Long-term treatment with a phosphodiesterase type 5 inhibitor improves pulmonary hypertension secondary to heart failure through enhancing the natriuretic peptides-cGMP pathway.
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.
Yamamoto
Takashi
T
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Wada
Atsuyuki
A
Tsutamoto
Takayoshi
T
Ohnishi
Masato
M
Horie
Minoru
M
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000284:Administration, Oral; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002304:Cardiac Pacing, Artificial / Q000379:methods; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D004285:Dogs; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006333:Heart Failure / Q000150:complications* / Q000188:drug therapy; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000188:drug therapy* / Q000517:prevention & control; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000097:blood / Q000494:pharmacology; D007564:Japan; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D045265:Natriuretic Peptides / Q000378:metabolism* / Q000627:therapeutic use; D009638:Norepinephrine / Q000097:blood; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011134:Polysaccharides / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D011725:Pyridines / Q000097:blood / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
C072551:HS 142-1; D007546:Isoquinolines; D045265:Natriuretic Peptides; D010726:Phosphodiesterase Inhibitors; D011134:Polysaccharides; D011725:Pyridines; D009320:Atrial Natriuretic Factor; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP; C412889:T 1032; D009638:Norepinephrine