Pharmacological IKs Activation Slows Cardiac Conduction and Exacerbates the Effect of INa Blockade

Abstract

Background: The Kv7.1 channel underlies the IKs current and plays a key role in cardiac repolarization. Loss of IKs function can lead to the type 1 long QT syndrome (LQT1). The Kv7.1 activator R-L3 has been suggested as a potential antiarrhythmic therapy in LQT1. Having previously demonstrated that other K+ currents can modulate cardiac conduction, we tested here the effects of pharmacological IKs activation on cardiac conduction and its dependence on the sodium current (INa).Methods and Results: Conduction velocity (CV) was quantified by optical mapping during LV or RV pacing. Under control conditions transverse CV (CVT) was significantly greater (15±1 %, p<0.05) in RV than LV with no difference in longitudinal CV (CVL) between ventricles. During partial blockade of INa (flecainide, 1 µM), RV CVT decreased by 36±5 % while LV CVT decreased by 24±5 %. These data demonstrate greater RV conduction dependence on sodium channel availability. Partial IKs blockade by R-L3 (10 µM) significantly decreased both CVT (by 15±4 % in RV & 8±2 % in LV) and CVL (by 11±2% in RV & 6±1 % in LV) relative to control. Further, R-L3 exacerbated the effects of INa blockade: 1 µM flecainide now decreased CVT by 45±3% and 28±4% in RV and LV respectively.Conclusion: Pharmacological IKs activation by R-L3 slows cardiac conduction and shifts the conduction velocity - INa relationship downward. These findings may have significant implications for the use of Kv7.1 activator as antiarrhythmic drugs.