Frequency- and orientation-dependent effects of mexiletine and quinidine on conduction in the intact dog heart

• Published in: Circulation (New York, N.Y.) N.Y.), 1987-05, Vol.75 (5), p.1065-1073
• Main Authors: BAJAJ, A. K, KOPELMAN, H. A, WIKSKO, J. P. JR, CASSIDY, F, WOOSLEY, R. L, RODEN, D. M
• Format: Article
• Language: English
• Subjects: Animals; Antiarythmic agents; Biological and medical sciences; Cardiac Pacing, Artificial; Cardiovascular system; Dogs; Drug Combinations; Electrocardiography; Heart Conduction System - drug effects; Ion Channels - drug effects; Medical sciences; Mexiletine - pharmacology; Myocardial Contraction - drug effects; Pharmacology. Drug treatments; Quinidine - pharmacology; Sodium - metabolism
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.75.5.1065

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 frequency- and 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.