1. The effects of diprafenone and propafenone on transmembrane action potential were examined and compared in papillary muscles and single ventricular myocytes isolated from guinea-pig hearts. 2. In papillary muscles, both diprafenone and propafenone > or = 10(-6) M caused a significant and dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential. 3. In the presence of either drug, trains of stimuli at rates > or = 0.1 Hz led to an exponential decline in Vmax. A time constant (tau R) for Vmax recovery from the use-dependent block was 15.5 s for diprafenone and 8.8 s for propafenone. 4. The use-dependent block of Vmax with diprafenone was enhanced when the resting potential was depolarized by high (8, 10 mM) [K+]o, whereas that with propafenone was virtually unchanged. tau R with diprafenone was shortened by the depolarization, while that with propafenone was rather prolonged. 5. In single myocytes perfused with diprafenone or propafenone, 10 ms conditioning clamp to 0 mV caused a significant decrease in Vmax of subsequent action potential. A prolongation of the clamp pulse duration resulted in a modest enhancement of the Vmax inhibition with diprafenone, while a large enhancement of the Vmax inhibition occurred with propafenone. 6. These findings suggest that diprafenone, like propafenone, may block the sodium channel during both the activated and inactivated states. The relative contribution of inactivation block is less important for diprafenone than for propafenone. The different voltage-dependence of use-dependent block with diprafenone from propafenone would contribute to its high antiarrhythmic potency.