Department of Anesthesiology and Critical Care, Hiroshima University, Hiroshima 734-8551, Japan.
Department of Anesthesiology, Hiroshima Prefectural Rehabilitation Center, Higashihiroshima 739-0036, Japan.
Biomed Res Int. 2021 Jan 4;2021:8845129. doi: 10.1155/2021/8845129. eCollection 2021.
We investigated the potential safety of remimazolam and propofol in malignant hyperthermia- (HM-) susceptible patients using ryanodine receptor 1- (RYR1-) expressing human embryonic kidney- (HEK-) 293 cells.
We compared the enhanced responsiveness of HEK-293 cells expressing wild-type with that of mutant to caffeine following perfusion with remimazolam or propofol. Furthermore, we investigated whether RYR1 enhanced the responsiveness of cells to remimazolam or propofol and compared the median effective concentration (EC; i.e., the concentration required to reach half-maximal activation) using an unpaired two-tailed -test while a < 0.05 was considered significant.
Remimazolam and propofol did not promote the caffeine-induced increase in intracellular Ca levels in HEK-293 cells expressing mutant RYR1 even with exposure to approximately 100-fold the clinically used concentration. In wild-type RYR1, EC values of remimazolam following refusion vs. nonperfusion were 2.86 mM vs. 2.75 mM ( = 0.76) while for propofol perfusion vs. nonperfusion, they were 2.76 mM vs. 2.75 mM, respectively ( = 0.83). In mutant RYR1, EC values of remimazolam refusion vs. nonperfusion were 1.58 mM vs. 1.71 mM, respectively ( = 0.63) while for propofol perfusion vs. nonperfusion, they were 1.65 mM vs. 1.71 mM, respectively ( = 0.73). Remimazolam and propofol increased intracellular Ca levels in a concentration-dependent manner, but the effect was not enhanced by RYR1. EC values of remimazolam with non-RYR1 vs. wild-type RYR1 were 1.00 mM vs. 0.92 mM, respectively ( = 0.91) while those of propofol were 1.09 mM vs. 1.05 mM, respectively ( = 0.84).
The increase in intracellular Ca concentration caused by remimazolam or propofol was not considered an RYR1-mediated reaction. We conclude that remimazolam and propofol can be safely used as an anesthetic in MH-susceptible patients with -mutation without causing MH and may be safely substituted for an MH-triggering anesthetic when RYR1-mediated MH occurs.
我们使用表达 Ryanodine 受体 1（RYR1）的人胚肾-293 细胞（HEK-293 细胞）研究了雷米唑仑和丙泊酚在恶性高热（HM）易感患者中的潜在安全性。
我们比较了用雷米唑仑或丙泊酚灌流后表达野生型 RYR1 的 HEK-293 细胞与表达突变型 RYR1 的 HEK-293 细胞对咖啡因的反应增强情况。此外，我们还研究了 RYR1 是否增强了细胞对雷米唑仑或丙泊酚的反应性，并使用未配对的双尾 -检验比较了中效浓度（EC；即达到半最大激活所需的浓度），当 < 0.05 时认为具有统计学意义。
雷米唑仑和丙泊酚均未促进表达突变型 RYR1 的 HEK-293 细胞中咖啡因诱导的细胞内 Ca 水平升高，即使暴露于接近临床使用浓度的 100 倍时也是如此。在野生型 RYR1 中，再灌注与非灌注时雷米唑仑的 EC 值分别为 2.86 mM 与 2.75 mM（ = 0.76），而丙泊酚再灌注与非灌注时的 EC 值分别为 2.76 mM 与 2.75 mM（ = 0.83）。在突变型 RYR1 中，再灌注与非灌注时雷米唑仑的 EC 值分别为 1.58 mM 与 1.71 mM（ = 0.63），而丙泊酚再灌注与非灌注时的 EC 值分别为 1.65 mM 与 1.71 mM（ = 0.73）。雷米唑仑和丙泊酚以浓度依赖性方式增加细胞内 Ca 水平，但 RYR1 并未增强该作用。无 RYR1 与野生型 RYR1 的雷米唑仑 EC 值分别为 1.00 mM 与 0.92 mM（ = 0.91），而丙泊酚的 EC 值分别为 1.09 mM 与 1.05 mM（ = 0.84）。
雷米唑仑或丙泊酚引起的细胞内 Ca 浓度增加被认为不是 RYR1 介导的反应。我们的结论是，雷米唑仑和丙泊酚可安全用于携带 -突变的 HM 易感患者作为麻醉剂，而不会引起 MH，并且当发生 RYR1 介导的 MH 时，它们可以安全替代引发 MH 的麻醉剂。
