Alkondon M, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore.
J Pharmacol Exp Ther. 1989 Sep;250(3):842-52.
The effects of SAD-128 [1,1'-oxybis(methylene) bis 4-(1,1-dimethylethyl) pyridinium dichloride], a nonoxime bispyridinium compound, were investigated on the nicotinic acetylcholine receptor-ion channels of frog muscle fibers using end-plate current (EPC) and single channel current measurement techniques. SAD-128 decreased the EPC peak amplitude in a concentration-dependent manner and caused nonlinearity in the current-voltage plots. The time constant of EPC decay was prolonged by SAD-128 (10-200 microM) at potentials between +50 and -90 mV without loss of the single exponential decay. However, at -100 mV and below, biphasic decays of the EPCs were observed in the presence of the drug. The time constant of the fast phase of the EPC decay decreased, whereas that of the slow phase increased, with either hyperpolarization or increasing concentration of the drug. SAD-128 weakly inhibited acetylcholinesterase in frog sartorius muscle. At the single-channel current level, SAD-128 reduced the mean channel open time and produced a blocked state evidenced as an additional phase in the closed time distribution. The agent induced a biphasic burst time distribution whose fast component became faster and slow component slower with increasing concentration and hyperpolarization. The present study provides more details regarding the kinetics of the nicotinic acetylcholine receptor ion channel-blocking mechanisms and a correlation between single-channel currents and macroscopic events. The ability of SAD-128 to block the nicotinic acetylcholine receptor may underlie its efficacy in counteracting lethal effect of organophosphorus compounds.
使用终板电流（EPC）和单通道电流测量技术，研究了非肟双吡啶化合物SAD-128 [1,1'-氧双（亚甲基）双4-（1,1-二甲基乙基）吡啶二氯化物] 对蛙肌纤维烟碱型乙酰胆碱受体离子通道的影响。SAD-128以浓度依赖性方式降低EPC峰值幅度，并导致电流-电压图出现非线性。在+50至-90 mV的电位下，SAD-128（10 - 200 microM）可延长EPC衰减的时间常数，且不丧失单指数衰减特性。然而，在-100 mV及以下，在药物存在下观察到EPC的双相衰减。随着超极化或药物浓度增加，EPC衰减快相的时间常数减小，而慢相的时间常数增加。SAD-128对蛙缝匠肌中的乙酰胆碱酯酶有弱抑制作用。在单通道电流水平，SAD-128缩短了平均通道开放时间，并产生了一种阻断状态，表现为关闭时间分布中的一个额外相位。该药物诱导了双相爆发时间分布，随着浓度增加和超极化，其快速成分变得更快，慢速成分变得更慢。本研究提供了关于烟碱型乙酰胆碱受体离子通道阻断机制动力学以及单通道电流与宏观事件之间相关性的更多细节。SAD-128阻断烟碱型乙酰胆碱受体的能力可能是其对抗有机磷化合物致死作用有效性的基础。
