Potassium channel activators differentially modulate the effect of sodium channel blockade on cardiac conduction

Aims: Diminished repolarization reserve contributes to the arrhythmogenic substrate in many disease states. Pharmacological activation of K + channels has been suggested as a potential antiarrhythmic therapy in such conditions. Having previously demonstrated that IK1 and IKr can modulate cardiac conduction, we tested here the effects of pharmacological IKATP and IKs activation on cardiac conduction and its dependence on the sodium current (INa). Methods and Results: Bath electrocardiograms (ECGs) recorded from Langendorff-perfused guinea pig ventricles revealed QRS prolongation during IKATP activation by pinacidil but not during IKs activation by R-L3 relative to control. In contrast, when INa was partially blocked by flecainide, R-L3 but not pinacidil prolonged the QRS relative to flecainide alone. Conduction velocity (h) was quantified by optical mapping during epicardial pacing. Both longitudinal (hL) and transverse (hT) h were reduced by pinacidil (by 10 ± 1a nd 9± 3%, respectively) and R-L3 (by 11 ± 2% and 15 ± 4%, respectively). Flecainide decreased hL by 33 ± 4% and hT by 36 ± 5%. Whereas pinacidil did not further slow h relative to flecainide alone, R-L3 decreased both hL and hT. Conclusion: Pharmacological activation of IKATP and IKs slows cardiac conduction; however, they demonstrate diverse effects on h dependence on INa blockade. These findings may have significant implications for the use of K + channel activators as antiarrhythmic drugs and for patients with Na + channel abnormalities or being treated with Na + channel blockers.