Antiarrhythmic drug action. Blockade of the inward sodium current.

THE mechanisms of action of antiarrhythmic drugs were discussed in these reviews over a decade ago (Rosen and Hoffman, 1973). Since then, important new concepts of the blocking action of drugs have been proposed and tested experimentally. Several attempts at a quantitative voltage clamp analysis of the blocking action of antiarrhythmic drugs have been made. The mechanism of the blocking action of local anesthetics has been studied in nerves to the limit of current electrical techniques—that of gating currents (Cahalan, 1980; Yeh, 1982). The volume of data dictates that we restrict the studies covered. We shall focus on the mechanism of the blockade of the sodium current. We neglect discussion of many otherwise important studies which do not have this focus. Knowledge of the number, kinetics, and relative importance of the individual pacemaker currents is sufficiently incomplete as to limit a discussion on the drug action on the individual currents. Blockade of membrane sodium conductance (GNa) is probably a major mechanism of action of antiarrhythmic drugs. To obtain a quantitative analysis of the kinetic and steady state effects of drugs on the sodium conductance, it is necessary to measure the sodium current, INa, in a stable system with the temperature and extracellular milieu that may be obtained in both normal and diseased tissues in vivo. The strategies that have been exploited for the study of INa in heart muscle include: (1) indirect estimation from Vmax of action potentials, (2) direct measurement of macroscopic sodium currents in multicellular and isolated cell preparations under voltage clamp, and (3) direct recording of unitary sodium conductance using the extracellular patch clamp technique. All these techniques use measurement of electrical properties to assess the binding kinetics of drugs to their receptor site(s). The quantitative precision of these techniques may vary. However, it is important to establish their ability to produce qualitatively similar results.