| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Kuniaki Hokkaido Univ., Grad. School of Dental Medicine, Prof., 大学院・歯学研究科, 教授 (40133748)
FUKUSHIMA Kazuaki Hokkaido Univ., Grad. School of Dental Medicine, Prof., 大学院・歯学研究科, 教授 (00002361)
KIMURA Yukifumi Hokkaido Univ., Dental Hospital, Inst., 歯学部・附属病院, 助手 (00292037)
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| Research Abstract |
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
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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
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