ANTAGONISM OF TYPE-II, BUT NOT TYPE-I GLUCOCORTICOID RECEPTORS RESULTS IN ELEVATED BASAL LUTEINIZING-HORMONE RELEASE IN MALE-RATS

The present studies utilized a pharmacologic approach to evaluate the role of corticosterone-preferring mineralocorticoid receptors (type I or MR) versus classic glucocorticoid receptors (type II or GR) in the regulation of basal pituitary luteinizing hormone (LH) secretion in vi vo in male rats. Animals bearing indwelling intracardiac venous cathet ers received a subcutaneous (s.c.) injection of either vehicle, the MR antagonist, RU 752 (0.5 or 5.0 mg/kg body weight), or the GR antagoni st, RU 486 (0.5 or 5.0 mg/kg body weight). Additional groups of rats w ere implanted with indwelling intracerebroventricular (i.c.v.) cannula s and intravenous catheters for drug administration and blood withdraw al, respectively, and injected i.c.v. with vehicle or graded doses (0. 1, 1.0 or 10.0 mu g/rat) of RU 752 or RU 486. The MR RU 752 failed to alter plasma LH concentrations regardless of dose or route of administ ration. In contrast, the GR antagonist, RU 486, elicited significant, dose-dependent increases in circulating LH when given either s.c. or i .c.v. Animals injected s.c. with either 0.5 or 5.0 mg RU 486/kg body w eight showed elevated plasma LH levels; while the magnitude of this se cretory response was not different between the two drug-treated groups , hormone levels remained elevated over baseline for a longer period o f time in rats given the higher dose. Central administration of RU 486 at a dose of either 1.0 or 10.0 mu g also resulted in elevated LH rel ease; both the magnitude and duration of this increase in plasma LH we re dose-dependent. In additional experiments, groups of rats were pret reated with vehicle or the synthetic GR agonist, RU 362, before admini stration of RU 486. These studies showed that the stimulatory effect o f RU 486 on peripheral LH was abolished by prior interaction of GR wit h the exogenous ligand. In summary, the ability of the GR antagonist, RU 486, to promote an increase in plasma LH concentrations in intact m ale rats suggests that endogenous glucocorticoids exert a tonic inhibi tory tonus on in vivo LH release in these animals, and that GR mediate these suppressive effects. Observations that drug-induced elevations in circulating LH were abolished by pretreatment with the GR agonist, RU 362, suggest that the stimulatory effects of RU 486 on hormone rele ase were achieved by an antiglucocorticoid action. The current finding s that plasma LH was increased following intracranial administration o f RU 486 implicate central CR in neuroendocrine mechanisms governing p ituitary LH.