Abstract 1. Conventional microelectrode techniques were used to study the effect of quinidine (10 μM), lidocaine (20 μM), and verapamil (3–10 μM) on action potential upstroke ( V + max) in frog skeletal muscle and dog Purkinje fiber. 2. The frequency-dependent nature of V + max depression induced by these drugs was similar in both preparations, however, quinidine was more potent in skeletal muscle while lidocaine was in Purkinje fibers. 3. In skeletal muscle tetrodotoxin (3 and 15 nM) and low concentrations of antiarrhythmic drugs proportionally reduced the maximum velocity of depolarization and repolarization ( V + max and V − max, respectively), whereas V − max was more depressed than V + max by high concentrations (50–200 μM) of antiarrhythmics. Decreases in the overshoot potential were proportional to the V + max block in the case of each drug. 4. These results indicate that therapeutically relevant concentrations of quinidine and lidocaine inhibit skeletal muscle Na + channels in a use-dependent manner similar to heart, while at higher concentrations the K + channels may also be blocked. Therapeutic implications of the results are discussed.