Stimulation of the Schaffer collateral projection to the CA1 region in rat hippocampal slices at 1 Hz for 15 min produced a N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) of synaptic responses and, when given after tetanic stimulation, reversed long-term potentiation (LTP). Both LTD and the reversal of LTP were blocked by the nitric oxide (NO) inhibitor L-NG-monomethylargine (L-NMMA). L-NG-nitroarginine (L-NOArg) and hemoglobin also blocked LTD. The inhibition of LTD by L-NMMA was overcome by L- but not D-arginine. Sodium nitroprusside and S-nitrosocysteine, agents that spontaneously release NO, mimicked the effect of 1 Hz stimulation. These results indicate that NO mediates LTD produced by sustained 1 Hz activation of CA1 synapses and support the hypothesis that NO mediates the inhibition of LTP produced by untimely activation of NMDA receptors.