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

• Published in: American journal of physiology. Heart and circulatory physiology 2020-08, Vol.319 (2), p.H251-H261
• Main Authors: Shi, Yu Patrick, Pang, ZhaoKai, Venkateshappa, Ravichandra, Gunawan, Marvin, Kemp, Jacob, Truong, Elson, Chang, Cherlene, Lin, Eric, Shafaattalab, Sanam, Faizi, Shoaib, Rayani, Kaveh, Tibbits, Glen F, Claydon, Victoria E, Claydon, Thomas W
• Format: Article
• Language: English
• Subjects: Action potential; Arrhythmia; Cardiac arrhythmia; Chemical compounds; Danio rerio; Deactivation; HERG protein; Inactivation; Kinetics; Long QT syndrome; Pharmacology; Potassium channels (voltage-gated); Prolongation; Refractory period; Restoration; Thermal resistance; Triangulation; Ventricle; Zebrafish
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00038.2020

Human ether-à-go-go related gene (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 overcorrection leading to short QT syndrome. Enhanced risk by overcorrection 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 investigated the antiarrhythmic capability of a hERG activator, RPR260243, which primarily augments channel function by slowing deactivation kinetics in ex vivo zebrafish whole hearts. We show that 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 the refractory period. 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.