Effects of Mexiletine on Transmembrane Action Potentials as Affected by External Potassium Concentration and by Rate of Stimulation in Guinea‐pig Papillary Muscles

The effects of mexiletine and quinidine were compared on transmembrane potentials in guinea-pig papillary muscles, using conventional microelectrode techniques. 2. Mexiletine (23.1 mumol/l) decreased the maximum rate of rise of the action potential (Vmax) and increased the ratio of the effective refractory period to the action potential duration at 90% repolarization level (ERP/APD90); these effects were prominent with elevation of the external potassium concentration ([K]o) from 2.7 to 5.4, 8.1 and 10.0 mmol/l. 3. The percentage decrease in Vmax induced by 5 and 10 mumol/l of quinidine was approximately constant in 2.7, 5.4 and 10.0 mmol/l [K]o solutions. 4. The decrease in Vmax produced by mexiletine was progressively increased as the driving rate was raised from 0.25 to 5Hz. This rate-dependent change was pronounced when the concentration was raised from 23.1 to 46.2 and 92.4 mumol/l. 5. Mexiletine in concentrations of 23.1 and 92.4 mumol/l delayed the recovery of Vmax in a premature action potential to the level of Vmax in the conditioning action potentials at the driving rate of 0.25 Hz. 6. It appears that mexiletine exerts its anti-arrhythmic action by a selective depressant effect on depolarized cells (high [K]0) and cells with high frequency discharges, as is the case with lignocaine.