INFLUENCE OF ISRADIPINE, NIGULDIPINE AND DANTROLENE ON THE ANTICONVULSIVE ACTION OF CONVENTIONAL ANTIEPILEPTICS IN MICE

We report the effects of two new dihydropyridine derivatives, isradipi ne -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methylisopr opylester) and niguldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl acid 3-(4,4-diphenyl-1-piperidinyl)-propyl methyl ester hydrochloride) , and of dantrolene (1-{(5-{p-nitrophenyl}furfurylidene)-amino} hydant oin sodium, an inhibitor of Ca2+ release from intracellular stores) on the protective efficacy of antiepileptic drugs against maximal electr oshock-induced seizures. It was shown that dantrolene (5-20 mg/kg), is radipine (5-10 mg/kg) and niguldipine (up to 2.5 mg/kg) did not influe nce the electroconvulsive threshold in mice, although a higher dose of niguldipine (5 mg/kg) significantly elevated it. Dantrolene (10-20 mg /kg) and isradipine (1 mg/kg) did not affect the anticonvulsive activi ty of conventional antiepileptic drugs. In contrast, niguldipine (2.5- 5 mg/kg) impaired the protective action of carbamazepine and phenobarb ital. No effect of niguldipine (2.5-5 mg/kg) was observed upon the ant iconvulsive efficacy of diphenylhydantoin and valproate. BAY k-8644 ,6 -dimethyl-5-nitro-4-{(2-trifluoromethyl)-phenyl} an L-type Ca2+ channe l agonist) did not reverse the action of niguldipine alone or the nigu ldipine-induced impairment of the anticonvulsive action of carbamazepi ne and phenobarbital. Niguldipine did not influence the free plasma le vels of carbamazepine and phenobarbital, so a pharmacokinetic interact ion is not probable. The results suggest that in contrast to the antic onvulsive activity of niguldipine against electroconvulsions, this Ca2 + channel inhibitor significantly weakened the protective action of bo th carbamazepine and phenobarbital. These effects do not seem to resul t from the blockade of voltage-dependent Ca2+ channels. Isradipine and dantrolene did not have a modulatory action on the threshold for elec troconvulsions or on the anticonvulsive activity of antiepileptic drug s. It may be concluded that the use of niguldipine, isradipine, and da ntrolene in epileptic patients seems questionable. (C) 1997 Elsevier S cience B.V.