Ischemic Postconditioning Reduces Reperfusion Arrhythmias by Adenosine Receptors and Protein Kinase C Activation but Is Independent of KATP Channels or Connexin 43

Abstract

Ischemic postconditioning (IPoC) reduces reperfusion arrhythmias but the antiarrhythmic mechanisms remain unknown. The aim of this study was to analyze IPoC electrophysiological effects and the role played by adenosine A1, A2A and A3 receptors, protein kinase C, ATP-dependent potassium (KATP) channels, and connexin 43. IPoC reduced reperfusion arrhythmias (mainly sustained ventricular fibrillation) in isolated rat hearts, an effect associated with a transient delay in epicardial electrical activation, and with action potential shortening. Electrical impedance measurements and Lucifer-Yellow diffusion assays agreed with such activation delay. However, this delay persisted during IPoC in isolated mouse hearts in which connexin 43 was replaced by connexin 32 and in mice with conditional deletion of connexin 43. Adenosine A1, A2A and A3 receptor blockade antagonized the antiarrhythmic effect of IPoC and the associated action potential shortening, whereas exogenous adenosine reduced reperfusion arrhythmias and shortened action potential duration. Protein kinase C inhibition by chelerythrine abolished the protective effect of IPoC but did not modify the effects on action potential duration. On the other hand, glibenclamide, a KATP inhibitor, antagonized the action potential shortening but did not interfere with the antiarrhythmic effect. The antiarrhythmic mechanisms of IPoC involve adenosine receptor activation and are associated with action potential shortening. However, this action potential shortening is not essential for protection, as it persisted during protein kinase C inhibition, a maneuver that abolished IPoC protection. Furthermore, glibenclamide induced the opposite effects. In addition, IPoC delays electrical activation and electrical impedance recovery during reperfusion, but these effects are independent of connexin 43.

Atrial Dyssynchrony Measured by Strain Echocardiography as a Marker of Proarrhythmic Remodeling and Oxidative Stress in Cardiac Surgery Patients

“…The lateralization of Cx40 and Cx43 shown in Figure 5 could support these findings at the beginning of the action potentials. Still, the concurrent increase in Cx43 at the intercalated discs goes against this idea, but agrees with previous reports that reduce the link with action potential morphology [ 34 ]. The reduced amplitude and maximal rate of depolarization indicate an impairment in the sodium currents.…”

Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease

“…This phenomenon, termed “the Good Samaritan effect”, is not contradictory to the previously discussed spread of injury, as it is conceivable that chemical coupling through gap junctions moves in one or the other direction, depending on the intensity of the insult [ 84 ]. In contrast to ischemic preconditioning, however, Cx43 seems not to play a role in postconditioning protection, a protective maneuver consisting of brief cycles of ischemia/reperfusion applied at the time of flow restoration, immediately after the sustained ischemia [ 460 , 461 ].…”

“…In this way, it might be involved in the protective effect of fibroblast growth factor 2 (FGF-2) [ 556 ], which is dependent on Cx43 phosphorylation at Ser262 [ 310 ]. However, and in contrast to ischemic preconditioning, Cx43, including mitochondrial Cx43, is not involved in postconditioning protection [ 460 , 461 ].…”

Cardiac Connexin-43 Hemichannels and Pannexin1 Channels: Provocative Antiarrhythmic Targets

“…HCs and Panx1 channel-mediated purinergic signaling fulfills an important function in cardiac and vascular pathophysiology [ 22 , 79 ]. This includes ischemia, infarction, cardiomyopathy, hypertrophy, coronary artery disease, and ventricular and supraventricular arrhythmias [ 81 , 143 , 144 ]. The release of ATP via HCs or Panx1 channels in pathological conditions could induce post-depolarization triggered activity.…”