Abstract
Indomethacin exerts a strong tocolytic effect by suppressing uterine contractions mediated by prostaglandins. However, indomethacin also induces in utero closure of fetal ductus arteriosus (DA), leading to serious neonatal consequences. Using rats, we tested the effect of an agonist for a subtype of prostaglandin E2 receptor (EP4), ONO-AE1-437 and its prodrug ONO-4819, as a DA dilator during indomethacin treatment. In vitro, ONO-AE1-437 exhibited a potent dilatory effect on DA against O2- and indomethacin-induced contractions in a concentration-dependent manner. In vivo, rat dams were given indomethacin (10 mg/kg, p.o.) alone or with ONO-4819 (0.3 μg/kg/h, s.c.) on d 21 of gestation and pups were delivered 4 h later through cesarean section to evaluate the ratio of diameter of DA to that of pulmonary artery. Pups from dams with no drug had DA/PA ratio of 0.9 ± 0.05, whereas those from dams with indomethacin alone had a decreased ratio of 0.2 ± 0.03. When ONO-4819 was co-administered to the dams, the ratio recovered significantly to 0.7 ± 0.06. The administration of ONO-4819 to the dams did not induce any increase in the uterine activity. These results suggest that administration of an EP4 agonist in addition to indomethacin might prevent adverse reactions of indomethacin on fetal DA without restricting its tocolytic effects.
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Abbreviations
- COX:
-
cyclooxygenase (EC 1.14.99.1)
- DA:
-
ductus arteriosus
- NSAID:
-
nonsteroidal antiinflammatory drugs
- PA:
-
pulmonary artery
- PG:
-
prostaglandin
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Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, by a grant from the Smoking Research Foundation of Japan, and by a grant from the Ono Cancer Research Foundation.
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Kajino, H., Taniguchi, T., Fujieda, K. et al. An EP4 Receptor Agonist Prevents Indomethacin-Induced Closure of Rat Ductus Arteriosus In Vivo. Pediatr Res 56, 586–590 (2004). https://doi.org/10.1203/01.PDR.0000139409.25014.35
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DOI: https://doi.org/10.1203/01.PDR.0000139409.25014.35
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