OBJECTIVE We sought to determine the electrophysiologic mechanisms explaining the efficacy of combination therapy with DL-sotalol and a type Ia drug in the treatment of ventricular tachycardia (VT). BACKGROUND Combination antiarrhythmic drug therapy with low dose DL-sotalol plus a type Ia antiarrhythmic agent has been shown to prevent spontaneous and induced VT. The mechanisms underlying the efficacy of this drug combination have not been fully elucidated. METHODS We studied 32 patients with spontaneous sustained VT by using programmed electrical stimulation in the drug-free condition and after treatment with DL-sotalol (average dose [mean +/- SE] 151 +/- 8 mg/day) and a class Ia agent (quinidine, 1,337 +/- 59 mg/day, or procainamide, 2,083 +/- 327 mg/day). Sustained VT was induced in all patients at baseline study, and induction was reattempted during drug therapy. Monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (ERP) were recorded with use of a contact electrode. RESULTS Ventricular ERP increased from 258 +/- 4 ms at baseline to 310 +/- 6 ms at a 600-ms drive cycle length (DCL600) with treatment (p < 0.001). APD90 increased from 288 +/- 6 ms by +10.1% at DCL600 and from 267 +/- 7 ms by +13.3% at a 400-ms drive cycle length (DCL400) (p < 0.001). Paced QRS duration increased from 141 +/- 3 to 158 +/- 6 ms at DCL400 (p < 0.05). At baseline, the shortest achieved coupling interval between successive propagated extrastimuli decreased progressively with respect to the first extrastimulus, following double and triple extrastimuli, at both DCL600 (-14.0% and -20.0%, respectively) and at DCL400 (-16.4% and -22.4%, respectively). This "peeling back" of refractoriness was attenuated on therapy with sotalol plus a class Ia antiarrhythmic agent to -6.7% and -10.5% (DCL600, p < 0.05), and -8.1%, -9.5% (DCL400, p < 0.05), for double and triple extrastimuli, respectively. The absolute prolongation of functional refractory periods by the drug combination increased with successive extrastimuli, from 55 +/- 6 ms for the V1V2 interval to 75 +/- 6 ms for V2V3 and 67 +/- 6 ms for V3V4 at DCL600, and from 51 +/- 5 ms for V1V2 to 69 +/- 6 ms for V2V3 and 74 +/- 7 ms for V3V4 at DCL400 (p < 0.001). CONCLUSIONS The combination of low dose sotalol and a class Ia agent greatly prolongs refractoriness. The magnitude of the effect increases at shorter coupling intervals.