Effects of flecainide and quinidine on action potential and ventricular arrhythmogenic properties in Scn3b knockout mice

Summary 1. Flecainide and quinidine exert contrasting pro‐arrhythmic and anti‐arrhythmic effects in mouse hearts containing the loss‐of‐function, Scn5a+/−, and the gain‐of‐function, Scn5a+/ΔKPQ, mutations in their sodium channel α‐subunits. 2. The following properties were accordingly compared in wild‐type and Scn3b−/− hearts modelling modifications in the β‐subunit, before and after introduction of either agent: (i) ventricular arrhythmogenecity and effective refractory periods (VERP) in response to programmed electrical stimulation (PES); (ii) monophasic action potential waveforms recorded from the left ventricular epicardium and endocardium; (iii) action potential durations (APD) obtained from the monophasic action potentials; and (iv) critical intervals derived from the APD and VERP values. 3. Ventricular tachycardia was induced by PES in 11 out of 15 Scn3b−/− hearts and 0 out of 17 wild‐type hearts. This incidence was reduced to three out of eight Scn3b−/− hearts but increased to three out of eight wild‐type hearts with flecainide. 4. Arrhythmogenic incidence was reduced to two out of eight Scn3b−/− hearts and remained at 0 out of eight wild‐type hearts in the presence of quinidine. 5. Ventricular effective refractory periods were prolonged and endocardial and epicardial APD shortened, resulting in negative critical intervals in both Scn3b−/− and wild‐type hearts treated by either flecainide or quinidine. Nevertheless, endocardial APD remained consistently longer than epicardial APD, leaving similar, positive endocardial–epicardial, differences, ΔAPD, in treated and untreated Scn3b−/− and wild‐type hearts. 6. It is concluded that both flecainide and quinidine exert anti‐arrhythmogenic effects in Scn3b−/− hearts, doing so through modifying VERP rather than ΔAPD, in contrast to their differing effects in Scn5a+/− and Scn5a+/ΔKPQ hearts.