Effect of a phosphodiesterase 5 inhibitor on pulmonary and cerebral arteries of newborn piglets with chronic hypoxia-induced pulmonary hypertension

Neonatology. 2012;101(1):28-39. doi: 10.1159/000326270. Epub 2011 Jul 26.

Abstract

Background: The use of phosphodiesterase 5 (PDE5) inhibitors to treat newborns with pulmonary hypertension is increasing. The effect of PDE5 inhibitors on the neonatal cerebral circulation remains unknown. The neonatal piglet model of chronic hypoxia-induced pulmonary hypertension allows the study of the effects of PDE5 inhibitors on both the pulmonary and cerebral circulations.

Objectives: To determine whether the PDE5 inhibitor, zaprinast, causes dilation in pulmonary and middle cerebral arteries (MCA) of normoxic newborn piglets and those with chronic hypoxia-induced pulmonary hypertension, and to evaluate whether zaprinast alters responses to increased pressure (autoregulatory ability) of the MCA.

Methods: Two-day-old piglets were raised in normoxia or hypoxia for 3 or 10 days. Pulmonary arteries and MCA were isolated and pressurized, after which changes in diameter to zaprinast were measured. MCA pressure-diameter relationships were determined.

Results: Dilation to zaprinast was similar in pulmonary arteries from normoxic and hypoxic piglets. Zaprinast dilated MCA from all groups but the response was diminished in MCA from piglets raised in hypoxia for 10 days. MCA pressure-diameter relationships (autoregulation) did not differ between the groups.

Conclusions: Pulmonary artery dilation to zaprinast supports the use of PDE5 inhibitors to treat pulmonary hypertension in neonates. PDE5 inhibitors function as MCA dilators but do not impair the pressure-diameter behavior of the cerebral circulation of either normoxic newborn piglets or those with chronic hypoxia-induced pulmonary hypertension. These findings suggest that cerebral autoregulation is likely to be intact with acute PDE5 inhibitor treatment in infants with pulmonary hypertension in conditions associated with chronic hypoxia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Animals
  • Animals, Newborn
  • Chronic Disease
  • Disease Models, Animal
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / etiology
  • Hypoxia / complications*
  • Middle Cerebral Artery / drug effects*
  • Middle Cerebral Artery / physiopathology
  • Phosphodiesterase Inhibitors / pharmacology*
  • Pulmonary Artery / drug effects*
  • Pulmonary Artery / physiopathology
  • Purinones / pharmacology*
  • Swine
  • Vasodilation / drug effects

Substances

  • Phosphodiesterase Inhibitors
  • Purinones
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • zaprinast