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

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(+/DeltaKPQ), mutations in their sodium channel alpha-subunits. 2. The following properties were accordingly compared in wild-type and Scn3b(-/-) hearts modelling modifications in the beta-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, DeltaAPD, 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 DeltaAPD, in contrast to their differing effects in Scn5a(+/-) and Scn5a(+/DeltaKPQ) hearts.