J. P. Hinson

The neuroendocrinology of the adrenal cortex.

Although until relatively recently assumed to be devoid of innervation, there is now ample proof that the adrenal cortex receives specific neurones of several types. A general interpretation of their roles in the regulation of adrenocortical function has not been forthcoming, probably because of the variety of the different experimental approaches which have been used, and the heterogeneous observations which have been made. We here summarize the evidence which is available, and offer the view that neural inputs may provide fine tuning of the responses to systemic factors such as ACTH, through direct actions on specific adrenocortical cells. However, neural regulation also provides an integrative function, through actions on the flow of blood through the gland, which itself exerts a powerful influence on adrenocortical function.

Neuropeptide Y and the adrenal gland: a review.

This paper sets out to review several aspects of NPY and adrenal function, starting with the localisation of NPY in the adrenal, then describing the regulation of NPY release and considering whether the adrenal is a significant source of circulating NPY. The review then describes the regulation of adrenal content of peptide, and finally covers the actions of NPY on the adrenal gland, and the receptor subtypes thought to mediate these effects. The regulation and actions of NPY are discussed with reference to both the adrenal cortex and the medulla.

The relationship between adrenal vascular events and steroid secretion: the role of mast cells and endothelin.

The actions of ACTH on the adrenal cortex are known to be 2-fold. In addition to increased steroidogenesis, ACTH also causes marked vasodilation, reflected by an increased rate of blood flow through the gland. Our studies, using the in situ isolated perfused rat adrenal preparation, have shown that zona fasciculata function and corticosterone secretion are closely related to vascular events, with an increase in perfusion medium flow rate causing an increase in corticosterone secretion, in the absence of any known stimulant. These observations give rise to two important questions: how does ACTH stimulate blood flow; and how does increased blood (or perfusion medium) flow stimulate steroidogenesis? Addressing the first question, we have recently identified mast cells in the adrenal capsule, and shown that Compound 48/80, a mast cell degranulator, mimics the actions of ACTH on adrenal blood flow and corticosterone secretion. We have also demonstrated an inhibition of the adrenal vascular response to ACTH in the presence of disodium cromoglycate, which prevents mast cell degranulation. We conclude, therefore, that ACTH stimulates adrenal blood flow by its actions on mast cells in the adrenal capsule. Addressing the second question, we looked at the role of endothelin in the rat adrenal cortex. Endothelin 1, 2 and 3 caused significant stimulation of steroid secretion by collagenase dispersed cells from both the zona glomerulosa and the zona fasciculata. A sensitive response was seen, with significant stimulation at an endothelin concentration of 10(-13) mol/l or lower. Endothelin secretion by the in situ isolated perfused rat adrenal gland was measured using the Amersham assay kit. Administration of ACTH (300 fmol) caused an increase in the rate of immunoreactive endothelin secretion, from an average of 28.7 +/- 2.6 to 52.6 +/- 6 fmol/10 min (P less than 0.01, n = 5). An increase in immunoreactive endothelin secretion was also seen in response to histamine, an adrenal vasodilator, which stimulates corticosterone secretion in the intact gland, but has no effect on collagenase-dispersed cells. From these data we conclude that endothelin may mediate the effects of vasodilation on corticosterone secretion, and this mechanism may explain some of the differences in response characteristics between the intact gland and dispersed cells.

The role of neuropeptides in the regulation of adrenal vascular tone: effects of vasoactive intestinal polypeptide, substance P, neuropeptide Y, neurotensin, Met-enkephalin, and Leu-enkephalin on perfusion medium flow rate in the intact perfused rat adrenal

There is evidence that adrenal blood flow may be regulated in part by neuropeptides released from the capsular region of the adrenal gland in response to splanchnic nerve stimulation. The present study investigated the effects of various neuropeptides on the rate of perfusion medium flow through an intact in situ perfused rat adrenal preparation. Vasoactive intestinal polypeptide (VIP) had the greatest effect, causing a 136% increase in flow at the highest dose used (10 nmol in a 200 microliters bolus). Of the other peptides tested Met-enkephalin caused a 50% increase in flow, and the others (Leu-enkephalin, neurotensin and substance P) had only a minor effect, increasing perfusion medium flow rate by no more than around 35%. Neuropeptide Y, in contrast, caused a significant decrease in perfusion medium flow rate: the maximum effect was a 30% decrease with a dose of 1 nmol in a 200 microliters bolus. The significance of this observation awaits elucidation. It is clear from the actions of the neuropeptides tested that they may have a significant role in the regulation of adrenal blood flow. In view of the findings of other authors: that VIP is released in response to splanchnic nerve stimulation, and that it is specifically localised in the capsular region of the adrenal, it seems most likely that VIP is the major peptide involved in mediating the increased adrenal blood flow following splanchnic nerve stimulation.

The role of neuropeptides in the regulation of adrenal zona fasciculata/reticularis function : effects of vasoactive intestinal polypeptide, substance P, neuropeptide Y, Met- and Leu-enkephalin and neurotensin on corticosterone secretion in the intact perfused rat adrenal gland in situ

There is much evidence to suggest that glucocorticoid secretion may be influenced by the splanchnic innervation to the adrenal gland, and that this effect may be mediated by neuropeptides. The present studies investigated the effects of several neuropeptides on corticosterone secretion by the intact perfused rat adrenal gland in situ. Both vasoactive intestinal polypeptide and Met-enkephalin caused a dose-dependent increase in corticosterone secretion, with a maximum response of 450% and 370% increment in corticosterone respectively. Of the other peptides tested, Leu-enkephalin, substance P and neurotensin all stimulated corticosterone secretion, with a maximum response of around 160% increase in each case. Neuropeptide Y on the other hand, had only a minor effect, which was only apparent over a small dose range. These results support the theory that adrenal neuropeptides may have a role in the regulation of glucocorticoid secretion.

Neuropeptides in the adrenal gland: Distribution, localization of receptors, and effects on steroid hormone synthesis

In this review we defined and classified the neuropeptides (NPs) related to the adrenal gland, according to Palkovits (Frontiers Neuroendocrinol 10:1 1988). The concentration (RIA) and distribution (immunohistochemistry) of NPs, as well as the localization of the receptors (radioligand studies) were summarized. Direct effects of NPs on aldosterone and corticosterone synthesis obtained by in vivo, in situ perfusion, and in vitro experimental approaches were reviewed. Data (from different rat strains and genders) for 35 NPs are presented.

Actions of Neuropeptide Y on the Rat Adrenal Cortex1

Although several studies have demonstrated the presence of neuropeptide Y (NPY) in nerves supplying the mammalian adrenal cortex, its function in this tissue remains unclear, with reports of both stimulatory and inhibitory effects on aldosterone secretion apparently depending on the tissue preparation used. In the present study the effects of NPY on rat adrenal capsular tissue were investigated. NPY significantly stimulated aldosterone secretion in a dose-dependent manner, and this effect was abolished by atenolol, a β1-adrenergic antagonist. NPY also stimulated the release of catecholamines from intact rat adrenal capsular tissue with the same dose-dependent relationship as the stimulation of aldosterone release. These observations suggest that the actions of NPY may be mediated by the local release of catecholamines from chromaffin cells within adrenal capsular tissue, as we have previously described for vasoactive intestinal peptide. The second part of this study concerned the NPY receptor subtype medi...

Effect of the endothelins on aldosterone secretion by rat zona glomerulosa cells In vitro

Endothelins are thought to be involved in the local regulation of blood flow and tissue function. These experiments were carried out to investigate the possible role of endothelins in the control of aldosterone secretion by the rat adrenal. Suspensions of zona glomerulosa cells were prepared by collagenase digestion of capsular tissue, and incubated in the presence of increasing concentrations of endothelin. Aldosterone was measured by RIA. All three peptides caused a dose-dependent increase in the secretion rate of aldosterone by zona glomerulosa cells. The minimum concentration of peptide required to give a significant response was 10(-14) mol/l for endothelins 2 and 3 and 10(-13) mol/l for endothelin 1. At a concentration of 10(-7) mol/l endothelin 2 elicited a 20-fold increase over basal aldosterone secretion, while both endothelins 1 and 3 elicited a 30-fold increase (P less than 0.001 in all cases). These results show that the endothelins are potent stimulators of aldosterone secretion, and suggest that these peptides may have a role in the control of zona glomerulosa function.

Differential effects of endogenous and exogenous nitric oxide on the release of endothelin-1 from the intact perfused rat adrenal gland in situ

Studies using an inhibitor of nitric oxide (NO) synthesis have suggested that endogenous NO may have a role in regulating endothelin release. We investigated the effect of endogenous and exogenous nitric oxide (NO) on the release of irET‐1. l‐NAME stimulated, but l‐arginine inhibited irET‐1 release. Perfusing sodium nitroprusside (SNP), however, did not inhibit irET‐1 secretion. CyclicGMP, the second messenger for NO action, was stimulated by SNP but not by l‐arginine. These data demonstrate that endogenous NO inhibits of irET‐1, in a manner which is independent of cGMP, and suggest that this action may contribute to the vasodilatory effect of NO.

Adrenomedullin and CGRP receptors mediate different effects in the rat adrenal cortex

Adrenomedullin (AM) exerts its effects through two distinct receptor subtypes: the AM receptor, and the CGRPI receptor. In most tissues activation of these subtypes brings about similar effects, with only the magnitude of the effect varying. In the rat adrenal cortex, however, this does not appear to be the case. Both CGRPI and AM receptors are present in the rat adrenal cortex. Incubation of zona glomerulosa cells with AM caused an increase in aldosterone secretion, but AM had no effect on angiotensin II-stimulated aldosterone secretion. The action of AM was not affected by CGRP8-37, the CGRP receptor antagonist, suggesting that its effect was mediated by the adrenomedullin receptor. CGRP on the other hand, did not significantly affect basal aldosterone although it attenuated the response to angiotensin II. These data suggest that the CGRP receptor and the AM receptor mediate different effects in the rat adrenal zona glomerulosa.