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-degrees-C. Disopyramide (40-mu-M) 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-mu-M) to the solution containing disopyramide (40-mu-M) 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-mu-M) 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.