TY - JOUR

T1 - Inhibition of KCa2 Channels Decreased the Risk of Ventricular Arrhythmia in the Guinea Pig Heart During Induced Hypokalemia

AU - Diness, Jonas Goldin

AU - Abildgaard, Lea

AU - Bomholtz, Sofia Hammami

AU - Skarsfeldt, Mark Alexander

AU - Edvardsson, Nils

AU - Sørensen, Ulrik S.

AU - Grunnet, Morten

AU - Bentzen, Bo Hjorth

PY - 2020

Y1 - 2020

N2 - 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 Ca2+-activated K+-channels (KCa2) are a promising new atrial selective target for treatment of atrial fibrillation. Under physiological conditions KCa2 plays a minor role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in ventriculay -60r intracellur Ca2+. Purpose: To study the effects of pharmacological KCa2 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 KCa2.3 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 KCa2.3 current compared to normokalemia. Application of KCa2 channel inhibitors and dofetilide prolonged the QT interval corrected for heart rate. Dofetilide, but none of the KCa2 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 KCa2 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 KCa2 channel inhibitors, ICA, AP14145, and AP30663 protected the heart from hypokalemia induced VF. These results support that KCa2 inhibition may be associated with a better safety and tolerability profile than dofetilide.

AB - 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 Ca2+-activated K+-channels (KCa2) are a promising new atrial selective target for treatment of atrial fibrillation. Under physiological conditions KCa2 plays a minor role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in ventriculay -60r intracellur Ca2+. Purpose: To study the effects of pharmacological KCa2 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 KCa2.3 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 KCa2.3 current compared to normokalemia. Application of KCa2 channel inhibitors and dofetilide prolonged the QT interval corrected for heart rate. Dofetilide, but none of the KCa2 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 KCa2 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 KCa2 channel inhibitors, ICA, AP14145, and AP30663 protected the heart from hypokalemia induced VF. These results support that KCa2 inhibition may be associated with a better safety and tolerability profile than dofetilide.

KW - antiarrhythmic drug

KW - arrhythmia

KW - dofetilide

KW - hypokalemia

KW - K2 channel inhibitor

KW - Kv11.1 blockers

KW - SK channel

KW - SK channel inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85085898228&partnerID=8YFLogxK

U2 - 10.3389/fphar.2020.00749

DO - 10.3389/fphar.2020.00749

M3 - Journal article

C2 - 32508659

AN - SCOPUS:85085898228

VL - 11

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

M1 - 749

ER -