Abstract 11498: Inhibition of Phosphodiesterase Type 3 Dilates the Rat Ductus Arteriosus Without Inducing Intimal Thickening and Respiratory Distress
Prostaglandin E1 (PGE1), via cAMP, dilates the ductus arteriosus (DA). For patients with DA-dependent congenital heart diseases, PGE1 is the sole DA dilator used until surgery. However, PGE1 has a short duration of action and frequently induces apnea. Most importantly, PGE1 increases hyaluronan production, leading to intimal thickening and DA stenosis after long-term use. The aim of this study was to examine whether phosphodiesterase3 (PDE3) inhibitors, via increasing cAMP, dilate the DA without inducing intimal thickening. Tissues were obtained from Wistar rat fetuses. Expression of mRNAs was examined by quantitative RT-PCR. Vasodilatory effects of PDE3 inhibitors were examined using a rapid whole body freezing method. Hyaluronan and cAMP production were measured by a latex agglutination method and radioimmunoassay, respectively. Cell migration and proliferation were examined by a boyden chamber method and MTT assay, respectively. Immunohistochemical analysis was performed in human DA tissues from patients with various congenital heart diseases.PDE3a and PDE3b mRNAs in rat DA tissues were higher than those in the aorta and pulmonary arteries (PA) (PDE3a: 1.4±0.15- and 2.1±0.14-fold vs. aorta and PA, respectively, PDE3b: 1.6±0.11- and 1.6±0.12-fold vs. aorta and PA, respectively, p<0.05, n=5). Intraperitoneal administration of milrinone (1-10mg/kg) and olprinone (0.5-5mg/kg) into rat neonates induced maximal dilatation of the DA (vs. control, p<0.001, n=4-6) lasting for up to 2 hours. In contrast, vasodilation and respiratory distress induced by PGE1 (10μg/kg) were diminished within 2 hours (n=4-6). No respiratory distress was observed with milrinone or olprinone (n=5-9). Although milrinone (10μM) significantly increased cAMP accumulation (2.57±0.22-fold, p<0.01, n=4) in rat DA smooth muscle cells (SMCs), milrinone (10μM), unlike PGE1, did not induce hyaluronan production, migration and proliferation in DA SMCs (n=4-8). Furthermore, in the human DA tissues, both PDE3a and PDE3b protein were abundant in the smooth muscle layer (n=8). These data suggest that PDE3 inhibitors induce longer-lasting vasodilation without intimal thickening and respiratory distress. PDE3 inhibitors may be good alternatives to PGE1.
- © 2012 by American Heart Association, Inc.