Abstract 4627: Specifically Enhancing Inward Rectifying Potassium Current (iK1) : A New Antiarrhythmic Strategy
Background: The inward rectifier K+ current (IK1) plays a significant role in the final repolarization and resting phases of the ventricular action potential. Modulation of IK1 would likely have a profound effect on cardiac excitability and arrhythmogenesis. However, there has been no IK1-specific pharmacologic agent found so far. We identified zacopride, a benzamide derivatives acting on 5-HT4 receptor, as a specific agonist of IK1 and effective antiarrhythmic drug.
Methods and results: Part I. The whole-cell patch-clamp technique was used to record effect of zacopride on membrain ionic current IK1, ICa-L, INa, Ito, INa/Ca, Ipump, and action potential (AP). We found that zacopride in 0.1~10μmol/L had no effects on ICa-L, INa, Ito, INa/Ca, Ipump, but enhanced IK1 concentration-dependently. The optimal concentration appeared in 1~3μmol/L with approximately 30% increase which can be abolished by low concentration of BaCl2 (1 μmol/L), or 10μmol/L 5-HT4-receptor antagonist RS23597. Otherwise, zacopride could increase resting membrane potential from −81.3±0.9 up to −87.5±1.7mv (P < 0.01) with APD90 slightly shorten. Part II. Langendorff-perfused hearts were subjected to either coronary artery occlusion for 30 minutes, or 15 minutes followed by 15minutes reperfusion. We monitored and compared the rhythm disturbances in experimental vs. placebo-treated hearts (n = 16 in each group). Zacopride in 1μmol/L was supplied 3 minutes before ischemia or reperfusion treatment. Far more dramatic protection was observed during ischemia. Zacopride treatment reduced the incidence of ventricular tachycardia from 100% to 25% (P<0.01) and ventricular fibrillation from 75% to 12.5% (P < 0.01), the number of premature ventricular beats from 173±26 to 9±4 (P< 0.05). Less protection was observed during reperfusion. The incidence of ventricular tachycardia and ventricular fibrillation declined from 100% to 68.8% (P<0.05) and from 75% to 25% (P < 0.05) respectively. The number of premature ventricular beats decreased but without statistical significance. Conclusion: Zacopride in 0.1~10μmol/L specifically enhanced IK1. It would be used as the first specific IK1 agonist and showed a significant antiarrhythmic effect during acute myocardial ischemia and reperfusion.