ELEVATION OF PULMONARY PDE5-SPECIFIC ACTIVITY IN AN EXPERIMENTAL FETAL OVINE PERINATAL PULMONARY HYPERTENSION MODEL. † 1990

Mechanisms contributing to altered pulmonary vascular tone, reactivity and structure in persistent pulmonary hypertension of the neonate (PPHN) are poorly understood. Closure of the ductus arteriosus (DA) in the late-gestation ovine fetus increases pulmonary vascular resistance (PVR), alters vascular reactivity and structure, and causes failure of postnatal adaptation at delivery. Perinatal pulmonary vascular tone is modulated by the NO-cGMP cascade, with increased cGMP causing vasodilation. cGMP-specific phosphodiesterase (PDE5) is the predominant cGMP phosphodiesterase in vascular smooth muscle. Since elevated PDE5 leads to lowered cGMP levels, we hypothesized that failure of post-natal adaptation in experimental PPHN would be associated with elevated PDE5 activity. To test this hypothesis we measured PDE5 hydrolytic activity in lung homogenates from both 6 fetal lambs 8-10 days after DA occlusion and 6 age-matched controls. At sacrifice, lungs were immediately removed, frozen with liquid N₂ and stored at -70° until homogenization and assay. PDE5 activity was defined as 1uM cGMP hydrolytic activity that was suppressed by the presence of 4uM Zaprinast. Prior to performing these assays, full dose-inhibition curves for Zaprinast were performed on fetal lung homogenates to determine the EC₅₀ for PDE5 inhibition. All assays were performed in the presence of 0.8mM EGTA to inhibit PDE1 activity. Results were as follows: Table These findings suggest that elevated PDE5 activity may contribute to high PVR in experimental PPHN. We speculate that inhibition of PDE5 may be an important therapy in the treatment of PPHN.

Table 1