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

TY - JOUR

T1 - The KCa2 Channel Inhibitor AP14145, But Not Dofetilide or Ondansetron, Provides Functional Atrial Selectivity in Guinea Pig Hearts

AU - Kirchhoff, Jeppe Egedal

AU - Skarsfeldt, Mark

AU - Muthukumarasamy, Kalai Mangai

AU - Simó-Vicens, Rafel

AU - Bomholtz, Sofia Hammami

AU - Abildgaard, Lea

AU - Jespersen, Thomas

AU - Sørensen, Ulrik S

AU - Grunnet, Morten

AU - Bentzen, Bo Hjorth

AU - Diness, Jonas Goldin

PY - 2019/6/19

Y1 - 2019/6/19

N2 - 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.

AB - 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.

KW - Faculty of Health and Medical Sciences

KW - Arrhythmia

KW - heart rhythm disorders

KW - dofetilide

KW - Ondansetron

KW - AP14145

KW - QT prolongation

U2 - 10.3389/fphar.2019.00668

DO - 10.3389/fphar.2019.00668

M3 - Journal article

C2 - 31275147

SN - 1663-9812

VL - 10

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

M1 - 668

ER -