Modulation of the Electrophysiologic Actions of E-4031 and Dofetilide by Hyperkalemia and Acidosis in Rabbit Ventricular Myocytes

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Abstract
Background: E-4031 and dofetilide are new class III antiarrhythmic agents that inhibit the rapid component of the delayed rectifier potassium channel (IKr); however, the effectiveness of many antiarrhythmic drugs in ischemic conditions is uncertain. Methods and Results: We modeled two components of ischemia, hyperkalemia (9.6 mM) and acidosis (pH 6.8), in voltage-clamped single rabbit ventricular myocytes to help deter mine the effect of ischemia on the action of these two drugs. In physiologic solution both E- 4031 and dofetilide blocked IKr and significantly reduced total outward current. In hyper kalemic solution, both E-4031 and dofetilide showed significantly reduced blockade of IKr, while in acidotic solution dofetilide showed significantly reduced blockade of IKr and E-4031 showed a trend to reduced blockade. Neither drug significantly reduced total outward current in hyperkalemic or acidotic solutions. Conclusions: In these conditions, E-4031 and dofetilide demonstrate reduced blockade of I Kr, resulting in loss of class III effect. Furthermore, the complete loss of blocking effect on total outward current during simulated ischemia suggests increases of other repolarizing cur rents also contribute to loss of class III effect.

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