We investigated the electrophysiological actions of dofetilide upon the ventricular myocardium to determine whether the drug modifies the inhibitory effects of subthreshold stimuli trains upon ventricular refractoriness. In nine Langendorff perfused rabbit hearts, ventricular epicardial electrodes were used to determine the following parameters at baseline and during dofetilide perfusion (0.5 micromolar): effective (ERP) and functional (FRP) refractory periods, conduction velocity (CV), wavelength (WL), and ERP prolongation (inhibitory effect) induced by subthreshold stimuli trains (STr) at pulse frequencies of 100, 300, and 600 Hz. Dofetilide significantly prolongs ventricular refractoriness and WL: ERP increment (Dofetilide-baseline, 300 ms cycle length) = 33 +/- 20 ms (24 +/- 12%, P < 0.01); FRP increment = 37 +/- 19 ms (23%+/- 10%, P < 0.01); WL increment = 4.1 +/- 3.2 cm (27%+/- 20%, P < 0.01), without modifying CV. These effects are diminished upon increasing the stimulation frequency: ERP increment (Dofetilide-baseline, 150 ms cycle length) = 18 +/- 10 ms (18%+/- 12%, P < 0.05); FRP increment = 15 +/- 4 ms (14%+/- 5%, P < 0.01); WL increment = 1.9 +/- 1.7 cm (18%+/- 10%, P < 0.01). The STr significantly prolong ERP, and the increments obtained at baseline and during dofetilide perfusion are similar. In both cases the inhibitory effect is slight for STr of 100 Hz (baseline = 5 +/- 3 ms, dofetilide = 6 +/- 5 ms, with nonsignificant (ns) differences between them) and highly manifest for STr of 300 Hz (baseline = 76 +/- 33 ms, dofetilide = 87 +/- 32 ms, ns) and 600 Hz (baseline = 109 +/- 39 ms, dofetilide = 89 +/- 34 ms, ns). Dofetilide prolongs ventricular refractoriness and WL, exerting a reverse-frequency dependent effect without modifying CV. The inhibitory effect of STr is greater when their pulse frequency is increased, and its magnitude is similar under the influence of dofetilide. During dofetilide perfusion the inhibitory effect of STr adds to the ERP prolongation induced by the drug.