In rat glial cells, arginine analogs N(G)-nitroarginine methyl ester (both D- and L-stereoisomer) and L-canavanine lower the intracellular levels of reduced glutathione, stimulate the pentose phosphate pathway, increase the level of malonyldialdehyde, and increase the leakage of lactate dehydrogenase. These effects are not related to the inhibition of nitric oxide synthase and depend on the oxidation of intracellular thiols; indeed, there are no signs of lipoperoxidation and cytotoxicity in cells previously loaded with glutathione. Furthermore, these arginine analogs elicit an oxidative burst in N11 cells and decrease the detectable level of both glutathione and dithiothreitol in cell-free experiments. These effects were not observed with the arginine analog N(G)-monomethyl-L-arginine, suggesting that the substituting moiety in (or near) the guanidine group could modify the reactivity of the arginine analogs with thiol compounds.