Circulation. 2001;104:424-428
doi: 10.1161/hc2901.093117
doi: 10.1161/hc2901.093117
(Circulation. 2001;104:424.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension
From the Section on Clinical Pharmacology (L.Z., N.A.M., N.W.M., M.R.W.), Imperial College School of Medicine, Hammersmith Hospital, London, UK, and National Centre of Cardiology (B.K., A.S., A.M., M.M.M., A.A.), Bishkek, Kyrghyz Republic.
Correspondence to Professor Martin Wilkins, Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, Ducane Rd, London, W12 ONN, UK. E-mail m.wilkins{at}ic.ac.uk
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% O2 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% O2) 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.
Key Words: hypertension, pulmonary • hypoxia • pharmacology
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