Inhibition of K(Ca)2 Channels Decreased the Risk of Ventricular Arrhythmia in the Guinea Pig Heart During Induced Hypokalemia

BACKGROUND: Hypokalemia reduces the cardiac repolarization reserve. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that is exacerbated by administration of classical class 3 anti-arrhythmic agents. Small conductance Ca(2+)-activated K(+)-channels (K(Ca)2) are a promising new atrial selective target for treatment of atrial fibrillation. Under physiological conditions K(Ca)2 plays a minor role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in ventriculay -60r intracellur Ca(2+). PURPOSE: To study the effects of pharmacological K(Ca)2 channel inhibition by the compounds AP14145, ICA, or AP30663 under hypokalemic conditions as compared to dofetilide and hypokalemia alone time-matched controls (TMC). METHODS: The current at +10 mV was compared in HEK293 cells stably expressing K(Ca)2.3 perfused first with normo- and then hypokalemic solutions (4 mM K(+) and 2.5 mM K(+), respectively). Guinea pig hearts were isolated and perfused with normokalemic (4 mM K(+)) Krebs-Henseleit solution, followed by perfusion with drug or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K(+)) in presence of drug. 30 animals were randomly assigned to 5 groups: ICA, AP14145, AP30663, dofetilide, or TMC. QT-interval, the interval from the peak to the end of the T wave (Tp–Te), ventricular effective refractory period (VERP), arrhythmia score, and ventricular fibrillation (VF) incidence were recorded. RESULTS: Hypokalemia slightly increased K(Ca)2.3 current compared to normokalemia. Application of K(Ca)2 channel inhibitors and dofetilide prolonged the QT interval corrected for heart rate. Dofetilide, but none of the K(Ca)2 channel inhibitors increased Tp–Te during hypokalemia. During hypokalemia 4/6 hearts in the TMC group developed VF (two spontaneously, two by S1S2 stimulation) whereas 5/6 hearts developed VF in the dofetilide group (two spontaneously, three by S1S2 stimulation). In comparison, 0/6, 1/6, and 1/6 hearts developed VF when treated with the K(Ca)2 channel inhibitors AP30663, ICA, or AP14145, respectively. CONCLUSION: Hypokalemia was associated with an increased incidence of VF, an effect that also seen in the presence of dofetilide. In comparison, the structurally and functionally different K(Ca)2 channel inhibitors, ICA, AP14145, and AP30663 protected the heart from hypokalemia induced VF. These results support that K(Ca)2 inhibition may be associated with a better safety and tolerability profile than dofetilide.