THE SELECTIVE PROSTAGLANDIN ENDOPEROXIDE SYNTHASE-2 INHIBITOR, NS-398, REDUCES PROSTAGLANDIN PRODUCTION AND OVULATION IN-VIVO AND IN-VITRO IN THE RAT

Two isoforms of prostaglandin G/H synthase, PGS-1 and PGS-2, catalyze the formation of prostaglandins (PC). Nonselective PCS inhibitors, e.g ., indomethacin, reduce the number of ovulations and PC levels in many animal models. This study evaluated the effects of the selective PGS- 2 inhibitor NS-398, compared to indomethacin, on ovulation number and on PC and steroid production both in vivo and in vitro in the rat. NS- 398 reduced the synthesis of PGE(2) in isolated, LH-stimulated preovul atory follicles incubated in vitro. The inhibition by NS-398 was simil ar to that of indomethacin. Maximal inhibition was noted from 0.1 mu M . Neither progesterone nor cAMP production was affected by NS-398 or i ndomethacin. The effect of in vivo administration of NS-398 (1, 3, or 10 mg/kg BW, s.c.) to proestrous rats 1 h after the injection of an ov ulatory dose of hCG was monitored in follicles extirpated 10 h after h CG. These follicles were incubated in vitro, and NS-398 dose-dependent ly reduced PGE(2) production. The synthesis of cAMP and progesterone w as not altered. In separate experiments, the same doses of NS-398 were injected to determine their effect on ovulation in vivo. The number o f ovulations was decreased by the highest dose of NS-398. In the in vi tro ovarian perfusion model, NS-398 (10 mu M) reduced the number of ov ulations initiated by LH and isobutylmethylxanthine. Lower doses of NS -398 (0.1 and 1 mu M) were less effective. The production of prostanoi ds (PGE(2), PGF(2 alpha), and 6-keto-PGF(1 alpha)) was reduced in a do se-dependent manner by NS-398. The secretion of steroids was not affec ted. This study demonstrates that selective inhibition of PGS-2 by NS- 398 reduces LH/hCG-stimulated production of prostanoids and the number of ovulations both in vivo and in vitro. These results provide direct evidence to strengthen the role of the inducible, granulosa cell-expr essed PGS-2 as one of the key regulators in the ovulatory process and also document that the elevated and perhaps sustained levels of PC are obligatory for ovulation.