Dexmedetomidine Exerted Anti-arrhythmic Effects in Rat With Ischemic Cardiomyopathy via Upregulation of Connexin 43 and Reduction of Fibrosis and Inflammation.

Shu-Jie Wu,Lei Li,Jia-Feng Lin,Yuan-Zheng Lin,Zhi-Heng Rao,Lian-Pin Wu,Zhong-Hao Lin

doi:10.3389/fphys.2020.00033

Abstract

BackgroundPersistent myocardial ischemia post-myocardial infarction can lead to fatal ventricular arrhythmias such as ventricular tachycardia and fibrillation, both of which carry high mortality rates. Dexmedetomidine (Dex) is a highly selective α2-agonist used in surgery for congenital cardiac disease because of its antiarrhythmic properties. Dex has previously been reported to prevent or terminate various arrhythmias. The purpose of the present study was to determine the anti-arrhythmic properties of Dex in the context of ischemic cardiomyopathy (ICM) after myocardial infarction.Methods and ResultsWe randomly allocated 48 rats with ICM, created by persistent ligation of the left anterior descending artery for 4 weeks, into six groups: Sham (n = 8), Sham + BML (n = 8), ICM (n = 8), ICM + BML (n = 8), ICM + Dex (n = 8), and ICM + Dex + BML (n = 8). Treatments started after ICM was confirmed (the day after echocardiographic measurement) and continued for 4 weeks (inject intraperitoneally, daily). Dex inhibited the generation of collagens, cytokines, and other inflammatory mediators in rats with ICM via the suppression of NF-κB activation and increased the distribution of connexin 43 (Cx43) via phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK). Dex reduced the occurrence of spontaneous ventricular arrhythmias (ventricular premature beat or ventricular tachycardia), decreased the inducibility quotient of ventricular arrhythmias induced by PES, and partly improved cardiac contraction. The AMPK antagonist BML-275 dihydrochloride (BML) partly weakened the cardioprotective effect of Dex.ConclusionDex conferred anti-arrhythmic effects in the context of ICM via upregulation of Cx43 and suppression of inflammation and fibrosis. The anti-arrhythmic and anti-inflammatory properties of Dex may be mediated by phosphorylation of AMPK and subsequent suppression of NF-κB activation.

Highlights

Coronary artery disease is the leading cause of morbidity and mortality around the world (Hayashi et al, 2015)
We found that limiting the process of fibrosis and restoring the loss of gap-junctional protein inhibited the structural remodeling of the injured ventricle via suppression of persistent ischemia-induced inflammatory responses in the myocardium following myocardial infarction (Wu et al, 2017; Lin et al, 2019)
Rats developing Ischemic cardiomyopathy (ICM) had longer QTc intervals than did sham-operated rats, and Dex inhibited the effect of ischemia on the prolongation of QTc (Sham vs. ICM, ICM + Dex vs. ICM; QTc: 51.03 ± 6.15 vs. 85.52 ± 6.76, p < 0.05; 67.94 ± 4.96 vs. 85.52 ± 6.76, p < 0.05)

Summary

Introduction

Coronary artery disease is the leading cause of morbidity and mortality around the world (Hayashi et al, 2015). There are interrelated causes contributing to the occurrence of arrhythmias after myocardial infarction, and persistent ischemiainduced inflammation and fibrosis followed by myocardial structural and electrical remodeling are crucial factors in the pathogenesis of these complications (Pahor et al, 1991; De Jesus et al, 2017; Mollenhauer et al, 2017). The uncoupling of intercellular electrical connections in the myocardium participates in the creation of the proarrhythmic substrate in the diseased heart, especially after myocardial infarction (Severs, 2002). Persistent myocardial ischemia post-myocardial infarction can lead to fatal ventricular arrhythmias such as ventricular tachycardia and fibrillation, both of which carry high mortality rates. The purpose of the present study was to determine the anti-arrhythmic properties of Dex in the context of ischemic cardiomyopathy (ICM) after myocardial infarction

Objectives

Methods

Results