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Proceedings of the National Academy of Sciences
Volume 93, Number 13; Pages: 6770-6774
Medical Sciences

Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury

Yong Xia, Valina L. Dawson, Ted M. Dawson, Solomon H. Snyder, Jay L. Zweier

© 1996 by the National Academy of Sciences

ABSTRACT   Besides synthesizing nitric oxide (NO), purified neuronal NO synthase (nNOS) can produce superoxide (·O2-) at lower L-Arg concentrations. By using electron paramagnetic resonance spin-trapping techniques, we monitored NO and ·O2- formation in nNOS-transfected human kidney 293 cells. In control transfected cells, the Ca2+ ionophore A23187 triggered NO generation but no ·O2- was seen. With cells in L-Arg-free medium, we observed ·O2- formation that increased as the cytosolic L-Arg levels decreased, while NO generation declined. ·O2- formation was virtually abolished by the specific NOS blocker, N-nitro-L-arginine methyl ester (L-NAME). Nitrotyrosine, a specific nitration product of peroxynitrite, accumulated in L-Arg-depleted cells but not in control cells. Activation by A23187 was cytotoxic to L-Arg-depleted, but not to control cells, with marked lactate dehydrogenase release. The cytotoxicity was largely prevented by either superoxide dismutase or L-NAME. Thus, with reduced L-Arg availability NOS elicits cytotoxicity by generating ·O2- and NO that interact to form the potent oxidant peroxynitrite. Regulating arginine levels may provide a therapeutic approach to disorders involving ·O2-/NO-mediated cellular injury.

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