Robertson S J, Pennington A J, Evans A M, Martin R J
University of Edinburg, Department of Preclinical Veterinary Sciences, Royal Dick School of Veterinary Sciences, Summerhall, UK.
Eur J Pharmacol. 1994 Dec 27;271(2-3):273-82. doi: 10.1016/0014-2999(94)90784-6.
The anthelmintic pyrantel is believed to act as an agonist at acetylcholine receptors on somatic muscle from the parasite Ascaris suum. This study aimed to confirm this mode of action of pyrantel. Single-channel recordings from muscle vesicles formed from the extrasynaptic region of the bag of somatic muscle cells of Ascaris suum were made using the patch-clamp technique. Pyrantel (0.03-100 microM) activated cation-selective channels with at least 2 conductance levels: main conductance 41 +/- 2.04 pS (mean +/- S.E., n = 28), smaller conductance 22.4 +/- 0.34 pS (mean +/- S.E., n = 8). The current/voltage plots showed a linear relationship. Detailed kinetic analysis revealed that activation of the receptor by pyrantel resulted in at least 2 distinct open and burst states and at least 3 distinct closed states. The mean open time of the channel, with 0.1 microM pyrantel, was 1.53 +/- 0.22 ms (mean +/- S.E., n = 7) at -75 mV. We have previously shown that acetylcholine activated channels with similar properties to the pyrantel-activated channels (Pennington, A.J. and R.J. Martin, 1990, J. Exp. Biol. 154, 201) confirming that pyrantel is an acetylcholine agonist. With high concentrations (100 microM) of pyrantel a sequence of rapid openings and closings of the channel was observed, indicating the presence of an open channel block. Previous experiments have shown that the anthelmintic levamisole, which also acts as an acetylcholine agonist on this preparation, induced channel block at hyperpolarised potentials with high concentrations (Robertson, S.J. and R.J. Martin, 1993, Br. J. Pharmacol. 108, 170). A comparison is made of the actions of the 3 agonists pyrantel, levamisole and acetylcholine at the nicotinic receptor in Ascaris muscle, and implications for the therapeutic use of the compounds are discussed.
驱虫药噻嘧啶被认为可作为猪蛔虫体肌上乙酰胆碱受体的激动剂。本研究旨在证实噻嘧啶的这种作用方式。采用膜片钳技术，对从猪蛔虫体肌细胞包囊的突触外区域形成的肌小泡进行单通道记录。噻嘧啶（0.03 - 100微摩尔）激活了具有至少2种电导水平的阳离子选择性通道：主要电导为41±2.04皮安（平均值±标准误，n = 28），较小电导为22.4±0.34皮安（平均值±标准误，n = 8）。电流/电压图显示出线性关系。详细的动力学分析表明，噻嘧啶对受体的激活导致至少2种不同的开放和爆发状态以及至少3种不同的关闭状态。在 - 75毫伏时，0.1微摩尔噻嘧啶作用下通道的平均开放时间为1.53±0.22毫秒（平均值±标准误，n = 7）。我们之前已经表明，乙酰胆碱激活的通道与噻嘧啶激活的通道具有相似的特性（彭宁顿，A.J.和R.J.马丁，1990年，《实验生物学杂志》154卷，201页），这证实了噻嘧啶是一种乙酰胆碱激动剂。在高浓度（100微摩尔）的噻嘧啶作用下，观察到通道有一系列快速的开放和关闭，表明存在开放通道阻滞。先前的实验表明，驱虫药左旋咪唑在该制剂上也作为乙酰胆碱激动剂起作用，在高浓度时在超极化电位下诱导通道阻滞（罗伯逊，S.J.和R.J.马丁，1993年，《英国药理学杂志》108卷，170页）。对噻嘧啶、左旋咪唑和乙酰胆碱这3种激动剂在蛔虫肌肉烟碱样受体上的作用进行了比较，并讨论了这些化合物在治疗应用中的意义。
