Abstract
Background and Purpose: Prolongation of cardiac action potentials is considered antiarrhythmic in the atria but can be proarrhythmic in ventricles if the current carried by Kv11.1-channels (IKr) is inhibited. The current mediated by KCa2-channels, IKCa, is considered a promising new target for treatment of atrial fibrillation (AF). Selective inhibitors of IKr (dofetilide) and IKCa (AP14145) were used to compare the effects on ventricular and atrial repolarization. Ondansetron, which has been reported to be a potent blocker of both IKr and IKCa, was included to examine its potential atrial antiarrhythmic properties. Experimental Approach: The expression of KCa2- and Kv11.1-channels in the guinea pig heart was investigated using quantitative polymerase chain reaction (qPCR). Whole-cell patch clamp technique was used to investigate the effects of dofetilide, AP14145, and ondansetron on IKCa and/or IKr. The effect of dofetilide, AP14145, and ondansetron on atrial and ventricular repolarization was investigated in isolated hearts. A novel atrial paced in vivo guinea pig model was further validated using AP14145 and dofetilide. Key Results: AP14145 increased the atrial effective refractory period (AERP) without prolonging the QT interval with Bazett’s correction for heart rate (QTcB) both ex vivo and in vivo. In contrast, dofetilide increased QTcB and, to a lesser extent, AERP in isolated hearts and prolonged QTcB with no effects on AERP in the in vivo guinea pig model. Ondansetron did not inhibit IKCa, but did inhibit IKr in vitro. Ondansetron prolonged ventricular, but not atrial repolarization ex vivo. Conclusion and Implications: IKCa inhibition by AP14145 selectively increases atrial repolarization, whereas IKr inhibition by dofetilide and ondansetron increases ventricular repolarization to a larger extent than atrial repolarization.
Highlights
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia and is associated with reduced quality of life and increased mortality and morbidity (Heeringa et al, 2006; Piccini et al, 2012)
Effect of Ondansetron on KCa2 Channels Cells were dialyzed with 400 nM intracellular calcium and KCa2.2 channels activated until IKCa reached a steady state
We have previously shown that the IC50 of AP14145 on Kv11.1 was: 71.8 μM (Diness et al, 2017), and in this study we confirm that dofetilide, which is a known Kv11.1 blocker, has an IC50 = 0.03 μM (n = 14) while ondansetron blocks Kv11.1 with an IC50 = 2.79 ± 0.03 μM (n = 6, Figure 5)
Summary
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia and is associated with reduced quality of life and increased mortality and morbidity (Heeringa et al, 2006; Piccini et al, 2012). Class III antiarrhythmic compounds exert their effects by decreasing cardiac K+ currents leading to delayed repolarization and a concomitant increased effective refractory period. Prolonging the atrial effective refractory period (AERP) is antiarrhythmic, whereas drug induced prolongation of the ventricular repolarization that manifests as prolongation of the QT interval on a surface ECG is a risk marker for potentially lethal ventricular arrhythmias such as torsades de pointes for a wide range of drugs. Prolongation of cardiac action potentials is considered antiarrhythmic in the atria but can be proarrhythmic in ventricles if the current carried by Kv11.1-channels (IKr) is inhibited. Wholecell patch clamp technique was used to investigate the effects of dofetilide, AP14145, and ondansetron on IKCa and/or IKr. The effect of dofetilide, AP14145, and ondansetron on atrial and ventricular repolarization was investigated in isolated hearts. A novel atrial paced in vivo guinea pig model was further validated using AP14145 and dofetilide
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