dexniguldipine and Disease-Models--Animal

The α1-adrenergic receptors (α1-ARs), which belong to a G protein-coupled receptor family, consist of three highly homologous subtypes known as α1A-ARs, α1B-ARs, and α1D-ARs. Our previous findings suggested that α1A-ARs are an important target for imipramine and electroconvulsive therapy. The current study sought to evaluate whether S-(+)-niguldipine and B8805-033, two selective antagonists of α1A-ARs, can evoke antidepressant-like effects in the forced swim test in rats. Both compounds were administered at three time points (24, 5, and 1 h before testing), and the effects of three doses (2, 5, and 10 mg/kg) of each compound were investigated. S-(+)-Niguldipine produced no antidepressant-like effects other than a 14% reduction in immobility time at the highest dose. Although B8805-033 at a dose of 2 mg/kg did not influence the rats' behavior, higher B8805-033 doses (5 and 10 mg/kg) produced significant reductions in immobility time (approximately 42 and 44% vs. controls, respectively; P<0.01). However, this effect was abolished by the concomitant administration of WAY100135, a serotonin receptor antagonist, suggesting that the observed antidepressant-like effects of B8805-033 are unrelated to α1A-ARs. Nevertheless, given the current dearth of selective α1A-AR agonists, the question of whether this particular subtype could be involved in antidepressant therapy mechanisms remains unresolved.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antidepressive Agents; Dihydropyridines; Dioxins; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Piperazines; Pyrimidinones; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Swimming; Time Factors

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.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Calcium Channel Agonists; Calcium Channel Blockers; Carbamazepine; Dantrolene; Dihydropyridines; Disease Models, Animal; Drug Interactions; Electroshock; Epilepsy; Female; Isradipine; Lethal Dose 50; Mice; Motor Activity; Phenobarbital; Phenytoin; Random Allocation; Seizures; Valproic Acid