by acetylcholine increases metabolism of arachidonic acid to EETs (31). It is now clear that there is a relationship between adrenal cortical cells and chromaffin cells of the adrenal medulla and that some chromaffin cells are found scattered within the adrenal cortex of adult rats (33). The adrenal cortex has extensive afferent innervation, both from the adrenal medulla and from neurons with cell bodies outside the adrenal gland, with a wide range of neuropeptides, catecholamines, and acetylcholine transmitters identified in the cortex (1, 34). Splanchnic nerve stimulation regulates adrenocortical activity, including that of compensatory adrenal hypertrophy (35), and splanchnic nerve sectioning decreases the adrenal response to ACTH and blood flow (16, 36). One can speculate that neurotransmitters such as acetylcholine released from synapses on adrenal cortical steroidogenic cells influence the production of EETs, which modulate the adrenal responses to ACTH. Hypothalamic control of afferent signals to the adrenal gland could be the mechanism for the circadian changes in the responsiveness of adrenal corticosteroid-secreting cells to ACTH under physiological conditions.
In summary, the control of adrenal corticosteroid synthesis is complex and involves both direct actions of the well known secretagogues and the complex interaction of humoral and neural control of blood flow to and through the gland. It has also now become clear that, rather than forming discrete, functionally isolated layers, the different types of cells of the adrenal communicate with and modulate each others’ activity when stimulated by an agonist such as ACTH.
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Abbreviation: EET, Epoxyeicosatrienoid acid.
Received April 30, 2007.
Accepted for publication May 14, 2007.
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