Zacopride enhances inward rectifier potassium current (IK1) to antagonize arrhythmias |
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Authors: | LIU Qing-hua WU Bo-wei ZHANG Yang LIN Yuan-yuan |
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Institution: | 1.Department of Pathophysiology, 2Department of Physiology, 3Co-constructing Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China. E-mail: Liuqh20041206@163.com |
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Abstract: | AIM: To investigate the effects of zacopride on aconitine or BaCl2-induced arrhythmias and involved ionic mechanisms. METHODS: The whole-cell patch-clamp technique was used to record the inward rectifier K+ current (IK1), Ca+ current (ICa-L), Na+ current (INa), transient outward K+ current (Ito), the resting membrane potential (RMP) and action potential (AP) in the single cell of rat ventricular myocardium. Two arrhythmic models were elicited by injection of 30 μg/kg aconitine or 4 mg/kg BaCl2 intravenously. Zacopride at dose of 15 μg/kg was administered immediately after the development of first sinus rhythm disorders to observe its effects on arrhythmias. The ECGs were recorded simultaneously. RESULTS: In voltage clamp mode, 0.1-10.0 μmol/L zacopride dose-dependently enhanced IK1 with no significant effects on ICa-L, INa and Ito (P>0.05). Zacopride at concentration of 1.0 μmol/L showed the most potent activity on IK1 with approximately 30% increment both in inward current and outward current (P<0.01). Correspondingly, 0.1-10.0 μmol/L zacopride hyperpolarized RMP and shortened the action potential duration (APD) in a concentration-dependent manner (P<0.01). Furthermore, 1.0 μmol/L zacopride abolished aconitine-induced delayed afterdepolarization (DAD) and triggered activity (TA). In vivo, zacopride (15 μg/kg) significantly shortened the duration of arrhythmias elicited by aconitine [from (57.58±3.21) min to (38.25±2.59) min] or BaCl2 [from (49.31±2.46) min to (30.94±1.73) min]. CONCLUSION: As an agonist of IK1, zacopride enhanced IK1, hyperpolarized RMP and shortened APD, which may be the fundamental mechanisms underlying its antiarrhythmic effect. Enhancing IK1 might be a new antiarrhythmic strategy. |
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