抗心律失常药物作用的新靶点--M3-R/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(IKM3 ),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 (IKM3 ),并在维持心脏离子通道平衡中起重要作用。M3受体 /IKM 可能是抗心律失常新靶点。

M3 -R/IKM3--a new target of antiarrhythmic agents

Aim To investigate the relationship between M_3-R/IK_M_3 and arrhythmia in order to find a new target for antiarrhythmic agents. Methods Using the acute ischemic model of rats and patch-clamp techniques, the effects of the M_3 receptor on the occurrence of arrhythmias and its possible mechanisms were studied. Results In acute ischemic model of rats, the M_3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine-methiodide (4DAMP) increased the occurrence of arrhythmias, and the M_3 receptor agonist choline suppressed the onset and the development of arrhythmias (P<0.01). No change was observed after treatment with other receptor antagonists (M_1, M_2, and M_4). With patch-clamp techniques, it was found that choline induced K current could be inhibited by 4DAMP. Antagonists toward M_1, M_2,_ and M_4 receptors all failed to alter the current. Conclusion Choline modulates the cellular electrical properties of the heart, probably by activating a K current via stimulation of the M_3 receptor. M_3-R/IK_M_3 may act as a new target for antiarrhythmic agents.