t-1032 and Disease-Models--Animal

In advanced heart failure (HF), the compensatory pulmonary vasodilation is attenuated due to the relative insufficiency of cGMP despite increased secretion of natriuretic peptides (NPs). Phosphodiesterase type 5 (PDE5) inhibitors prevent cGMP degradation, and thus may potentiate the effect of the NPs-cGMP pathway. We orally administered a specific PDE5 inhibitor, T-1032 (1 mg/kg; twice a day, n = 7) or placebo (n = 7) for 2 weeks in dogs with HF induced by rapid pacing (270 bpm, 3 weeks) and examined the plasma levels of atrial natriuretic peptide (ANP), cGMP, and hemodynamic parameters. We also examined the hemodynamic changes after injection of a specific NPs receptor antagonist, HS-142-1 (3 mg/kg), under treatment with T-1032. T-1032 significantly increased plasma cGMP levels compared with the vehicle group despite low plasma ANP levels associated with improvement in cardiopulmonary hemodynamics. HS-142-1 significantly decreased plasma cGMP levels in both groups, whereas it did not change all hemodynamic parameters in the vehicle group. In contrast, in the T-1032 group, HS-142-1 significantly increased pulmonary arterial pressure and pulmonary vascular resistance. These results indicated that long-term treatment with a PDE5 inhibitor improved pulmonary hypertension secondary to HF and the NPs-cGMP pathway contributed to this therapeutic effect.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dogs; Drug Administration Schedule; Drug Evaluation, Preclinical; Heart Failure; Heart Rate; Heart Ventricles; Hypertension, Pulmonary; Injections, Intravenous; Isoquinolines; Japan; Lung; Myocardial Contraction; Natriuretic Peptides; Norepinephrine; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Polysaccharides; Pyridines; Receptors, Atrial Natriuretic Factor; Time Factors; Vascular Resistance