Cardiac Small Conductance Calcium-Activated K Channels Maintain Repolarization Reserve in a Pharmacological Model of Type 3 Long QT Syndrome

Abstract

Drug-induced long QT syndrome (diLQT) is a major public health problem. Whether small conductance calcium-activated K (SK) channels are involved in modulating cardiac repolarization reserve in diLQT is unclear. To examine their role in diLQT, we determined the effects of SK current inhibition on optically measured action potential duration at 80% repolarization (APD80) in isolated perfused, immobilized (10 microM ±-blebbistatin) mouse hearts, in which ventricular repolarization was prolonged by the late Na current (INa-L) activator ATX-II (15 nM). ATX-II at this concentration had no significant effect on the activity of cardiac SK channels expressed in HEK293 cells, but significantly (P 0.05). Vehicles for ATX-II and apamin did not significantly alter APD80 (n = 3; P>0.05). Identical results were obtained in isolated perfused rabbit hearts (n = 2), indicating that apamin effects on APD80 were not species-specific. In conclusion, these findings suggest that SK currents are acutely upregulated in a pharmacological model of type 3 LQT syndrome. Increased SK channel activity may serve as an endogenous rescue mechanism protecting normal and diseased ventricles from arrhythmias associated with reduced repolarization reserve. Apamin caused further prolongation of the APD80. Therefore, SK channel blockade removes this rescue mechanism, unmasking diLQT.