ELECTROPHYSIOLOGICAL EFFECTS OF THE COMBINATION OF MEXILETINE AND FLECAINIDE IN GUINEA-PIG VENTRICULAR FIBERS

1 The effects of flecainide alone, mexiletine alone and their combination at the Na+ channel level were studied in guinea-pig papillary muscles. The maximum upstroke velocity (V(max)) was used as an indirect index of the magnitude of the fast inward Na+ current (I(Na)). 2 In muscles driven at 0.02 Hz, neither mexiletine (10(-5)M) nor flecainide (10(-6) M) nor the combination of both drugs modified the action potential characteristics. Mexiletine, but not flecainide, increased the effective refractory period/action potential duration ratio; this enhancement was greater when flecainide was also present. 3 Mexiletine or flecainide alone produced a frequency-dependent V(max) block. Although at 0.5 Hz the blockade induced by the combination of flecainide and mexiletine was similar to that produced by flecainide alone, in muscles driven at 1 and 2 Hz the combination increased the magnitude and the onset rate of the V(max) block. 4 The time constant of recovery of V(max) block was similar in the presence of flecainide or the combination mexiletine plus flecainide (tau-re = 16.4 +/- 2.3 s and 16.7 +/- 2.7 s, respectively), but the combination decreased the magnitude of the slow component of reactivation induced by flecainide (93.8 +/- 1.5% versus 68.9 +/- 1.7%). Moreover, the combination of both drugs was more effective in inhibiting the V(max) of early test stimuli than either drug alone. 5 It is concluded that the combination of mexiletine and flecainide is synergistic at driving rates faster than 0.5 Hz without detracting from the characteristics of flecainide.