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Inhibition of Prostaglandin Production by Nimesulide Is Accompanied by Changes in Expression of the Cassette of Uterine Labor-Related Genes in Pregnant Sheep¹

Laboratory of Pregnancy and Newborn Research (W.X.W., X.H.M., P.W.N.), Physiology Department, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853; Department of Obstetrics and Gynecology (N.U.), Faculty of Medicine, University of Tokyo, Tokyo, Japan

Address all correspondence and requests for reprints to: Dr. Peter W. Nathanielsz, Laboratory for Pregnancy and Newborn Research, Department of Physiology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401. E-mail: pwn1{at}cornell.edu

The present study was designed to characterize effects of inhibiting PG production by infusing nimesulide (CAS 51803–78-2) on PGE₂ production and expression of uterine labor-related genes in pregnant sheep. Myometrium, endometrium, and placenta were collected following 6 h of iv nimesulide or vehicle infusion. Infusions were commenced 9 h after onset of spontaneous term labor. Tissues were also collected from term control ewes not in labor. PGE₂ was measured in fetal plasma by RIA. ER, OTR, Hsp 70 and 90, cPLA2, and PGHS-2 messenger RNA (mRNA) abundance in myometrium, endometrium, and PGHS-2 in placenta were quantified by Northern blot analysis. Fetal plasma PGE₂ decreased during nimesulide infusion (P < 0.05). ER, OTR, Hsp 70, and Hsp 90 mRNA increased during spontaneous term labor in vehicle infused ewes in both myometrium and endometrium. In myometrium after nimesulide infusion, OTR and Hsp 70 mRNA decreased significantly (P < 0.05) compared with vehicle infused animals, but the decrease in Hsp 90 and ER mRNA fell outside the level of significance. In the endometrium, nimesulide produced a decrease in ER and OTR mRNA (P < 0.05) compared with vehicle infused animals, but the changes in Hsp 90 and 70 mRNA fell outside the level of significance. Nimesulide reversed the up-regulation of PGHS-2 mRNA that occurred in myometrium, endometrium, and placenta during vehicle infusion (P < 0.05). cPLA2 was only elevated in the endometrium in vehicle infused ewes and did not change in either endometrium or myometrium after nimesulide infusion. Conclusions: Inhibition of PG production resulted in decreased fetal plasma PGE₂. The decreased abundance of mRNA for several of the well described cassette of utero-placental labor-related genes following nimesulide inhibition may result from altered PG production.

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