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Voltage-Dependent Potassium Current Recording on H9c2 Cardiomyocytes via the Whole-Cell Patch-Clamp Technique
Published on: November 11, 2022
A carvedilol analogue, VK-II-86, prevents hypokalaemia-induced ventricular arrhythmia through novel multi-channel
Victoria M Robinson1,2, Izzeddin Alsalahat1, Sally Freeman1
1Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
Insights
VK-II-86 effectively prevents hypokalaemia-induced ventricular arrhythmias by normalizing calcium handling and repolarization. This RyR2 inhibitor shows promise for treating arrhythmias linked to delayed repolarization or calcium overload.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Pharmacology
Background:
- Hypokalaemia-induced ventricular arrhythmias are primarily driven by QT prolongation and intracellular calcium overload via ryanodine receptors (RyR2).
- Investigating novel antiarrhythmic agents targeting RyR2 is crucial for managing these dangerous cardiac events.
Purpose of the Study:
- To evaluate the antiarrhythmic efficacy of two RyR2 inhibitors, dantrolene and VK-II-86, in a hypokalaemia model.
- To elucidate the electrophysiological and ionic mechanisms underlying VK-II-86's antiarrhythmic effects.
Main Methods:
- Utilized Langendorff-perfused murine hearts to assess arrhythmia incidence under low potassium conditions with and without RyR2 inhibitors.
- Employed whole-cell patch clamping in cardiomyocytes and HEK-293 cells to analyze ion channel currents (IK1, INa_L, ICa, IKr) and action potential parameters.
- Quantified oxidative stress using a fluorogenic probe.
Main Results:
- Dantrolene reduced hypokalaemia-induced ventricular arrhythmias by 94%; VK-II-86 completely prevented them.
- VK-II-86 normalized hypokalaemia-induced action potential prolongation and depolarization without affecting normal conditions.
- VK-II-86 counteracted hypokalaemia-associated alterations in IK1, INa_L, ICa, IKr, and oxidative stress.
Conclusions:
- VK-II-86 effectively prevents hypokalaemia-induced arrhythmogenesis by restoring calcium homeostasis and repolarization reserve.
- VK-II-86 demonstrates significant potential as a therapeutic agent for hypokalaemia and other arrhythmias characterized by delayed repolarization or calcium overload.
Background And Purpose:
QT prolongation and intracellular Ca2+ loading with diastolic Ca2+ release via ryanodine receptors (RyR2) are the predominant mechanisms underlying hypokalaemia-induced ventricular arrhythmia. We investigated the antiarrhythmic actions of two RyR2 inhibitors: dantrolene and VK-II-86, a carvedilol analogue lacking antagonist activity at β-adrenoceptors, in hypokalaemia.
Experimental Approach:
Surface ECG and ventricular action potentials (APs) were recorded from whole-heart murine Langendorff preparations. Ventricular arrhythmia incidence was compared in hearts perfused with low [K+ ], and those pretreated with dantrolene or VK-II-86. Whole-cell patch clamping was used in murine and canine ventricular cardiomyocytes to study effects of dantrolene and VK-II-86 on AP parameters in low [K+ ] and effects of VK-II-86 on the inward rectifier current (IK1 ), late sodium current (INa_L ) and the L-type Ca2+ current (ICa ). Effects of VK-II-86 on IKr were investigated in transfected HEK-293 cells. A fluorogenic probe quantified the effects of VK-II-86 on oxidative stress in hypokalaemia.
Key Results:
Dantrolene reduced the incidence of ventricular arrhythmias induced by low [K+ ] in explanted murine hearts by 94%, whereas VK-II-86 prevented all arrhythmias. VK-II-86 prevented hypokalaemia-induced AP prolongation and depolarization but did not alter AP parameters in normokalaemia. Hypokalaemia was associated with decreased IK1 and IKr , and increased INa-L , and ICa . VK-II-86 prevented all hypokalaemia-induced changes in ion channel activity and oxidative stress.
Conclusions And Implications:
VK-II-86 prevents hypokalaemia-induced arrhythmogenesis by normalizing calcium homeostasis and repolarization reserve. VK-II-86 may provide an effective treatment in hypokalaemia and other arrhythmias caused by delayed repolarization or Ca2+ overload.
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