肟类化合物对离子通道的阻断作用及体外梭曼中毒膈肌肌肉功能的恢复
Ion channel blockade by oximes and recovery of diaphragm muscle from soman poisoning in vitro.
作者信息
Tattersall J E
机构信息
Biology Division, Chemical and Biological Defence Establishment, Salisbury.
出版信息
Br J Pharmacol. 1993 Apr;108(4):1006-15. doi: 10.1111/j.1476-5381.1993.tb13498.x.
Abstract
- The actions of oximes and related compounds on the nicotinic acetylcholine receptor ion channel at the adult mouse muscle endplate were investigated by use of single-channel recording techniques. The aim of the study was to determine whether the channel-blocking properties of the compounds could contribute to their therapeutic effectiveness against soman poisoning in vitro. 2. Therapeutic effectiveness was assessed in guinea-pig phrenic nerve-hemidiaphragm preparations by measuring the degree of recovery of neuromuscular function produced by the compounds following poisoning by soman. A number of the compounds, including some which lacked the oxime group, produced a significant recovery of neuromuscular function which was unrelated to acetylcholinesterase (AChE) reactivation; this was reversed by washing off the compound, and was therefore attributed to a direct pharmacological action on the muscle. 3. Single channel recordings showed that some of the compounds blocked open nicotinic receptor ion channels in preparations of mouse muscle fibres. The compounds which showed the greatest direct pharmacological actions in diaphragms produce a very fast, flickering blockade of the channels. Several quantitative measures of channel-blocking activity correlated very well with the direct pharmacological action. Furthermore, for two compounds studied in greater detail, the direct action and channel-blocking showed similar concentration-response relationships. 4. The results of this study indicate that the direct pharmacological action of oximes and their analogues against neuromuscular blockade by soman in vitro is due to their channel-blocking activity. The direct action does not correlate well with protection against soman poisoning in vivo, however, which suggests that additional non-reactivating properties of these compounds, at sites other than the neuromuscular junction, may also be important for their therapeutic effectiveness.
摘要
- 运用单通道记录技术，研究了肟类及相关化合物对成年小鼠肌肉终板烟碱型乙酰胆碱受体离子通道的作用。本研究的目的是确定这些化合物的通道阻断特性是否有助于其体外抗梭曼中毒的治疗效果。2. 通过测量化合物在梭曼中毒后对豚鼠膈神经-半膈肌标本神经肌肉功能的恢复程度，评估其治疗效果。许多化合物，包括一些不含肟基团的化合物，都能使神经肌肉功能显著恢复，这与乙酰胆碱酯酶（AChE）的重新激活无关；冲洗掉化合物后这种恢复作用会逆转，因此归因于对肌肉的直接药理作用。3. 单通道记录显示，一些化合物能阻断小鼠肌肉纤维标本中开放的烟碱型受体离子通道。在膈肌中表现出最大直接药理作用的化合物对通道产生非常快速的、闪烁式的阻断。通道阻断活性的几个定量指标与直接药理作用高度相关。此外，对两种更详细研究的化合物而言，直接作用和通道阻断表现出相似的浓度-反应关系。4. 本研究结果表明，肟类及其类似物体外对梭曼所致神经肌肉阻滞的直接药理作用归因于其通道阻断活性。然而，这种直接作用与体内抗梭曼中毒的保护作用相关性不佳，这表明这些化合物在神经肌肉接头以外部位的其他非重新激活特性，可能对其治疗效果也很重要。
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