The KCa2 Channel Inhibitor AP14145, But Not Dofetilide or Ondansetron, Provides Functional Atrial Selectivity in Guinea Pig Hearts

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 (I_Kr) is inhibited. The current mediated by K_Ca2-channels, I_KCa, is considered a promising new target for treatment of atrial fibrillation (AF). Selective inhibitors of I_Kr (dofetilide) and I_KCa (AP14145) were used to compare the effects on ventricular and atrial repolarization. Ondansetron, which has been reported to be a potent blocker of both I_Kr and I_KCa, was included to examine its potential atrial antiarrhythmic properties.

Experimental Approach: The expression of K_Ca2- and K_v11.1-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 I_KCa and/or I_Kr. 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 I_KCa, but did inhibit I_Krin vitro. Ondansetron prolonged ventricular, but not atrial repolarization ex vivo.

Conclusion and Implications: I_KCa inhibition by AP14145 selectively increases atrial repolarization, whereas I_Kr inhibition by dofetilide and ondansetron increases ventricular repolarization to a larger extent than atrial repolarization.