Effects of a novel 21-amino steroid, U74006F, on the rat pituitary-adrenocortical axis

The 21-amino steroid U74006F is a potent inhibitor of lipid peroxidation and has been shown to affect beneficially the acutely injured central nervous system. Therapeutically, it is desirable for this compound to be devoid of steroid side-effects. We have demonstrated a significant (P less than 0.001) inhibition of basal ACTH secretion from cultured rat pituitary cells during a 24-h incubation at concentrations (10-100 mumols/l) previously demonstrated to inhibit lipid peroxidation in vitro. U74006F also inhibited corticotrophin-releasing factor (CRF)-stimulated ACTH secretion significantly and the combination of dexamethasone and U74006F completely blocked CRF-41-stimulated ACTH secretion. Administration of U74006F in vivo (30 mg/kg, orally, every 6 h for 30 h) had no effect on ACTH levels in normal rats (84 +/- 38 vs 45 +/- 6 ng/l in control animals) but increased ACTH levels in adrenalectomized rats (1330 +/- 295 vs 464 +/- 79 ng/l in control animals, P less than 0.02). This increase in ACTH was not observed when adrenalectomized animals were maintained on the same regime of U74006F for 5 days. Our data suggest that U74006F is capable of exerting inhibitory effects on ACTH secretion in vitro. In vivo, effects on ACTH secretion were stimulatory rather than inhibitory and only occurred short-term in adrenalectomized animals or chronically in adrenalectomized rats maintained on dexamethasone. No effects on the pituitary-adrenocortical axis were seen following short-term or chronic administration of U74006F in normal rats.