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Approach to reaction mechanism of general anesthetics by biological and physicochemical methods from new viewpoint

新视角下生物物理化学方法探讨全麻药反应机理

基本信息

批准号：
11470428
负责人：
SUZUKI Kuniaki
金额：
$ 6.78万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

l) We studied the effects of volatile anesthetics, benzodiazepines, ketamine and droperidol on Na^+, K^+-ATPase activity; (1) All of anesthetics except fentanyl inhibited Na, K-ATPase activity and its partial reactions in a dose dependent manner. There were certain patterns, characteristic of each category of the anesthetics, in the order of IC50 values of Na, K-ATPase activity and its partial reactions. Effects of the anesthetics on the phosphointermediate (EP) formation differed among the anesthetics. Benzodiazepine inhibited the EP formation, whereas isoflurane and ketamine did not. The sensitivity of EP to potassium was increased by ketamine but was decreased by isoflurane. These findings suggest that the inhibitory mechanisms of general anesthetics against Na, K-ATPase activity are diverse among the categories of anesthetics. (2) Benzodiazepines inhibited Na, K-ATPase activity by inhibiting the step after EP formation and the inhibition was partialy reversible, and that binding sites of Na, K-ATPase for benzodiazepines were different from those of GABAA receptor.(3)Droperidoi inhibited the ATPase activity of Na, K-ATPase by decreasing the rate of dephosphorylation of EP and that the inhibition was reversible. 2) To better understand the effects of volatile anesthetics on proteins, we studied the effects of volatile anesthetics on Na^+, K^+-ATPase that requires lipids for activity and alkaline phosphatase (ALP) that does not require lipids for activity. The results suggested that lipid is not always necessary for the action of volatile anesthetics, and that the action of volatile anesthetics is influenced by the slight difference of isozymes, for example, primary structure and by the change of slight subunit -subunit interaction or alteration of surface structure caused by SDS.

l)研究了挥发性麻醉剂、苯二氮卓类药物、氯胺酮和哌啶醇对Na^+、K^+- atp酶活性的影响；(1)除芬太尼外，所有麻醉药均能抑制Na、k - atp酶活性及其部分反应，且呈剂量依赖性。在Na、k - atp酶活性及其部分反应的IC50值排序中，每种麻醉药都有一定的规律。不同麻醉药对磷中间体（EP）形成的影响不同。苯二氮卓类药物抑制EP的形成，而异氟醚和氯胺酮则没有。氯胺酮可提高EP对钾的敏感性，异氟醚可降低EP对钾的敏感性。这些结果表明，不同种类的麻醉药对Na， k - atp酶活性的抑制机制是不同的。(2)苯二氮卓类药物通过抑制EP形成后的步骤抑制Na， k - atp酶活性，且抑制是部分可逆的，且Na， k - atp酶对苯二氮卓类药物与GABAA受体的结合位点不同。(3)黄芪可通过降低EP的去磷酸化速率来抑制Na， k - atp酶的活性，且这种抑制是可逆的。2)为了更好地了解挥发性麻醉药对蛋白质的影响，我们研究了挥发性麻醉药对Na^+， K^+- atp酶（需要脂质才能活性）和碱性磷酸酶（ALP）的影响。结果表明，脂质对挥发性麻醉药的作用并不一定是必需的，挥发性麻醉药的作用受同工酶（如初级结构）的微小差异和SDS引起的亚基-亚基相互作用的微小变化或表面结构的改变的影响。