Study for the action and side effects of anesthetics using plasma membrane Ca-ATPase as a model

以质膜Ca-ATP酶为模型研究麻醉药的作用和副作用

基本信息

批准号：
12671919
负责人：
IIDA Akira
金额：
$ 2.18万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671919/
关键词：
Na^+,K^+-ATPase flunitrazepam midazolam diazepam flumazenil lidocaine isoflurane procaine Na, K-ATPase NMR

项目摘要

Recently it was reported that the activity of Na^+,K^+-ATPase was inhibited by benzodiazepines, but detail was not yet clear. We aimed to clarify the inhibition mechanism of benzodiazepines for Na^+,K^+-ATPase. The effects of benzodiazepines (midazolam, diazepam and flunitrazepam), on Na^+,K^+-ATPase and Na^+-ATPase activities, and phosphointemiediate (EP) of Na^+,K^+-ATPase were tested using Na^+,K^+-ATPase purified from rabbit brain. The following results were obtained. All three benzodiazepines inhibited Na^+,K^+-ATPase and Na^+ -ATPase activities, and EP formation in a dose-dependent manner and the half maximal inhibition concentrations (Ki 0.5) for Na^+,K^+ATPase activity were 0.6, 0.42 and 0.25 mM, for diazepam, midazolam and flunitrazepam, respectively. Tlie orders of Ki 0.5 values were EP formation > Na^+,K^+-ATPase activity > Na^+-ATPase activity for all benzodiazepines, suggesting that inhibition of Na^+,K^+-ATPase by benzodiazepines was mainly caused by inhibiting the reacti … More on sequence after EP formation. The activities were partially recovered for all benzodiazepines by dilution of their concentrations. Flumazenil did not affect the inhibition of Na^+,K^+-ATPase activity and EP formation by benzodiazepines, and recovery test of inhibition, suggesting that flumazenil did not compete with the reactions of benzodiazepines on Na^+,K^+-ATPase and mat the.structure of binding sites of Na^+,K^+-ATPase for benzodiazepines are different from those of GABA_A receptor. In other experiments, we showed that local anesthetics, lidocaine, procaine and dibucaine, inhibited Na^+,K^+-ATPase activity by inhibition of EP formation and some aspects of local anesthesia may relate to the inhibition of Na^+,K^+-ATPase activity. We also showed that the inhibitory mechanisms of general anesthetics against Na^+,K^+-ATPase activity are diverse among the different categories of anesthetics and that isoflurane inhibit the activity by decrease in the sensitivity of EP to potassium ions. Less

最近有报道说，苯二氮卓类药物抑制了Na^+，K^+ATPase的活性，但细节尚不清楚。我们旨在阐明苯二氮卓类药物对Na^+，K^+ATPase的抑制作用。使用Na^+，k^+ - ATPase和Na^+ - ATPase活动以及Na^+，K^+ - ATPase的phosphointemiaDiate（EP）对Na^+，K^+ - ATPase活动的苯二氮卓类药物的影响，使用Na^+，k^+ - atpase的磷体emiAdiate（EP）使用Na^+，k^+，k^+，k^+ - Atpase frof cabbit Brine。获得以下结果。所有三个苯二氮卓类药物均以剂量依赖性的方式抑制Na^+，K^+ATPase和Na^+-ATPase活性以及EP形成，而Na^+，K^+ATPase活性的一半最大抑制浓度（Ki 0.5）为0.6、0.42和0.25 mm，diazepam，indazepam，indazepam，indazepam和flunitraz，均为0.6、0.42和0.25 mm。 Ki 0.5值的顺序为EP的形成> Na^+，K^+ATPase活性> Na^+ - ATPase Atpase Attpase Attive to linzodiazepines的活性，这表明抑制Na^+，K^+ - ATPase bi binzodiazepines的抑制作用主要是由EPERICE抑制epectie在EP形成后抑制反应引起的。通过稀释其浓度，将所有苯二氮卓类药物部分回收。氟马兹尼不影响苯二氮卓类药物对Na^+，K^+ATPase活性和EP形成的抑制作用，以及对抑制作用的恢复测试，这表明氟马兹尼在Na^+，K^+ - ^+ - atpase和Mat at的ben+ats k^+ats k^^+syz^^+s的benzodiazepine竞争的反应中没有竞争。 gaba_a受体。在其他实验中，我们表明局部麻醉药，利多卡因，普罗帕因和二丁用于抑制Na^+，K^+ - ATPase活性，通过抑制ep的形成和局部麻醉的某些方面可能与Na^+，K^+ - ATPase活性的抑制有关。我们还表明，全身麻醉剂对Na^+，K^+ATPase活性的抑制作用机制在不同类别的麻醉剂中是多种多样的，并且异氟烷通过降低EP对钾离子的敏感性而抑制活性。较少的