L-ARGININE ENHANCES INJURY IN THE ISOLATED RABBIT LUNG DURING HYPEROXIA

L-Arginine is the substrate for synthesis of nitric oxide (NO .) by NO synthase which physiologically produces vasodilation. The reaction of NO . or its metabolites with O-2 or its metabolites, however, can produce toxic reactive species which may cause cellular injury. We hypothesized that excessive NO . production in isolated perfused rabbit lungs at elevated PO2 could support the production of toxic nitrogen metabolites. In isolated perfused rabbit lungs ventilated with 95% O-2, 1.0 mM L-arginine caused significant pulmonary hypertension and edema. These effects of L-arginine were attenuated by the NO . synthase inhibitor, L-NAME (0.5 mM), not affected by SOD pretreatment (100 u/ml) and reversed by pretreatment with catalase (200 u/ml), suggesting a mechanism involving H2O2. This mechanism was supported by producing L-arginine mediated injury in normoxic lungs in the presence of a H2O2 generating system. This injury also was attenuated by L-NAME. On the basis of these results, we conclude that H2O2 interacts with NO . or one of its oxidized metabolites to contribute to acute lung injury during hyperoxia. Such a mechanism may involve peroxynitrite anion, although direct proof of its formation is lacking under these conditions.