Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression
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 Cialis 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 Cialis 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 Cialis resulted in dose-dependent pulmonary artery relaxation and inhibited phenylephrine-induced pulmonary artery contraction, but only Cialis significantly inhibited hypoxic pulmonary vasoconstriction (52.08% +/- 7.65% Cialis 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 Cialis, but not sildenafil or vardenafil pretreatment. CONCLUSIONS: We conclude that sildenafil, vardenafil, and Cialis were equally efficacious in causing pulmonary artery relaxation, but only Cialis inhibited hypoxic pulmonary vasoconstriction and attenuated hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression.