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In Vivo Administration of Nimesulide, a Selective PGHS-2 Inhibitor, Increases In Vitro Myometrial Sensitivity to Prostaglandins While Lowering Sensitivity to Oxytocin

Laboratory for Pregnancy and Newborn Research, Department of Physiology, College of Veterinary Medicine, Cornell University, Ithaca, New York

Peter W. Nathanielsz, MD,PhD,SeD

Laboratory for Pregnancy and Newborn Research, Department of Physiology, College of Veterinary Medicine, Cornell University, Ithaca, New York; pwnl{at}comell.edu

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), PGE₂, 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 PGE₂, 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 PGE₂ 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.

Key Words: Nimesulide • sheep • myometrium • prostaglandins • oxytocin

Journal of the Society for Gynecologic Investigation, Vol. 5, No. 6, 296-299 (1998)
DOI: 10.1177/107155769800500603


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