The effects of propafenone alone, mexiletine alone, and their combination at the sodium channel level were studied in isolated guinea pig papillary muscles. The maximum upstroke velocity (Vmax) was used as an indirect index of the magnitude of the sodium inward current. In muscles driven at 0.02 Hz, neither mexiletine (10(-5) M) nor propafenone (5 X 10(-6) M) had any effect on action potential characteristics, but their combination decreased Vmax. In the presence of mexiletine and propafenone, trains of stimuli at 1 Hz led to a use-dependent block (onset rate 0.11 +/- 0.008 and 0.19 +/- 0.02 per action potential, respectively). The combination of mexiletine plus propafenone increased the onset rate of the use-dependent Vmax block (0.32 +/- 0.04 per action potential), but did not modify the time-constant of recovery of Vmax block or the magnitude of the slow component of reactivation induced by propafenone. Moreover, the combination of both drugs was more effective in suppressing early test stimuli than either drug alone. We conclude that the combination of mexiletine and propafenone is a synergistic one that affects only the onset kinetics of use-dependent Vmax block without detracting from the characteristics of the propafenone.