Document Detail


Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression.
MedLine Citation:
PMID:  16368379     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Perioperative pulmonary hypertension is a challenging clinical problem with numerous etiologies including hypoxia, adrenergic stimulation, and local inflammation. New oral phosphodiesterase-5 (PDE-5) inhibitors used for the treatment of erectile dysfunction may have beneficial effects on the pulmonary vasculature owing to the abundance of PDE-5 receptors in the lung. The purpose of this study was to compare the efficacy of sildenafil, vardenafil, and tadalafil in preventing acute hypoxic pulmonary vasoconstriction and hypoxia-induced pulmonary artery tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta) expression. METHODS: Isolated rat pulmonary arteries suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), sildenafil, vardenafil, or tadalafil to assess (1) pulmonary artery relaxation; (2) inhibition of phenylephrine-induced pulmonary artery contraction; (3) inhibition of hypoxic pulmonary vasoconstriction (pO2 = 30-35 mm Hg); and (4) hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression (reverse transcriptase-polymerase chain reaction). RESULTS: Sildenafil, vardenafil, and tadalafil resulted in dose-dependent pulmonary artery relaxation and inhibited phenylephrine-induced pulmonary artery contraction, but only tadalafil significantly inhibited hypoxic pulmonary vasoconstriction (52.08% +/- 7.65% tadalafil versus 88.63% +/- 8.96% vehicle; 98.61% +/- 10.04% sildenafil; 68.46% +/- 15.84% vardenafil). Hypoxia-induced upregulation of TNF-alpha and IL-1beta mRNA in pulmonary artery was significantly decreased by tadalafil, but not sildenafil or vardenafil pretreatment. CONCLUSIONS: We conclude that sildenafil, vardenafil, and tadalafil were equally efficacious in causing pulmonary artery relaxation, but only tadalafil inhibited hypoxic pulmonary vasoconstriction and attenuated hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression.
Authors:
Ben M Tsai; Mark W Turrentine; Brett C Sheridan; Meijing Wang; Andrew C Fiore; John W Brown; Daniel R Meldrum
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Annals of thoracic surgery     Volume:  81     ISSN:  1552-6259     ISO Abbreviation:  Ann. Thorac. Surg.     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2005-12-21     Completed Date:  2006-08-25     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  15030100R     Medline TA:  Ann Thorac Surg     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  272-8     Citation Subset:  AIM; IM    
Affiliation:
Section of Cardiothoracic Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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MeSH Terms
Descriptor/Qualifier:
3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
Animals
Anoxia / drug therapy,  enzymology,  prevention & control*
Carbolines / pharmacology,  therapeutic use*
Cyclic Nucleotide Phosphodiesterases, Type 5
Drug Evaluation, Preclinical
Gene Expression Regulation / drug effects*
Hypertension, Pulmonary / drug therapy,  enzymology,  prevention & control*
Imidazoles / pharmacology,  therapeutic use*
Interleukin-1 / biosynthesis*,  genetics
Isometric Contraction / drug effects
Male
Phenylephrine / antagonists & inhibitors,  pharmacology
Phosphodiesterase Inhibitors / pharmacology,  therapeutic use*
Piperazines / pharmacology,  therapeutic use*
Pulmonary Artery / drug effects*,  metabolism
Purines
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Sulfones / pharmacology,  therapeutic use
Triazines / pharmacology,  therapeutic use
Tumor Necrosis Factor-alpha / biosynthesis*,  genetics
Vasoconstriction / drug effects
Grant Support
ID/Acronym/Agency:
R01GM070628/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Carbolines; 0/Imidazoles; 0/Interleukin-1; 0/Phosphodiesterase Inhibitors; 0/Piperazines; 0/Purines; 0/Sulfones; 0/Triazines; 0/Tumor Necrosis Factor-alpha; 0/tadalafil; 139755-83-2/sildenafil; 224785-90-4/vardenafil; 59-42-7/Phenylephrine; EC 3.1.4.35/3',5'-Cyclic-GMP Phosphodiesterases; EC 3.1.4.35/Cyclic Nucleotide Phosphodiesterases, Type 5; EC 3.1.4.35/Pde5a protein, rat

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