A mechanism of paraquat toxicity involving nitric oxide synthase

(PQ) is a well described pneumotoxicant that produces toxicity by redox cycling with cellular diaphorases, thereby elevating intracellular levers of superoxide O-2(radical anion). NO synthase (NOS) has been shown to participate in PQ-induced lung injury. Current theory holds that NO reacts with O-2(radical anion) generated by PQ to produce the toxin peroxynitrite. We asked whether NOS might alternatively function as a PO diaphorase and reexamined the question of whether NO/O-2(radical anion) reactions were toxic or protective. Here, we show that: (i) neuronal NOS has PQ diaphorase activity that inversely correlates with NO formation; (ii) PQ-induced endothelial cell toxicity is attenuated by inhibitors of NOS that prevent NADPH oxidation, but is not attenuated by those that do not; (iii) PQ inhibits endothelium-derived, but not NO-induced, relaxations of aortic rings; and (iv) PQ-induced cytotoxicity is potentiated in cytokine-activated macrophages in a manner that correlates with its ability to block NO formation. These data indicate that NOS is a PO diaphorase and that toxicity of such redox-active compounds involves a loss of NO-related activity.