Shimokawa M, Yamamoto K, Kawakami J, Sawada Y, Iga T
Department of Pharmacy, University of Tokyo Hospital Faculty of Medicine, Japan.
Toxicol Appl Pharmacol. 1996 Feb;136(2):317-23. doi: 10.1006/taap.1996.0038.
Convulsive potency was evaluated to investigate the mechanism of neurotoxic convulsion induced by histamine H2 receptor antagonists (H2 blockers). Four H2 blockers, cimetidine (721-1236 nmol), ranitidine (477-954 nmol), famotidine (7.4-44 nmol), and nizatidine (226-603 nmol) were administered intracerebrally (i.c.) to mice. Dose dependency of clonic and/or tonic convulsion was observed, and the ED50 values of convulsive occurrence for cimetidine, ranitidine, famotidine, and nizatidine were 997, 662, 23.4, and 404 nmol, respectively. Intraperitoneal pretreatment of muscimol, aminooxy acetic acid, diazepam, (+/-)2-amino-7-phosphonoheptanoic acid (APH), or (+)MK801 suppressed the tonic convulsion after i.c. administration of ranitidine, but had no effect on clonic convulsion. Furthermore, the convulsive threshold concentration in the brain determined by constant rate infusion of ranitidine was not affected by the pretreatment of muscimol, diazepam, APH, and MK801. Ed50 values for convulsive occurrence after i.c. administration of four H2 blockers correlated well with the EC50 values for gastric acid secretion inhibition. The convulsive threshold concentrations of cimetidine and ranitidine in the brain were 11 and 2.5 microM, respectively, which were similar to the dissociation constants determined from the inhibition of gastric acid output in mice. From these results, tonic convulsion induced by H2 blockers can be suppressed by GABAergic or glutamatergic anticonvulsants, while clonic convulsion induced by H2 blockers may be associated with the blockade of H2 receptor in the brain and not be directly associated with the GABA and glutamate-mediated neurotransmission.
为研究组胺H2受体拮抗剂（H2阻滞剂）诱导神经毒性惊厥的机制，对惊厥效能进行了评估。将四种H2阻滞剂西咪替丁（721 - 1236纳摩尔）、雷尼替丁（477 - 954纳摩尔）、法莫替丁（7.4 - 44纳摩尔）和尼扎替丁（226 - 603纳摩尔）脑内注射（i.c.）给小鼠。观察到阵挛性和/或强直性惊厥的剂量依赖性，西咪替丁、雷尼替丁、法莫替丁和尼扎替丁惊厥发生的半数有效剂量（ED50）值分别为997、662、23.4和404纳摩尔。腹腔内预先给予蝇蕈醇、氨氧基乙酸、地西泮、（±）2 - 氨基 - 7 - 膦酰庚酸（APH）或（ + ）MK801可抑制雷尼替丁脑内注射后的强直性惊厥，但对阵挛性惊厥无影响。此外，通过雷尼替丁恒速输注测定的脑内惊厥阈值浓度不受蝇蕈醇、地西泮、APH和MK801预处理的影响。四种H2阻滞剂脑内注射后惊厥发生的Ed50值与胃酸分泌抑制的半数有效浓度（EC50）值密切相关。西咪替丁和雷尼替丁在脑内的惊厥阈值浓度分别为11和2.5微摩尔，这与从小鼠胃酸分泌抑制实验中确定的解离常数相似。从这些结果来看，H2阻滞剂诱导的强直性惊厥可被GABA能或谷氨酸能抗惊厥药抑制，而H2阻滞剂诱导的阵挛性惊厥可能与脑内H2受体的阻断有关，与GABA和谷氨酸介导的神经传递无直接关联。
