Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension

Abstract

Background This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice. Methods and Results In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O 2 for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean±SD mm Hg]: normoxia 16.0±2.1 versus hypoxia 25.0±4.8) was almost abolished by sildenafil (normoxia 16.0±2.1 versus hypoxia 18.0±3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg · kg −1 · d −1 ) throughout 3 weeks of exposure to hypoxia (10% O 2 ) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3±9.9 versus 29.9±9.7 mm Hg, P <0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling. Conclusions Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.