Introduction: Cyclic guanosine-monophosphate (cGMP) is critical in determining pulmonary vascular tone and reactivity. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases-5 (PDE-5). We hypothesized that enhanced PDE-5 activity contributes to consequences of chronic pulmonary hypertension in the perinatal lung. To test this hypothesis, we investigated the pulmonary vascular effects of prophylactic use of sildenafil - a specific PDE-5 inhibitor- in chronically - prepared late-gestation fetal lambs with chronic pulmonary hypertension. Methods: 10 fetal lambs were operated between 128 and 130 days gestation (term=147 days). An inflatable vascular occluder was placed around the ductus arteriosus (DA). DA was compressed for 8 full days, starting 24 hours after the surgery, to cause chronic pulmonary hypertension. To test the hypothesis, the animals were treated with continuous infusion of sildenafil (24 mg/day; sildenafil group; n=5) or with saline (control group; n=5). Treatment was begun before DA compression and continued during the study period. Pulmonary hemodynamic responses to increase in shear stress and in fetal PaO₂ were studied at respectively day 4 and day 6. Percent wall thickness of the small pulmonary arteries (%WT) and the right ventricle-to-left ventricle plus septum ratio (RVH) were measured after the completion of the study. Results: In the control group, chronic DA compression increased PA pressure (48±5 to 72±8 mmHg (p<0.01)) and pulmonary vascular resistance (PVR) (0.62±0.08 to 1.15±0.11 mmHg/ml/min (p<0.05)). Similar increase in PAP was observed in the sildenafil group, but PVR did not change significantly (0.54±0.06 to 0.64±0.09 mmHg/ml/min). At day 4, acute DA compression -after a brief decompression- elevated PVR by 25 % in the control group. At the opposite, DA compression at day 4 decreased PVR by 35 % in the sildenafil group. At day 6, increase in fetal PaO₂ did not change PVR in the control group. Similar increase in fetal PaO₂ decreased PVR by 60% in the sildenafil group. %WT and RVH in control and sildenafil groups were not different. Conclusion: Prophylactic sildenafil treatment prevents from the rise in pulmonary vascular tone and from altered vasoreactivity caused by DA compression in fetal lambs. These results support the hypothesis that elevation of PDE-5 activity is involved in the consequences of chronic pulmonary hypertension in the perinatal lung.