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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
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The finding that incubation of rat adrenal capsules (largely zona glomerulosa) with trypsin reproducibly releases aldosterone and 18-hydroxycorticosterone (18-OH-B) from tightly protein-bound tissue stores leads to the hypothesis that the secretion of these steroids may be under the control of endogenous proteases.
Rat adrenal capsule whole tissue and collagenase-dispersed cells were incubated under conditions of stimulation by (1–24)ACTH (10−7 mol/l), potassium (8·4 × 10−3 mol/l) or dibutyryl cyclic AMP (dbcAMP) (10−4 mol/l) with the addition in some flasks of one of the following protease inhibitors at the appropriate concentration for their known actions: Nα-p-tosyl-l-arginine methyl ester (TAME; 10−2 mol/l), 2-nitro-4-carboxyphenyl-N,N′-diphenylcarbamate (NCDC; 2×10−6 mol/l), Nα-benzoyl-l-arginine (BA; 10−2 mol/l), p-nitrophenyl-Nα-benzyloxycarbonyl-l-lysinate (CBZ-NL; 2×10−6 mol/l) and soybean trypsin inhibitor (STI; 1 mg/ml). The (1–24)ACTH-stimulated steroid output in dispersed cells was not affected by NCDC, BA or CBZ-NL. However, all of the inhibitors except STI produced selective effects on aldosterone and 18-OH-B production by whole capsule tissue under certain conditions. Thus TAME and NCDC significantly inhibited the dbcAMP-stimulated production of these two steroids (aldosterone values decreased from 328±35 to 128±15 and 157±32 ng/gland pair respectively) and furthermore NCDC elicited the same effect in potassium- or ACTH-stimulated whole tissue (e.g. in K+-stimulated tissue aldosterone decreased from 79±15 to 40±7 ng/gland pair). The reverse effect was shown by BA and CBZ-NL in potassium-stimulated whole tissue, and yields of aldosterone and 18-OH-B were significantly enhanced (aldosterone increased from 79±15 ng/pair to 151±14 ng in the presence of BA). The high molecular weight inhibitor STI had no effect on potassium-stimulated whole tissue, but enhanced the yield of extractable aldosterone from 9·±1·7 to 16·9±2·3 ng/pair when added to incubations of a cytosol preparation.
The results suggest that endogenous proteases in rat adrenal whole capsule tissue play specific roles in the control of aldosterone and 18-OH-B secretion. Some (type 1) whose action is mimicked by trypsin, are inhibited by TAME and NCDC and appear to be involved in the release of these two steroids from their tight (apparently covalent) binding to protein. Others (type 2) are inhibited by BA, CBZ-NL and STI, and one interpretation of their function is that they are concerned with the activation of type 1 proteases.
The mechanisms envisaged provide a selective means for control of secretion of the late-pathway steroid products in the rat adrenal zona glomerulosa. These mechanisms are not apparent in dispersed cell incubations, probably because of the loss of steroid–protein complexes in these preparations.
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.
