Sildenafil inhibits hypoxia-induced pulmonary hypertension

Background-This study investigated the effect of the phosphodiesterase 5 in hibitor 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 I hour before breathin g 11% O-2 for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PA-P pr oduced by hypoxia during placebo treatment (mean PAP [mean +/- SD mm Hg]: n ormoxia 16.0 +/-2.1 versus hypoxia 25.0 +/-4.8) was almost abolished by sil denafil (non-noxia 16.0 +/-2.1 versus hypoxia 18.0 +/-3.6), with no signifi cant effect on systemic blood pressure. In the isolated perfused lung of wi ld-type and endothelial nitric oxide synthase (eNOS)-deficient mice, silden afil. 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 ve ntricular 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 ventricu lar hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mu tant 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 condi tion. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, b ut other biochemical sources of cGMP also play a role. Sildenafil has benef icial pulmonary hemodynamic effects even when eNOS activity is impaired.