173 Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in The Fetal Lamb

Abstract

Background: Nitric Oxide (NO) released by pulmonary vascular endothelium is a potent vasodilator related to increased cGMP content. Hydrolysis of cGMP is achieved predominantly by cGMP–specific phosphodiesterases (PDEs). Sildenafil (SILD) is a selective phosphodiesterase–5 (PDE–5) inhibitor. The purpose of the study was to assess the effects of sildenafil on pulmonary vascular circulation during the perinatal period.Methods: 12 pregnant ewes were operated on between 128 and 130 days gestation (term = 145 d). Catheters were placed into the ascending aorta, superior vena cava, main pulmonary artery and left atrium. An ultrasonic flow transducer was placed around left pulmonary artery (LPA). An inflatable vascular occluder was placed around ductus arteriosus (DA). Acute DA compression increases pulmonary artery pressure (PAP) causing an increase in pulmonary blood flow (Q) and a progressive decline in pulmonary vascular resistance (PVR). Fetal lambs were divided in two groups: 1) a SILD group infused continuously with SILD at a rate of 24 mg/day (n=6) and; 2/ control group (CONT) infused with saline (n=6). After 24 hrs of infusion, we compared the hemodynamic response of LPA to: 1) increased fetal PaO2 (maternal O2 inhalation for 30 min), and; 2) increase in vascular shear-stress (flow-induced pulmonary vasodilatation related to DA compression).Results: Mean PAP, Q and PVR were similar in both groups before and after 24 h of SILD or saline infusion. Despite similar baseline values, PVR during maternal O2 inhalation was lower in SILD than in CONT group (0.23±0.01 vs 0.27±0.01 mmHg/ml.min−1 respectively) (p<0.01). Furthermore, drop in PVR during acute DA compression was greater in the SILD group (from 0.54±0.03 to 0.26±0.02 mmHg/ml.min−1) than in the CONT group (from 0.55±0.04 to 0.39±0.02 mmHg/ml.min−1) (p<0.01).Conclusion: Although no difference was found in the basal pulmonary vascular tone, sildenafil increases pulmonary vascular reactivity in the ovine fetus. These data suggest that PDE–5 is involved in the regulation of pulmonary vascular reactivity during the perinatal period. We further speculate that specific inhibitor of PDE–5 may potentiate birth related pulmonary vasodilator stimuli and could improve conditions associated with failure to circulatory adaptation at birth.