Pulmonary Vascular Effects of Selective cGMP-Specific (Type V) Phosphodiesterase Inhibitors in the Ovine Fetus. ♦ 314

The nitric oxide (NO) - cGMP cascade modulates perinatal pulmonary vascular tone. cGMP-specific (type V) phosphodiesterase (PDE5) hydrolyzes cGMP, limiting vasodilation and maintaining high pulmonary vascular resistance (PVR) in the fetus. Two new drugs, E4021 (Eisai) and DMPPO (Glaxo-Welcome), have been developed which cause potent and selective inhibition of PDE5 activity. To test the hypothesis that PDE5 activity contributes to high PVR in the fetal lung, we studied the hemodynamic effects of these novel PDE5 antagonists in 11 chronically-prepared, late gestation fetal lambs (mean gestational age, 132 days; 147 days, term). At surgery, we placed catheters in the main pulmonary artery (PAP), aorta (AoP), left atrium (LAP) and amniotic cavity to measure pressure. A catheter was placed in the left pulmonary artery (LPA) to infuse drug directly into the left lung. An ultrasonic flow transducer was placed on the LPA to measure left lung blood flow. After at least 48 hours recovery from surgery, E4021 (doses: 0.04 - 4 mg) were infused over 10 minutes into the LPA. Hemodynamic measurements were recorded at baseline and at 10 minute intervals for 60 minutes. E4021 caused dose-related pulmonary vasodilation, decreasing PVR from baseline by 30% (0.04 mg) to 58% (4 mg; p 1 mg. Equimolar infusions of DMPPO caused a similar fall in PVR(61%). To determine the importance of endogenous NO in stimulation of cGMP production, E4021 (1 mg) was infused before and after treatment with nitro-L-arginine (L-NA), a selective inhibitor of NO synthase. L-NA completely blocked E4021 -induced pulmonary vasodilation. We conclude that E4021 and DMPPO cause potent pulmonary vasodilation in the ovine fetus. These findings support the hypothesis that PDE5 plays a critical role in regulation of pulmonary vascular tone in the developing lung. We speculate that PDE5 inhibitors may provide a new therapy for pulmonary hypertension.