特异性抑制Ik1具有抗心律失常作用.docVIP

特异性抑制Ik1具有抗心律失常作用 　［摘要］ 目的 探讨特异性抑制内向整流性钾电流(Ik1)是否具有抗心律失常的作用。方法 采用特异性抑制心脏Ik1转基因小鼠，改良的Langendorff小鼠心脏灌注系统同步记录心电图、单向动作电位(MAP)及复极离散度。并采用房室结机械消融及氟烷诱发心律失常。结果 转基因组小鼠房室结消融前后室性早搏的发生率明显低于对照组，且其诱发室速(VT)的氟烷阈值浓度显著高于对照组。其发生机制可能与转基因组MAP时间及复极离散度较对照组低有关。结论 Ik1在心律失常的发生中起着重要作用，特异性抑制Ik1可能为未来抗心律失常的有效策略之一。 ［关键词］ 内向整流性钾电流；小鼠；心律失常 Antiarrhythmic effects of specific inhibition of Ik1 in mouse heart ［Abstract］ Objective To gain further insights into the role of specific inhibition of IK1 in arrhythmogenesis.Methods Using transgenic mice expressing dominant negative Kir2.1-AAA subunits in the heart(TG)and wild-type control mice(WT)，we studied the response of specific inhibition of IK1 to atrial-ventricular node ablation and halothane challenges in Langendorff-perfused heart models.Isolated heart ECG and monophasic action potentials were measured.The number of premature ventricular contractions(PVCs)and ventricular tachycardia(VT) were calculated during the 5 minutes period after above challenges.Results In isolated hearts，the threshold concentration for halothane-induced VT was～1.7 fold higher in the TG than in the WT type hearts.The number of PVCs induced by AV node ablation was reduced in TG hearts and increased in WT mice.Analysis of monophasic action potentials in isolated hearts shows a significant reduction in the dispersion of action potential repolarization in mice with suppressed IK1.Conclusion The data strongly support the hypothesis that IK1 plays a significant role in the generation of cardiac arrhythmias，and that IK1 blockade in cardiac myocytes may be a potentially useful antiarrhythmic strategy. ［Key words］ specific inhibition IK1;mouse;arrhythmia 临床上心肌病及各种原因所致的心衰均伴随着内向整流性钾电流(Ik1)的下调［1］。由于目前缺乏特异性的Ik1抑制剂，对其下调是否具有有益的抗心律失常作用则仍存在争议。理论上讲，抑制IK1会降低静息膜电位的稳定性，促进除极化，使自律性增加，而具有导致心律失常的作用［2］。但是抑制IK1可均一地延长动作电位时间和不应期，降低心室复极离散度而防止折返的形成，延缓异常兴奋的传播，又具有抗心律失常的作用［3］。本研究采用转基因特异性抑制Ik1小鼠，使用Langendorff离体心脏模型，以房室结机械消融和氟烷诱导心律失常，并检测了单向动作电位时间和复极离散度，为探讨上述争议提供了有力的依据。 1 对象与方法 1.1 特异性抑制心脏Ik1转基