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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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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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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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Kelly De Sousa, Alaa B Abdellatif, Rami M El Zein, and Maria-Christina Zennaro

Primary aldosteronism (PA) is the most common form and an under-diagnosed cause of secondary arterial hypertension, accounting for up to 10% of hypertensive cases and associated to increased cardiovascular risk. PA is caused by autonomous overproduction of aldosterone by the adrenal cortex. It is mainly caused by a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Excess aldosterone leads to arterial hypertension with suppressed renin, frequently associated to hypokalemia. Mutations in genes coding for ion channels and ATPases have been identified in APA, explaining the pathophysiology of increased aldosterone production. Different inherited genetic abnormalities led to the distinction of four forms of familial hyperaldosteronism (type I to IV) and other genetic defects very likely remain to be identified. Somatic mutations are identified in APA, but also in aldosterone-producing cell clusters (APCCs) in normal adrenals, in image-negative unilateral hyperplasia, in transitional lesions and in APCC from adrenals with bilateral adrenal hyperplasia (BAH). Whether these structures are precursors of APA or whether somatic mutations occur in a proliferative adrenal cortex, is still a matter of debate. This review will summarize our knowledge on the molecular mechanisms responsible for PA and the recent discovery of new genes related to early-onset and familial forms of the disease. We will also address new issues concerning genomic and proteomic changes in adrenals with APA and discuss adrenal pathophysiology in relation to aldosterone-producing structures in the adrenal cortex.

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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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T. C. LEE, B. van der WAL, and D. de WIED


Studies of the rate of aldosterone production in vitro of adrenals of rats hypophysectomized before dietary sodium restriction showed that hypophysectomy not only prevented the increases in aldosterone production observed in intact, Na-deprived rats, but also depressed the level of aldosterone production to below that of intact rats maintained on a normal diet. Rats hypophysectomized for a similar period of time but maintained on the normal diet showed a similar decrease.

Experiments on adeno- and neuro-hypophysectomized rats indicated that the pituitary factor required for the normal mineralocorticoid response to dietary sodium restriction resides in the anterior pituitary.

Treatment of hypophysectomized rats during dietary sodium restriction with doses of a long-acting corticotrophin (ACTH) prevented adrenal atrophy and maintained a normal glucocorticoid response to intravenous injections of ACTH, but failed to increase aldosterone production rates in vitro to levels above that of intact rats on a normal diet; it also failed to restore the enhanced adrenocortical sensitivity to the stimulating effect of aldosterone production of intravenously injected ACTH which is characteristic of acutely hypophysectomized, Na-deficient rats. Treatment with anterior pituitary powder (8–12 mg./day) for similar periods, however, restored the aldosterone production of adrenals in vitro of hypophysectomized, Na-deprived rats to levels nearly indistinguishable from those of acutely hypophysectomized, Na-deprived controls. The same doses of anterior pituitary powder were shown not to have any demonstrable effect on the aldosterone production of adrenals in vitro of intact rats on a normal diet.

These results are interpreted as indicating the existence of a pituitary factor other than ACTH which stimulates aldosterone secretion. This factor does not appear to act directly on the adrenal cortex or to stimulate the secretion of specific glomerulotropic substances, but probably exerts its effect by maintaining the normal functional capacity of some as yet undefined tissues which secrete glomerulotropic substances in response to dietary sodium restriction.

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Aldosterone production by isolated adrenal glomerulosa cells from the rat was estimated in the presence of varying concentrations of sodium ion. The reduction of sodium concentration by 5–20 mmol/l, with or without osmotic changes, did not influence the rate of aldosterone production. Aldosterone response to angiotensin II was not modified by varying the sodium concentration.

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Prostaglandin E2 increased aldosterone output by superfused capsular adrenal glands obtained from sodium-repleted, hypophysectomized rats but corticosterone did not show a statistically significant increase. Prostaglandin A2 increased corticosterone but not aldosterone production by incubated capsular glands obtained from sodium-repleted, hypophysectomized rats. Both aldosterone and corticosterone production rates were increased by PGA2 after previous sodium restriction. Corticosterone production rate of the decapsulated adrenal gland was not significantly modified by prostaglandin A2 in a concentration effective on the capsular adrenal gland. A possible role of prostaglandins in the regulation of aldosterone secretion is discussed.

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A L Markel, O E Redina, M A Gilinsky, G M Dymshits, E V Kalashnikova, Yu V Khvorostova, L A Fedoseeva, and G S Jacobson

The functions of the hypothalamic adrenal cortical and sympathetic adrenal medullary systems were studied in rats with inherited stress-induced arterial hypertension (ISIAH strain). A characteristic feature of the ISIAH strain is an increase in arterial blood pressure measured both under basal conditions and after restraint stress in particular. In the control ISIAH rats, the basal plasma ACTH concentration was slightly lower than that in the normotensive Wistar albino Glaxo (WAG) rats, and no differences were found in plasma corticosterone. However, the 0.5-h restraint stress produced higher activation of the adrenal cortex in the ISIAH rats. Gluco- and mineralocorticoid responses to the blood volume reduction stresses and ACTH and corticosterone responses to social stress were stronger in the ISIAH than in the control WAG rats. An increase in epinephrine content in adrenals in the basal state and enhanced response of the sympathetic adrenal medullary system to handling stress were observed in the ISIAH rats. Restraint stress produced significantly higher expression of genes encoding corticotropin-releasing hormone-mRNA in hypothalamus and proopiomelanocortin-mRNA in pituitary in the ISIAH than in the WAG rats. Restraint stress produced a decrease in glucocorticoid receptor (GR) gene expression (GR-mRNA) in hippocampus in the ISIAH, but not in the WAG rats. A persistent increase in tyrosine hydroxylase-mRNA in adrenals of the ISIAH rats was found. It is concluded that the ISIAH rat strain is an appropriate model of stress-sensitive hypertension with the predominant involvement of the hypothalamic adrenal cortical and sympathetic adrenal medullary systems in its pathogenesis.

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A case is described in which the presence of an adrenal cortical adenoma was predicted from the association of hypertension, hypokalaemia, raised aldosterone secretion and depressed plasma renin concentration.

Pre-operatively, administration of a spironolactone for a period of 10½ months corrected the electrolyte abnormalities, increased the plasma renin concentration to normal and lowered the blood pressure, although the raised aldosterone secretion was unchanged.

At operation a typical adrenal cortical adenoma was found.

Renal biopsy at operation showed arteriolar fibrinoid lesions, although no retinal lesions were seen at any stage.