Evaluation of RU28318 and RU40555 as selective mineralocorticoid receptor and glucocorticoid receptor antagonists, respectively: Receptor measures and functional studies

Corticosterone regulates a wide range of physiological parameters. Two rece ptors for corticosterone have been identified, the mineralocorticoid (type I) receptor (MR) and the glucocorticoid (type II) receptor (GR). To determi ne the relative role of these two receptors in mediating the effects of end ogenous corticosterone, many studies have relied on the use of putative sel ective corticosteroid receptor antagonists. This study further examined the in vivo receptor selectivity of two compounds, RU28318 and RU40555 that ar e believed to be selective antagonists for MR and GR, respectively. Acute t reatment of adrenalectomized rats with RU28318 (10-50 mg/kg) selectively de creased ex-vivo available MR binding in the hippocampus, whereas acute trea tment with RU40555 (10-30 mg/kg) selectively decreased available GR binding in the hippocampus and pituitary. These receptor binding measures suggest that RU28318 in vivo selectively occupied MR, and that RU40555 in vivo sele ctively occupied GR. In functional studies, RU28318 (50 mg/kg) blocked the normalizing effect of aldosterone (120 mu g/kg) on saline intake of adrenal ectomized rats. RU40555 (30 mg/kg) blocked the suppressive effect of dexame thasone (50 mu g/kg) on acute stress-induced corticosterone secretion. Thes e studies further support the in vivo corticosteroid receptor selectivity o f these two compounds and confirms their effective corticosteroid antagonis tic properties. (C) 1998 Elsevier Science Ltd. All rights reserved.