1 The effects of mexiletine (Kö1173) were investigated in canine isolated cardiac Purkinje fibres and ventricular muscle with microelectrodes. Some Purkinje fibres were depolarized by mechanical stretch to induce spontaneous activity with slow upstroke velocity. The preparations were stimulated at rates of 1, 2, 3 and 4 Hz. The drug concentrations tested were 0.4, 2 and 10 μg/ml in Tyrode solution (KCl = 5.4 mM).

2 The `therapeutic' drug concentration (2 μg/ml) shortened action potential duration and effective refractory period of Purkinje fibres, the effect being pronounced at lower stimulation rates. In ventricular fibres, action potential duration changes were not consistent while the effective refractory period was prolonged.

3 In depolarized Purkinje fibres showing automatic activity, the drug (0.4 or 2 μg/ml) depressed phase 4 depolarization and reduced the firing rate without changing maximum diastolic potential. However, when depolarized Purkinje fibres were electrically driven at a constant rate, the maximum diastolic potential became more negative with a concomitant decrease of pacemaker slope and increase of maximum rate of rise (_max) of action potentials.

4 Moderate (2 μg/ml) to high (10 μg/ml) concentrations of the drug depressed _max in Purkinje fibres stimulated at 2 Hz by 12 and 42% respectively and depressed `membrane responsiveness'. The decrease in _max depended upon the stimulation rate, being minimum at the lowest (1 Hz) and maximum at the highest (4 Hz) stimulation rate.

5 The drug (2 μg/ml) improved _max of the earliest propagated premature action potentials by shifting the takeoff potential to more negative levels in both Purkinje and ventricular fibres.

6 Membrane conductance in fibres mounted in a single sucrose gap chamber was increased by the drug (2 μg/ml) in both fibre types in normal and in Na⁺-deficient solutions. This increase was attributed to an increase in membrane K⁺ permeability produced by the drug.

7 All these effects are similar to those of lignocaine, diphenylhydantoin or aprindine, and can explain the antiarrhythmic action of mexiletine.

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