HYPOXIA COMPARED WITH NORMOXIA ALTERS THE EFFECTS OF NITRIC-OXIDE IN ISCHEMIA-REPERFUSION LUNG INJURY

Because both the biosynthesis of nitric oxide NO . and its metabolic f ate are related to molecular O-2, we hypothesized that hypoxia would a lter the effects of NO . during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either no rmoxic IR (AI), in which lungs were ventilated with 21% O-2 during isc hemia and reperfusion, or hypoxic IR (NI), in which lungs were ventila ted with 95% N-2 during ischemia followed by reoxygenation with 21% O- 2. Lung weight gain (WG) and pulmonary artery pressure (P-pa) were mon itored continuously, and microvascular pressure (P-mv) was measured af ter reperfusion to calculate pulmonary vascular resistance. We found t hat both AI and NI produced acute lung injury, as shown by increased W G and P-pa during reperfusion. In AI, where perfusate PO2 was >100 mmH g, the administration of the NO . synthase inhibitor N-nitro-L-arginin e methyl ester (L-NAME) before ischemia worsened WG and P-pa. P-mv als o increased, suggesting a hydrostatic mechanism involved in edema form ation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO . donors before ischemia or before reperfusion. Parti al protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-N AME; this effect could be reversed by L-arginine. Exogenous NO . donor s given either before ischemia or before reperfusion, however, did not increase lung injury. NO . production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The averag e rate of NOx accumulation was greater in AI than in NI. We conclude t hat hypoxia prevented the protective effects of NO . on AI lung injury . The effects of hypoxia may be related to lower NO . production relat ive to oxidant stress during LR and/or altered metabolic fates of NO . -mediated production of peroxynitrite by hypoxic ischemia.