Document Detail

Sildenafil inhibits hypoxia-induced pulmonary hypertension.
MedLine Citation:
PMID:  11468204     Owner:  NLM     Status:  MEDLINE    
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.
L Zhao; N A Mason; N W Morrell; B Kojonazarov; A Sadykov; A Maripov; M M Mirrakhimov; A Aldashev; M R Wilkins
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Publication Detail:
Type:  Clinical Trial; In Vitro; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  104     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 Jul 
Date Detail:
Created Date:  2001-07-24     Completed Date:  2001-09-06     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  424-8     Citation Subset:  AIM; IM    
Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
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MeSH Terms
Anoxia / complications*
Cyclic GMP / metabolism
Double-Blind Method
Heart Ventricles / drug effects,  metabolism,  pathology
Hypertension, Pulmonary / etiology,  physiopathology,  prevention & control*
Lung / drug effects,  metabolism,  physiopathology
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
Ventricular Function, Right / drug effects
Reg. No./Substance:
0/Phosphodiesterase Inhibitors; 0/Piperazines; 0/Purines; 0/Sulfones; 139755-83-2/sildenafil; 7665-99-8/Cyclic GMP; EC protein, human; EC Oxide Synthase; EC Oxide Synthase Type II; EC Oxide Synthase Type III; EC protein, mouse

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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