Ifenprodil and eliprodil are both non-competitive NMDA receptor antagonists which have been shown to inhibit neuronal Ca2+ channel currents. We have examined the effects of these agents on two defined subtypes of voltage-dependent Ca2+ channels and in the gerbil model of global cerebral ischaemia. Recombinantly expressed human alpha 1B-1 alpha 2b beta 1-3 Ca2+ subunits in HEK293 cells, which results in an omega-conotoxin-sensitive neuronal N-type voltage-dependent Ca2+ channel and omega-Aga IVA sensitive Ca2+ channels (P-type) in acutely isolated cerebellar Purkinje neurones were reversibly inhibited by ifenprodil and eliprodil. Human N-type Ca2+ channel currents were inhibited by ifenprodil and eliprodil with IC50 values of 50 microM and 10 microM respectively whereas P-type Ca2+ channel currents were inhibited reversibly by ifenprodil and eliprodil with approximate IC50 values of 60 microM and 9 microM respectively. Maximum current block observed for both channel subtypes was approximately 80% for both ifenprodil and eliprodil. For neuroprotection studies, animals were subjected to 5 min bilateral carotid artery occlusion with or without administration of either ifenprodil or eliprodil (5, 10 or 20 mg/kg i.p.) immediately after surgery followed by two further doses (2.5, 5 or 10 mg/kg, respectively) at 3 and 6 h post-occlusion. Both compounds provided significant protective effects against ischaemia-induced neurodegeneration in the CA1 region of the hippocampus. These results indicate that both ifenprodil and eliprodil protect against ischaemia-induced neurodegeneration when administered post-occlusion and that they also block N and P-type voltage-dependent Ca2+ channels.