Using standard microelectrode techniques, the authors compared the effects of 15 to 125 microM concentrations of mexiletine, 31 to 500 microM concentrations of sotalol and 15 to 125 microM of mexiletine combined with 125 microM sotalol, on the beat-to-beat maximum rate of depolarization of phase 0 of the action potential (Vmax) of porcine papillary muscles and Purkinje fibres stimulated by 30 beat trains at a frequency of 1 Hz. Sotalol alone had no effect on Vmax. Mexiletine caused both tonic and use-dependent depression of Vmax in papillary muscle. In the presence of sotalol, tonic Vmax depression was exaggerated, while use-dependent depression was attenuated. In Purkinje fibres, mexiletine exposure resulted in tonic Vmax depression, but no use-dependence could be demonstrated at this frequency. These results are best explained in the context of the modulated receptor hypothesis with the added consideration of two receptors--one within and one external to the sodium channel.