P703The small conductance Ca2+-activated K+-channel inhibition tool compound AP14145 protected the guinea pig heart from ventricular arrhythmia during hypokalemia whereas dofetilide was pro-arrhythmic

Background Hypokalemia is commonly encountered in the clinic. Hypokalemia reduces the cardiac repolarization reserve and causes increases in intracellular calcium. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that can be further exacerbated by concomitant administration of classical class 3 anti-arrhythmic agents. Small conductance Ca2+-activated K+-channels (SK-channels) are a promising new atrial selective target for treatment of atrial fibrillation (AF). Under physiological conditions SK channels play an insignificant role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in intracellur calcium. Purpose To study the effects of SK channel inhibition with the tool compound AP14145 or ICA under hypokalemic conditions as compared to the class 3 anti-arrhythmic agent dofetilide and time matched controls (TMC). Methods Guinea pig hearts were isolated and retrogradely perfused with normokalemic (4.5 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 for 20 min, followed by 20 min perfusion with normokalemic solution in presence of drug. A total of 24 animals were included in the study and randomly assigned to 4 groups: ICA, AP14145, dofetilide or TMC. QT-interval, ventricular effective refractory period, extra systoles and incidence of ventricular tachycardia (VT) or fibrillation (VF) were recorded for each perfusion period. Results Hypokalemia caused a small increase in QT-interval. Application of SK channel inhibitors did not cause further changes, whereas dofetilide prolonged QT compared to hypokalemia alone. During hypokalemia 3 out of 6 hearts in the TMC group developed VF (one spontaneously, two following S1S2 stimulation) whereas 4 out of 6 hearts developed VF in the dofetilide group (one spontaneously, three following S1S2 stimulation). In comparison only 1 heart out of 6 developed VF when treated with the SK channel inhibitor ICA (spontaneously) or AP14145 (following S1S2 stimulation). Conclusion Hypokalemia was associated with an increased risk of VF, an effect that was exaggerated by co-administration of dofetilide. In comparison, the structurally and functionally different SK channel inhibitors, ICA and AP14145, protected the heart from hypokalemia induced VF. These results with the tool compound AP14145 support that SK inhibition may be associated with a better safety and tolerability profile than dofetilide. Acknowledgement/Funding Innovation Fund Denmark