Drug development for treatment of cardiac arrhythmias: targeting the gap junctions

摘要

(12) is likely the most important mechanism for serious life-threatening arrhythmias. Traditionally, a major focus of antiarrhythmic drug development has been to explore the actions of drugs designed to block conduction in reentrant pathways(s). During the latter part of the 20th century, numerous new drugs were introduced clinically. Their major targets were and still are sarcolemmal ion channels (mainly Na+, Ca2+, and K+), reducing current flow to prolong refractoriness and to slow or block conduction (23). The overall experience with the lack of uniform efficacy of these antiarrhythmic drugs suggests that there is a missing factor that is important for successful pharmacological therapy of reentrant arrhythmias. Although the role of intercellular communication through gap junctions has long been known to be an important factor governing conduction properties (24), it was not considered as a major target for antiarrhythmic drug development during this time. It was not until the important studies of Spach et al. (32, 33) beginning in the 1980s on anisotropic propagation that the significance of intercellular coupling as a cause of reentry rose to a level of prominence. Therefore, it became logical to test the concept that drugs acting on gap junctions might have antiarrhythmic actions (35). Our approach, and that of others working in this area at that time (early 1990s), was to elucidate the effects of blocking gap junctional conductance on reentrant excitation (3, 4, 22). Although there were no drugs available that had a specific blocking effect on cell coupling, some chemicals that decreased gap junctional conductance, such as heptanol (3, 4, 22, 34), were used as model drugs. We showed that a preferential slowing of conduction and eventual conduction block caused by heptanol stopped anisotropic reentry in a rabbit model (22). Another approach that we took was to increase intracellular calcium to block gap junctions and reentrant excitation with the L-type cardiac-specific calcium current "enhancer" Bay Y 5959 (5). These studies indicated that the block of gap junction function can be antiarrhythmic. In contrast, rotigaptide, a drug specifically developed to target gap junctions for the treatment of arrhythmias, enhances coupling (8, 11, 17). The studies described in the article published in this issue of the American Journal of Physiology-Heart and Circulatory Physiology by Kjolbye et al. (16) from the laboratory of Rosenbaum show how enhanced coupling may have an important antiarrhythmic effect.