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-type voltage dependent calcium channel, at the dose of 5 mg/kg (s.c.) did not significantly affect the threshold for electroconvulsions, but impaired the protective efficacy of flunarizine (15 and 20 mg/kg, i.p.) in the electroconvulsive test. Interestingly, the calcium channel agonist (at 1 and 5 mg/kg) distinctly diminished the protection offered by conventional anti-epileptic drugs (carbamazepine, diphenylhydantoin and phenobarbital) against maximal electroshock-induced seizures in mice. A pharmacokinetic interaction does not seem to be involved in the effect of BAY k-8644, since total plasma levels of these anti-epileptics (measured by immunofluorescence) were not affected by the calcium channel agonist. The only anti-epileptic drug resistant to BAY k-8644 (up to 5 mg/kg) was valproate, whose ED50 (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 maximal electroshock-induced convulsions. The calcium channel agonist (5 mg/kg) reversed the flunarizine-induced augmentation of the anticonvulsive activity of carbamazepine. It may be concluded that carbamazepine, diphenylhydantoin and phenobarbital partially exert their anticonvulsive 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 calcium channel blockade.
Gasior
M
M
Department of Pharmacology and Toxicology, Medical School, Lublin, Poland.
Kleinrok
Z
Z
Czuczwar
S J
SJ
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004597:Electroshock; D005444:Flunarizine / Q000494:pharmacology; D008297:Male; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D005444:Flunarizine; D010634:Phenobarbital