Inhibition of phosphodiesterase type 3 dilates the rat ductus arteriosus without inducing intimal thickening.
BACKGROUND
Prostaglandin E(1) (PGE(1)), via cAMP, dilates the ductus arteriosus (DA). For patients with DA-dependent congenital heart disease (CHD), PGE(1) is the sole DA dilator that is used until surgery, but PGE(1) has a short duration of action, and frequently induces apnea. Most importantly, PGE(1) increases hyaluronan (HA) production, leading to intimal thickening (IT) and eventually DA stenosis after long-term use. The purpose of this study was therefore to investigate potential DA dilators, such as phosphodiesterase 3 (PDE3) inhibitors, as alternatives to PGE(1).


RESULTS
Expression of PDE3a and PDE3b mRNAs in rat DA tissue was higher than in the pulmonary artery. I.p. milrinone (10 or 1mg/kg) or olprinone (5 or 0.5mg/kg) induced maximal dilatation of the DA lasting for up to 2h in rat neonates. In contrast, vasodilation induced by PGE(1) (10μg/kg) was diminished within 2h. No respiratory distress was observed with milrinone or olprinone. Most important, milrinone did not induce HA production, cell migration, or proliferation when applied to cultured rat DA smooth muscle cells. Further, high expression of both PDE3a and PDE3b was demonstrated in the human DA tissue of CHD patients.


CONCLUSIONS
Because PDE3 inhibitors induced longer-lasting vasodilation without causing apnea or HA-mediated IT, they may be good alternatives to PGE(1) for patients with DA-dependent CHD.
Cardiovascular Research Institute, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Yasuhiro
Y
Ichikawa
Utako
U
Yokoyama
Mari
M
Iwamoto
Jin
J
Oshikawa
Satoshi
S
Okumura
Motohiko
M
Sato
Shumpei
S
Yokota
Munetaka
M
Masuda
Toshihide
T
Asou
Yoshihiro
Y
Ishikawa
D000527:Alprostadil / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000096:biosynthesis*; D004373:Ductus Arteriosus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*
D058987:Phosphodiesterase 3 Inhibitors; D012333:RNA, Messenger; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human; C517291:PDE3B protein, human; C517290:Pde3a protein, rat; C517294:Pde3b protein, rat; D000527:Alprostadil