The IK1-Kir2.1 channel agonist zacopride prevents and cures acute ischemic arrhythmias in the ratReport as inadecuate

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Arrhythmogenesis in acute myocardial infarction MI is associated with depolarization of resting membraine potential RMP and decrease of inward rectifier potassium current IK1 in cardiomyocytes. However, clinical anti-arrhythmic agents that primarily act on RMP by enhancing the IK1 channel are not currently available. We hypothesized that zacopride, a selective and moderate agonist of the IK1-Kir2.1 channels, prevents and cures acute ischemic arrhythmias. To test this viewpoint, adult Sprague-Dawley SD rats were subjected to MI by ligating the left main coronary artery. The antiarrhythmic effects of zacopride i.v. infusion were observed in the settings of pre-treatment zacopride given 3 min prior to coronary occlusion, post-treatment zacopride given 3 min after coronary occlusion and therapeutic treatment zacopride given 30 s after the onset of the first sustained ventricular tachycardia VT-ventricular fibrillation VF post MI. In all the three treatment modes, zacopride 15 μg-kg inhibited MI-induced ventricular tachyarrhythmias, as shown by significant decreases in the premature ventricular contraction PVC and the duration and incidence of VT or VF. In Langendorff perfused rat hearts, the antiarrhythmic effect of 1 μmol-L zacopride were reversed by 1 μmol-L BaCl2, a blocker of IK1 channel. Patch clamp results in freshly isolated rat ventricular myocytes indicated that zacopride activated the IK1 channel and thereby reversed hypoxia-induced RMP depolarization and action potential duration APD prolongation. In addition, zacopride 1 μmol-L suppressed hypoxia- or isoproterenol- induced delayed afterdepolarizations DADs. In Kir2.x transfected Chinese hamster ovary CHO cells, zacopride activated the Kir2.1 homomeric channel but not the Kir2.2 or Kir2.3 channels. These results support our hypothesis that moderately enhancing IK1-Kir2.1 currents as by zacopride rescues ischemia- and hypoxia- induced RMP depolarization, and thereby prevents and cures acute ischemic arrhythmias. This study brings a new viewpoint to antiarrhythmic theories and provides a promising target for the treatment of acute ischemic arrhythmias.

Author: Xu-Wen Zhai, Li Zhang, Yun-Fei Guo, Ying Yang, Dong-Ming Wang, Yan Zhang, Pan Li, Yi-Fan Niu, Qi-Long Feng, Bo-Wei Wu, Ji-Min Cao



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