title: Biphasic effects of oxethazaine, a topical anesthetic, on the intracellular Ca(2+) concentration of PC12 cells.
abstract: There have been few reports on the mechanism(s) of action of oxethazaine (OXZ) despite its potent local anesthetic action. Generally, local anesthetics (LAs) not only inhibit Na(+) channels but also affect various membrane functions. In the present study, using PC12 cells as a nerve cell model, the effects of OXZ on intracellular Ca(2+) concentration ([Ca(2+)](i)) were examined in relation to cytotoxicity and dopamine release. [Ca(2+)](i) was determined by the quin2 method. In resting cells, (6-10)x10(-5)M OXZ produced lactate dehydrogenase leakage, which was Ca(2+)-dependent, inhibited by metal Ca(2+) channel blockers, and preceded by a marked increase in [Ca(2+)](i). Some other LAs showed no cytotoxicity at these concentrations. In K(+)-depolarized cells, however, lower concentrations of OXZ (10(-6)-10(-7)M), that had no effect on resting [Ca(2+)](i), inhibited both the dopamine release and the increase of [Ca(2+)](i) in parallel. The inhibitory potency against the [Ca(2+)](i) increase was in the order of nifedipine>OXZ approximately verapamil>diltiazem, and OXZ acted additively on the Ca(2+) channel blockers. OXZ showed the least effect on K(+)-depolarization as determined by bisoxonol uptake. OXZ also inhibited the increase in [Ca(2+)](i) induced by S(-)-BAY K 8644, a Ca(2+) channel agonist. These observations suggested that low concentrations of OXZ interact with L-type Ca(2+) channels. The biphasic effects of OXZ on Ca(2+) movement may be due to a unique chemical structure, and may participate in and complicate the understanding of the potent pharmacological and toxicological actions of OXZ.
authors.affiliation: Division of Toxicology, Niigata College of Pharmacy, 5-13-2, Kamishin'ei-cho, Japan. masuda@niigata-pharm.ac.jp
authors.forename: Yasusuke
authors.initials: Y
authors.lastname: Masuda
authors.forename: Tamami
authors.initials: T
authors.lastname: Oguma
authors.forename: Akira
authors.initials: A
authors.lastname: Kimura
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D004983:Ethanolamines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D016716:PC12 Cells; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
chemical_list: D000777:Anesthetics; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004983:Ethanolamines; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C100289:oxethazaine; D011188:Potassium; D002118:Calcium; D004298:Dopamine