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Background: Life-threatening arrhythmias resulting from ischemia is important for risk stratification of patients and for the development of interventions to decrease mortality caused by coronary artery disease.However, antiarrhythmic drugs, with the exception of β-adrenergic receptor blocking drugs and amiodarone,are largely ineffective or even harmful.Arrhythmogenesis in acute myocardial ischemia is associated with the decrease of resting potential (RP) and inward rectifier potassium current (IK1).However, there are no clinical antiarrhythmic agents mainly acted on resting potential or IK1 up to date.Recently, we reported firstly a selective agonist of IK1, zacopride.With this pharmacological tool, we hypothesize that moderate enhancing IK1, accordingly enhancing or restoring resting potential may play important roles against ischemic arrhythmias.Methods: The antiarrhythmic effects of zacopride were tested in Langendorff-perfused rat hearts or anesthetized rats subjected to coronary artery ligation for 15 minutes.Further using the model of myocardial hypoxia (PO2<50 mmHg)induced by unmixed and saturated nitrogen, the effects of 1-10 μmol/L zacopride on IK1 and RP in hypoxic rat ventricular myocytes were observed by whole-cell patch-clamp technique.Finally, we subjected freshly isolated cardiomyocytes to 45-minute simulated ischemia (the solution containing cardiomyocytes were covered by mineral oil) to assessed the expression of IK1 in presence and absence of 1 μmol/L zacopride by Western blot analysis.Results: During ischemia, ventricular arrhythmias in Langendorff-perfused hearts were concentration-relatively attenuated by zacopride 3 minutes prior to occlusion.At the optimal dose of 1.0 μmol/L, zacopride reduced the incidence of ventricular tachycardia (VT) from 100% to 25% (P<0.01), the incidence of ventricular fibrillation from 75% to 12.5% (P<0.01), the duration of VT from 8.58m3.65 s to 2.69±2.24 s (P<0.01), the duration of VF from 23.51±15.77 s to 1.67±1.33 s (P<0.01), and the number of premature ventricular beats (PVB) from 173+26 to 9±4 (P<0.01).Based on patch clamp result that 1 μmol/L BaCl2 could abolish the IK1 increment induced by 1μmol/L zacopride, 1 μmol/L BaCl2 reversed significantly the antiarrhythmic effect of zacopride.Similar protection of zacopride were also observed in anesthetized rats underwent 15-minute occlusion of coronary artery.At the dose of 15 μg/kg, zacopride showed the most potent antiarrhythmic action which compared favourably with lidocaine (7.5 mg/kg), a classical antiarrhythmic agent.In hypoxic atmosphere, IK1 curerent and RP were decreased (P<0.01).Addition of 0.1-10 μmol/L zacopride dose-dependently enhanced IK1 current and hyperpolarized RP.The optimal dose was 1 μmol/L (P<0.01) which consisted with that of zacopride in normoxia condition.Western blot showed that the levels of IK1 were down-regulated after 45minute-simulated ischemia and could be reversed by 0.3-3 μmol/L zacopride (P<0.01).Conclusion: Agonizing IK1 by zacopride exibits significant effect against ischemic arrhythmias.It might bring a new idea to antiarrhythmic theories and imaging a development of new antiarrhythmic drugs, especially the ones against ischemic arrhythmias.