Hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels regulate membrane potential, neurotransmitter release, and patterning of synchronized neuronal activity. Currently, there is an intense debate as to whether or not these ion channels play a pro- or anticonvulsant role in vivo. To gain an insight into this question, we have examined how inhibitors of the response mediated by HCN channels (referred to as I(h)) affect epileptiform activity induced in adult hippocampal slices. The archetypal I(h) blocker ZD-7288 produced a concentration-dependent inhibition of both nonsynaptic- (low Ca(2+)/elevated K(+) aCSF) and synaptic- (low Mg(2+) aCSF, elevated K(+) aCSF or convulsant application (bicuculline or pentylenetetrazol)) based epileptiform activities. The IC(50) value for ZD-7288 induced inhibition of epileptiform activity was similar across all forms of epileptiform response and was below concentrations producing nonspecific inhibition of glutamatergic synaptic transmission. Furthermore, capsazepine, which exhibits similar potency to ZD-7288 at inhibiting I(h), failed to inhibit glutamatergic synaptic transmission per se but produced a significant inhibition of bicuculline-induced epileptiform activity. These data suggest that broad spectrum inhibition of I(h) reduces neuronal hyperexcitability in the hippocampus.