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The role of aldosterone in regulating epithelial sodium transport is well established as is the concept of a specific intracellular aldosterone or mineralocorticoid receptor (MR). Specific details on the molecular mechanism of this well-characterized physiology have, however, remained sketchy. Two recently published studies offer important insights into two separate aspects of aldosterone action (Shimkets et al. 1994, Wilson et al. 1995). As in many other areas of biology, naturally occurring mutations have again provided key insights.

The syndrome of apparent mineralocorticoid excess (AME) was first characterized by Ulick et al. in 1979. The condition presents in childhood with hypertension, severe hypokalaemic alkalosis, low plasma renin activity and low circulating levels of aldosterone. Treatment with the MR antagonist spironolactone is effective, paradoxically suggesting mineralocorticoid excess. That this condition could be due to a failure of the metabolism of cortisol to cortisone in aldosterone target tissues, such as the kidney or the

In some fields of steroid endocrinology, it has long been accepted that the potency of a hormone may depend not only on its secretion rate and rate of hepatic clearance but also on specific metabolic transformation at the site of the target cell. The crucial role of tissue 5α reductase activity on the action of testosterone is a spectacular example (Peterson, ImperatoMcGinley, Gautier & Sturla, 1977). Curiously—it is easy to be wise after the event—this line of thought seems rarely to have been exercized in explanations of corticosteroid action. Clearly, the severity of diseases of corticosteroid excess, of which Cushing's and Conn's syndromes are the best known examples, is strongly correlated with the secretion rate of cortisol and aldosterone respectively. However, in some forms of hypertension where deranged corticosteroid action might be expected to provide an acceptable explanation (e.g. increased mineralocorticoid secretion in low-renin essential hypertension), no abnormalities of secretion

The effects on sodium transport of several steroids physiologically secreted or possibly involved in pathological disorders were compared with those of aldosterone in the isolated toad skin.

The 18-hydroxylated derivatives of deoxycorticosterone and corticosterone, in contrast to their parent compounds, significantly enhanced sodium transport at a concentration of 50 nmol/l. In the presence of glucose, 18-hydroxydeoxycorticosterone increased trans-epithelial potential difference, as did aldosterone. The 19-nor derivative of deoxycorticosterone, recently implicated in the aetiology of adrenal regeneration hypertension, stimulated sodium transport, unlike 19-nor-corticosterone and 16-oxo-androstenediol. Insulin significantly increased sodium transport in aldosterone-treated skin and lowered the resistance. The natriferic response to vasopressin was potentiated fivefold by exposure of the skin to aldosterone and was doubled in skin exposed to 19-nor-deoxycorticosterone.

We conclude that 18-hydroxylated adrenocortical steroids can play a physiological role in salt retention; furthermore, these steroids, as well as 19-nor-deoxycorticosterone, could be involved in pathological conditions such as low renin hypertension. Caution should be exercised in evaluating mineralocorticoid potency solely in terms of the urinary sodium to potassium ratio.

SUMMARY

The hypothesis that experimental renal hypertension results from increased activity of the renin-angiotensin-aldosterone system has been tested by determining aldosterone secretion in six dogs during the rising phase of pressure in Goldblatt hypertension. Hypertension was produced by placing a Goldblatt clamp on one kidney followed by removal of the second kidney. The animals were kept on a normal diet with a constant sodium and potassium content. The mean control blood pressure was 127 ± 6 (s.e.m.) mm. Hg and the pressure in the hypertensive stage 169 ± 5 mm. Hg. Control aldosterone secretion was 29·1 ± 7·0 μg./24 hr., but fell to 8·6 ± 1·1 μg./24 hr. in the 1st week after application of the clamp during which the arterial pressure was rising to hypertensive levels. After the blood pressure had reached its maximum value, the rate of aldosterone secretion had risen slightly to 14·5 ± 2·7 μg./24 hr. These results show that the rate of aldosterone secretion is not necessarily increased during the developing phase of benign renal hypertension.

ABSTRACT

Blood pressure and selected putatively influential hormones were measured in Brattleboro rats which were without diabetes insipidus and which were subjected to various manipulations in dietary sodium intake. Rats fed a control diet from weaning to 16 weeks of age showed a slow increase in blood pressure whereas rats fed a sodium-enriched diet for the same period exhibited sustained hypertension (115±3 versus 169±5 (s.e.m.) mmHg). In animals fed a sodium-enriched diet plasma concentrations of antidiuretic hormone (ADH) were significantly increased from 55±8 to 108±5 fmol/l. Rats fed the control diet from weaning (group A) and subsequently maintained on that diet or changed to a sodium-enriched diet or sodium-deficient diet showed no differences in their blood pressure. Plasma hormone concentrations were similar in these groups, with the exception of aldosterone suppression in rats switched from control to a sodium-enriched diet (0·26±0·04 versus 0·08±0·03 nmol/l; P <0·001). Animals fed the sodium-enriched diet from weaning to 16 weeks of age (group b) and either maintained on that diet or changed to a control diet showed little change in their established hypertension. Transfer to the control diet was associated with increased plasma renin concentrations (PRC) (13·8±2·1 to 122·6±6·2 nmol/l) and plasma aldosterone concentrations (0·04±0·01 to 0·08±0·01 nmol/l; P<0·001) but corticosteroids and ADH concentrations were unchanged. Rats maintained on the sodium-enriched diet from weaning to 16 weeks of age and transfered to a sodium-deficient diet exhibited increases in their established hypertensive blood pressures (maximally 205±4 versus 170±4 mmHg) together with significant increases in PRC (13·8 ±2·1 to 297±79 nmol/l; P< 0·001), aldosterone (0·04±0·01 to 0·23±0·07 nmol/l; P <0·001) and ADH (82·9±15·5 to 466±118 fmol/l; P <0·001), although plasma concentrations of corticosteroids were again unaffected. Thus it would appear that there is a critical developmental stage at which exposure to a sodium-enriched diet subsequently leads to hypertension. Abrupt withdrawal of the sodium-enriched diet produces an exaggerated hypertension involving changes in both ADH and the renin-angiotensin-aldosterone system.

Journal of Endocrinology (1990) 127, 243–248

SUMMARY

A woman with recurrent urinary infection, bilateral renal calculi, and an abnormal pattern of plasma proteins was unable to reduce urinary sodium excretion when sodium intake was restricted.

When the intake of sodium was reduced depletion developed rapidly, and severe hyponatraemia was associated with increased plasma renin and aldosterone concentrations, and a less marked although definite, increase in plasma corticosterone. Plasma cortisol was unchanged during sodium depletion, although it increased normally after the administration of corticotrophin.