抗心律失常药物作用的新靶点M3R/IKM3

目的研究心脏M₃受体/M₃受体介导的钾通道与心律失常的关系，寻找抗心律失常药物的新靶点。方法 分别以结扎大鼠左冠状动脉前降支所致急性心律失常模型和膜片钳技术为基础，观察M₃受体的干预作用及作用机制。结果M₃受体阻断剂4DAMP(4-diphenylacetoxy-n-methylpiperidine-methiodide)加重结扎大鼠冠状动脉前降支所致心律失常，而M₃受体激动剂胆碱能明显对抗其作用。其他亚型受体阻断剂，M₁受体阻断剂(prienzepine)、M₂受体阻断剂(methotramine)和M₄受体阻断剂(tropicamide)对结扎大鼠左冠状动脉前降支所致急性心律失常无影响。在膜片钳实验中发现，胆碱可激活一种延迟整流钾电流(IK_M3)，此电流可被M₃受体阻断剂4DAMP明显抑制。而M₁，M₂和M₄受体阻断剂对胆碱介导的电流无作用。结论胆碱通过激动心肌M₃受体诱发一外向钾电流(IK_M3)，并在维持心脏离子通道平衡中起重要作用。M₃受体/IK_M3可能是抗心律失常新靶点。

M3-R/IKM3a new target of antiarrhythmic agents

AimTo investigate the relationship between M₃-R/IKM₃ and arrhythmia in order to find a new target for antiarrhythmic agents. MethodsUsing the acute ischemic model of rats and patch-clamp techniques, the effects of the M₃ receptor on the occurrence of arrhythmias and its possible mechanisms were studied. ResultsIn acute ischemic model of rats, the M₃ receptor antagonist 4-diphenylacetoxy-n-methylpiperidine-methiodide (4DAMP) increased the occurrence of arrhythmias, and the M₃ receptor agonist choline suppressed the onset and the development of arrhythmias (P<0.01). No change was observed after treatment with other receptor antagonists (M₁, M₂, and M₄). With patch-clamp techniques, it was found that choline induced K⁺ current could be inhibited by 4DAMP. Antagonists toward M₁, M₂,and M₄ receptors all failed to alter the current. ConclusionCholine modulates the cellular electrical properties of the heart, probably by activating a K⁺ current via stimulation of the M₃ receptor. M₃-R/IK_M3 may act as a new target for antiarrhythmic agents.