Abstract 1841 Poster Session I, Saturday, 5/1 (poster 93)

Background: NO relaxes vascular smooth muscle by increasing intracellular concentrations of cGMP, which in pulmonary vessels is inactivated by PDE5. We studied the effects of PDE5 inhibition in lambs with PPHN using UK114542-27, a novel, injectable PDE5 inhibitor which has a PDE5 to PDE1 selectivity profile similar to Sildenafil (Viagra). Methods and Results: PPHN was induced in fetal lambs by surgical ligation of the ductus artoriosus 9 days prior to delivery. Fifth generation pulmonary arteries (PA) were isolated from control (n=8) and hypertensive (n=5) fetal lambs, and studied using conventional tissue bath techniques. Vessels were constricted with norepinephrine following pretreatment with indomethacin and propranolol. Some vessels were also pretreated with LNA (10-3 M, a non-specific NO synthase antagonist) or ODQ (3×10-6 M, an inhibitor of soluble guanylate cyclase). Cumulative concentration response curves were generated for UK114542-27 (Pfizer, 10-9 to 10-5 M). UK 114542-27 relaxed isolated PA from both control and hypertensive lambs, with a significantly blunted response observed in PA isolated from hypertensive lambs (hypertensive vs control EC50:23.1±5.1 µM vs. 0.09±0.03 µM; p<0.05). UK114542-27 did not enhance relaxations to the NO donor SNAP in PA from control or hypertensive lambs. Endothelium removal or LNA pretreatment only partially inhibited relaxations to UK114542-27. Surprisingly, ODQ pretreatment enhanced relaxations to UK 114542-27 in hypertensive PA (EC50 0.16±0.03 µM with ODQ vs 23.13±5.0 µM without ODQ; p<0.005). Physiologic studies were performed in 5 intact PPHN lambs. Lambs were fully instrumented at delivery for measurement of PA pressure (PAP), pulmonary blood flow (Qp), left atrial pressure and aortic pressure. Following initial stabilization, intravenous infusion of 0.1 µg/kg/min of UK114542-27 over 30 minutes resulted in significant improvement in pulmonary hemodynamics. PA pressure decreased by 19.2±4.1% and pulmonary vascular resistance by 22.3±15%; Qp improved by 32±32% and PaO2 improved by 101±80%. A modest decrease of 10.6±2.7% was observed in systemic blood pressure. Infusion of a higher dose of UK114542-27 (1 µg/kg/min) was associated with a significant decrease in systemic blood pressure without further improvement in pulmonary hemodynamics. Conclusions: We conclude that UK114542-27, a highly soluble, injectable PDE5 inhibitor, selectively improves pulmonary hemodynamics in lambs with PPHN when infused at a dose of 0.1 meg/kg/min. Higher doses appear to lead to systemic hypotension. Our results from isolated vessels indicate that the action of UK114542-27, is in part mediated by PDE5-independent mechanisms. The ODQ enhancement of UK114542-27 relaxations in PA from hypertensive lambs needs further evaluation, but may indicate a role for PDE2, a cGMP stimulated-PDE which is present in fetal lung.

Funded by NIH 54705 and ABA 9740024N