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P J Fuller and S Lim-Tio

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

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R. Fraser

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

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Renaud Beauwens, Marion Birmingham, and Jean Crabbé

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.

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Ding Xie and Wendy B Bollag

Obesity is a serious health hazard with rapidly increasing prevalence in the United States. In 2014, the World Health Organization estimated that nearly 2 billion people worldwide were overweight with an estimated 600 million of these obese. Obesity is associated with many chronic diseases, including cardiovascular disease and hypertension. Data from the Framingham Heart study suggest that approximately 78% of the risk for hypertension in men and 65% in women is related to excess body weight, a relationship that is further supported by studies showing increases in blood pressure with weight gain and decreases with weight loss. However, the exact mechanism by which excess body fat induces hypertension remains poorly understood. Several clinical studies have demonstrated elevated plasma aldosterone levels in obese individuals, especially those with visceral adiposity, with decreased aldosterone levels measured in concert with reduced blood pressure following weight loss. Since aldosterone is a mineralocorticoid hormone that regulates blood volume and pressure, serum aldosterone levels may link obesity and hypertension. Nevertheless, the mechanism by which obesity induces aldosterone production is unclear. A recent study by Belin de Chantemele and coworkers suggests that one adipose-released factor, leptin, is a direct agonist for aldosterone secretion; other adipose-related factors may also contribute to elevated aldosterone levels in obesity, such as very low-density lipoprotein (VLDL), the levels of which are elevated in obesity and which also directly stimulates aldosterone biosynthesis. This focused review explores the possible roles of leptin and VLDL in modulating aldosterone secretion to underlie obesity-associated hypertension.

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Ying-Ying Tsai, William E Rainey, and Wendy B Bollag

Aldosterone, secreted by the adrenal zona glomerulosa, enhances sodium retention, thus increasing blood volume and pressure. Excessive production of aldosterone results in high blood pressure and contributes to cardiovascular and renal disease, stroke and visual loss. Hypertension is also associated with obesity, which is correlated with other serious health risks as well. Although weight gain is associated with increased blood pressure, the mechanism by which excess fat deposits increase blood pressure remains unclear. Several studies have suggested that aldosterone levels are elevated with obesity and may represent a link between obesity and hypertension. In addition to hypertension, obese patients typically have dyslipidemia, including elevated serum levels of very low-density lipoprotein (VLDL). VLDL, which functions to transport triglycerides from the liver to peripheral tissues, has been demonstrated to stimulate aldosterone production. Recent studies suggest that the signaling pathways activated by VLDL are similar to those utilized by AngII. Thus, VLDL increases cytosolic calcium levels and stimulates phospholipase D (PLD) activity to result in the induction of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression. These effects seem to be mediated by the ability of VLDL to increase the phosphorylation (activation) of their regulatory transcription factors, such as the cAMP response element-binding (CREB) protein family of transcription factors. Thus, research into the pathways by which VLDL stimulates aldosterone production may identify novel targets for the development of therapies for the treatment of hypertension, particularly those associated with obesity, and other aldosterone-modulated pathologies.

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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.

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N. Hazon and I. W. Henderson


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

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Nicole Draper and Paul M Stewart

Two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2) catalyse the interconversion of hormonally active cortisol and inactive cortisone. The enzyme evolved from a metabolic pathway to a novel mechanism underpinning human disease with the elucidation of the role of the type 2 or ‘kidney’ isozyme and an inherited form of hypertension, ‘apparent mineralocorti-coid excess’. ‘Cushing’s disease of the kidney’ arises because of a failure of 11β-HSD2 to inactivate cortisol to cortisone resulting in cortisol-induced mineralocorticoid excess.

Conversely, 11β-HSD1 has been linked to human obesity and insulin resistance, but also to other diseases in which glucocorticoids have historically been implicated (osteoporosis, glaucoma). Here, the activation of cortisol from cortisone facilitates glucocorticoid hormone action at an autocrine level. The molecular basis for the putative human 11β-HSD1 ‘knockout’ – ‘cortisone reductase deficiency’ - has recently been described, an observation that also answers a long standing conundrum relating to the set-point of 11β-HSD1 activity. In each case, these clinical studies have been underpinned by studies in vitro and the manipulation of enzyme expression in vivo using recombinant mouse models.

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John M C Connell and Eleanor Davies

Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific ‘aldosterone-induced’ proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety of actions of aldosterone that contribute to blood pressure homeostasis. These include key actions on endothelial cells and on cardiac tissue.

There is also evidence that aldosterone can be synthesised in other tissues; the most convincing evidence relates to the central nervous system. However, suggestions that aldosterone is produced in the heart remain controversial, and adrenal derived aldosterone is the principal source of circulating and locally available hormone.

Recent studies have shown major therapeutic benefits of mineralocorticoid receptor antagonism in cardiac failure, which emphasise the importance of aldosterone in causing adverse cardiovascular pathophysiological effects. Additional evidence demonstrates that aldosterone levels predict development of high blood pressure in normotensive subjects, while it is now clear that increased aldosterone action contributes to hypertension and cardiovascular damage in approximately 10% of patients with established hypertension.

These new findings highlight the role of aldosterone as a key cardiovascular hormone and extend our understanding of its role in determining adverse cardiovascular outcomes.

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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.