Frequency- and Voltage-Dependent Effects of Aprindine on the Upstroke Velocity of Action Potential in Guinea Pig Ventricular Muscles

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Abstract
The effects of aprindine on transmembrane action potentials were examined in isolated papillary muscles of guinea pig. Aprindine (10-6-10-5M) caused a dose-dependent decrease in the .ovrhdot.Vmax of the action potential without affecting the resting potential. In the presence of aprindine, trains of stimuli at rates >0.1 Hz led to an exponential decline in .ovrhdot.Vmax. This use-dependent block was enhanced at the higher stimulation frequency. The time constant for the recovery of .ovrhdot.Vmax from the use-dependent block (offset) was 6.2-7.8 s. In depolarized papillary muscles with high [K+]o, the inhibitory action of aprindine on .ovrhdot.Vmax after a long quiescent period (tonic block) was augmented markedly, but the rates of onset and offset of the use-dependent block were similar to those in normally polarized preparations. The curves relating membrane potential and .ovrhdot.Vmax were shifted by 7.3 mV with aprindine at 3 .times. 10-6 M in the direction of more negative potentials. These findings suggest that aprindine has quinidinelike use-dependent inhibitory action on the fast sodium channels of cardiac muscles. This use-dependency and its greater inhibition of .ovrhdot.Vmax in depolarized muscles through the augmentation of tonic block may play a major role for the drug action to prevent ventricular arrhythmias.