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 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.
Tsai
Ben M
BM
Section of Cardiothoracic Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Turrentine
Mark W
MW
Sheridan
Brett C
BC
Wang
Meijing
M
Fiore
Andrew C
AC
Brown
John W
JW
Meldrum
Daniel R
DR
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002243:Carbolines / Q000494:pharmacology / Q000627:therapeutic use*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control*; D000860:Hypoxia / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D000068581:Tadalafil; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D000069058:Vardenafil Dihydrochloride; D014661:Vasoconstriction / Q000187:drug effects
D002243:Carbolines; D007093:Imidazoles; D007375:Interleukin-1; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D010656:Phenylephrine; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat