Acute and chronic effects of T-1032, a novel selective phosphodiesterase type 5 inhibitor, on monocrotaline-induced pulmonary hypertension in rats.

Abstract

We examined the hemodynamic property of T-1032 (methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-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 micro g/kg, i.v.) significantly reduced mean arterial pressure (MAP) and right ventricular systolic pressure (RVSP) without a change in heart rate. The change in RVSP was more potent than that in MAP with 1 micro g/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 micro g/kg, respectively. In contrast, nitroglycerin (0.1, 1, 10 micro g/kg, i.v.) and beraprost (0.1, 1 micro g/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: 0.401+/-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.

• Authors: Hirotaka Inoue, Koji Yano, Tsunehisa Noto, Michino Takagi, Tomihiro Ikeo, Kohei Kikkawa
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 25 Issue 11 Pg. 1422-6 (Nov 2002) ISSN: 0918-6158 [Print] Japan
• PMID: 12419952 (Publication Type: Journal Article)

Chemical References

• Isoquinolines
• Phosphodiesterase Inhibitors
• Pyridines
• Monocrotaline
• Phosphoric Diester Hydrolases
• 3',5'-Cyclic-GMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Pde5a protein, rat
• T 1032

Topics

• 3',5'-Cyclic-GMP Phosphodiesterases
• Animals
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Hypertension, Pulmonary (chemically induced, drug therapy, enzymology)
• Isoquinolines (administration & dosage)
• Male
• Monocrotaline (toxicity)
• Phosphodiesterase Inhibitors (administration & dosage)
• Phosphoric Diester Hydrolases (metabolism)
• Pyridines (administration & dosage)
• Rats
• Rats, Wistar