BACKGROUND AND OBJECTIVES: The action potential duration (APD) restitution kinetics has been known to play a crucial role in the initiation and maintenance of ventricular tachycardia (VT)/fibrillation (VF). We hypothesized that "the anti-arrhythmic and proarrhythmic effects of d,l-sotalol are mediated by changing the APD restitution (APDR) kinetics". MATERIALS AND METHODS: The purposes of this study were: 1) to assess the effects of d,l-sotalol on the APDR kinetics, and 2) to correlate the anti-arrhythmic and proarrhythmic action using the APDR kinetics. We recorded the transmembrane potentials (TMPs), using the microelectrode technique, in seven isolated perfused swine right ventricles, at the baseline, and with 1, 5, 10 and 20 mg/L of d,l-sotalol, with a washout period of 1 hour. The ventricular effective refractory periods (VERP), APD at 90% repolarization (APD90), spontaneous defibrillation rate and VF inducibility were measured at each concentration. We plotted APDR curves of S1-S2 pacing against VF, and calculated the maximal slopes (Smax) of the APDR. RESULTS: Sotalol (10 mg/L) prolonged the APD90 (p<0.001) by reducing the Smax of the APDR (by S1-S2 pacing, p<0.01; during VF, p<0.05). Accordingly, 41.7% of the VT/VF was terminated spontaneously, and VT/VF inducibility reduced from 91.1% at the baseline to 25% with 10 mg/L sotalol. A higher dose of sotalol (20 mg/L) increased the Smax, despite continuous prolongation of the VERP and APD90, resulting in the increase in the VT/VF inducibility (36.4%). CONCLUSION: Sotalol produces its anti-fibrillatory effect by APD prolongation in parallel with a flattening of the Smax at therapeutic doses. However, a higher concentration of sotalol increased the Smax and VF inducibility in isolated swine ventricular tissue.