Effects of TAK-044, a nonselective endothelin receptor antagonist, on the spontaneous and indomethacin- or methylene blue-induced constriction of the ductus arteriosus in rats.
We studied the effects of TAK-044, a nonselective endothelin (ET) receptor antagonist, on the indomethacin- or methylene blue-induced constriction of the ductus arteriosus (DA) in rats and compared them with the effects on spontaneous DA constriction. Injection of TAK-044 into 21-day-old fetuses in utero was performed through the uterine wall of laparotomized mother rats under light ether anesthesia. The fetuses were autopsied 3 hr after treatment with TAK-044 (10 mg/kg) in utero and simultaneous administration to the laparotomized mother rats of indomethacin (3 mg/kg, p.o.) or methylene blue (100 mg/kg, i.p.). In the second experiment, pregnant rats were decapitated on day 21 of gestation to obtain newborn rats by cesarean delivery. Newborn rats which were given TAK-044 (2, 10 mg/kg) immediately after or 1 hr before cesarean delivery were autopsied at various times after birth. In both experiments, pups were rapidly frozen in an acetone-dry ice mixture at autopsy to evaluate the DA constriction by the whole-body freezing and shaving method. TAK-044 injection into the fetus 3 hr before autopsy completely inhibited the DA constriction induced by maternal treatment with indomethacin or methylene blue. TAK-044 caused dose-dependent inhibition of the spontaneous closure of the DA after birth. The inhibitory effect was more pronounced in pups which were given TAK-044 in utero 1 hr before birth; however, the inhibitory effect was incomplete in newborn pups. These results, together with the previous finding that BQ-123, an ETA-specific receptor antagonist, inhibits the ductal constriction induced by oxygen in vitro [Coceani et al., 1992], indicate that the ETA receptor plays a significant role in the indomethacin- or methylene blue-induced DA constriction as well as in the spontaneous DA constriction after birth, and also indicate that the inhibition of ETA receptor by TAK-044 was more easily achieved in fetuses than in neonates.
Takizawa
T
T
Department of Developmental Biotechnology, Azabu University School of Veterinary Medicine, Sagamihara, Kanagawa, Japan.
Horikoshi
E
E
Shen
M H
MH
Masaoka
T
T
Takagi
H
H
Yamamoto
M
M
Kasai
K
K
Arishima
K
K
D000818:Animals; D000831:Animals, Newborn; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002585:Cesarean Section / Q000662:veterinary; D004373:Ductus Arteriosus / Q000187:drug effects* / Q000196:embryology / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007213:Indomethacin / Q000494:pharmacology*; D007813:Laparotomy / Q000662:veterinary; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D002317:Cardiovascular Agents; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; C088196:TAK 044; D008751:Methylene Blue; D007213:Indomethacin