Delayed neonatal closure of the ductus arteriosus following early in utero exposure to indomethacin in the rat.
BACKGROUND
Indomethacin is used to close the patent ductus arteriosus in premature infants and for tocolysis of preterm labor. Clinically and experimentally, early in utero exposure to indomethacin induces the paradoxical delay of postnatal closure of the ductus arteriosus.


OBJECTIVE
To clarify the pharmacological nature of the delay of closure of the ductus arteriosus in the rat.


METHODS
We studied early in utero exposure to indomethacin (dose and timing) in addition to other drugs, inducing a delay in postnatal ductal closure. Pregnant rats at near term were studied by cesarean section on gestational day 21 (D21), incubated in room air at 33 degrees C, followed by rapid whole-body freezing.


RESULTS
The delay in closure of the ductus arteriosus was dose dependent. A large dose of indomethacin (10 mg/kg) 1 or 2 days before birth induced a delay of 3-4 times. A timing study revealed maximum delay with administration of indomethacin 2 days before birth and minimum delay with administration 5 days before. Aspirin, ibuprofen, the selective COX1 inhibitor SC 560, the selective COX2 inhibitor rofecoxib and a prostaglandin EP(4) receptor blocker, ONO-208, all delayed neonatal ductal closure following maternal administration on D19 and D20.


CONCLUSIONS
The delay by indomethacin was dose dependent. The maximum delay was induced by 2 doses of 10 mg/kg indomethacin on D19 and D20. The delay was induced by a decreased stimulus to the prostaglandin EP(4) receptor system in the last 2 days in utero. The delay was temporary with recovery 3 days or more after exposure.
Momma
Kazuo
K
Section of Pediatric Cardiology, Women's Medical University, Tokyo, Japan. kmomma@iris.ocn.ne.jp
Toyoshima
Katsuaki
K
Ito
Kiyomi
K
Sugiyama
Kiyoshi
K
Imamura
Shinichiro
S
Sun
Fang
F
Nakanishi
Toshio
T
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004373:Ductus Arteriosus / Q000002:abnormalities / Q000187:drug effects*; D004374:Ductus Arteriosus, Patent / Q000139:chemically induced* / Q000196:embryology / Q000473:pathology; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects; D005865:Gestational Age; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology; D007213:Indomethacin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; C115461:SC 560; D001241:Aspirin; D007052:Ibuprofen; D007213:Indomethacin