In vivo Dilatation of the Ductus Arteriosus by Rho Kinase Inhibition in the Rat

Background: Fasudil hydrochloride, a Rho kinase inhibitor, was reported to dilate the constricted ductus arteriosus in vitro, and was suggested as a neonatal bridge to heart surgery. Objectives: To clarify the in vivo effectiveness of fasudil to dilate the neonatal ductus arteriosus, and its usefulness as a bridge to heart surgery. Methods: We studied the dose and timing of administration of fasudil in the neonatal rat. Postnatal ductal closure was studied on the 21st gestational day following cesarean section and incubation for 30-480 min in room air at 33 degrees C, with a rapid whole-body freezing method. In control rats, the ductus closed rapidly after birth, and the ductal diameter was 0.80 and 0.12 mm at 0 and 30 min after birth. Fasudil was injected peritoneally into the neo-nate, and the ductus was studied 30 min after injection and 60 min after birth. Results: Fasudil, 10 mg/kg, injected within 5 min after birth, dilated the ductus completely to 0.8 mm, and the dose used clinically, 1 mg/kg, dilated the ductus to 0.4 mm. The ductus-dilating effect of fasudil decreased rapidly as the neonatal ductus constricted. Fasudil, 100 mg/kg, dilated the ductus completely, but induced severe respiratory depression and frequent death in 1-hour-old rats. Conclusions: Fasudil dilates the neonatal ductus arteriosus dose-dependently in the rat. Fasudil in large doses dilates the neonatal ductus completely, but is associated with fatal side effects, including respiratory depression. Copyright (c) 2008 S. Karger AG, Basel