The role of gap junctions in cardioprotection against the ischaemia and reperfusion-induced severe ventricular arrhythmias

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Ventricular tachyarrhythmias are one of the main causes responsible for sudden cardiac death. The prevention and treatment of these severe arrhythmias are still remained a challenge of cardiology in the industrialized countries. Since the generation of these life-threatening ventricular arrhythmias is associated with uncoupling of gap junctions (GJs), we aimed to examine, whether the GJ channels may have a role in the delayed antiarrhythmic effect of cardiac pacing (I), and also in the early cardioprotective effect of sodium nitrite (II). I. We have previous evidence that rapid cardiac pacing results in changes in the expression of the GJ forming protein connexion 43 (Cx43), and leads to functional and structural preservation of GJs. These effects may play a role in the delayed antiarrhythmic protection. The present study aimed to further investigate the involvement of GJs in the pacing-induced delayed antiarrhythmic effect, raising the question; whether the pharmacological inhibition of GJs prior to ischaemia would modify the pacing-induced cardioprotection. For this purpose we used carbenoxolone (CBX), a selective uncoupler of GJs, administered in two concentrations (50 and 100 µmol L-1) prior to and during a 25 min occlusion of left anterior descending (LAD) coronary artery in anaesthetized dogs, subjected to cardiac pacing, 24h previously. We have found that CBX both of the doses, attenuated the antiarrhythmic and the anti-ischaemic effects of cardiac pacing, and, in parallel, the pacing-induced reductions in tissue electrical impedance. These results confirm the role of GJs in the delayed antiarrhythmic effect of rapid cardiac pacing. II. There is evidence that nitric oxide (NO) regulates GJ function, and that this effect may have a role in the protection induced by preconditioning or by the administration of drugs, such as NO donors. Since we have previous evidence that the inorganic sodium nitrite provides marked protection against the ischaemia and reperfusion-induced arrhythmias in anaesthetized dogs, we wondered, whether GJs play a role in this protection. We have found that sodium nitrite infused in 0.2 µmol kg-1 min-1 before and during occlusion or 10 min just prior to reperfusion in anaesthetized dogs, significantly reduced the severity of ventricular arrhythmias and attenuated the marked impedance changes that resulted from coronary artery occlusion. These results suggest that in the antiarrhythmic effect of sodium nitrite the modulation of GJs may play a role.

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