AUTHOR=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 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00668

DOI=10.3389/fphar.2019.00668

ISSN=1663-9812

ABSTRACT=<p><bold>Background and Purpose:</bold> 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<sub>Kr</sub>) is inhibited. The current mediated by K<sub>Ca</sub>2-channels, I<sub>KCa</sub>, is considered a promising new target for treatment of atrial fibrillation (AF). Selective inhibitors of I<sub>Kr</sub> (dofetilide) and I<sub>KCa</sub> (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<sub>Kr</sub> and I<sub>KCa</sub>, was included to examine its potential atrial antiarrhythmic properties.</p><p><bold>Experimental Approach:</bold> The expression of K<sub>Ca</sub>2- and K<sub>v</sub>11.1-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<sub>KCa</sub> and/or I<sub>Kr</sub>. The effect of dofetilide, AP14145, and ondansetron on atrial and ventricular repolarization was investigated in isolated hearts. A novel atrial paced <italic>in vivo</italic> guinea pig model was further validated using AP14145 and dofetilide.</p><p><bold>Key Results:</bold> AP14145 increased the atrial effective refractory period (AERP) without prolonging the QT interval with Bazett’s correction for heart rate (QTcB) both <italic>ex vivo</italic> and <italic>in vivo</italic>. In contrast, dofetilide increased QTcB and, to a lesser extent, AERP in isolated hearts and prolonged QTcB with no effects on AERP in the <italic>in vivo</italic> guinea pig model. Ondansetron did not inhibit I<sub>KCa</sub>, but did inhibit I<sub>Kr</sub><italic>in vitro</italic>. Ondansetron prolonged ventricular, but not atrial repolarization <italic>ex vivo</italic>.</p><p><bold>Conclusion and Implications:</bold> I<sub>KCa</sub> inhibition by AP14145 selectively increases atrial repolarization, whereas I<sub>Kr</sub> inhibition by dofetilide and ondansetron increases ventricular repolarization to a larger extent than atrial repolarization.</p>