Laboratory Investigation Electrophysiology

Myocardial conduction depends on the magnitude of the fast inward sodium current as well as on cardiac fiber orientation, with more rapid propagation along myocardial fibers than across them. Although antiarrhythmic drugs depress the sodium current in a frequency-dependent fashion in vitro, their effects on conduction in the intact ventricle have been less well studied. We therefore evaluated the frequencyand orientation-dependent actions of mexiletine, quinidine, and their combination on epicardial conduction in 24 pentobarbital-anesthetized dogs. These interventions were chosen because the time constant of recovery from sodium-channel blockade by mexiletine in vitro is shorter than that from blockade by quinidine, and because we have previously shown that the combination of these drugs is often clinically effective when single-agent therapy fails. An electrode array that permitted measurement of conduction times in multiple orientations over short segments of epicardium without contamination by rapid Purkinje fiber propagation or by latency or virtual cathode effects at the stimulus site was developed for these studies. In all animals, the atrioventricular node was destroyed by injection of formalin to permit measurements over a wide range of cycle lengths (250 to 1500 msec). In the absence of drugs, conduction in any direction was frequency independent. In the presence of mexiletine, however, frequency-dependent increases in conduction times were found at cycle lengths of 600 msec or less; these changes were significantly greater in orientations for which baseline conduction was rapid. Quinidine, on the other hand, increased conduction times at all tested cycle lengths without significant orientation-dependent effects. The combination, like quinidine, increased conduction times at all cycle lengths in both orientations, but like mexiletine, increased conduction times further with very rapid pacing. The time constant for recovery from frequency-dependent conduction depression by mexiletine was 223 ± 23 msec, while even with pauses of up to 4000 msec, recovery from frequency-dependent conduction depression by quinidine was incomplete indicating, as in vitro, a longer time constant. In the presence of both drugs, fitting to biexponential functions indicated that the time course of recovery was made up of a faster mexiletine component and a slower quinidine one. These data indicate that conduction depression by antiarrhythmic agents in the intact canine ventricle is a function of stimulation frequency, with a correspondence between effects in vitro on fast sodium current and effects in vivo on conduction. Moreover, the direction dependence of these effects indicates that depression of rapid conduction (i.e., that along myocardial fibers) may be more susceptible to sodium-channel blockers than is conduction across fibers. Circulation 75, No. 5, 1065-1073, 1987. From the Departments of Medicine, Pharmacology, and Physics, Vanderbilt University School, Nashville. Supported in part by grants from the United States Public Health Service (GM31304 and HL36724), a grant-in-aid from the American Heart Association, and a contract from the Office of Naval Research (N00014-82-K-0107). Dr. Roden was a recipient of the Clinician-Scientist Award of the American Heart Association during the conduct of this work. Address for correspondence: Dan M. Roden, M.D., Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232. Received June 16, 1986; revision accepted Jan. 16, 1987. *Current address: Philadelphia Heart Institute, 39th and Market Sts., Philadelphia, PA 19104. A PRIMARY effect in vitro of many antiarrhythmic agents is blockade of the fast inward sodium current. ' While this action has long been recognized in vitro to be a function of stimulation rate,5 it has been more difficult to study in vivo. In theory, conduction velocity is one suitable variable for studies in vivo since it is a function of the magnitude of the sodium current, at least in a one-dimensional cable.6 Studies in vitro by Buchanan et al.7 in a one-dimensional test system (guinea pig papillary muscle) confirmed the predicted Vol. 75, No. 5, May 1987 1065 by gest on July 6, 2017 http://ciajournals.org/ D ow nladed from