INHIBITION OF ALDOSTERONE TURN-OFF PHENOMENON FOLLOWING CHRONIC ADRENOCORTICOTROPIN TREATMENT WITH IN-VIVO ADMINISTRATION OF ANTIGLUCOCORTICOID AND ANTIOXIDANTS IN RATS

Chronic adrenocorticotropin (ACTH) treatment in rats leads to a fall i n aldosterone secretion (aldosterone turn-off or ''aldosterone escape' ' phenomenon) with a concomitant rise in corticosterone. To elucidate whether ACTH-induced aldosterone suppression is mediated by steroid ty pe II receptor or related to a free-radical effect by over-synthesized corticosterone, we examined the effects of a glucocorticoid antagonis t, RU486, and antioxidants dimethyl sulfoxide (DMSO) and vitamin E, on the aldosterone turn-off phenomenon in rats. Each rat received daily for 5 days a different dose of ACTH-Z (5, 10, 20 or 40 mu g/100 g body weight) 1 mg RU486/100 g body weight, 100 mu l (1.3 mmol) DMS0/100 g body weight or 2 mg vitamin E/100 g body weight with subcutaneous inje ction. Plasma steroid levels and in vitro release of steroids from the adrenal capsule were measured. The ACTH-Z treatment caused a dose-dep endent increase in corticosterone and a decrease in aldosterone in bot h plasma and adrenal capsule experiments, as well as an increase in ad renal weights. For the following study 5 mu g/100 g body weight of ACT H-Z was used. Administration of RU486 alone caused no change in plasma aldosterone level compared to controls, even though the steroid type II receptor was blocked, as evidenced by significant increases in plas ma ACTH and corticosterone levels, Concomitant administration of RU486 and ACTH-Z increased both plasma corticosterone and aldosterone level s (p< 0.01) but decreased adrenal capsule corticosterone production (p < 0.05) compared to the rats treated with ACTH-Z alone. Treatment with DMSO alone caused a significant increase in plasma ACTH and corticost erone level (p< 0.05) but no change in plasma aldosterone level or adr enal capsule corticosterone and aldosterone production, The ACTH-induc ed aldosterone decrease was completely prevented by DMSO administratio n in both plasma and adrenal capsule experiments (p< 0.01). Vitamin E administration resulted in the elevation of plasma levels of ACTH and corticosterone (P< 0.01 and < 0.05) but not aldosterone, and it also i ncreased adrenal capsule corticosterone production (p< 0.01) but not a ldosterone production. By vitamin E administration, the ACTH-induced a ldosterone decrease was suppressed almost completely in plasma (p< 0.0 1) and partially in adrenal capsule experiments (p< 0.01) compared to rats treated with ACTH-Z alone. Our findings suggest that RU486, DMSO and vitamin E inhibit the ACTH-induced aldosterone turn-off phenomenon iri plasma, possibly due to the increase in activity of P-450(aldo), through antioxidant action or a steroid type II receptor blocking acti on.