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: Hirotaka Inoue, Koji Yano, Tsunehisa Noto, Michino Takagi, Tomihiro Ikeo, Kohei Kikkawa
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 443 Issue 1-3 Pg. 179-84 (May 17 2002) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12044807 (Publication Type: Journal Article)

Chemical References

• Isoquinolines
• Phosphodiesterase Inhibitors
• Pyridines
• Phosphoric Diester Hydrolases
• 3',5'-Cyclic-GMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 5
• T 1032

Topics

• 3',5'-Cyclic-GMP Phosphodiesterases
• Animals
• Cardiomyopathies (enzymology, mortality)
• Cricetinae
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Dose-Response Relationship, Drug
• Hemodynamics (drug effects)
• Injections, Intravenous
• Isoquinolines (blood, therapeutic use)
• Male
• Phosphodiesterase Inhibitors (blood, therapeutic use)
• Phosphoric Diester Hydrolases (metabolism)
• Pyridines (blood, therapeutic use)