A comparison of the effects of indomethacin and NS-398 (a selective prostaglandin H synthase-2 inhibitor) on implantation in the rat

Indomethacin (25 mu M) inhibited the amount of prostaglandin (PG) E-2, PGF( 2 alpha) and 6-keto-PGF(1 alpha) synthesized by homogenates of day 5 pregna nt rat uterus by 80-92%. In contrast, 25 mu M NS-398, a selective inhibitor of prostaglandin H synthase-2 (PGHS-2), inhibited the synthesis of these t hree prostaglandins by homogenates of the same tissue by only 37-60%. Since it has been reported that idomethacin and NS-398 inhibit PGHS-2 with simil ar potencies and that indomethacin (unlike NS-398) is a potent inhibitor of PGHS-1, it may be concluded that prostaglandin production by homogenates o f the rat uterus on day 5 of pregnancy is due to the activities of both PGH S-1 and PGHS-2. The administration of indomethacin (3 mg/kg) twice daily on days 3 and 4 of pregnancy reduced the implantation rate by 77%, whereas th e similar administration of NS-398 (6 mg/kg) had no significant effect on i mplantation. It may be concluded that either the dose of NS-398 used was to o low to affect uterine PGHS-2 activity in vivo sufficiently to prevent imp lantation, or that inhibiting uterine PGHS-2 activity in vivo has no effect on the implantation mechanisms or is compensated for by increased PGHS-1 a ctivity such that the implantation process is not impaired. (C) 1999 Harcou rt Publishers Ltd.