19-Oxo-deoxycorticosterone binds to the renal mineralocorticoid receptor and produces sodium retention but not potassium excretion.

Abstract

The affinity of 19-oxo-deoxycorticosterone (19-oxo-DOC), a steroid recently isolated from the rat adrenal gland, for rat renal mineralocorticoid and glucocorticoid receptors was determined. To do this, kidney slices from adrenalectomized rats were incubated with 5 × 10–9M[3H]aldosterone (type 1), with or without varying concentrations of unlabeled aldosterone, deoxycorticosterone, or 19-oxo-DOC. Protein-bound[3H]aldos-terone complexes were obtained after absorption of the complex from the high speed supernatant with cellulose DE-52 columns and elution with 0.35 M KC1. In such incubations, the apparentaffinity of DOC for type 1 receptors was 27% that of aldosterone, and that of 19-oxo-DOC was 8% that of aldosterone, as determined by the Ki values. Kidney slices were also incubated with 5 × 10–8M[3H]dexamethasone (type II), with and without varying concentrations of unlabeled dexamethasone, deoxycor-ticosterone (DOC), or 19-oxo-DOC. DOC had 20% the affinity of dexamethasone for[3H]dexamethasone-binding sites, while 19-oxo-DOC had an affinity about 6% that of dexamethasone. The addition of 1-fold aldosterone, which, by preferentially binding the type I receptor, limits the access of[3H]dexameth-asone to them, decreased the[3H]dexamethasone-displacing ability of DOC to 8% and that of 19-oxo-DOC to 1% that of cold dexamethasone. This indicates that competitive binding of DOC and 19-oxo-DOC to the type I receptor predominates over the binding of these steroids to the type II receptor. Cell-free incu-bations of rat liver cytosol were also performed with 5 × 10–9M[3H]dexamethasone, with and without varying concentrations of dexamethasone and 19-oxo-DOC. The relative affinity of 19-oxo-DOC was less than 1% that of dexamethasone by this assay. Furthermore, the affinity of 19-oxo-DOC for binding to plasma corticosteroid-binding globulin was approximately 1% that of cortisol. The biological activity of 19-oxo-DOC using a rat bioassay was found to be approximately 1% that of aldosterone when sodium retention was calculated. It did not appear to antagonize aldosterone when injected together. The administration of maximal antinatriuretic doses of aldosterone induced significant kaliuresis; however, similar antinatriuretic doses of 19-oxo-DOC has no kaliuretic effects in two different bioassays. These studies show that 19-oxo-DOC both binds to type I renal mineralocor-ticoid receptors and produces the expected antinatriuretic effect of maximal doses of mineralocorticoids. This lack of a kaliuretic effect suggests that either 1) the kaliuretic effect of steroids such as aldosterone is mediated by a binding site other than the type I receptors, or 2) that potassium secretion mediated by aldoster-one-type I receptor interactions in discrete nephron target segments can be influenced by a steroid-sensitive potassium-recycling system in a more distal nephron site. Why such a system would be stimulated by aldosterone and not by 19-oxo-DOC is unclear. (Endocrinology113: 517, 1983)