Kinetics of rate-dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo

Abstract

1. The effects of the class I antiarrhythmic agent, tocainide, on intraventricular conduction were assessed in guinea-pigs, anaesthetized with pentobarbitone sodium 60 mg kg-1, i.p. 2. After electrical ablation of the sinus node, heart rate was controlled by atrial pacing. His bundle electrograms were recorded by means of an epicardial bipolar electrode. 3. During continuous stimulation, comparison of HV intervals measured at a cycle length of 475 ms, with HV intervals measured at a cycle length of 250 ms yielded the following results: 25.26 +/- 0.64 ms versus 25.02 +/- 0.70 ms (NS), at baseline, 26.65 +/- 0.80 ms versus 29.88 +/- 1.13 ms (P < 0.001) after i.v. administration of 30 mg kg-1 tocainide, and 28.04 +/- 0.64 ms versus 36.24 +/- 1.31 ms (P < 0.001), after addition of 20 mg kg-1 tocainide. Thus, tocainide caused HV intervals to increase in a strictly rate-dependent fashion. 4. In order to characterize the rate-dependent class I activity of tocainide in terms of its binding kinetics to sodium channels, fractional sodium channel block was estimated from drug induced reductions of intraventricular conduction velocity (delta theta). On abruptly changing the drive cycle length from 500 ms to 250 ms, delta theta reached a new steady state with rate constants of 1.23 +/- 0.09 beat-1 and 1.28 +/- 0.09 beat-1, after administration of 30 mg kg-1 and addition of 20 mg kg-1 tocainide, respectively. At a basic drive cycle length of 250 ms delta theta recovered with time constants of 250.29 +/- 23.32 ms and 183.04 +/- 8.03 ms after administration of 30 mg kg-1 and addition of 20 mg kg-1 tocainide, respectively.5. The experimentally determined kinetic parameters were implemented into a mathematical model that assumes drug binding to sodium channels in terms of a periodical two-state process. Rate-dependent reductions in conduction velocity during continuous stimulation after administration of tocainide were closely approximated by steady state reductions in sodium channel availability as calculated on the basis of the aforementioned model.6. In agreement with previously published in vitro studies, our data, obtained in vivo, confirm the classification of tocainide as a class I antiarrhythmic agent with fast onset and offset kinetics. The kinetic parameters obtained in vivo can be used in order to predict steady state reductions in conduction velocity at a wide range of frequencies.