THE CGMP PHOSPHODIESTERASE INHIBITOR ZAPRINAST ENHANCES THE EFFECT OF NITRIC-OXIDE

We investigated the effect of zaprinast (M&B 22948), a specific cGMP phosphodiesterase inhibitor, on pulmonary arteries isolated from lambs with persistent pulmonary hypertension following prenatal ligation of the ductus arteriosus. Relaxations to sodium nitroprusside, which donates nitric oxide inside the smooth muscle cell, were significantly decreased in pulmonary arteries from ligated lambs. Pretreatment with 3 x 10(-5) M zaprinast restored them to levels close to those observed in untreated arteries from control animals. Further studies in intact newborn lambs were then conducted under three experimental conditions: (1) NO inhalation at 6 ppm, (2) zaprinast infusion at 0.05 mg/kg/min, and (3) combination therapy of zaprinast infusion in addition to inhaled NO at 6 ppm. Combined therapy with NO and zaprinast decreased the pulmonary artery pressure (34.3 +/- 3%) and pulmonary vascular resistance (64 +/- 7%) and increased pulmonary blood Row (88 +/- 34%) and postductal Pa-O2 (287 +/- 34%) to a significantly greater extent than NO alone, zaprinast alone, or the sum of these two responses, indicating a true synergistic effect. Zaprinast pretreatment also markedly increased the duration of pulmonary vasodilation to nitric oxide. There was no effect on systemic blood pressure with the combined therapy. We conclude that zaprinast pretreatment significantly enhances the effect of sodium nitroprusside on isolated pulmonary arteries, as well the effect of inhaled NO at 6 ppm in newborn lambs with persistent pulmonary hypertension. We speculate that phosphodiesterase inhibition may increase the response rate to NO or allow the use of much lower inhaled concentrations of NO.