Inhibition of in vivo constriction of fetal ductus arteriosus by endothelin receptor blockade in rats.
The fetal ductus can be constricted by drugs, including cyclooxygenase inhibitors (indomethacin), nitric oxide synthesis antagonists [N-nitro-L-arginine monomethyl ester (L-NAME)], and glucocorticoid hormones (dexamethasone). Constriction of the fetal ductus by endothelin (ET) 1 was reported in an in vitro study. We studied the preventive effect of a dual ET receptor antagonist (bosentan) and a selective ET-A blocker (CI-1020) on pharmacologic fetal ductal constriction in rats. Near-term pregnant Wistar rats at d 21 and preterm rats at d 19 were used. The fetal ductus was constricted by four medications: orogastric administration of indomethacin (10 mg/kg) on fetal d 21, orogastric indomethacin 1 mg/kg combined with muscular injection of L-NAME (10 mg/kg) on fetal d 21, and muscular injection of L-NAME or dexamethasone (1 mg/kg) on fetal d 19. Bosentan (0.1, 1, 10, or 100 mg/kg) was injected intraperitoneally either simultaneously with indomethacin, L-NAME, or dexamethasone, or 4 h after administration of 10 mg/kg indomethacin. CI-1020 (0.01, 0.1, 1, or 10 mg/kg) was injected intraperitoneally simultaneously with indomethacin. After maternal atlas dislocation, cesarean section, fetal whole-body freezing, and cutting on the freezing microtome, measurements were made of the inner diameters of the ductus, main pulmonary artery, and ascending aorta. Bosentan blocked fetal ductal constriction by indomethacin, indomethacin plus L-NAME in the near-term rats, and constriction by L-NAME and dexamethasone in the preterm rats dose dependently. Fetal ductal constriction was nearly completely blocked by simultaneously administered 100 mg/kg of bosentan or 10 mg/kg of CI-1020. Dual ET receptor antagonist (bosentan) and selective ET-A blocker (CI-1020) prevent constriction of the fetal ductus arteriosus induced by ductus-constricting agents in rats, indicating that ET and ET-A receptors are essential in fetal ductal constriction.
Momma
Kazuo
K
Department of Pediatric Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Tokyo, Japan. prmomma@nora.hij.twmu.ac.jp
Nakanishi
Toshio
T
Imamura
Shinichiro
S
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D002317:Cardiovascular Agents / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004347:Drug Interactions; D004373:Ductus Arteriosus / Q000187:drug effects / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D013449:Sulfonamides / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D000959:Antihypertensive Agents; D002317:Cardiovascular Agents; D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; C093321:PD 156707; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D003907:Dexamethasone; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin