We tested the hypothesis that transient, partial inhibition of the Na,K-pumps could produce lasting effects on synaptic efficacy in brain tissue by applying a low concentration of the ouabain analogue, dihydroouabain (DHO), to hippocampal slices for 15 min and studying the effects on field excitatory postsynaptic potentials (fEPSPs). DHO caused a suppression of fEPSPs during the application period, but this recovered only partially, to approximately 80% of control levels, after washout lasting as long as 2 h. The lasting suppression had several properties in common with low-frequency stimulation induced long-term depression (LFS-LTD), including an ability to depotentiate long-term potentiated responses. However, DHO-LTD was insensitive to blockade of N-methyl-d-aspartate or mGlu receptors or to inhibitors of protein kinase C or p38 MAP kinase. DHO-LTD did not co-occlude with LFS-LTD and therefore appears to represent a novel form of LTD. Interestingly, DHO-LTD could be prevented by pretreating slices with iberiotoxin, the selective blocker of large, Ca(2+)-dependent K+ channels ("big K," BK channels), although this toxin did not affect basal fEPSPs. Certain pathological conditions, including hypoxia and ischemia, are associated with a decrease in Na,K-pump activity and hence DHO-LTD may serve as a model for the effects on neuronal function in these conditions.