Gap junctional uncoupling plays a trigger role in the antiarrhythmic effect of ischaemic preconditioning

Objective: The aim of this study was to determine whether uncoupling of gap junctions (GJ) prior to ischaemia would modify the antiarrhythmic effect of ischaemic preconditioning (PC) in a canine model of ischaemia/reperfusion. Methods: Twenty control dogs, anaesthetised with chloralose and urethane, were thoracotomised and subjected either to a 25 or a 60 min occlusion of the left anterior descending (LAD) coronary artery. This prolonged ischaemia was preceded 20 min earlier by a single 5 min LAD occlusion in preconditioned dogs (PC group; n = 14) or by a 20 min intracoronary infusion of 50 mu M carbenoxolone (CBX group; n=15), a relatively selective uncoupler of gap junctions. CBX was also infused in PC dogs (CBX +PC group; n=11). The severity of ischaemia (epicardial ST-segment changes, inhomogeneity of electrical activation) and of ventricular arrhythmias, such as ventricular premature beats (VPBs), ventricular tachycardiac (VT) episodes and ventricular fibrillation (VF), as well as changes in electrical impedance was assessed throughout the experiments. Connexin 43 (Cx43) phosphorylation and GJ permeability were determined at the end of the occlusion periods. Results: Compared to the controls PC and, interestingly, CBX markedly reduced, e.g. the total number of VPBs (440 104 vs 47 11 and 60 15; P<0.05) during the prolonged occlusion. This protection was, however, attenuated when CBX was infused in PC dogs (VPBs: 203 32). Changes in electrical impedance, GJ permeability and Cx43 dephosphorylation were significantly less in the PC and CBX groups than in the controls but these were again increased in the CBX+PC group. Conclusions: Uncoupling of GJs prior to ischaemia either by PC or CBX preserves the electrical coupling of cells and results in an antiarrhythmic effect during a subsequent ischaemic insult, indicating that a partial closure of gap junctions may play a trigger role in the protection. In contrast, when CBX is administered in PC dogs the protection both against GJ uncoupling and arrhythmias is markedly attenuated, suggesting that the antiarrhythmic protection, at least in part, is mediated through Ws. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.