Antiarrhythmic drugs and the cardiac sodium channel: current models.

Abstract

Abstract The major electrophysiological effect of Class I antiarrhythmic drugs is blockade of the cardiac sodium channel, thereby reducing the initial depolarization of the action potential and slowing impulse propagation. Despite the widespread use of these drugs our understanding of their mechanism of action is incomplete. Models based on electrophysiological studies predict that a receptor for Class I drugs is associated with the sodium channel, and that occupancy of this receptor causes blockade of the sodium channel. Recent radioligand studies with [3H]batrachotoxinin-A benzoate have identified a binding site for Class I drugs associated with rat cardiac myocyte sodium channels, which may be the predicted receptor. Binding of drugs to this site is saturable, reversible, stereospecific, and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. Drugs appear to bind preferentially to a closed state of the channel, thereby preventing channel opening and subsequent sodium influx.