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The classical perspective of the adrenal gland has, in general, treated the cortex and medulla as functionally independent tissues which, by chance, are located together. Recent data challenge this outlook, and there is now evidence of regulatory mechanisms which are common to both the cortex and the medulla. There is, additionally, more evidence that the products of each of these tissues may influence the function of the other.
In mammals the arrangement of the adrenal gland is such that the adrenal cortex forms the outer part of the gland and totally encloses the medulla. Indeed, a close anatomical relationship, between the morphologically and functionally distinct steroid-secreting tissue and chromaffin tissue in the adrenal gland, is seen in most vertebrate groups. Why should these embryologically unrelated tissues be located together, and what is their functional link?
There is a wealth of experimental evidence to support the contention that these tissues have
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ABSTRACT
The present studies were designed to investigate the role of nitric oxide (NO) in the regulation of adrenocortical function, using the intact rat adrenal gland in situ, perfused with medium (Hank's balanced salt solution) containing a range of concentrations of l-arginine, the substrate for NO production. In addition, the effects of NG-nitro-l-arginine methylester (l-NAME), an inhibitor of NO production, were investigated. Results showed that l-arginine caused a dose-dependent increase in the flow rate of the perfusion medium through the adrenal gland. This effect was specific, as neither d-arginine nor l-lysine had an effect. The presence of l-NAME (5 mmol/l) in perfusion medium containing l-arginine caused a decrease in flow rate to levels seen in the absence of l-arginine. In the presence of concentrations of l-arginine up to 500 μmol/l, corticosterone secretion rates were also stimulated in a dose-dependent manner. Further studies, investigating the effect of l-arginine on the response to ACTH(1–24) stimulation, found that the percentage increase in flow rate, aldosterone secretion and corticosterone secretion caused by ACTH were not significantly different using media containing 230 μmol l-arginine/l or in the absence of l-arginine.
These results suggest a role for NO derived from l-arginine in the regulation of basal levels of adrenal vascular tone in the rat isolated adrenal gland preparation. They do not suggest an obligatory role for NO in either the vascular or steroidogenic response to ACTH stimulation.
Journal of Endocrinology (1993) 139, 415–423
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Abstract
There are several neuropeptides, present in nerves supplying the rat adrenal zona glomerulosa, which have been shown to stimulate aldosterone secretion in the intact perfused rat adrenal preparation. The purpose of the present study was twofold: first, to determine whether these peptides acted directly on adrenocortical cells by examining their effects on collagenase-dispersed rat zona glomerulosa cells, and second, to investigate the likely physiological significance of these actions, by determining whether the responses of zona glomerulosa cells to neuropeptides were changed by prior sodium depletion.
Of the peptides tested, neuropeptide Y (NPY) and substance P had only a minor effect on aldosterone secretion, which was not substantially affected by sodium depletion. Corticotrophin-releasing hormone (CRH) had a significant stimulatory effect on aldosterone secretion, but neither the threshold concentration for significant stimulation nor the maximal response to stimulation were altered by prior sodium depletion.
Vasoactive intestinal peptide (VIP), on the other hand, had little effect on aldosterone secretion by cells from normal animals, but was a potent stimulus to aldosterone secretion in cells obtained from sodium-depleted animals. The response to the Met-enkephalin analogue, [d-Ala2-Met2]-enkephalinamide (DALA), was also significantly enhanced by prior sodium depletion. Experiments using the angiotensin II receptor blocker, saralasin, were carried out to determine whether the enhanced actions of DALA and VIP seen in sodium depletion may be a result of activation of angiotensin II receptors, known to be increased in sodium depletion. Saralasin did not affect the response to either peptide.
These data suggest that all the peptides tested may be able to stimulate aldosterone secretion. However, the data obtained with substance P, NPY and CRH do not support a major role for these peptides in the regulation of aldosterone secretion either under control conditions, or in sodium depletion. The finding that the responses to VIP and DALA were altered by sodium depletion suggests that the actions of VIP and opioid peptides may have physiological significance in the regulation of aldosterone secretion in response to sodium depletion. Furthermore, the observation that saralasin does not inhibit the responses to these peptides strongly suggests that they are not acting through angiotensin II receptors, and may indicate altered VIP- and opioid-receptor regulation in sodium depletion.
Journal of Endocrinology (1995) 146, 209–214
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Abstract
While there have been several studies on the actions of opioid peptides on adrenocortical steroidogenesis, the results of these studies have failed to resolve the question as to whether these peptides exert a direct action on the adrenal cortex. The present studies were designed to address this question directly, using collagenase-dispersed rat zona glomerulosa and zonae fasciculata/reticularis cells incubated in vitro. The results obtained clearly show that the opioid peptides tested (β-endorphin, Leu-enkephalin, Met-enkephalin, and its long-acting analogue, DALA) all exerted a significant stimulatory effect on aldosterone secretion by zona glomerulosa cells and all, except Leuenkephalin, stimulated corticosterone secretion by inner zone cells. The response was shown to be inhibited by naloxone. There did not appear to be a significant interaction between the effects of ACTH and the opioid peptides on adrenocortical cells.
Studies using specific agonists for opioid receptor subtypes (DAMGO, DPDPE and U-50488H, specific for μ, δ and κ receptors respectively) showed that the effect of opioid peptides on the zona glomerulosa appeared to be mediated exclusively by μ receptors while the response of inner zone cells was mediated by both μ and, to a lesser extent, κ receptors. Finally, studies on the second messenger systems activated by the opioid peptides and the receptor agonists showed that these peptides act to increase labelling of inositol trisphosphate, and strongly suggest that, in the rat adrenal cortex, both μ and κ opioid receptors are linked to the activation of phospholipase C.
Journal of Endocrinology (1995) 144, 503–510
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ABSTRACT
Using the in-situ, isolated, perfused rat adrenal preparation, we have investigated the effects of changes in the rate of perfusate flow through the gland, brought about both mechanically and by the use of vasoactive agents, in the absence of known adrenocortical stimulants. Adenosine caused a significant increase in the rate of perfusate flow through the adrenal, with a concomitant rise in corticosterone, but not aldosterone, secretion. Adrenaline, on the other hand, caused a decrease in the rate of perfusate flow through the gland, accompanied by a decrease in the rate of steroid secretion. Futhermore, increases in the rate of delivery of perfusate to the gland, brought about by increasing the peristaltic pump rate, caused a large increase in corticosterone secretion, although aldosterone was unaffected. Neither adenosine nor a mechanically increased rate of perfusate delivery increased steroid secretion by collagenase-dispersed rat adrenocortical cells superfused on a Sephadex column. These results suggest the existence of hitherto unsuspected intraglandular mechanisms for the control of steroid secretion.
J. Endocr. (1986) 111, 391–396
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ABSTRACT
The effects of prior sodium depletion on the steroidogenic responses of the rat adrenal gland have been investigated using a method of perfusing the isolated adrenal gland of the rat in situ. Secretion rates of aldosterone in response to the known adrenocortical stimulants ACTH, angiotensin II amide and α-MSH were measured. In each case, the adrenals from sodium-deplete animals responded to a lower dose of the stimulant than the normal animals. This resulted in a 10-fold increase in sensitivity to ACTH, a 100-fold increase in sensitivity to angiotensin II amide, and a 1000-fold increased sensitivity to α-MSH, bringing the threshold concentration required for aldosterone secretion into the physiological range of α-MSH concentrations.
The perfused adrenal gland is particularly sensitive to angiotensin II amide; a bolus administration of 1 amol gave a significant increase in aldosterone secretion in the sodium-deplete group.
These data confirm previous reports of increased adrenal sensitivity to α-MSH and angiotensin II in sodium depletion, and also suggest the existence of intraglandular mechanisms for signal amplification which may be involved in mediating the adrenal response to very small concentrations of stimulant.
J. Endocr. (1988) 119, 83–88
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ABSTRACT
The rate of blood flow through the intact adrenal gland is closely linked to steroid hormone secretion, and although the mechanism involved is unknown, it is thought to involve secretory products of the vascular endothelium.
In dispersed cell preparations, endothelin-1 and -3 both caused a dose-dependent and highly sensitive increase in steroid secretion by zona glomerulosa and zona fasciculata cells of the rat and human adrenal cortex. In addition, when the perfused rat adrenal was stimulated with ACTH, significant increases in steroid secretion and perfusion medium flow rate were accompanied by significantly increased secretion of immunoreactive endothelin into the adrenal vein. It is proposed that endothelin has a role in mediating the adrenocortical response to ACTH stimulation.
Journal of Endocrinology (1991) 128, 275–280
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Introduction
'Welcome to ouabain – a new steroid hormone' was the title of the Lancet Editorial in June 1991, published in response to a series of articles by John Hamlyn and co-workers claiming to have conclusively identified the elusive 'endogenous digitalis-like factor' (EDLF) as ouabain or a closely related isomer. The group of drugs known as cardiac glycosides, which includes digoxin, ouabain and other digitalis-like compounds, are members of a class of steroids termed cardenolides, which were originally obtained from plants. The efficacy of cardiac glycosides in the treatment of congestive heart failure led Rein in 1942 to suggest that there may be an endogenous compound which could improve heart contractility (see Goto et al. 1992), although the existence of an EDLF in mammals was proposed as early as 1885 (Ringer 1885). Later, in 1953, Szent-Gyorgyi suggested that cardiac glycosides might replace a deficiency of a natural hormone which acts
William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine and Dentistry, University of London, London, UK
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William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine and Dentistry, University of London, London, UK
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William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine and Dentistry, University of London, London, UK
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William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine and Dentistry, University of London, London, UK
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The adrenal gland of the rat is continuously regenerated through proliferation of a stem cell population in the outer part of the gland. To clarify the location of proliferative events within the adrenal gland, and the factors that stimulate them, rat adrenal capsule preparations, consisting of capsule, zona glomerulosa (ZG) and the outer zona fasciculata (ZF) were maintained in vitro under different conditions of stimulation, for varying periods. Sites of proliferation were identified by 5-bromo-2′-deoxy-uridine (BrdU) staining, and the distribution of classical MAP kinase (MAPK) family members, extracellular signal-regulated kinase (ERK) 1 and 2, immunoreactivity was determined using immunocytochemistry. BrdU staining was limited to the outer glomerulosa and the capsule, where it was enhanced by angiotensin II, but not by a high potassium ion concentration nor by ACTH. In contrast, ERK1/2 immunoreactivity was distributed throughout the ZG and in the medulla, with none detectable in the ZF and reticularis. Furthermore, angiotensin II, potassium ions and ACTH were all shown to induce ERK1 and ERK2 phosphorylation in the ZG. Treatment of adrenal capsule tissue with the specific MAPK kinase inhibitor PD98059 revealed inhibition of ERK1/2 phosphorylation, but no effect on angiotensin II-induced aldosterone secretion. Although the distribution and activation of the MAPK pathway suggest a link with proliferation, the findings clearly designated only the outer part of the glomerulosa and capsule as a potential stem cell population. Further functions should be sought for the apparently silent major part of the glomerulosa.
Metabolic and Clinical Trials Unit, Department of Mental Health Sciences, Royal Free and University College Medical School, UCL, London, UK
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Metabolic and Clinical Trials Unit, Department of Mental Health Sciences, Royal Free and University College Medical School, UCL, London, UK
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Metabolic and Clinical Trials Unit, Department of Mental Health Sciences, Royal Free and University College Medical School, UCL, London, UK
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Metabolic and Clinical Trials Unit, Department of Mental Health Sciences, Royal Free and University College Medical School, UCL, London, UK
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The exploratory behaviour of the genetically derived Maudsley rat model of emotionality has been well characterized. Maudsley reactives (MR) present with more ‘anxious-like’ behaviour than Maudsley nonreactives (MNR). Although this behaviour is assumed to be associated with altered adrenocortical function, the few studies addressing this issue have produced inconsistent findings. We therefore set out to investigate the adrenal endocrinology of the MR and MNR strains. Control Wistars, the ancestors of the Maudsleys, have been used for the first time to set the baseline for all the experiments carried out. It was found that the MNR strain had a significantly blunted adrenocorticotrophic hormone (ACTH) response to restraint stress compared with Wistars, but a normal corticosterone response. Conversely, the MR had a significantly exaggerated ACTH response to restraint stress, but a normal corticosterone response. This finding suggested that the MR adrenal is less sensitive to ACTH than the MNR. This was confirmed by investigating the corticosterone dose–response to ACTH in adrenals from the two strains incubated in vitro. Several possible intra-adrenal regulators were investigated, but the only significant molecular difference in the adrenal glands from the two strains was the level of expression of neuropeptide Y (NPY), which is known to be a stress-responsive peptide in the adrenal. We propose that intra-adrenal NPY is responsible for blunting adrenocortical responses to ACTH stimulation in the MR strain. The observed changes in adrenal NPY suggest that this rat strain may serve as a model of chronic stress, with the MR phenotype representing maladaptation.
