Site-specific effect of guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition in isolated lamb lungs

Robin H Steinhorn, John B. Gordon, Mary L. Tod

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Objective: To determine the effect of combining inhaled nitric oxide (NO) with an inhibitor of guanosine 3',5'-cyclic monophosphate-specific phosphodiesterase on total and segmental lung resistances. Study Design: A controlled laboratory study in isolated blood-perfused lungs prepared from lambs. Setting: Animal research facility affiliated with a university teaching hospital. Subjects: Five newborn lambs at <48 hrs of life. Interventions: Isolated blood-perfused lungs were prepared and treated with indomethacin (40 μg/mL) to inhibit prostaglandin synthesis. After a baseline period of normoxia (28% oxygen), pulmonary hypertension was induced with the thromboxane mimetic U46619 (0.1-0.4 μg/kg/min). During pulmonary hypertension, lungs were studied with inhaled NO only, with infusion of zaprinast only (0.25 mg/kg bolus and 0.05 mg/kg/min infusion), and with a combination of the two. For each study condition, the total pressure decrease across the lung was measured, and the inflow-outflow occlusion technique was used to partition the total pressure gradient measured at constant flow (100 mL/kg/min) into gradients across relatively noncompliant large arteries and veins and more compliant small arteries and veins. Measurements and Main Results: U46619 infusion produced significant pulmonary vasoconstriction. The combination of inhaled NO and zaprinast decreased the total pressure decrease across the lung significantly more than NO alone. This effect was primarily attributable to a significantly greater decrease in gradient across the small artery segment after inhaled NO and zaprinast compared with NO alone. Conclusions: Guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition with zaprinast enhances the effect of inhaled NO, particularly in conditions in which small arteries represent the site of resistance. Phosphodiesterase inhibition may be a promising adjunct to inhaled NO for the treatment of persistent pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)490-495
Number of pages6
JournalCritical Care Medicine
Volume28
Issue number2
StatePublished - 2000
Externally publishedYes

Keywords

  • Isolated perfused lung
  • Newborn
  • Nitric oxide
  • Nitrovasodilator
  • Phosphodiesterase
  • Pulmonary artery
  • Pulmonary hypertension
  • Pulmonary vascular resistance
  • Thromboxane A'
  • Zaprinast

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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