So Edmund Cheung, Wu King Chuen, Kao Feng Chen, Wu Sheng Nan
Department of Anesthesia, Tainan Municipal An-Nan Hospital, China Medical University, 66# Cheung Ho Road, An-Nan District, Tainan, Taiwan; Department of Anesthesia, China Medical University, 91# Hsueh-Shih Road, Taichung, Taiwan; Department of Cell Biology and Anatomy, Cheng Kung University, 1# University Road, Tainan City, Taiwan; Department of Anesthesia, Taishan Medical University, 619 Chang Cheng Road, Taian 271016, Shandong Province, PR China; Department of Anesthesia, Nan Shan branch of Gilu Hospital, Shandong University, Shandong Province, PR China.
Department of Anesthesiology, Eda-Hospital/I-Shou University, 1# Yida Road, Jiaosu Village, Yanchao District, Kaohsiung, Taiwan.
Eur J Pharmacol. 2014 Feb 5;724:152-60. doi: 10.1016/j.ejphar.2013.12.034. Epub 2013 Dec 27.
Midazolam (MDL) was known to act through stimulation of benzodiazepine receptors (GABA). Whether midazolam affects ion currents and membrane potential in neurons remains largely unclear. Electrophysiological studies of midazolam actions were performed in differentiated motor neuron-like (NSC-34 and NG108-15) cells. Midazolam suppressed the amplitude of delayed rectifier K(+) current (IK(DR)) in a time- and concentration-dependent manner with an IC50 value of 10.4 µM. Addition of midazolam was noted to enhance the rate of IK(DR) inactivation. On the basis of minimal binding scheme, midazolam-induced block of IK(DR) was quantitatively provided with a dissociation constant of 9.8 µM. Recovery of IK(DR) from inactivation in the presence of midazolam was fitted by a single exponential. midazolam had no effect on M-type or erg-mediated K(+) current in these cells. Midazaolam (30 µM) suppressed the peak amplitude of voltage-gated Na(+) current (INa) with no change in the current-voltage relationships of this current. Inactivation kinetics of INa remained unaltered in the presence of this agent. In current-clamp configuration, midazolam (30 µM) prolonged the duration of action potentials (APs) and reduce AP amplitude. Similarly, in differentiated NG108-15 cells, the exposure to midazolam also suppressed IK(DR) with a concomitant increase in current inactivation. Midazolam can act as an open-channel blocker of delayed-rectifier K(+) channels in these cells. The synergistic blocking effects on IK(DR) and INa may contribute to the underlying mechanisms through which midazolam affects neuronal function in vivo.
已知咪达唑仑（MDL）通过刺激苯二氮䓬受体（GABA）发挥作用。咪达唑仑是否影响神经元中的离子电流和膜电位在很大程度上仍不清楚。在分化的运动神经元样（NSC - 34和NG108 - 15）细胞中进行了咪达唑仑作用的电生理研究。咪达唑仑以时间和浓度依赖性方式抑制延迟整流钾电流（IK(DR)）的幅度，IC50值为10.4 μM。注意到添加咪达唑仑可提高IK(DR)的失活速率。基于最小结合方案，咪达唑仑诱导的IK(DR)阻断的解离常数为9.8 μM。在咪达唑仑存在下，IK(DR)从失活状态恢复的过程符合单指数函数。咪达唑仑对这些细胞中的M型或erg介导的钾电流没有影响。咪达唑仑（30 μM）抑制电压门控钠电流（INa）的峰值幅度，而该电流的电流 - 电压关系没有变化。在该药物存在下，INa的失活动力学保持不变。在电流钳模式下，咪达唑仑（30 μM）延长动作电位（AP）的持续时间并降低AP幅度。同样，在分化的NG108 - 15细胞中，暴露于咪达唑仑也抑制IK(DR)，同时电流失活增加。咪达唑仑可作为这些细胞中延迟整流钾通道的开放通道阻滞剂。对IK(DR)和INa的协同阻断作用可能有助于解释咪达唑仑在体内影响神经元功能的潜在机制。
