The KCa2 Channel Inhibitor AP14145, But Not Dofetilide or Ondansetron, Provides Functional Atrial Selectivity in Guinea Pig Hearts
Research output: Contribution to journal › Journal article › Research › peer-review
Jeppe Egedal Kirchhoff, Mark Skarsfeldt, Kalai Mangai Muthukumarasamy, Rafel Simó-Vicens, Sofia Hammami Bomholtz, Lea Abildgaard, Thomas Jespersen, Ulrik S Sørensen, Morten Grunnet, Bo Hjorth Bentzen, Jonas Goldin Diness
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.
|Journal||Frontiers in Pharmacology|
|Publication status||Published - 19 Jun 2019|
- The Faculty of Health and Medical Sciences - Arrhythmia, heart rhythm disorders, dofetilide, Ondansetron, AP14145, QT prolongation