STIMULATORY EFFECT OF A SPECIFIC SUBSTANCE-P ANTAGONIST (RPR-100893) OF THE HUMAN NK1 RECEPTOR ON THE ESTRADIOL-INDUCED LH AND FSH SURGES IN THE OVARIECTOMIZED CYNOMOLGUS MONKEY

Utilizing a human NK1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substa nce P (SP) modulates the action of 17 beta-estradiol in inducing lutei nizing hormone (LH) and follicle stimulating hormone (FSH) surges in o variectomized cynomolgus monkey. Plasma concentrations of LH and FSH a s well as NK1 receptor antagonist and SP were measured during the deve lopment of the negative and positive feedback phases which follow a si ngle administration of estradiol benzoate (50 mu g/kg) to long-term ov ariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals f or at least 6 hr after its administration. These levels are in agreeme nt with the experimentally determined IC50 value of the antagonist. Th e most striking finding of this study is that LH and FSH releases are enhanced during the descending arm of the estradiol benzoate-induced L H and FSH surges, which suggests that endogenous SP normally has an in hibitory role during this time. The enhancement of LH release is appro ximately 50%, regardless of the amount of the NK1 antagonist used. How ever, the enhanced FSH release is more important. Furthermore, blockad e of the NK1 receptor with the smaller dose of the antagonist leads to a small, but significant, increase in plasma levels off SP, indicatin g that blockade of SP receptors leads to an increased release of SP. C ollectively, these results further substantiate the link which exists between the ovarian steroid 17 beta-estradiol and SP systems. Also, fo r the first time, these results demonstrate an inhibitory involvement of the human NK1 receptor in the 17 beta-estradiol-induced pseudoovula tory gonadotropin surges in the ovariectomized monkey. (C) 1997 Wiley- Liss, Inc.