SELECTIVE PULMONARY VASODILATION INDUCED BY AEROSOLIZED ZAPRINAST

Background: Zaprinast, an inhibitor of guanosine-3',5'-cyclic monophos phate (cGMP)-selective phosphodiesterase, augments smooth muscle relax ation induced by endothelium-dependent vasodilators (including inhaled nitric oxide [NO]), The present study was designed to examine the eff ects of inhaled nebulized zaprinast, alone, and combined with inhaled NO, Methods: Eight awake lambs with U46619-induced pulmonary hypertens ion sequentially breathed two concentrations of NO (5 and 20 ppm), fol lowed by inhalation of aerosols generated from solutions containing fo ur concentrations of zaprinast (10, 20, 30, and 50 mg/ml), The deliver ed doses of nebulized zaprinast at each concentration (mean +/- SD) we re 0.23 +/- 0.06, 0.49 +/- 0.14, 0.71 +/- 0.24, and 1.20 +/- 0.98 mg.k g(-1).min(-1), respectively, Each lamb also breathed NO (5 and 20 ppm) and zaprinast (0.23 +/- 0.06 mg.kg(-1).min(-1)) in combination after a 2-h recovery period. Results: Inhaled NO selectively dilated the pul monary vasculature, Inhaled zaprinast selectively dilated the pulmonar y circulation and potentiated and prolonged the pulmonary vasodilating effects of inhaled NO, The net transpulmonary release of cGMP was Inc reased by inhalation of NO, zaprinast, or both. The duration of the va sodilation induced by zaprinast inhalation was greater than that induc ed by NO inhalation. Conclusions: Aerosolization of a cGMP-selective p hosphodiesterase inhibitor alone or combined with NO may be a useful n oninvasive therapeutic method to treat acute or chronic pulmonary hype rtension.