Wamil A W, McLean M J
Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.
J Pharmacol Exp Ther. 1992 Jan;260(1):376-83.
The anticonvulsant, (+/-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), blocked single postsynaptic responses of mouse spinal cord neurons in cell culture to N-methyl-D-aspartate (NMDA). The block was concentration dependent with IC50 = 10(-7) M against 10(-5) M NMDA and 2 x 10(-7) M against 10(-3) M NMDA. Serial responses were blocked in use-dependent manner by 10 times lower doses of MK-801, depending on rate of NMDA application. MK-801 (approximate IC50, 8 x 10(-8) M) also limited sustained high-frequency repetitive firing of sodium-dependent action potentials (AP) elicited by long (400 msec) depolarizing pulses. Without changing resting membrane potential, single AP elicited by short (0.5-1 msec) depolarizing current pulses were blocked in voltage-, use- and frequency-dependent manner. Maximal rate of rise of individual AP elicited by short or long pulses decreased progressively until failure to fire. The time constant of recovery of AP from inactivation in a paired pulse protocol was prolonged from about 1 msec in control solution to 12 msec in solution containing 3 x 10(-7) M MK-801. These characteristics suggest that MK-801 blocks voltage-sensitive sodium current, which generates the upstroke of the AP. Overlap of concentrations blocking NMDA responses and sustained repetitive firing suggests that both actions may contribute to anticonvulsant efficacy of MK-801.
抗惊厥药（±）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺（MK-801）可阻断细胞培养的小鼠脊髓神经元对N-甲基-D-天冬氨酸（NMDA）的单突触后反应。该阻断作用呈浓度依赖性，对10⁻⁵ M NMDA的IC50 = 10⁻⁷ M，对10⁻³ M NMDA的IC50 = 2×10⁻⁷ M。根据NMDA的给药速率，低10倍剂量的MK-801以使用依赖性方式阻断系列反应。MK-801（近似IC50，8×10⁻⁸ M）还可限制由长（400毫秒）去极化脉冲引发的钠依赖性动作电位（AP）的持续高频重复发放。在不改变静息膜电位的情况下，短（0.5 - 1毫秒）去极化电流脉冲引发的单个AP以电压、使用和频率依赖性方式被阻断。短脉冲或长脉冲引发的单个AP的最大上升速率逐渐降低直至无法发放。在配对脉冲方案中，AP从失活状态恢复的时间常数从对照溶液中的约1毫秒延长至含有3×10⁻⁷ M MK-801的溶液中的12毫秒。这些特性表明MK-801可阻断电压敏感性钠电流，该电流产生AP的上升支。阻断NMDA反应和持续重复发放的浓度重叠表明这两种作用可能都有助于MK-801的抗惊厥功效。
