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

• 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

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

最近有报道称Na^+,K^+-ATPase的活性受到苯二氮卓类药物的抑制，但具体情况尚不清楚。我们的目的是阐明苯二氮卓类药物对Na^+,K^+-ATP酶的抑制机制。使用兔脑纯化的Na^+,K^+-ATP酶测试苯二氮卓类药物（咪达唑仑、地西泮和氟硝西泮）对Na^+,K^+-ATP酶和Na^+-ATP酶活性以及Na^+,K^+-ATP酶磷酸中间酯（EP）的影响。得到以下结果。所有三种苯二氮卓类药物均以剂量依赖性方式抑制 Na^+、K^+-ATPase 和 Na^+ -ATPase 活性以及 EP 形成，地西泮、咪达唑仑和氟硝西泮对 Na^+、K^+ATPase 活性的半数最大抑制浓度 (Ki 0.5) 分别为 0.6、0.42 和 0.25 mM。对于所有苯二氮卓类药物，Ki 0.5 值的顺序为 EP 形成 > Na^+,K^+-ATPase 活性 > Na^+-ATPase 活性，表明苯二氮卓类药物对 Na^+,K^+-ATPase 的抑制主要是通过抑制 EP 形成后的序列反应引起的。通过稀释浓度，所有苯二氮卓类药物的活性均得到部分恢复。氟马西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，且抑制恢复试验表明氟马西尼不与苯二氮卓类药物竞争Na^+,K^+-ATPase反应，Na^+,K^+-ATPase与苯二氮卓类药物的结合位点结构与苯二氮卓类药物不同。 GABA_A 受体。在其他实验中，我们发现局部麻醉药利多卡因、普鲁卡因和地布卡因通过抑制EP形成来抑制Na^+,K^+-ATP酶活性，局部麻醉的某些方面可能与抑制Na^+,K^+-ATP酶活性有关。我们还表明，全身麻醉剂对 Na^+,K^+-ATPase 活性的抑制机制在不同类别的麻醉剂中是不同的，异氟烷通过降低 EP 对钾离子的敏感性来抑制 Na^+,K^+-ATPase 活性。较少的

项目成果

Itaru Kawada: "Diverse Inhibitory Effects of General Anesthetics on Na+, K+-ATPase Activity in Rabbit Brain"Na/K-ATPase and Related ATPases, International Congress Series. 1207. 701-704 (2000)

Itaru Kawada：“全身麻醉药对兔脑 Na、K-ATP 酶活性的多种抑制作用”Na/K-ATP 酶和相关 ATP 酶，国际大会系列。

飯田 彰: "ベンゾジアゼピン系薬物がウサギ脳Na^+,K^+-ATPaseに及ぼす影響"北海道歯学雑誌. 21. 266-276 (2000)

Akira Iida：“苯二氮卓类药物对兔脑 Na^+,K^+-ATP 酶的影响”《北海道牙科杂志》21. 266-276 (2000)。

Itaru Kawada: "Inhibition of Na^+, K^+-ATPase Activity in Rabbit Kidney by General Anesthetics"Oral Therapeutics and Pharmacology(歯科薬物療法). 18(1). 17-28 (1999)

Itaru Kawada：“全身麻醉对兔肾中 Na^+、K^+-ATP 酶活性的抑制”口腔治疗和药理学 18(1) (1999)。

Kuniaki Suzuki: "Inhibition of Na, K-ATPase Activity by Local Anesthetics in Rat Brain and Rabbit Brain and Kidney"Na/K-ATPase and Related ATPases International Congress Series. 1207. 747-750 (2000)

Kuniaki Suzuki：“局麻药对大鼠脑和兔脑和肾脏中 Na、K-ATP 酶活性的抑制”Na/K-ATP 酶和相关 ATP 酶国际大会系列。

Kuniaki Suzuki et al.: "Inhibition mechanism of Na, K-ATPase activity by local anesthetics and its reversibility"Oral Therapeutics and Pharmacology. 18(2). 79-83 (1999)

Kuniaki Suzuki 等人：“局麻药对 Na、K-ATP 酶活性的抑制机制及其可逆性”口腔治疗与药理学。