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

Victoria Robinson, Izzeddin Alsalahat, Sally Freeman, Charles Antzelevitch, Héctor Barajas-Martinez, Luigi Venetucci

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)2713-2732
Number of pages20
JournalBritish Journal of Pharmacology
Issue number11
Publication statusPublished - 5 May 2022


  • animal models of human disease
  • arrhythmias
  • basic science research
  • electrophysiology
  • pharmacology


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