INFLUENCE OF BAY K-8644, A CALCIUM-CHANNEL AGONIST, ON THE ANTICONVULSANT ACTIVITY OF CONVENTIONAL ANTI-EPILEPTICS AGAINST ELECTROCONVULSIONS IN MICE

BAY k-8644, an agonist at the dihydropyridine binding site of the L-ty pe voltage dependent calcium channel, at the dose of 5 mg/kg (s.c.) di d not significantly affect the threshold for electroconvulsions, but i mpaired the protective efficacy of flunarizine(15 and 20 mg/kg, i.p.) in the electroconvulsive test. Interestingly, the calcium channel agon ist (at 1 and 5 mg/kg) distinctly diminished the protection offered by conventional anti-epileptic drugs (carbamazepine, diphenylhydantoin a nd phenobarbital) against maximal electroshock-induced seizures in mic e. A. pharmacokinetic interaction does not seem to be involved in the effect of BAY k-8644, since total plasma levels of these anti-epilepti cs (measured by immunofluorescence) were not affected by the calcium c hannel agonist. The only anti-epileptic drug resistant to BAY k-8644 ( up to 5 mg/kg) was valproate, whose ED(50) (in mg/kg) was not changed in the presence of the calcium channel agonist. Further, BAY k-8644 (5 mg/kg) did not influence the flunarizine (a calcium channel blocker) -induced potentiation of the protective action of valproate against ma ximal electroshock-induced convulsions. The calcium channel agonist (5 mg/kg) reversed the flunarizine-induced augmentation of the anticonvu lsive activity of carbamazepine. It may be concluded that carbamazepin e, diphenylhydantoin and phenobarbital partially exert their anticonvu lsive effects via blockade of calcium influx whilst valproate does not seem to. In this context, the flunarizine-induced potentiation of the anticonvulsive activity of valproate is probably independent of calci um channel blockade.