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

Emiliano Diez,Amira Ponce Zumino,David García-Dorado,Antonio Rodríguez-Sinovas,Natalia Prado,Roberto Miatello,Jose Sánchez

doi:10.3390/ijms20235927

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.

Highlights

Severe ventricular arrhythmias are potentially lethal events during acute myocardial infarction [1]
This work aims to assess the effects of Ischemic postconditioning (IPoC) on transmembrane action potential characteristics and electrical activation and to analyze the mechanims involved in these effects, including the role played by gap junctional communication through connexin 43 (Cx43), adenosine receptors, using subtype-selective receptor blockers, and that of protein kinase C activation and KATP channels
IPoC (3 cycles of 30 s of reperfusion and 30 s of regional ischemia) reduced the severity of reperfusion arrhythmia in isolated rat hearts when applied after 10 min of regional ischemia (Figure 1)

Summary

Introduction

Severe ventricular arrhythmias are potentially lethal events during acute myocardial infarction [1]. Sinus rhythm restoration by electrical or pharmacological antiarrhythmic therapies could be challenging or unavailable [2]. Reperfusion therapies are crucial during acute myocardial ischemia. An adverse effect of these therapies is the so-called reperfusion injury, that involves myocardial cell damage/death, mechanical and microvascular dysfunction, and arrhythmias [3,4]. Reperfusion arrhythmias are an early marker of myocardial damage [5]. The occurrence of ventricular tachycardia or fibrillation during primary angioplasty is a serious complication in acute myocardial infarction patients, and is associated with higher mortality [6,7,8]

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