Ca2+ channel blockade and the antielectroshock activity of NMDA receptor antagonists, CGP 40116 and CGP 43487, in mice.

Nicardipine, nifedipine and flunarizine showed anticonvulsive activity (reflected by significant elevations of the seizure threshold for tonic hindlimb extension) in doses of 20, 20 and 15 mg/kg, respectively. In combination studies, CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] or its methyl ester derivative (CGP 43487) was administered in a constant dose of 0.25 and 3.5 mg/kg, respectively. At these doses both competitive NMDA receptor antagonists were able to elevate significantly the convulsive threshold. Nicardipine, nifedipine, and flunarizine were administered at maximal doses (or lower) not affecting the convulsive threshold (15, 15 and 10 mg/kg, respectively). The protective activity of CGP 40116 and CGP 43487 was dose dependently potentiated by all three Ca2+ channel inhibitors. The combined treatment caused motor impairments (evaluated in the chimney test) and long-term memory deficits (measured in the passive avoidance task) similar to these produced by CGP 40116 or CGP 43487 alone. Our results indicate that nicardipine, nifedipine and flunarizine significantly potentiate the protective activity, but not the adverse effects, of CGP 40116 and CGP 43487 in mice.