The hERG channel activator, RPR260243, enhances protective IKr current in early refractory reducing arrhythmogenicity in zebrafish hearts.

hERG K+ channels are important in cardiac repolarization and their dysfunction causes prolongation of the ventricular action potential, Long QT Syndrome, and arrhythmia. As such, approaches to augment hERG channel function, such as activator compounds, have been of significant interest due to their marked therapeutic potential. Activator compounds that hinder channel inactivation abbreviate action potential duration (APD), but carry risk of over-correction leading to Short QT Syndrome. Enhanced risk by over-correction of the APD may be tempered by activator-induced increased refractoriness, however investigation of the cumulative effect of hERG activator compounds on the balance of these effects in whole organ systems is lacking. Here, we have investigate the antiarrhythmic capability of a hERG activator, RPR260243, which augments channel function by slowing deactivation kinetics, in ex vivo zebrafish whole hearts. We show that 30 mM RPR260243 abbreviates the ventricular APD, reduces triangulation, and steepens the slope of the electrical restitution curve. In addition, RPR260243 increases the post-repolarization refractory period. We provide evidence that this latter effect arises from RPR260243-induced enhancement of hERG channel protective currents flowing early in refractory. Finally, the cumulative effect of RPR260243 on arrhythmogenicity in whole organ zebrafish hearts is demonstrated by the restoration of normal rhythm in hearts presenting dofetilide-induced arrhythmia. These findings in a whole organ model demonstrate the antiarrhythmic benefit of hERG activator compounds that modify both APD and refractoriness. Furthermore, our results demonstrate that targeted slowing of hERG channel deactivation and enhancement of protective currents may provide an effective antiarrhythmic approach.