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 (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.

Development and Validation of Nomogram for the Prediction of Malignant Ventricular Arrhythmia Including Circulating Inflammatory Cells in Patients with Acute ST-Segment Elevation Myocardial Infarction

“…Hypokalemia can cause abnormal membrane potential of myocardial cells, which makes patients prone to potentially fatal arrhythmia. [27][28][29][30] In the present study, STEMI patients with MVA had a higher Killip class (OR=5.034, P=0.005), higher CK-MB levels (OR=1.002, P=0.022), and lower serum potassium levels (OR=0.618, P=0.020) compared with those without MVA, which is consistent with previous studies.…”

Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms

“…It has been known for a while that dantrolene improved contractile function in patients with heart failure [ 161 ] and animal models of cardiomyopathy [ 31 , 162 , 163 , 164 , 165 ]. Accordingly, dantrolene reduced arrhythmias in patients [ 166 ] and different arrhythmia models [ 32 , 33 , 34 , 167 , 168 , 169 , 170 ]. Plenty of studies demonstrated that multisite RyR2 hyperphosphorylation plays a significant role in the pathogenesis of cardiac disease; however, it has long been a highly controversial area.…”

Increased susceptibility to ventricular arrhythmia at low–normal and moderately low levels of extracellular potassium in catecholaminergic polymorphic ventricular tachycardia

“…Action potentials and pseudo-ECGs were recorded simultaneously (methodology detailed previously). 2 Time to occurrence of the first spontaneous ventricular arrhythmia was compared between control and CPVT mice, at both concentrations of K 1 . The percentage of mice that developed ventricular arrhythmia was also compared between groups.…”