Clinical experience suggests that sodium channel blockers are effective in converting atrial fibrillation of recent onset but not chronic atrial fibrillation. We investigated changes in the electrophysiologic effects of pilsicainide. a pure sodium channel blocker, on the canine atrium during chronic rapid pacing (400/min). Three pairs of bipolar electrodes were sutured to the right atrial appendage in six dogs. Five days later, rapid atrial pacing was started after baseline measurements of the effective refractory period (ERP), the intra-atrial conduction velocity, the atrial wavelength, and the inducibility of atrial fibrillation. These studies were repeated at 2, 7, and 14 days of pacing, both before and after pilsicainide administration. Before pacing, pilsicainide increased ERP more than it decreased conduction velocity, causing an increase of wavelength, particularly at faster rates. However, this use-dependent prolongation of ERP disappeared after 2 days of pacing. Thus, pilsicainide failed to prolong ERP during chronic pacing, allowing progressive shortening of wavelength in the remodeled atrium. The effect of sodium channel blockers on atrial refractoriness may decline as rapid atrial excitation persists, limiting the usefulness of these agents for the treatment of chronic atrial fibrillation.