The effects of the combined use of class-I antiarrhythmic drugs on the resting potentials (RP), amplitude of action potential (AMP), and V max of the action potential were investigated in guinea-pig ventricular papillary muscles that were superfused with oxygenated Krebs-Ringer solution at 35°C. Disopyramide (40 μM) reduced V max to 68.6 ± 3.1% (mean ± SE, n=5) of the control with minimal changes in RP and AMP when preparations were stimulated at 1 Hz. The addition of mexiletine (20 μM) to the solution containing disopyramide (40 μM) caused a minimal reduction of V max (less than 5%) for the stimulation of 1 Hz, but a significant reduction of V max (13% p<0.05) when stimulation was increased to 2 Hz. This amount of the reduction is compatible with that obtained by mexiletine alone, suggesting a simple additive Na+ channel inhibition by this drug combination. This additive effect was also observed in the recovery process of V max from the use-dependent block induced by train stimuli at 1 Hz. Flecainide (5 μM) reduced V max to 58.6±13.3% (n=5). The addition of mexiletine to the superfusate with flecainide produced a further depression of 14±2.6% of V max , even at 1 Hz. This depression was larger than that produced by mexiletine, suggesting a synergistic action of the two drugs on the Na+ channel. Such information about the interaction of the class I drug combinations with the Na+ channel may be clinically important.