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Ca(2+) waves can trigger ventricular arrhythmias such as catecholaminergic-polymorphic ventricular tachycardia (CPVT). Drugs that prevent Ca(2+) 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 Ca(2+) waves. Casq2-/- myocytes were imaged in line-scan mode and the following Ca(2+) wave parameters analyzed: wave incidence, amplitude, frequency, and propagation speed. IC(50) (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 (IC(50)<10 μM) and efficacy (>50% maximum wave inhibition). Category 2 drugs (encainide, quinidine, lidocaine, and verapamil) had intermediate potency (IC(50) 20-40 μM) and efficacy (20-40% maximum wave inhibition). Category 3 drugs (procainamide, disopyramide, mexiletine, cibenzoline, and ranolazine) had no significant effects on Ca(2+) waves at the highest concentration tested (100 μM). Propafenone was stereoselective, with R-propafenone suppressing waves more potently than S-propafenone (IC(50): R-propafenone 2 ± 0.2 μM vs. S-propafenone 54 ± 18 μM). Both flecainide and R-propafenone decreased Ca(2+) spark mass and converted propagated Ca(2+) 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 Ca(2+) waves with the highest potency and efficacy. Permeabilized casq2-/- myocytes are a simple in-vitro assay for finding drugs with activity against Ca(2+) waves. This article is part of a Special Issue entitled 'Possible Editorial'.
Copyright © 2011 Elsevier Ltd. All rights reserved.