Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents bu t have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained fr om late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb du ctus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the duct us lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE(2) synthesis was consistent with the immunohistochemical resul ts: in the intact ductus, PGE(2) formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 n o longer played a significant role in PGE(2) synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causi ng contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.