In vivo dilatation of the fetal and postnatal ductus arteriosus by inhibition of phosphodiesterase 3 in rats.
BACKGROUND
Clinically, it appears that phosphodiesterase 3 (PDE 3) inhibitors, which are used for acute cardiac failure in premature infants, dilate the ductus arteriosus (DA).


OBJECTIVE
To clarify the ductus-dilating effects of PDE 3 inhibitors in near-term rat pups and their differential effects in near-term and preterm fetal rats, in in vivo studies.


METHODS
The in vivo ductal diameter of rat pups and fetuses was measured using a rapid whole-body freezing method, by cutting on a freezing microtome and measuring with a microscope and micrometer. Eight to twenty pups and fetuses were studied in each group. Milrinone and amrinone (specific inhibitors of PDE 3) were injected into 1-hour-old pups and the DA was studied 0.5 and 1 h later. The differential effects of these PDE 3 inhibitors on the near-term and preterm ductus were studied by injecting indomethacin (10 mg/kg) and PDE 3 inhibitors into 21D (21st day of pregnancy: term-21.5 days) and 19D dams and studying the fetal ductus 4 and 8 h later.


RESULTS
Milrinone and amrinone dilated the postnatal ductus dose-dependently. Large doses of these drugs dilated it completely, and clinically equivalent doses dilated it minimally. Milrinone and amrinone prevented constriction of the fetal ductus by indomethacin. Their ductus-dilating effects were more potent in the preterm than in the near-term fetuses, and clinically equivalent doses of these PDE 3 inhibitors dilated preterm ductus completely.


CONCLUSIONS
In rats, PDE 3 inhibitors reopen the constricted postnatal DA slightly. PDE 3 inhibitors dilate the fetal DA constricted with indomethacin effectively and more sensitively in preterm than in near-term fetuses.
Toyoshima
Katsuaki
K
Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan. nqf37179@nifty.com
Momma
Kazuo
K
Imamura
Shinichiro
S
Nakanishi
Toshio
T
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004373:Ductus Arteriosus / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D020105:Milrinone / Q000494:pharmacology; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D047428:Protein Kinase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone; D007213:Indomethacin