Inhibition of aldosterone turn-off phenomenon following chronic adrenocorticotropin treatment with in vivo administration of antiglucocorticoid and antioxidants in rats

Abstract

Ni H, Mune T, Morita H, Daidoh H, Hanafusa J, Shibata T, Yamakita N, Yasuda K. Inhibition of aldosterone turn-off phenomenon following chronic adrenocorticotropin treatment with in vivo administration of antiglucocorticoid and antioxidants in rats. Eur J Endocrinol 1995;133:578–84. ISSN 0804–4643 Chronic adrenocorticotropin (ACTH) treatment in rats leads to a fall in 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 type II receptor or related to a free-radical effect by over-synthesized corticosterone, we examined the effects of a glucocorticoid antagonist, 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 μg/100 g body weight) 1 mg RU486/100 g body weight, 100 μl (1.3 mmol) DMSO/100 g body weight or 2 mg vitamin E/100 g body weight with subcutaneous injection. Plasma steroid levels and in vitro release of steroids from the adrenal capsule were measured. The ACTH-Z treatment caused a dose-dependent increase in corticosterone and a decrease in aldosterone in both plasma and adrenal capsule experiments, as well as an increase in adrenal weights. For the following study 5 μg/100 g body weight of ACTH-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 plasma ACTH and corticosterone levels. Concomitant administration of RU486 and ACTH-Z increased both plasma corticosterone and aldosterone levels (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 corticosterone level (p< 0.05) but no change in plasma aldosterone level or adrenal capsule corticosterone and aldosterone production. The ACTH-induced aldosterone decrease was completely prevented by DMSO administration 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 increased adrenal capsule corticosterone production (p< 0.01) but not aldosterone production. By vitamin E administration, the ACTH-induced aldosterone decrease was suppressed almost completely in plasma (p< 0.01) 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 in plasma, possibly due to the increase in activity of P-450aldo through antioxidant action or a steroid type II receptor blocking action. Keigo Yasuda, Third Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu MZ500, Japan