We report the effects of two new
dihydropyridine derivatives,
isradipine (4-(4'-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedic arboxylic 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ 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.