Abstract

The use of the antiarrhythmic agents mexiletine and quinidine in combination can be clinically beneficial when single agent therapy is ineffective in ventricular tachyarrhythmias. We therefore compared the effects of mexiletine (10 microM), quinidine (10 microM) and a series of their combinations (total concentration 10 microM) in canine cardiac Purkinje fibers driven at a wide range of stimulation frequencies. All treatments depressed Vmax in tissues driven rapidly (cycle length 300 msec), but only with greater than or equal to 5 microM quinidine was Vmax depressed at longer cycle lengths. Moreover, the time constants for development of and recovery from frequency-dependent block were different: short (200-500 msec) for mexiletine, long (3-5 sec) for quinidine and intermediate or biexponential for the combination. Although both drugs depressed Vmax (albeit with different time dependencies), action potential duration at all cycle lengths from 300 to 8000 msec was shortened by mexiletine, lengthened by quinidine and largely unaltered by combinations. Fibers treated with quinidine in low Ko and driven at slow rates developed marked action potential prolongation and abnormal automaticity in the form of early afterdepolarizations; the addition of mexiletine was sufficient to reverse this effect. In summary, mexiletine and quinidine produced different and frequency-dependent effects on depolarization and repolarization. The effects of their combinations reflected these actions, with opposing actions on repolarization at any stimulation rate but additive frequency-dependent depression of Vmax. We conclude that the clinically beneficial effects of this combination may reflect additive frequency-dependent effects on cardiac sodium channels in the face of unaltered repolarization time.