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 the action of prostaglandin synthesis inhibitors on uterine sensitivity to established stimulants of myometrial activity, we tested the effect of in vivo administration of nimesulide, a selective cyclooxygenase-2 inhibitor, into ovariectomized nonpregnant sheep on subsequent in vitro myometrial responsiveness to prostaglandin E₂ (PGE₂), PGE_2α, and oxytocin.

Methods: Sixteen ovariectomized ewes were infused intravenously with either estradiol (2 μg h, n = 8) or estradiol plus nimesulide (20 mg h, n = 8); for 48 h before necropsy. Longitudinal strips of myometrium were superfused with Krebs buffer solution and their spontaneous baseline contractility recorded after 1 hour. pD₂ values and maximum percentage increases in contractile tension were derived from dose-response curves to 10^-9 to 10^-5 mol/L PGE₂ and PGE_2α, and 10^-11 to 10^-7 mol/L oxytocin.

Results: Baseline activity was lower in myometrium from estradiol-treated ewes infused with nimesulide as compared with ewes infused with estradiol alone. Maximum tension increase in response to all three agonists was similar in myometrium from estradiol- and nimesulide-treated ewes, but the pD₂ in myometrium from nimesulide-treated ewes was higher in response to PGE₂ and PGE_2α and lower in response to oxytocin.

Conclusion: The results show that nimesulide lowers spontaneous myometrial contractility and sensitivity to oxytocin while increasing sensitivity to PGs, indicating a down-regulation of oxytocin receptor and an up-regulation of PG receptors and/or intracellular signaling events.