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Effects of mexiletine on delayed after-depolarization and triggered activity
H Uchida1, E Ozawa, Y Watanabe
1Cardiovascular Institute, Fujita Health University School of Medicine, Aichi, Japan.
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.
Insights
Mexiletine effectively suppressed delayed afterdepolarizations (DAD) and triggered activity (TA) in rabbit heart muscle. This antiarrhythmic effect was observed in 94% of preparations, suggesting mexiletine
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Cardiac Electrophysiology
Background:
- Delayed afterdepolarizations (DAD) and triggered activity (TA) are implicated in cardiac arrhythmias.
- Induction of DAD and TA is dependent on specific ionic conditions and stimulation protocols.
Purpose of the Study:
- To investigate the antiarrhythmic effects of mexiletine on DAD and TA in rabbit ventricular muscle.
- To explore the underlying mechanisms of mexiletine's action.
Main Methods:
- Rabbit ventricular muscle preparations were subjected to rapid stimulations under various perfusate conditions (modified Tyrode's, K(+)-free, low K(+)/high Ca2+).
- Delayed afterdepolarizations (DAD) and triggered activity (TA) were induced using specific stimulation protocols (300 ms cycle length, trains of 10-20 stimuli).
- The effects of mexiletine (5 mg/l) on DAD and TA were assessed, along with changes in electrophysiological parameters.
Main Results:
- DAD and TA were most readily induced in low K(+) + high Ca2+ solution (83% inducibility).
- Mexiletine completely suppressed DAD and TA in 94% of preparations within 20 minutes.
- Mexiletine reduced DAD amplitude and prolonged coupling intervals, potentially by affecting intracellular calcium or ion currents.
Conclusions:
- Mexiletine demonstrates significant efficacy in suppressing DAD and TA, key triggers for cardiac arrhythmias.
- The drug's mechanism likely involves modulation of intracellular calcium handling and ion channel activity.
- These findings support mexiletine's potential as an antiarrhythmic agent for conditions associated with DAD and TA.