Abstract-In the pulmonary vasculature, cGMP concentrations are regulated in part by a cGMP-dependent phosphodiesterase (PDE), PDE5. Infants with persistent pulmonary hypertension of the newborn (PPHN) are often mechanically ventilated with high oxygen concentrations. The effects of hyperoxia on the developing pulmonary vasculature and PDE5 are largely unknown. Here, we demonstrate that exposure of fetal pulmonary artery smooth muscle cells (FPASMCs) to high levels of oxygen for 24 hours leads to decreased responsiveness to exogenous NO, as determined by a decreased intracellular cGMP response, increased PDE5 mRNA and protein expression, as well as increased PDE5 cGMP hydrolytic activity. We demonstrate that inhibition of PDE5 activity with sildenafil partially rescues cGMP responsiveness to exogenous NO. In FPASMCs, hyperoxia leads to increased oxidative stress without increasing cell death. Treatment of normoxic FPASMCs with H 2 O 2 is sufficient to induce PDE5 expression and activity, suggesting that reactive oxygen species mediate the effects of hyperoxia in FPASMCs. In support of this mechanism, a chemical antioxidant, N-acetyl-cysteine, is sufficient to block the hyperoxia-mediated increase in PDE5 expression and activity and rescue cGMP responsiveness to exogenous NO. Finally, ventilation of healthy neonatal sheep with 100% O 2 for 24 hours leads to increased PDE5 protein expression in the resistance pulmonary arteries and increased PDE5 activity in whole lung extracts. These data suggest that PDE5 expression and activity play a critical role in modulating neonatal pulmonary vascular tone in response to common clinical treatments for PPHN, such as oxygen and inhaled NO. Key Words: pulmonary circulation Ⅲ persistent pulmonary hypertension of the newborn Ⅲ cyclic GMP Ⅲ phosphodiesterases P ersistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that results from a failure of the pulmonary vasculature to transition to extrauterine life. Infants typically present shortly after birth with respiratory distress and cyanosis but a structurally normal heart. The estimated incidence of PPHN is 0.2% of liveborn term infants. 1 PPHN is a manifestation of a heterogeneous group of disorders, and the response to therapy frequently depends on the underlying disease. Despite advances in clinical therapy, including high frequency ventilation, inhaled nitric oxide (iNO), and extracorporeal membrane oxygenation, there is still significant morbidity and mortality associated with this disease. Furthermore, iNO does not improve survival, and many infants do not respond or sustain their response to iNO for reasons that are unclear. 2,3 One factor that confounds the treatment of these infants is the use of supplemental oxygen. Oxygen has long been considered a vasodilator in the pulmonary circulation, and thus, 100% O 2 is considered a first-line therapy in infants with PPHN. 1,4 However, data from the adult acute respiratory distress syndrome literature, 5 from the neonatal bronchopulmonary dysplasia lite...

Intratracheal rhSOD and/or iNO rapidly increase oxygenation and reduce both vasoconstriction and oxidation in newborn lambs with PPHN. This has important implications for clinical trials of rhSOD and iNO in newborn infants with PPHN.