Zaprinast attenuates hypoxic pulmonary artery injury and causes less aortic relaxation than milrinone

Ben M. Tsai, Meijing Wang, Jeffrey M. Pitcher, Ajay Kher, Paul Crisostomo, Daniel R. Meldrum

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Hypoxic pulmonary vasoconstriction is a challenging clinical problem with limited therapeutic options. Milrinone, a phosphodiesterase (PDE)-3 inhibitor, is frequently used to treat perioperative pulmonary hypertension. However, recent evidence suggests that the PDE-5 isoform may be more specific for lung tissue. We hypothesized that the PDE-5 inhibitor zaprinast has greater efficacy for pulmonary vasorelaxation, attenuation of hypoxic pulmonary vasoconstriction, and inhibition of hypoxia-induced pulmonary artery cytokine expression when compared with milrinone. To study this, isolated rat pulmonary artery and thoracic aorta rings suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), milrinone, or zaprinast to assess pulmonary artery relaxation, thoracic aorta relaxation, inhibition of hypoxic (pO2 = 30-35 mmHg) pulmonary vasoconstriction, and hypoxia-induced pulmonary artery TNF-α and IL-1β expression (reverse transcriptase-PCR). Milrinone and zaprinast resulted in dose-dependent pulmonary artery and aortic relaxation, but zaprinast caused significantly less aortic relaxation compared with milrinone (50.12% ± 3.36% versus 91.03% ± 2.97%, P < 0.001). Zaprinast, but not milrinone, significantly inhibited hypoxic pulmonary vasoconstriction (zaprinast, 58.42% ± 5.37%; milrinone, 77.65% ± 4.42% versus vehicle: 74.42% ± 7.54%). Hypoxia-induced upregulation of TNF-α and IL-1β mRNA in pulmonary artery was decreased by zaprinast, but not milrinone, pretreatment. These results suggest that zaprinast, but not milrinone, preferentially vasodilates pulmonary artery over aorta, attenuates hypoxic pulmonary vasoconstriction, and inhibits hypoxia-induced pulmonary artery TNF-α and IL-1β expression. Therefore, PDE-5 inhibition may be advantageous in the treatment of pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)417-420
Number of pages4
JournalShock
Volume24
Issue number5
DOIs
StatePublished - Nov 1 2005

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Keywords

  • Hypoxia
  • Inflammation
  • Phosphodiesterase
  • Pulmonary hypertension
  • Vascular tone

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Physiology

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