Neurotoxic Study of H_2 Antagonists Using Xenopus Oocytes Injected with Mouse-Brain mRNA

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To clarify the dominant mechanism for the convulsant activity of H_2 antagonists, the effects of an H_2 antagonist, cimetidine, on membrane currents induced by various agonists were investigated. In Xenopus oocytes injected with mouse-brain mRNA, acetylcholine (ACh), serotonin (5-HT), γ-aminobutyric acid (GABA), glycine (Gly), glutamic acid (Glu), kainic acid (KA), quisqualic acid (QA) and N-methyl-D-aspartic acid (NMDA)-induced current responses were recorede under a voltage-clamp condition. Cimetidine inhibited GABA-induced currents in a concentration-dependent manner; however, the current responses induced by the other agonists were not modified. The IC_<50> of various H_2 antagonists, famotidine, nizatidine, cimetidine and ranitidine, for GABA (10 μM)-induced current response were 66,260,450 and 980 μM, respectively. However, these values of cimetidine and ranitidine were 40-400 times higher than the reported brain and cerebrospinal fluid (CSF) concentration of H_2 antagonists at the occurrence of a clonic convulsion in vivo. In conclusion, we observed an inhibitory effect of H_2 antagonists on the GABA response; however, this inhibition of GABA-mediated neurotransmission may not be the dominant mechanism for H_2 antagonist-induced clonic convulsion in vivo.
公益社団法人日本薬学会の論文
1997-09-15