CHRONIC PULMONARY-HYPERTENSION INCREASES FETAL LUNG CGMP PHOSPHODIESTERASE ACTIVITY

An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreac tivity and structure. Because past studies had suggested impaired nitr ic oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered v ascular reactivity and structure in experimental PPHN. Therefore, we s tudied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. In fusion of dipyridamole and zaprinast lowered pulmonary vascular resist ance by 55 and 35%, respectively, in hypertensive animals. In comparis on with control animals, lung cGMP PDE activity was elevated in hypert ensive fetal lambs (150%). Increased PDES activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemist ry demonstrated that PDES was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possi bly by posttranslational phosphorylation. We speculated that these inc reases in cGMP PDE activity contributed to altered pulmonary vasoreact ivity in experimental perinatal pulmonary hypertension.