title: 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 microg/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 microg/kg i.v.). T-1032 did not change the heart rate or left ventricular dp/dt(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<0.05 vs. control). It was concluded that T-1032 had beneficial hemodynamic effects on heart failure in Bio 14.6 cardiomyopathic hamsters, and the favorable hemodynamic changes induced by T-1032 were partly related to the increase in the survival of these hamsters. Phosphodiesterase type 5 inhibitors may have therapeutic potential for the treatment of chronic heart failure.
authors.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan. inoue-h@tanabe.co.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Inoue
authors.forename: Koji
authors.initials: K
authors.lastname: Yano
authors.forename: Tsunehisa
authors.initials: T
authors.lastname: Noto
authors.forename: Michino
authors.initials: M
authors.lastname: Takagi
authors.forename: Tomihiro
authors.initials: T
authors.lastname: Ikeo
authors.forename: Kohei
authors.initials: K
authors.lastname: Kikkawa
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology / Q000401:mortality*; D006224:Cricetinae; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011725:Pyridines / Q000097:blood / Q000627:therapeutic use*
chemical_list: D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C412889:T 1032