T-1032, a novel phosphodiesterase type 5 inhibitor, increases the survival of cardiomyopathic hamsters

Abstract To evaluate the influence of T-1032 (methyl2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate), a potent and relatively selective phosphodiesterase 5 inhibitor, on chronic heart failure, we examined the acute hemodynamic profile of T-1032 and its chronic effect on the survival of Bio 14.6 cardiomyopathic hamsters. In the acute study, T-1032 (1, 10, 100 μg/kg) was administered intravenously by means of a dose-escalating procedure in 55-week-old hamsters. T-1032 significantly reduced both the right and left ventricular end-diastolic pressure in a dose-dependent manner. T-1032 modestly reduced the systemic arterial pressure at the highest dose (100 μg/kg i.v.). T-1032 did not change the heart rate or left ventricular d p /d t max . In the survival study, chronic administration of T-1032 (50 and 500 ppm in a diet) increased survival, and the survival rate was 24.2%, 45.4% and 48.5% in the control, 50 and 500 ppm-treated groups, respectively. The median survival was 55, 58 and 58 weeks in control, 50 and 500 ppm-treated groups, respectively. Analysis of the survival curves revealed that T-1032 (500 ppm) significantly increased the survival of these hamsters ( P