A carvedilol analogue, VK-II-86, prevents hypokalaemia-induced ventricular arrhythmia through novel multi-channel effects

Abstract

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 (I_K1 ), late sodium current (I_{Na_L} ) and the L-type Ca²⁺ current (I_Ca ). Effects of VK-II-86 on I_Kr 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 I_K1 and I_Kr , and increased I_Na-L , and I_Ca . 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.

Keywords: animal models of human disease; arrhythmias; basic science research; electrophysiology; pharmacology.