Proarrhythmic effects of DPI 201-106 elicited with programmed electrical stimulation: a comparison with sotalol.
Among antiarrhythmic agents, those belonging to class III are considered most promising. Class III drugs act by prolonging the action potential duration (APD), which increases the effective refractory period (ERP). This effect can be achieved by several different cellular mechanisms. We hypothesized that among other variables the mechanism of action could be important for the propensity of class III agents to have proarrhythmic effects. We investigated the effects of sotalol (a potassium channel blocker) and DPI 201-106 (DPI, an activator of sodium channels) at doses causing the same increase in ERP, using programmed electrical stimulation (PES) in open-chest rabbits. After baseline measurements, 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 arrhythmias remained unchanged in the placebo group and decreased dose dependently with sotalol. DPI, however, increased the inducibility of arrhythmias in all animals at the third dose. The two agents differed with respect to their effect on ERP2, measured with a second extrastimulus. In contrast to ERP1, which was prolonged to the same extent by both drugs, ERP2 was prolonged more by sotalol than by DPI. Proarrhythmic effects of sotalol could not be shown in this model. Our results suggest that the cellular mechanism that causes the class III effect is an important factor with respect to the occurrence of proarrhythmic activity.
Novosel
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Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Hof
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Zierhut
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Hof
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D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology*
D010879:Piperazines; C046261:DPI 201-106; D013015:Sotalol