Use- and concentration-dependent effects of flecainide in guinea pig right ventricular muscle

In clinical studies, flecainide, a class IC antiarrhythmic drug, exhibited antiarrhythmic properties against supraventricular arrhythmias but also showed proarrhythmic effects in ventricular arrhythmias. We studied the effects of flecainide on action potential (AP) maximum rate of increase (Vmax) in guinea-pig right ventricular muscle. The effects of flecainide were studied at 3 concentrations (10(-5), 5 x 10(-6), 10(-6) M) and five frequencies (0.5, 1, 1.5, 2, and 3 Hz). At these three concentrations, flecainide caused little and not significant tonic block. In contrast, flecainide caused a frequency-and dose-dependent reduction in Vmax (at 3 Hz, the time constant of Vmax decrease was 3.6 +/- 0.2 s for 10(-5) M, 3.8 +/- 0.2 s for 5 x 10(-6) M, and 7.1 +/- 1.3 s for 10(-6) M). At 3 Hz, the time constants measured as number of APs were 11 +/- 2 for flecainide 10(-5) M, 12 +/- 2 for 5 x 10(-6) M, and 22 +/- 2 for 10(-6) M, respectively. At 10(-6) M, spontaneous arrhythmias occurred at all frequencies studied. Assuming that changes in Vmax reflect changes in Na+ fast current amplitude, our results suggest that flecainide is an open Na channel blocker showing frequency- and dose-dependent effects in the range of 0.5-3 Hz.