Influence of isradipine, niguldipine and dantrolene on the anticonvulsive action of conventional antiepileptics in mice

Abstract

We report the effects of two new dihydropyridine derivatives, isradipine (4-(4′-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methylisopropylester) and niguldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylic acid 3-(4,4-diphenyl-1-piperidinyl)-propyl methyl ester hydrochloride), and of dantrolene (1-{(5-{ p-nitrophenyl}furfurylidene)-amino}hydantoin sodium, an inhibitor of Ca 2+ release from intracellular stores) on the protective efficacy of antiepileptic drugs against maximal electroshock-induced seizures. It was shown that dantrolene (5–20 mg/kg), isradipine (5–10 mg/kg) and niguldipine (up to 2.5 mg/kg) did not influence 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 activity of conventional antiepileptic drugs. In contrast, niguldipine (2.5–5 mg/kg) impaired the protective action of carbamazepine and phenobarbital. No effect of niguldipine (2.5–5 mg/kg) was observed upon the anticonvulsive efficacy of diphenylhydantoin and valproate. BAY k-8644 (methyl-1,4-dihydro-2,6-dimethyl-5-nitro-4-{(2-trifluoromethyl)-phenyl}-pyridine-5-carboxylate, an L-type Ca 2+ channel agonist) did not reverse the action of niguldipine alone or the niguldipine-induced impairment of the anticonvulsive action of carbamazepine and phenobarbital. Niguldipine did not influence the free plasma levels of carbamazepine and phenobarbital, so a pharmacokinetic interaction is not probable. The results suggest that in contrast to the anticonvulsive activity of niguldipine against electroconvulsions, this Ca 2+ channel inhibitor significantly weakened the protective action of both carbamazepine and phenobarbital. These effects do not seem to result from the blockade of voltage-dependent Ca 2+ channels. Isradipine and dantrolene did not have a modulatory action on the threshold for electroconvulsions or on the anticonvulsive activity of antiepileptic drugs. It may be concluded that the use of niguldipine, isradipine, and dantrolene in epileptic patients seems questionable. © 1997 Elsevier Science B.V. All rights reserved.