Ascher P, Large W A, Rang H P
J Physiol. 1979 Oct;295:139-70. doi: 10.1113/jphysiol.1979.sp012958.
The mode of action of ACh antagonists on the parasympathetic neurones of the submandibular ganglion of the rat was studied by means of a two-micro-electrode voltage-clamp technique. The currents produced by various agonists (carbachol, ACh, suberylcholine) were studied in steady state and after voltage steps, before and after perfusion of various antagonists. 2. For three antagonists (tubocurarine, hexamethonium, decamethonium) the blocking action increases with hyperpolarization. For three other antagonists (surugatoxin, trimetaphan, mecamylamine) the effects observed at low concentrations appear to be independent of membrane potential, although in some cases voltage dependence of the block was observed for mecamylamine. 3. The blocks the 'open' channel-reception complex. The block produced by tubocurarine, hexamethonium and decamethonium increases with the agonist concentration, an observation which supports a 'sequential' scheme in which the antagonist blocks the 'open' channel-receptor complex. The block produced by trimetaphan and mecamylamine decreases slightly with increased agonist concentration, which in turn suggests that these two compounds are competitive antagonists, preventing binding of the agonists to the closed channel-receptor complex. 4. In the cases where the block is voltage dependent, voltage jumps trigger slow relaxations which are not present in control conditions. In the case of tubocurarine and hexamethonium, the relaxation following a hyperpolarizing voltage jump corresponds to a decrease in conductance. In the case of decamethonium, the slow relaxation is in the opposite direction. 5. The slow relaxations observed with tubocurarine and hexamethonium are speeded by an increase of the antagonist concentration; the slow relaxations observed with decamethonium are slowed by an increase of the decamethonium concentration. 6. The steady-state observations and the relaxations can be interpreted in terms of a scheme in which tubocurarine, hexamethonium and decamethonium act mainly by blocking the channels opened by the cholinergic agonists. 7. The two types of slow relaxation are those predicted if tubocurarine and hexamethonium dissociate slowly from the channel, and decamethonium rapidly. 8. An additional effect of tubocurarine is described, which consists of a potentiation of the rising phase of the response to an ionophoretic pulse. Possible mechanisms of this effect are discussed.
采用双微电极电压钳技术研究了乙酰胆碱（ACh）拮抗剂对大鼠下颌下神经节副交感神经元的作用方式。在灌注各种拮抗剂前后，研究了各种激动剂（卡巴胆碱、ACh、辛二酰胆碱）在稳态及电压阶跃后产生的电流。2. 对于三种拮抗剂（筒箭毒碱、六甲铵、十甲铵），阻断作用随超极化增强。对于另外三种拮抗剂（蛤蚌毒素、阿方那特、美加明），低浓度时观察到的效应似乎与膜电位无关，尽管在某些情况下美加明的阻断存在电压依赖性。3. 阻断“开放”通道 - 受体复合物。筒箭毒碱、六甲铵和十甲铵产生的阻断作用随激动剂浓度增加，这一观察结果支持“顺序”模式，即拮抗剂阻断“开放”通道 - 受体复合物。阿方那特和美加明产生的阻断作用随激动剂浓度增加略有降低，这反过来表明这两种化合物是竞争性拮抗剂，阻止激动剂与关闭的通道 - 受体复合物结合。4. 在阻断具有电压依赖性的情况下，电压阶跃会引发对照条件下不存在的缓慢松弛。对于筒箭毒碱和六甲铵，超极化电压阶跃后的松弛对应于电导降低。对于十甲铵，缓慢松弛方向相反。5. 筒箭毒碱和六甲铵观察到的缓慢松弛随拮抗剂浓度增加而加快；十甲铵观察到的缓慢松弛随十甲铵浓度增加而减慢。6. 稳态观察结果和松弛现象可以用一种模式来解释，即筒箭毒碱、六甲铵和十甲铵主要通过阻断胆碱能激动剂打开的通道起作用。7. 两种缓慢松弛现象是如果筒箭毒碱和六甲铵从通道缓慢解离，而十甲铵快速解离时所预测的。8. 描述了筒箭毒碱的一种额外效应，即增强对离子电泳脉冲反应的上升相。讨论了这种效应的可能机制。
