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.

• Authors: L Zhao, N A Mason, N W Morrell, B Kojonazarov, A Sadykov, A Maripov, M M Mirrakhimov, A Aldashev, M R Wilkins
• Journal: Circulation (Circulation) Vol. 104 Issue 4 Pg. 424-8 (Jul 24 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11468204 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphodiesterase Inhibitors
• Piperazines
• Purines
• Sulfones
• Sildenafil Citrate
• NOS3 protein, human
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Cyclic GMP

Topics

• Adolescent
• Adult
• Animals
• Cyclic GMP (metabolism)
• Double-Blind Method
• Genotype
• Heart Ventricles (drug effects, metabolism, pathology)
• Humans
• Hypertension, Pulmonary (etiology, physiopathology, prevention & control)
• Hypertrophy
• Hypoxia (complications)
• In Vitro Techniques
• Lung (drug effects, metabolism, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase (genetics, metabolism)
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Phosphodiesterase Inhibitors (therapeutic use)
• Piperazines (therapeutic use)
• Pulmonary Artery (drug effects, physiopathology)
• Purines
• Sildenafil Citrate
• Sulfones
• Ventricular Function, Right (drug effects)