Mechanistic Insights into Melatonin's Antiarrhythmic Effects in Acute Ischemia-Reperfusion-Injured Rabbit Hearts Undergoing Therapeutic Hypothermia

Overview

Journal Int J Mol Sci

Publisher MDPI

Date 2025 Jan 25

PMID 39859328

Authors

Hui-Ling Lee

Po-Cheng Chang

Hung-Ta Wo

Shih-Chun Chou

Chung-Chuan Chou

Affiliations

Soon will be listed here.

Abstract

The electrophysiological mechanisms underlying melatonin's actions and the electrophysiological consequences of superimposed therapeutic hypothermia (TH) in preventing cardiac ischemia-reperfusion (IR) injury-induced arrhythmias remain largely unknown. This study aimed to unveil these issues using acute IR-injured hearts. Rabbits were divided into heart failure (HF), HF+melatonin, control, and control+melatonin groups. HF was induced by rapid right ventricular pacing. Melatonin was administered orally (10 mg/kg/day) for four weeks, and IR was created by 60-min coronary artery ligation and 30-min reperfusion. The hearts were then excised and Langendorff-perfused for optical mapping studies at normothermia, followed by TH. Melatonin significantly reduced ventricular fibrillation (VF) maintenance. In failing hearts, melatonin reduced the spatially discordant alternans (SDA) inducibility mainly by modulating intracellular Ca dynamics via upregulation of sarcoplasmic reticulum Ca-ATPase (SERCA2a) and calsequestrin 2 and attenuating the downregulation of phosphorylated phospholamban protein expression. In control hearts, melatonin improved conduction slowing and reduced dispersion of action potential duration (APD) by upregulating phosphorylated connexin 43, attenuating the downregulation of SERCA2a and phosphorylated phospholamban and attenuating the upregulation of phosphorylated Ca/calmodulin-dependent protein kinase II. TH significantly retarded intracellular Ca decay slowed conduction, and increased APD, thereby facilitating SDA induction, which counteracted the beneficial effects of melatonin in reducing VF maintenance.

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