Kirchhoff Jeppe Egedal, Skarsfeldt Mark Alexander, Muthukumarasamy Kalai Mangai, Simó-Vicens Rafel, Bomholtz Sofia Hammami, Abildgaard Lea, Jespersen Thomas, Sørensen Ulrik S, Grunnet Morten, Bentzen Bo Hjorth, Diness Jonas Goldin
Acesion Pharma, Copenhagen, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Front Pharmacol. 2019 Jun 19;10:668. doi: 10.3389/fphar.2019.00668. eCollection 2019.
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) is inhibited. The current mediated by K2-channels, I, is considered a promising new target for treatment of atrial fibrillation (AF). Selective inhibitors of I (dofetilide) and I (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 and I, was included to examine its potential atrial antiarrhythmic properties. The expression of K2- and K11.1-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 and/or I. The effect of dofetilide, AP14145, and ondansetron on atrial and ventricular repolarization was investigated in isolated hearts. A novel atrial paced guinea pig model was further validated using AP14145 and dofetilide. AP14145 increased the atrial effective refractory period (AERP) without prolonging the QT interval with Bazett's correction for heart rate (QTcB) both and . In contrast, dofetilide increased QTcB and, to a lesser extent, AERP in isolated hearts and prolonged QTcB with no effects on AERP in the guinea pig model. Ondansetron did not inhibit I, but did inhibit I . Ondansetron prolonged ventricular, but not atrial repolarization . I inhibition by AP14145 selectively increases atrial repolarization, whereas I inhibition by dofetilide and ondansetron increases ventricular repolarization to a larger extent than atrial repolarization.
心脏动作电位的延长在心房中被认为具有抗心律失常作用，但如果Kv11.1通道（I）所携带的电流受到抑制，在心室中则可能促发心律失常。由K2通道介导的电流I被认为是治疗心房颤动（AF）的一个有前景的新靶点。使用I（多非利特）和I（AP14145）的选择性抑制剂来比较它们对心室和心房复极的影响。昂丹司琼据报道是I和I的强效阻滞剂，将其纳入以研究其潜在的心房抗心律失常特性。使用定量聚合酶链反应（qPCR）研究豚鼠心脏中K2和K11.1通道的表达。采用全细胞膜片钳技术研究多非利特、AP14145和昂丹司琼对I和/或I的影响。在离体心脏中研究多非利特、AP14145和昂丹司琼对心房和心室复极的影响。使用AP14145和多非利特进一步验证了一种新型心房起搏豚鼠模型。AP14145增加了心房有效不应期（AERP），且在和时均未通过Bazett心率校正（QTcB）延长QT间期。相比之下，多非利特在离体心脏中增加了QTcB，并在较小程度上增加了AERP，而在豚鼠模型中延长了QTcB但对AERP无影响。昂丹司琼不抑制I，但抑制I。昂丹司琼延长了心室复极，但未延长心房复极。AP14145对I的抑制选择性地增加了心房复极，而多非利特和昂丹司琼对I的抑制对心室复极的增加程度大于对心房复极的增加程度。
