Dilatation of the ductus arteriosus by diazoxide in fetal and neonatal rats.

Abstract

Diazoxide, an ATP-sensitive potassium channel opener, is the main therapeutic agent for treating hyperinsulinemic hypoglycemia. The aim of this study was to determine the invivo ductus arteriosus (DA)-dilating effects of diazoxide in fetal and neonatal rats. Near-term rat pups delivered via cesarean section were housed at 33°C. After rapid whole-body freezing, the ductus arteriosus (DA) diameter was measured using a microscope and a micrometer. Full-term pregnant rats (gestational day 21) were injected i.p. with diazoxide (10 and 100mg/kg) 4h before delivery,and the neonatal DA diameter was measured at 0, 30, or 60min after birth. The newborn rats were also injected i.p. with diazoxide (10 and 100mg/kg) at birth or 60min after birth. DA was measured at 0, 30, or 60min after injection. In the fetal investigation, the effect of diazoxide was studied via simultaneous application of indomethacin (10mg/kg) and L-nitroarginine methyl ester (L-NAME) on gestational days 21 and 19. The control rats had rapid postnatal DA constriction (diameter, 0.80 and 0.08mm at 0 and 60min after birth, respectively). Diazoxide had a dose-dependent inhibitory effect on postnatal DA constriction. Prenatal diazoxide (10mg/kg) inhibited postnatal DA closure (0.20mm at 60min after birth). The diazoxide injection (10mg) at birth inhibited postnatal DA closure (0.14mm at 60min after birth). Diazoxide injection in 60-min-old rats dilated the constricted DA at 60min (0.10mm vs. 0.02mm in the controls). In the fetal investigation, diazoxide inhibited the fetal DA constrictive effect of indomethacin and L-NAME. Diazoxide attenuates postnatal DA constriction and dilates a closing DA in fetal and neonatal rats.