PROARRHYTHMIC EFFECTS OF DPI 201-106 ELICITED WITH PROGRAMMED ELECTRICAL-STIMULATION - A COMPARISON WITH SOTALOL

Among antiarrhythmic agents, those belonging to class III are consider ed most promising. Class III drugs act by prolonging the action potent ial duration (APD), which increases the effective refractory period (E RP). This effect can be achieved by several different cellular mechani sms. We hypothesized that among other variables the mechanism of actio n could be important for the propensity of class III agents to have pr oarrhythmic effects. We investigated the effects of sotalol (a potassi um channel blocker) and DPI 201-106 (DPI, an activator of sodium chann els) at doses causing the same increase in ERP, using programmed elect rical stimulation (PES) in open-chest rabbits. After baseline measurem ents, three cumulative doses of DPI (0.3, 1, and 3 mg/kg) or sotalol ( 0.1, 0.3, and 1 mg/kg) or vehicle (placebo) were infused. Before drug administration, PES elicited arrhythmias in 11 of 21 animals. These ar rhythmias remained unchanged in the placebo group and decreased dose d ependently with sotalol. DPI, however, increased the inducibility of a rrhythmias in all animals at the third dose. The two agents differed w ith respect to their effect on ERP2, measured with a second extrastimu lus. In contrast to ERP1, which was prolonged to the same extent by bo th drugs, ERP2 was prolonged more by sotalol than by DPI. Proarrhythmi c effects of sotalol could not be shown in this model. Our results sug gest that the cellular mechanism that causes the class III effect is a n important factor with respect to the occurrence of proarrhythmic act ivity.