Jope R S, Johnson G V
Mol Pharmacol. 1986 Jan;29(1):45-51.
The effects of 2-(4-phenylpiperidino)cyclohexanol (AH5183) and quinacrine, two potent inhibitors of acetylcholine transport into vesicles isolated from Torpedo electric organ, were examined on acetylcholine metabolism in rat cortical slices. K+-stimulated acetylcholine release was reduced in a concentration-dependent manner by AH5183 and quinacrine, with IC50 values of 1 microM and 50 microM, respectively. Both drugs also reduced the synthesis of acetylcholine in slices and inhibited synaptosomal high affinity choline transport. The inhibitory effect of AH5183 appears to be directed primarily on the release of acetylcholine while the major effect of quinacrine is on the synthesis of acetylcholine. Examination of the subcellular distribution of acetylcholine in brain slices incubated in high K+ showed that AH5183 increased S3 (cytoplasmic) acetylcholine levels but did not alter P3 (vesicular) acetylcholine levels. P3 acetylcholine levels were reduced by AH5183 in a low K+ media while the S3 acetylcholine levels were the same as controls. These results are consistent with the concept that there is a small, active, highly labile fraction of vesicles that are the source of the released acetylcholine and that the loading of these vesicles is blocked by AH5183.
研究了2-(4-苯基哌啶基)环己醇(AH5183)和奎纳克林这两种从电鳐电器官分离出的乙酰胆碱转运到囊泡中的强效抑制剂对大鼠皮层切片中乙酰胆碱代谢的影响。AH5183和奎纳克林以浓度依赖性方式降低了K⁺刺激的乙酰胆碱释放，IC50值分别为1微摩尔和50微摩尔。两种药物还降低了切片中乙酰胆碱的合成，并抑制了突触体高亲和力胆碱转运。AH5183的抑制作用似乎主要针对乙酰胆碱的释放，而奎纳克林的主要作用是对乙酰胆碱的合成。对在高K⁺中孵育的脑切片中乙酰胆碱的亚细胞分布进行检查发现，AH5183增加了S3(细胞质)乙酰胆碱水平，但未改变P3(囊泡)乙酰胆碱水平。在低K⁺培养基中，AH5183降低了P3乙酰胆碱水平，而S3乙酰胆碱水平与对照相同。这些结果与以下概念一致，即存在一小部分活跃的、高度不稳定的囊泡，它们是释放的乙酰胆碱的来源，并且这些囊泡的装载被AH5183阻断。
