The PDE inhibitor zaprinast enhances NO-mediated protection against vascular leakage in reperfused lungs

Disruption of endothelial barrier properties with development of noncardiog enic pulmonary edema is a major threat in lung ischemia-reperfusion (I/R) i njury that occurs under conditions of lung transplantation. Inhaled nitric oxide (NO) reduced vascular leakage in lung I/R models, but the efficacy of this agent may be limited. We coadministered NO and zaprinast, a cGMP-spec ific phosphodiesterase inhibitor, to further augment the NO-cGMP axis. Isol ated, buffer-perfused rabbit lungs were exposed to 4.5 h of warm ischemia. Reperfusion provoked a transient elevation in pulmonary arterial pressure a nd a negligible rise in microvascular pressure followed by a massive increa se in the capillary filtration coefficient and severe lung edema formation. Inhalation of 10 parts/million of NO or intravascular application of 100 m u M zaprinast on reperfusion both reduced pressor response and moderately a ttenuated vascular leakage. Combined administration of both agents induced no additional vasodilation at constant microvascular pressures, but additiv ely protected against capillary leakage paralleled by a severalfold increas e in perfusate cGMP levels. In conclusion, combining low-dose NO inhalation and phosphodiesterase inhibition may be suitable for the maintenance of gr aft function in lung transplantation by amplifying the beneficial effect of the NO-cGMP axis and avoiding toxic effects of high NO doses.