In vivo dilation of fetal and neonatal ductus arteriosus by inhibition of phosphodiesterase-5 in rats.
A recent in vitro study showed that sildenafil, a type 5 phosphodiesterase inhibitor, dilated the constricted ductus arteriosus of neonatal rabbits. We studied the in vivo ductus-dilating effects of sildenafil in fetal and neonatal rats. Ductus diameters were measured with whole-body freezing and cutting on a freezing microtome. Indomethacin (10 mg/kg) constricted the fetal ductus severely at 4 and 8 h after orogastric administration to the dams. Sildenafil, administered orogastrically and simultaneously with indomethacin, dilated the near-term fetal [21 fetal days (FD)] ductus constricted by indomethacin completely with 1 mg/kg at 8 h after administration. The preterm fetal ductus was more sensitive to sildenafil at 19FD. The ductus constricted rapidly after birth, and the ductal diameter was only 10% of the fetal diameter at 1 h after birth. The ductus-dilating effect of sildenafil was studied by i.p. injection at 1 h after birth, and the ductus diameter was studied 30 and 60 min later. Sildenafil dilated the neonatal constricted ductus moderately with a massive dose (100 mg/kg) and only minimally with 1 mg/kg. In conclusion, sildenafil, a type 5 phosphodiesterase inhibitor, dilated the constricted fetal ductus completely at 8 h with 1 mg/kg in the near-term fetus and completely with a smaller dose (0.1 mg/kg) in the preterm fetus. However, sildenafil dilated the neonatal constricted ductus only moderately with large doses and minimally with 1 mg/kg. Probably, sildenafil is useful clinically for treating idiopathic and secondary fetal ductal constriction and not useful for dilation of the neonatal constricted ductus.
Momma
Kazuo
K
Department of Pediatric Cardiology, Tokyo Women's Medical University, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. prmomma@hij.twmu.ac.jp
Toyoshima
Katsuaki
K
Imamura
Shinichiro
S
Nakanishi
Toshio
T
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001835:Body Weight; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004373:Ductus Arteriosus / Q000187:drug effects* / Q000473:pathology*; D005615:Freezing; D007213:Indomethacin / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011458:Prostaglandins E / Q000378:metabolism; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011458:Prostaglandins E; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP; D007213:Indomethacin