IN-VIVO ADMINISTRATION OF NIMESULIDE, A SELECTIVE PGHS-2 INHIBITOR, INCREASES IN-VITRO MYOMETRIAL SENSITIVITY TO PROSTAGLANDINS WHILE LOWERING SENSITIVITY TO OXYTOCIN

OBJECTIVE: TO investigate die action of prostaglandin synthesis inhibi tors on uterine sensitivity to established stimulants of myometrial ac tivity, we tested the effect of in vivo administration of nimesulide, a selective cyclooxygenase-2 inhibitor, into ovariectomized nonpregnan t sheep on subsequent in vitro myometrial responsiveness to prostaglan din E-2 (PGE(2)), PGE(2 alpha), and oxytocin. METHODS: Sixteen ovariec tomized ewes were infused intravenously with either estradiol (2 mu g h, n = 8) or estradiol plus nimesulide (20 mg h, n = 8); for 48 h befo re necropsy. Longitudinal strips of myometrium were superfused with Kr ebs buffer solution and their spontaneous baseline contractility recor ded after 1 hour. pD(2) values and maximum percentage increases in con tractile tension were derived from dose-response curves to 10(-9) to 1 0(-5) mol/L PGE(2) and PGE(2 alpha), and 10(-11) to 10(-7) mol/L oxyto cin. RESULTS: Baseline activity was lower in myometrium from estradiol -treated elver infused with nimesulide as compared with ewes infused w ith estradiol alone. Maximum tension increase in response to all three agonists was similar in myometrium from estradiol- and nimesulide-tre ated ewes, but the pD(2) in myometrium from nimesulide-treated ewes wa s higher in response to PGE(2) and PGE(2 alpha) and lower in response to oxytocin. CONCLUSION: The results show that nimesulide lowers spont aneous myometrial contractility and sensitivity to oxytocin while incr easing sensitivity to PGs, indicating a down-regulation of oxytocin re ceptor and an up-regulation of PG receptors and/or intracellular signa ling events. Copyright (C) 1998 by the Society for Gynecologic Investi gation.