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Ann Thorac Surg 2006;81:272-278
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Differential Effects of Phosphodiesterase-5 Inhibitors on Hypoxic Pulmonary Vasoconstriction and Pulmonary Artery Cytokine Expression

Ben M. Tsai, MD a , Mark W. Turrentine, MD a , Brett C. Sheridan, MD b , Meijing Wang, MD a , Andrew C. Fiore, MD c , John W. Brown, MD a , Daniel R. Meldrum, MD a , *

a Section of Cardiothoracic Surgery, Indiana University School of Medicine, Indianapolis, Indiana
b Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
c Division of Cardiothoracic Surgery, Saint Louis University School of Medicine, St. Louis, Missouri

Accepted for publication June 10, 2005.

* Address correspondence to Dr Meldrum, Section of Cardiothoracic Surgery, Indiana University School of Medicine, 545 Barnhill Dr, EH 215, Indianapolis, IN 46202 (Email: dmeldrum{at}iupui.edu).

Presented at the Basic Science Forum of the Fifty-first Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 2–4, 2004.

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-1ß) 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-1ß 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-1ß 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-1ß expression.




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