Renal Receptor-Binding Activity of Reduced Metabolites of Aldosterone: Evidence for a Mineralocorticoid Effect outside of the Classic Aldosterone Receptor System*

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Abstract
Reduced metabolites of aldosterone have been shown to have antinatriuretic and kaliuretic effects. The ability of 4 reduced metabolites of aldosterone to compete with [3H]aldosterone and [3H]dexamethasone for binding to the mineralocorticoid and glucocorticoid receptors of the kidney was studied using adrenalectomized rat renal slices and cytosol, respectively, as sources of the binding proteins. 5.alpha.-Dihydroaldosterone had 18.9% the ability to compete with [3H]aldosterone for binding to the cytoplasmic receptor of adrenalectomized rat renal slices in comparison to unlabeled aldosterone. Its antinatriuretic potency varied between 7-17%. Its ability to compete with [3H]dexamethasone for binding to the renal glucocorticoid receptor was only 1.9% in comparison to unlabeled dexamethasone. The relative competitive activities of 3.beta.,5.alpha.-tetrahydroaldosterone and 3.beta.,5.beta.-tetrahydroaldosterone with [3H]aldosterone to adrenalectomized rat renal slices cytosol were 1.26% and 0.05%, respectively, in comparison to unlabeled aldosterone. Their reported mineralocorticoid activities using the adrenalectomized rat bioassay (antinatriuresis) were 0.1-0.4% and 0.15%, respectively, in comparison to aldosterone. The most important aldosterone metabolite 3.alpha.,5.beta.-tetrahydroaldosterone showed negligible competitive activity with [3H]aldosterone or [3H]dexamethasone for the renal corticoid type I or type II receptors, respectively. This compound has been reported and confirmed to have weak but clear-cut mineralocorticoid activity (.apprx. 1/100th that of aldosterone). The mineralocorticoid activity of 3.alpha.,5.beta.-tetrahydroaldosterone cannot be explained by a mechanism involving the classic renal mineralocorticoid receptor. The mechanism could involve an alternative receptor system, a nonreceptor-mediated renal mechanism, or the conversion to a metabolite that would interact with classic receptors.

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