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.


OBJECTIVE
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 neonate, 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.
Momma
Kazuo
K
Section of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan. kmomma@iris.ocn.ne.jp
Toyoshima
Katsuaki
K
Sun
Fang
F
Nakanishi
Toshio
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D013504:Cardiovascular Surgical Procedures / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004373:Ductus Arteriosus / Q000187:drug effects* / Q000502:physiology; D005260:Female; D008297:Male; D023421:Models, Animal; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012131:Respiratory Insufficiency / Q000139:chemically induced; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000009:adverse effects / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil