A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity.
A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity.
复制标题
进一步研究维沙考 (AH5183) 的神经肌肉作用及其对映体特异性。
DOI：
10.1111/j.1476-5381.1988.tb11460.x
复制
发表时间：
1988
影响因子：
7.3
通讯作者：
Marshall,IG
中科院分区：
文献类型：
--
作者：
Estrella,D;Green,KL;Prior,C;Dempster,J;Halliwell,RF;Jacobs,RS;Parsons,SM;Parsons,RL;Marshall,IG
1已研究了乙酰胆碱储存抑制剂vesamicol（2-（4-苯基哌啶子基）环己醇）及其两种光学异构体对大鼠和青蛙肌肉中神经肌肉传递以及青蛙神经中神经传导的影响。2外消旋vesamicol产生了抽搐张力的预阻断增强，这也发生在直接刺激的肌肉中。因此，这种效应至少部分是由于肌肉收缩性增加所致。3在阻断1 Hz引起的抽搐方面，（-）-维索霉素的效力比（+）-维索霉素强约20倍。这种程度的立体选择性是类似的，所测量的抑制乙酰胆碱摄取的孤立的突触囊泡。两种对映异构体在降低蛙神经中神经动作电位振幅方面同样弱。4对活性异构体（-）-vesamicol的进一步研究表明，与外消旋vesamicol一样，神经肌肉阻滞具有高度频率依赖性。胆碱或新斯的明不能逆转阻滞，但4-或3，4-氨基吡啶可部分逆转阻滞。5初步电生理研究表明，在快速刺激的蛙神经肌肉制备物中，vesamicol可降低微终板电位振幅。添加镧离子增加了微型终板电位的频率，并导致在振幅降低的电位中出现明显正常大小的电位。6结果显示药理学和生化观察结果之间的密切一致性，表明大鼠膈肌适合作为这种性质物质的试验模型。氨基吡啶类药物引起的维索霉素诱导的神经肌肉阻滞的可逆性程度出乎意料，这表明在存在极大增加释放的药物的情况下，能够释放一种乙酰胆碱池，而这种乙酰胆碱池在维索霉素阻断储存后通常不会释放。它也被认为是可能的，从细胞内记录研究的结果可以解释这些条款。
1The effects of vesamicol (2‐(4‐phenylpiperidino) cyclohexanol), an inhibitor of acetylcholine storage, and its two optical isomers have been studied on neuromuscular transmission in rat and frog muscle, and on nerve conduction in frog nerve.2Racemic vesamicol produced a pre‐block augmentation of twitch tension that also occurred in directly‐stimulated muscle. This effect is thus at least partially due to an increase in muscle contractility.3(—)‐Vesamicol was approximately 20 times more potent than (+)‐vesamicol in blocking twitches elicited at 1 Hz. This degree of stereoselectivity is similar to that measured for inhibition of acetylcholine uptake by isolated synaptic vesicles. Both enantiomers were equally weak in reducing nerve action potential amplitude in frog nerve.4Further studies with the active isomer, (—)‐vesamicol, showed that, like that produced by racemic vesamicol, the neuromuscular block was highly frequency‐dependent. The block was not reversed by choline or neostigmine, but was partially reversed by 4‐ or 3,4‐aminopyridine.5Preliminary electrophysiological studies showed that vesamicol reduced miniature endplate potential amplitude in rapidly‐stimulated frog nerve‐muscle preparations. Addition of lanthanum ions increased the frequency of miniature endplate potentials and led to the appearance of apparently normal‐sized potentials amongst those of reduced amplitude.6The results show the close agreement between pharmacological and biochemical observations indicating the suitability of the rat diaphragm as a test model for substances of this nature. The degree of reversibility of the vesamicol‐induced neuromuscular block by aminopyridines was unexpected, and it is suggested that in the presence of a drug which greatly increases release, a pool of acetylcholine is capable of being released which is not normally releasable after block of storage by vesamicol. It is also considered possible that the results from the intracellular recording studies may be explained in these terms.