Each year in the United States alone, 400,000 deaths are attributed to sudden cardiac death (33). Clinically (31) and experimentally (20,25,43), the predominant underlying etiology for sudden cardiac death or malignant ventricular arrhythmias appears to be ventricular reentry. Reentry can result in tachycardia-induced hemodynamic instability (syncope), or may degenerate into more serious ventricular flutter or fibrillation from which the patient usually requires cardioversion in order to be resuscitated. While all of the determinants of reentry are not fully understood, it is widely accepted that in many instances (e.g., ischemia) the combination of conduction slowing (19,20) and reduction of refractoriness (1) contributes to the development and sustaining of the arrhythmia (37). In the early part of this century, Mines (36) described reentrant circus movement in rings cut from isolated tortoise hearts. He concluded that, if the wave of excitation is slow enough and/or the duration of the wave (refractory period) short enough, the reentry will continue unless interfered with by some external stimulus. However, if the propagating wave is fast enough and/or the duration long enough, the excitation will extinguish itself and die out. Since that time, other investigators have described and mapped in more detail similar findings in mammalian hearts (6,8,17,44). Mines' initial description of reentry laid the theoretical groundwork for the development of antiarrhythmic agents. The reentrant circuit can be interrupted either by decreasing excitability or by increasing refractoriness. Class I antiarrhythmic agents decrease excitability by inhibiting sodium channel conductance (54) and, therefore, the conduction velocity. While theoretically efficacious, the use of these agents (specifically the class Ic agents, flecainide and encainide) has recently fallen out of favor due to the excessive proarrhythmia and death associated with their use (53). While the reasons for this are not entirely understood, excessive slowing of conduction has been implicated as a possible cause (52). Recently, the safety and use of other class I antiarrhythmics (quinidine and procainamide) have also been questioned (23). In 1953, Matsuda and co-workers (7) demonstrated that selective prolongation of the action potential duration by veratrum alkaloids could reduce the excitability of the dog heart. In 1968, Kaumann and Aramendia (32) demonstrated that the antiarrhythmic effects of sotalol were distinct from its beta-receptor blocking properties, and finally Strauss et al. (49) and Singh and Vaughan Williams (46) described the cellular electrophysiological properties of sotalol and amiodarone, respectively, concluding that the action potential duration-prolonging properties (class III) of these compounds formed the basis of their antiarrhythmic efficacy. Since that time, action potential-prolonging properties have been ascribed to other agents with antiarrhythmic activity including bretylium (57), DPI 201-106 (45), melperone (5), quinidine (14,30), procainamide, and N-acetylprocain amide (18). Sematilide differs from the above-mentioned drugs in that it was designed specifically as a class III antiarrhythmic having no other significant electrophysiological properties associated with it, such as sodium channel blockade. In this article, a brief review of the cellular electrophysiology, mechanism of action, antiarrhythmic efficacy, pharmacodynamics, and toxicology of sematilide in experimental animals and in human clinical trials will be discussed.
