In Vivo Constriction of the Ductus Arteriosus by Nonsteroidal Antiinflammatory Drugs in Near-Term and Preterm Fetal Rats

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Abstract
Herein we report age differences of in vivo constriction of the fetal ductus arteriosus by nonsteroidal antiinflammatory drugs in near-term and preterm rats. Two potent nonsteroidal antiinflammatory drugs, indomethacin and flurbiprofen, were studied in preterm (19th and 20th day) and near-term (21st day) rats, whose gestational period was 21.5 days. The time course of fetal ductus constriction was studied on the 20th (preterm fetus) and the 21st (near-term fetus) days of gestation with indomethacin (1 mg/kg, 10 mg/kg) and flurbiprofen (10 mg/kg). In addition, 5 mg/kg of indomethacin was used on the 21st day. Maximal ductal constriction was noticed 8 h after administration. Constriction of the ductus was significantly weaker on the 20th day than on the 21st day in all three studies including indomethacin 1 mg/kg, 10 mg/kg, and flurbiprofen, 10 mg/kg. Dose-response curves were studied at 4 h following administration of indomethacin on the 19th, 20th, and 21st days, and flurbiprofen on the 20th and 21st days. With both drugs, the ductus constricted more vigorously on the 21st day than on the 20th or 19th day. These studies showed a weaker constrictive response of the ductus to nonsteroidal antiinflammatory drugs in the preterm fetus than in the near-term fetus. Twenty-four h after administration of indomethacin on the 20th day, the fetal ductus was dilated, although its plasma indomethacin concentration was high and comparable with that obtained 4 h after administration. These results show that the response of the fetal ductus to indomethacin decreased further at 24 h after administration to preterm rats.