Inhibitory effect of indomethacin on neonatal lung catabolism of prostaglandin E2: possible mechanism of the re-opening of the ductus arteriosus after indomethacin therapy.
Indomethacin has been used to treat patent ductus arteriosus (PDA). Re-opening of the ductus arteriosus (DA) after indomethacin therapy, however, is common, although the reason is unclear. Patency of the ductus arteriosus is thought to be maintained primarily by the vasodilatory effect of PGE2 in fetuses and neonates. The enzyme, 15-hydroxy prostaglandin dehydrogenase (15-PGDH) catalyzes the initial reactions converting the biologically active PGE2 to its inactive metabolite 15-keto-PGE2, and the lungs are a major site of this inactivation. In the present study, the effect of prenatal indomethacin treatment on the activity of neonatal rat lung 15-PGDH, and the effect of prenatal indomethacin on the re-opening of the DA induced by PGE2 were examined in rats. Indomethacin treatment at 3 mg/kg/day from day 18 to day 20 of gestation significantly decreased the activity of 15-PGDH in neonatal lungs. In a subsequent experiment, subcutaneous injection of PGE2 (4 micrograms) was given to newborn rats 3 hr after Cesarean delivery from pregnant females administered indomethacin (1, 3 mg/kg/day) as in the above experiment. The ratio of the DA to pulmonary artery was determined at intervals after injection. Maternal indomethacin treatment significantly increased the re-opening of the DA and prolonged the duration of re-opening induced by PGE2. These results suggest that the decrease in the catabolism of PGE2 in the lung is partly responsible for the failure of indomethacin therapy for PDA.
Takizawa
T
T
Department of Developmental Biotechnology, Azabu University School of Veterinary Medicine, Kanagawa, Japan.
Ikeda
Y
Y
Togashi
H
H
Yamamoto
M
M
Arishima
K
K
Akahori
F
F
Masaoka
T
T
D000818:Animals; D015232:Dinoprostone / Q000378:metabolism*; D004374:Ductus Arteriosus, Patent / Q000139:chemically induced* / Q000378:metabolism; D005260:Female; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors; D007213:Indomethacin / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone; D007213:Indomethacin