The electromechanical effects of a new antidepressant, (S)-nafenodone, were studied in isolated guinea-pig atrial and ventricular muscle fibres. In spontaneously beating right atria, (S)-nafenodone decreased the rate and amplitude of contractions and lengthened the sinus node recovery time. In electrically driven atria, the negative inotropic effect of (S)-nafenodone was less marked than that of imipramine and desipramine but similar to that of lofepramine. (S)-Nafenodone had no effect on the resting membrane potential but decreased the amplitude and maximum upstroke velocity (Vmax) both in atrial and ventricular muscle fibres; this effect was less marked than that produced by imipramine and desipramine. In atrial fibres, but not in ventricular fibres, (S)-nafenodone lengthened the action potential duration, but in both tissues it increased the duration of the effective refractory period out of proportion to the change in action potential duration. Moreover, it shifted the concentration-response curve for Ca2+ downwards and decreased the amplitude of the slow atrial contractions induced by histamine as well as the amplitude and Vmax of the slow action potentials induced by isoprenaline in papillary muscles. It is concluded that (S)-nafenodone exerted fewer cardiodepressant effects than imipramine and desipramine in isolated guinea-pig atrial and ventricular muscle fibres less.