Neurotoxic study of H2 antagonists using Xenopus oocytes injected with mouse-brain mRNA.
To clarify the dominant mechanism for the convulsant activity of H2 antagonists, the effects of an H2 antagonist, cimetidine, on membrane currents induced by various agonists were investigated. In Xenopus oocytes injected with mouse-brain mRNA, acetylcholine (ACh), serotonin (5-HT), gamma-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 recorded 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 IC50 of various H2 antagonists, famotidine, nizatidine, cimetidine and ranitidine, for GABA (10 microM)-induced current response were 66, 260, 450 and 980 microM, respectively. However, these values of cimetidine and ranitidine were 40-400 times higher than the reported brain and cerebrospinal fluid (CSF) concentration of H2 antagonists at the occurrence of a clonic convulsion in vivo. In conclusion, we observed an inhibitory effect of H2 antagonists on the GABA response; however, this inhibition of GABA-mediated neurotransmission may not be the dominant mechanism for H2 antagonist-induced clonic convulsion in vivo.
Kawakami
J
J
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
Yamamoto
K
K
Shimokawa
M
M
Sawada
Y
Y
Asanuma
A
A
Yanagisawa
K
K
Iga
T
T
D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D002927:Cimetidine / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000633:toxicity*; D008297:Male; D051379:Mice; D008845:Microinjections; D009498:Neurotoxins / Q000633:toxicity*; D009865:Oocytes / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000096:biosynthesis*; D014981:Xenopus
D006635:Histamine H2 Antagonists; D009498:Neurotoxins; D012333:RNA, Messenger; D002927:Cimetidine