A Carvedilol Analogue, VKII-86, Prevents Hypokalaemia- induced Ventricular Arrhythmia through Novel multi-Channel Effects.

Background and Purpose: QT prolongation and intracellular Ca ²⁺ loading with diastolic Ca ²⁺ 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 Ca ²⁺ 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 Ca ²⁺ overload.