| Sildenafil inhibits hypoxia-induced pulmonary hypertension. | |
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MedLine Citation:
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PMID: 11468204 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Clinical Trial; In Vitro; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Circulation Volume: 104 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2001 Jul |
Date Detail:
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Created Date: 2001-07-24 Completed Date: 2001-09-06 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 424-8 Citation Subset: AIM; IM |
Affiliation:
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Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, London, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Adult Animals Anoxia / complications* Cyclic GMP / metabolism Double-Blind Method Genotype Heart Ventricles / drug effects, metabolism, pathology Humans Hypertension, Pulmonary / etiology, physiopathology, prevention & control* Hypertrophy 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 Sulfones Ventricular Function, Right / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Phosphodiesterase Inhibitors; 0/Piperazines; 0/Purines; 0/Sulfones; 139755-83-2/sildenafil; 7665-99-8/Cyclic GMP; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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