Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression

Ben M. Tsai, Mark Turrentine, Brett C. Sheridan, Meijing Wang, Andrew C. Fiore, John Brown, Daniel R. Meldrum

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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-α) and interleukin-1-beta (IL-1β) 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-α and IL-1β 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-α and IL-1β 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-α and IL-1β expression.

Original languageEnglish (US)
Pages (from-to)272-278
Number of pages7
JournalAnnals of Thoracic Surgery
Volume81
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

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Phosphodiesterase 5 Inhibitors
Vasoconstriction
Pulmonary Artery
Cytokines
Lung
Interleukin-1beta
Tumor Necrosis Factor-alpha
Phenylephrine
Type 5 Cyclic Nucleotide Phosphodiesterases
Tadalafil
Erectile Dysfunction
Dimethyl Sulfoxide
Reverse Transcriptase Polymerase Chain Reaction
Baths
Pulmonary Hypertension
Adrenergic Agents
Vardenafil Dihydrochloride
Sildenafil Citrate
Up-Regulation
Hypoxia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression. / Tsai, Ben M.; Turrentine, Mark; Sheridan, Brett C.; Wang, Meijing; Fiore, Andrew C.; Brown, John; Meldrum, Daniel R.

In: Annals of Thoracic Surgery, Vol. 81, No. 1, 01.2006, p. 272-278.

Research output: Contribution to journalArticle

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abstract = "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-α) and interleukin-1-beta (IL-1β) 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-α and IL-1β 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-α and IL-1β 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-α and IL-1β expression.",
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T1 - Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression

AU - Tsai, Ben M.

AU - Turrentine, Mark

AU - Sheridan, Brett C.

AU - Wang, Meijing

AU - Fiore, Andrew C.

AU - Brown, John

AU - Meldrum, Daniel R.

PY - 2006/1

Y1 - 2006/1

N2 - 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-α) and interleukin-1-beta (IL-1β) 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-α and IL-1β 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-α and IL-1β 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-α and IL-1β expression.

AB - 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-α) and interleukin-1-beta (IL-1β) 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-α and IL-1β 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-α and IL-1β 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-α and IL-1β expression.

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