Inhibition of Phosphodiesterase Type 3 Dilates the Rat Ductus Arteriosus Without Inducing Intimal Thickening

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Background: Prostaglandin E1 (PGE1), via cAMP, dilates the ductus arteriosus (DA). For patients with DA-dependent congenital heart disease (CHD), PGE1 is the sole DA dilator that is used until surgery, but PGE1 has a short duration of action, and frequently induces apnea. Most importantly, PGE1 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 PGE1. Methods and 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 PGE1 (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 PGE1 for patients with DA-dependent CHD. (Circ J 2012; 76: 2456–2464)
2012-09-25