Efficacy and potency of class I antiarrhythmic drugs for suppression of Ca2+ waves in permeabilized myocytes lacking calsequestrin

Ca2+ waves can trigger ventricular arrhythmias such as catecholaminergic-polymorphic ventricular tachycardia (CPVT). Drugs that prevent Ca2+ waves may have antiarrhythmic properties. Here, we use permeabilized ventricular myocytes from a CPVT mouse model lacking calsequestrin (casq2) to screen all clinically available class I antiarrhythmic drugs and selected other antiarrhythmic agents for activity against Ca2+ waves. Casq2-/- myocytes were imaged in line-scan mode and the following Ca2+ wave parameters analyzed: wave incidence, amplitude, frequency, and propagation speed. IC50 (potency) and maximum inhibition (efficacy) were calculated for each drug. Drugs fell into 3 distinct categories. Category 1 drugs (flecainide and R-propafenone) suppressed wave parameters with the highest potency (IC50<10 mu M) and efficacy (>50% maximum wave inhibition). Category 2 drugs (encainide, quinidine, lidocaine, and verapamil) had intermediate potency (IC50 20-40 mu M) and efficacy (20-40% maximum wave inhibition). Category 3 drugs (procainamide, disopyramide, mexiletine, cibenzoline, and ranolazine) had no significant effects on Ca2+ waves at the highest concentration tested (100 mu M). Propafenone was stereoselective, with R-propafenone suppressing waves more potently than S-propafenone (IC50: R-propafenone 2 +/- 0.2 mu M vs. S-propafenone 54 +/- 18 mu M). Both flecainide and R-propafenone decreased Ca2+ spark mass and converted propagated Ca2+ waves into non-propagated wavelets and frequent sparks, suggesting that reduction in spark mass, not spark frequency, was responsible for wave suppression. Among all class I antiarrhythmic drugs, flecainide and R-propafenone inhibit Ca2+ waves with the highest potency and efficacy. Permeabilized casq2-/- myocytes are a simple in-vitro assay for finding drugs with activity against Ca2+ waves. This article is part of a Special Issue entitled 'Possible Editorial'. (C) 2011 Elsevier Ltd. All rights reserved.