Effects of mexiletine on delayed after-depolarization and triggered activity

Abstract

The effects of mexiletine on delayed afterdepolarization (DAD) and triggered activity (TA) were studied in the rabbit ventricular muscle using standard microelectrode techniques. First, three kinds of perfusate (modified Tyrode's solution, K(+)-free solution, and 1 mM K+ + 5.4 mM Ca2+ solution) were used to see whether DAD and TA could be induced by rapid stimulations (cycle lengths of 1000, 600, and 300 ms with trains of 10 and 20 stimuli). The inducibility of DAD and TA in modified Tyrode's solution, in K(+)-free solution, and in low K+ + high Ca2+ solution was 0%, 8%, and 83%, respectively. The last value was significantly higher than the former values. DAD and TA were induced only by stimulation at the shortest cycle length of 300 ms, and the inducibility was significantly higher with trains of 20 than with those of 10 stimuli. When DAD and/or TA were induced, the effects of mexiletine (5 mg/l) were tested. Mexiletine totally suppressed DAD and TA in 94% of the preparations within 20 min after its addition. Abolition of DAD and TA was associated with a failure of the 1:1 response to the stimuli in 53% of the preparations. The drug tended to prolong the coupling interval of DAD and TA, and significantly reduced the DAD amplitude. Possible mechanisms of action are: (1) lowered intracellular Ca2+ concentration either via the blocking of the fast Na+ current or the reduction of the number of action potentials; and (2) a decrease in the transient inward current due to blockage of the Ca2+ current.