Electrophysiological and antiarrhythmic actions of tocainide in isolated heart preparations of the guinea pig

Abstract

Comparison of the action of tocainide in guinea pig atrial and ventricular myocardium has led to the following results: 1. Tocainide effects a similar increase in threshold of alternating current induced arrhythmias in spontaneously beating right atria as well as stimulated left atria and papillary muscles. 2. APD30 and APD90 (action potential duration at 30 and 90% repolarization) are decreased by tocainide in papillary muscles, especially at a low stimulation rate, but increased in left atria. On the other hand, maximum upstroke velocity of the action potential (V̇(max)) is decreased at a high stimulation rate (use-dependence) in both tissues. These effects are completely reversed by washing with drug-free solution within 15 min in papillary muscles and 60 min in left atria. 3. Resting state block of Na-channels by tocainide occurs in left atria to a small degree (10-20%), but is negligible in ventricular myocardium. 4. Recovery of V̇(max) following stimulus-induced inactivation is delayed by tocainide in papillary muscles and left atria. 5. Functional refractory period is increased in left atria and in papillary muscles by tocainide. In the concentration range above 75 μol/l the concentration response curve reaches a plateau in papillary muscles but shows a further steep increase in left atria. 6. Quantitative analysis of the dynamic Na-channel blockade by tocainide in atrial myocardium using the modulated receptor hypothesis suggests that the drug shows a high affinity to activated and a low affinity to inactivated Na-channels. The time constant for the dissociation from the inactivated channel amounts to 1420 ms which is greater than that for lidocaine (280 ms) and more than one order of magnitude less than that of quinidine (16 s).