The effects of nitric oxide (NO) synthase inhibitors on the hypoxia/hypoglycemia-induced decrease in CA1 presynaptic fiber spikes elicited by stimulation of the Schaffer collaterals were investigated using rat hippocampal slices. Drugs were added to normal medium for 10 min before incubation under hypoxic/hypoglycemic conditions (15 min), and after a 3-h washout, the CA1 presynaptic potential was measured. Treatment with NG-nitro-L-arginine methyl ester but not with NG-nitro-D-arginine methyl ester produced a concentration-dependent attenuation of the hypoxia/hypoglycemia-induced decrease in presynaptic fiber spikes. In contrast, treatment with precursors of NO in the arginine-to-NO pathway, such as sodium nitroprusside, S-nitro-N-acetylpenicillamine and N-morpholino sydnonimine exacerbated the 15-min hypoxia/hypoglycemia-induced decrease in the CA1 presynaptic potential. The neuroprotective effect of NG-nitro-L-arginine methyl aster was significantly attenuated by co-treatment with L-arginine. The present results suggest a facilitatory role of NO production in hypoxia/hypoglycemia-induced presynaptic dysfunction in CA1 regions of hippocampal slices.