The nitric oxide (NO)/cGMP signal transduction system plays a critical role in the pulmonary vascular adaptation to extrauterine life. In the lung, PDE5 modulates NO responsiveness by decreasing intracellular cGMP concentrations. We have previously observed attenuated pulmonary vascular responses to NO in newborn lambs with PPHN following ligation of the ductus arteriosus 10 days prior to delivery. In addition, zaprinast, an inhibitor of the cGMP-specific PDE (PDE5), significantly enhances the pulmonary vascular response to inhaled NO in this model. To further investigate the role of PDE5 in regulating NO responsiveness in this ovine model of PPHN, we measured PDE5 mRNA levels and zaprinast-inhibitable PDE enzyme activity in peripheral lung samples isolated from late gestation lambs with PPHN (n=4) and from age-matched controls (n=4). Cyclic cGMP PDE activity and zaprinast-inhibitable cGMP hydrolysis, an estimate of PDE5 activity, were both 2-fold greater in lung extracts from lambs with PPHN compared to controls (p < 0.05). In contrast, RNA blot hybridization using an ovine PDE5 cDNA probe revealed decreased PDE5 mRNA in the lungs of PPHN lambs compared to controls. These results demonstrate that the gene encoding PDE5, an enzyme responsible for metabolizing cGMP, is modulated in this model of pulmonary hypertension. This may be in response to elevated PDE5 enzyme activity. Increased PDE5 enzyme activity may contribute to impaired responsiveness to NO in PPHN, and explain the significant enhancement of NO effect produced by zaprinast. Selective inhibitors of cGMP PDE activity may provide a useful adjunctive therapy to inhaled NO in patients with PPHN.

Funded by NIH #HL54705, AHA, and WCRF of Buffalo.