Clyman R I, Hardy P, Waleh N, Chen Y Q, Mauray F, Fouron J C, Chemtob S
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143-0544, USA.
Am J Physiol. 1999 Mar;276(3):R913-21. doi: 10.1152/ajpregu.1999.276.3.R913.
Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but 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 from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus 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 ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 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 causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.
非选择性环氧化酶（COX）抑制剂是有效的宫缩抑制剂，但对胎儿动脉导管有不良影响。我们推测，如果主要的COX同工型是COX-1，那么COX-2抑制剂可能不会影响动脉导管。为了验证这一假设，我们使用了来自妊娠晚期胎羊的动脉导管。与我们的假设相反，胎羊动脉导管表达了COX-1和COX-2免疫反应性蛋白（通过蛋白质印迹分析）。虽然在内皮细胞和平滑肌细胞中都发现了COX-1，但通过免疫组织化学发现COX-2仅存在于动脉导管腔内衬的内皮细胞中。COX-1和COX-2对前列腺素E2（PGE2）合成的相对贡献与免疫组织化学结果一致：在完整的动脉导管中，COX-1和COX-2以相等的比例催化PGE2的形成；在内皮剥脱的动脉导管中，COX-2在PGE2合成中不再起重要作用。COX-2的选择性抑制剂NS-398在体外引起动脉导管收缩方面的效果是选择性COX-1抑制剂戊酰水杨酸和非选择性COX抑制剂吲哚美辛的66%。此时，在推荐COX-2抑制剂用于孕妇时应谨慎。
