title: Efficacy and potency of class I antiarrhythmic drugs for suppression of Ca2+ waves in permeabilized myocytes lacking calsequestrin.
abstract: 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'.
authors.affiliation: Division of Clinical Pharmacology and Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Nashville, USA.
authors.forename: Eleonora Savio
authors.initials: ES
authors.lastname: Galimberti
authors.forename: Björn C
authors.initials: BC
authors.lastname: Knollmann
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002155:Calsequestrin / Q000172:deficiency* / Q000235:genetics; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004194:Disease; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D057054:Molecular Imaging; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011405:Propafenone / Q000494:pharmacology; D012503:Saponins / Q000494:pharmacology; D013237:Stereoisomerism; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000889:Anti-Arrhythmia Agents; D002155:Calsequestrin; D012503:Saponins; D011405:Propafenone; D005424:Flecainide; D002118:Calcium