A comparison of the effects of indomethacin and NS-398 (a selective prostaglandin H synthase-2 inhibitor) on implantation in the rat.
Indomethacin (25 microM) inhibited the amount of prostaglandin (PG) E2, PGF2alpha and 6-keto-PGF1alpha synthesized by homogenates of day 5 pregnant rat uterus by 80-92%. In contrast, 25 microM NS-398, a selective inhibitor of prostaglandin H synthase-2 (PGHS-2), inhibited the synthesis of these three 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 similar potencies and that indomethacin (unlike NS-398) is a potent inhibitor of PGHS-1, it may be concluded that prostaglandin production by homogenates of the rat uterus on day 5 of pregnancy is due to the activities of both PGHS-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 the similar administration of NS-398 (6 mg/kg) had no significant effect on implantation. It may be concluded that either the dose of NS-398 used was too low to affect uterine PGHS-2 activity in vivo sufficiently to prevent implantation, or that inhibiting uterine PGHS-2 activity in vivo has no effect on the implantation mechanisms or is compensated for by increased PGHS-1 activity such that the implantation process is not impaired.
Poyser
N L
NL
Department of Pharmacology, University of Edinburgh Medical School, UK.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015237:Dinoprost / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D010064:Embryo Implantation / Q000187:drug effects* / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D007527:Isoenzymes / Q000494:pharmacology*; D009578:Nitrobenzenes / Q000494:pharmacology*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015121:6-Ketoprostaglandin F1 alpha; D015237:Dinoprost; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin