Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats

摘要

We examined the hemodynamic property of T-1032 (methyl) 2-(4-aaminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,5-trimethoxy-phenyl)-3-isoquinoline carboxylate sulfate, a novel selective phosphodiesterase type 5 (PDE5) inhibitor, and evaluated the chronic effect of T-1032 on cardiac remodeling and its related death in monocrotaline (MCT)-induced pulmonary hypertensive rats. T-1032 (1,10,,100 μg/kg, i.v.) significantly reduced mean arterial pressure (MAP) and right ventricular systolic pressure (RVSP) without a change in heart ate. The change in RVSP was more potent than that in MAP with 1 μg/kg T-1032 treatment (RVSP: -8.2 ± 1.2%, mean arterial pressure: -5.7 ± 1.2%), and reductions in RVSP and MAP reached a peak at doses of 1 and 10 μg/kg, respectively. In contrast, nitroglycerine (0.1,1,10 μg/kg, i.v.) and beraprost (0.1,1 μg/kg, i.v.) did not cause a selective reduction in RVSP at any dose. When T-1032 (300 ppm in diet) was chronically administered, it delayed the death, and significantly suppressed right ventricular remodeling (T-1032-treated: 0.318 ± 0.021 g, control: 0.40 ± 0.013 g, P < 0.05). Our present results suggest that T-1032 selectively reduces RVSP, and resulting in the suppression of right ventricular remodeling with a delay of the death in MCT-induced pulmonary hypertensive rats.