The purpose of the study is to determine the mechanisms of cycle length-dependent changes of action potential duration in Purkinje and ventricular cardiac fibers. We propose a scheme whereby the duration of each action potential is determined by the combined actions of two processes, i.e restitution and memory of the maximum action potential duration obtained after a long period of rest. In vitro experiments to be carried in dog fibers using intracellular microelectrode techniques are designed to establish in a quantitative manner the time- and cycle length-dependent and the pharmacological characteristics of these two processes. As the initial step toward identification of the physiological basis of memory, we will study its kinetics of development and dissipation after varying durations of drive at different cycle lengths. We will test the hypothesis that the process of restitution is influenced by the kinetics of recovery of a Na plateau current, related to the Na inward current, and postulate that pharmacologic agents may influence the restitution by delaying the recovery of Vmax. This hypothesis will be tested using Class I antiarrhythmic drugs selected for their ability to induce time-dependent recovery of the rapid Na inward current. In a comparative study of the behavior of Purkinje and ventricular fibers we will focus on a non-monotonic component of restitution that is specific to ventricular fibers. Since the duration of action potential is an important determinant of dispersion of repolarization, antiarrhythmic drugs may be expected to involve changes in dispersion of repolarization by virtue of their combined effects on the following factors: refractoriness, basic action potential duration, kinetics of restitution, and duration of the earliest prematures action potential. We propose to study the effects of antiarrhythmic drugs on these four factors. The increased knowledge of the behavior and mechanisms of cycle-length dependent changes of action potential duration and of the effects of antiarrhythmic drugs will contribute to better understanding of the mechanism of dispersion of repolarization and thus the mechanism of reentrant arrhythmias.
| Elharrar, V (1988) Recovery from use-dependent block of Vmax and restitution of action potential duration in canine cardiac Purkinje fibers. J Pharmacol Exp Ther 246:235-42 |
