The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure

J Am Coll Cardiol. 2004 Dec 21;44(12):2339-48. doi: 10.1016/j.jacc.2004.09.041.

Abstract

Objectives: We sought to investigate the effects of sildenafil, a phosphodiesterase-5 (PDE(5)) inhibitor, on lung function and exercise performance in chronic heart failure (CHF).

Background: In CHF, nitric oxide-mediated regulation of lung vascular tone and alveolar-capillary membrane conductance is impaired and contributes to exercise intolerance. The potential for benefits due to increased nitric-oxide availability is unexplored.

Methods: In 16 patients with CHF and 8 normal subjects, we measured-before and 60 min after sildenafil (50 mg) or placebo-ejection fraction, pulmonary hemodynamics, carbon monoxide diffusion capacity (DLco), with its membrane (D(M)) and capillary blood volume (V(c)) subcomponents, endothelial function (brachial reactive hyperemia) at rest, peak oxygen uptake (VO(2)), increments in VO(2) versus work rate (DeltaVO(2)/DeltaWR), changes in ventilation versus CO(2) production (VE/VCO(2)) slope, and recovery VO(2) time constant (tau) on exertion.

Results: In CHF, sildenafil did not affect cardiac index, wedge pulmonary pressure, or ejection fraction; it significantly (p < 0.01) decreased pulmonary mean artery pressure (-20.4%) and arteriolar resistance (-45.1%), VE/VCO(2) slope (-9.0%) and recovery tau (-25.8%), and increased (p < 0.01) DLco (+11.1%), D(M) (+9.9%) peak VO(2) (+19.7%), DeltaVO(2)/DeltaWR (+11.0%), and brachial reactive hyperemia (+33.3%). No variations occurred in normal subjects and after placebo. Changes in DLco were related to those in VE/VCO(2) slope (r = -0.71; p = 0.002), and changes in brachial hyperemia correlated with those in DeltaVO(2)/DeltaWR (r = 0.80; p = 0.0002).

Conclusions: This study shows that in CHF PDE(5) inhibition modulates pulmonary pressure and vascular tone, and improves DLco, exercise peak VO(2), aerobic (DeltaVO(2)/DeltaWR) and ventilatory (VE/VCO(2) slope) efficiencies, and oxygen debt (recovery tau). Endothelial mechanisms may underlie these effects.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cardiac Output, Low / drug therapy*
  • Cardiac Output, Low / physiopathology*
  • Chronic Disease
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Exercise
  • Exercise Tolerance / drug effects*
  • Female
  • Hemodynamics / drug effects
  • Humans
  • Kinetics
  • Male
  • Middle Aged
  • Oxygen Consumption / drug effects
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Phosphoric Diester Hydrolases / drug effects*
  • Piperazines / therapeutic use*
  • Pulmonary Circulation / drug effects
  • Pulmonary Diffusing Capacity / drug effects*
  • Purines
  • Respiration / drug effects
  • Sildenafil Citrate
  • Sulfones

Substances

  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Sulfones
  • Sildenafil Citrate
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human