Short-term "preconditioning" with inhaled nitric oxide protects rabbit lungs against ischemia-reperfusion injury

Background. Pulmonary edema, owing to an impairment of microvascular barrie r function, is an important feature in lung ischemia/reperfusion (IR) injur y. Inhalation of nitric oxide (NO) during the period of reperfusion has pre viously been shown to reduce this leakage response. Methods. We investigated the impact of short-term (30 min) low-dose (10 ppm ) pre-ischemic NO inhalation on IR injury in buffer-perfused rabbit lungs, subsequently undergoing 210 min of warm, anoxic-ventilated ischemia. Results. Far-reaching suppression of the leakage response, reflected by man ifold increased capillary filtration coefficients and edema formation, was noted in lungs with pre-ischemic NO administration, corresponding to the be neficial effect of NO inhalation during reperfusion. The effect of NO pre-e xposure was not related to vasodilation, because microvascular pressures we re unchanged, and was mimicked by pre-ischemic intravascular administration of sodium nitroprusside with subsequent washout of this agent. NO inhalati on during reperfusion, but not pre-ischemic, short-term NO administration, provoked a manifold increase in the accumulation of guanosine 3',5'-cyclic monophosphate (cGMP) in the perfusate. The cGMP-analogue, 8-Br-cGMP, mimick ed the anti-edematous effect of NO when present during reperfusion, but pre ischemic, short-term administration of S-Br-cGMP provided only limited prot ection. The guanylate cyclase-inhibitor, 1H-[1, 2, 4]-Oxadiazolo-[4,3-a]-qu inoxalin-1-one (ODQ), largely antagonized the beneficial effects of NO inha lation during reperfusion but had only minor influence on the effect of NO pre-exposure. Conclusions. "Preconditioning" of the lung vasculature with short-term NO a dministration maintains endothelial integrity in a subsequent ischemia/repe rfusion maneuver, with nonvasodilatory and non-cGMP-related mechanisms sugg ested to be largely responsible. This finding may offer interesting perspec tives for donor management in clinical lung transplantation.