The effects of (S)-nafenodone, a new antidepressant, on transmembrane action potentials were studied in guinea-pig papillary muscles. In muscles driven at 0.02 and 1 Hz, (S)-nafenodone, 10(-6) mol/l and 10(-5) mol/l, produced a concentration-dependent decrease in the maximum upstroke velocity of the action potential, but it had no effect of the resting membrane potential. In the presence of 10(-5) mol/l (S)-nafenodone, trains of stimuli at rates between 0.5 and 2 Hz led to an exponential decline in maximum upstroke velocity to a new steady-state level [K = 0.152 +/- 0.03 (action potential)-1 at 2 Hz]. This frequency-dependent maximum upstroke velocity block increased at higher stimulation frequencies and at higher drug concentrations. (S)-Nafenodone also prolonged the time constant of recovery of maximum upstroke velocity from the frequency-dependent block to 2.3 +/- 0.6 s, this value being independent of the drug concentration. These values of onset and offset kinetics of (S)-nafenodone lie between those of drugs with fast and intermediate kinetic properties. (S)-nafenodone also shifted the curve relating membrane potential and maximum upstroke velocity in hyperpolarizing direction. All these results indicated that (S)-nafenodone produced a frequency- and voltage-dependent inhibition of the fast sodium channels similar to that exhibited with imipramine.