Regulation of gap junctions by nitric oxide influences the generation of arrhythmias resulting from acute ischemia and reperfusion in vivo

Myocardial ischemia resulting from sudden occlusion of a coronary artery is one of the major causes in the appearance of severe, often life-threatening ventricular arrhythmias. Although the underlying mechanisms of these acute arrhythmias are many and varied, there is no doubt that uncoupling of gap junctions (GJs) play an important role especially in arrhythmias that are generated during phase Ib, and often terminate in sudden cardiac death. In the past decades considerable efforts have been made to explore mechanisms which regulate the function of GJs, and to find new approaches for protection against arrhythmias through the modulation of GJs. These investigations led to the development of GJ openers and inhibitors. The pharmacological modulation of GJs, however, resulted in conflicting results. It is still not clear whether opening or closing of GJs would be advantageous for the ischemic myocardium. Both maneuvers can result in protection, depending on the models, endpoints and the time of opening and closing of GJs. Furthermore, although there is substantial evidence that preconditioning decreases or delays the uncoupling of GJs, the precise mechanisms by which this attains have not yet been elucidated. In our own studies in anesthetized dogs preconditioning suppressed the ischemia and reperfusion-induced ventricular arrhythmias, and this protection was associated with the preservation of GJ function, manifested in less marked changes in electrical impedance, as well as in the maintenance of GJ permeability and phosphorylation of connexin43. Since we have substantial previous evidence that nitric oxide (NO) is an important trigger and mediator of the preconditioning-induced antiarrhythmic protection, we hypothesized that NO, among its several effects, may lead to this protection by influencing cardiac GJs. The hypotheses and theories relating to the pharmacological modulation of GJs will be discussed with particular attention to the role of NO.