Potassium Channel Openers Antagonize the Effects of Class III Antiarrhythmic Agents in Canine Purkinje Fiber Action Potentials. Implications for Prevention of Proarrhythmia Induced by Class III Agents.

We studied the effects of potassium channel openers (PCOs) on frequency dependent prolongations of action potential duration (APD), triggered activities and oscillatory action potentials (OSC) induced by E-4031 and dofetilide. The action potentials of canine Purkinje fibers were recorded by a glass microelectrode technique. The effects of E-4031 (10(-6)M) as well as that of additional nicorandil (2 x 10(-5) M) on the APD were examined. When abnormal automaticity was observed under perfusion of E-4031 (10(-5) M) or dofetilide (10(-5) M), action potentials were recorded continuously to estimate the sequential effects of additional perfusion of nicorandil (6 x 10(-5) M) or Y-26763 (10(-5) M) on triggered activities and OSC. APD prolongation by E-4031 at slower stimulation rates (cycle lengths > or = 1,000 msec) was suppressed by nicorandil in a dose dependent manner. Both nicorandil and Y-26763 abolished the train of early afterdepolarization (EAD) due to E-4031 or dofetilide with a shifting of the resting membrane potential to a more negative level. PCOs also normalized dofetilide induced abnormal automaticities (EAD, OSC). The antagonistic actions of PCOs on changes in action potential induced by class III antiarrhythmic agents may prevent the development of proarrhythmias produced by these agents.