NITRIC-OXIDE AS A MEDIATOR OF OXIDANT LUNG INJURY DUE TO PARAQUAT

At low concentrations, nitric oxide is a physiological transmitter, bu t in excessive concentrations it may cause cell and tissue injury. We report that in acute oxidant injury induced by the herbicide paraquat in isolated guinea pig lungs, nitric oxide synthesis was markedly stim ulated, as evidenced by increased levels of cyclic GMP in lung perfusa te and of nitrite and L-citrulline production in lung tissue. All sign s of injury, including increased airway and perfusion pressures, pulmo nary edema, and protein leakage into the airspaces, were dose-dependen tly attenuated or totally prevented by either N-G-nitro-L-arginine met hyl ester or N-omega-nitro-L-arginine, selective and competitive inhib itors of nitric oxide synthase. Protection was reversed by excess L-ar ginine but not by its enantiomer D-arginine. When blood was added to t he lung perfusate, the paraquat injury was moderated or delayed as it was when paraquat was given to anesthetized guinea pigs. The rapid ons et of injury and its failure to occur in the absence of Ca2+ suggest t hat constitutive rather than inducible nitric oxide synthase was respo nsible for the stimulated nitric oxide synthesis. The findings indicat e that nitric oxide plays a critical role in the production of lung ti ssue injury due to paraquat, and it may be a pathogenetic factor in ot her forms of oxidant tissue injury.