Melatonin receptor activation protects against low potassium‐induced ventricular fibrillation by preserving action potentials and connexin‐43 topology in isolated rat hearts

Abstract

Hypokalemia prolongs the QRS and QT intervals, deteriorates intercellular coupling, and increases the risk for arrhythmia. Melatonin preserves gap junctions and shortens action potential as potential antiarrhythmic mechanisms, but its properties under hypokalemia remain unknown. We hypothesized that melatonin protects against low potassium-induced arrhythmias through the activation of its receptors, resulting in action potential shortening and connexin-43 preservation. After stabilization in Krebs-Henseleit solution (4.5 mEq/L K + ), isolated hearts from Wistar rats underwent perfusion with low-potassium (1 mEq/L) solution and melatonin (100 μmol/L), a melatonin receptor blocker (luzindole, 5 μmol/L), melatonin + luzindole or vehicle. The primary endpoint of the study was the prevention of ventricular fibrillation.Electrocardiography was used, and epicardial action potentials and heart function were measured and analyzed. The ventricular expression, dephosphorylation, and distribution of connexin-43 were examined. Melatonin reduced the incidence of low potassium-induced ventricular fibrillation from 100% to 59%, delayed the occurrence of ventricular fibrillation and induced a faster recovery of sinus rhythm during potassium restitution. Melatonin prevented QRS widening, action potential activation delay, and the prolongation of action potential duration at 50% of repolarization. Other ECG and action potential parameters, the left ventricular developed pressure, and nonsustained ventricular arrhythmias did not differ among groups. Melatonin prevented connexin-43 dephosphorylation and its abnormal topology (lateralization). Luzindole abrogated the protective effects of melatonin on electrophysiological properties and connexin-43 misdistribution. Our results indicate that melatonin receptor activation protects against low potassium-induced ventricular fibrillation, shortens action potential duration, preserves ventricular electrical activation, and prevents acute changes in connexin-43 distribution. All of these properties make melatonin a remarkable antifibrillatory agent. K E Y W O R D Saction potential, arrhythmias, connexin-43, hypokalemia, melatonin, QRS

Reperfusion Arrhythmias Increase after Superior Cervical Ganglionectomy Due to Conduction Disorders and Changes in Repolarization

“…Both mechanisms are potential explanations of sustained reperfusion tachycardia. Conduction disturbances in SCGx hearts could be related to the redistribution of connexin 43, and the lateralization of unphosphorylated forms of the Cx43 reported here and concurred with previous studies [23]. Our results are also relevant for other diseases with increased arrhythmic risk and chronodisruption like coronary artery disease, non-dipping hypertension, sleep apnea, obesity, and chronic kidney disease [5,10,16].…”

“…The APD prolongation could be related to the loss of melatonin receptors at cardiomyocyte membranes. Melatonin receptors are coupled to Kir3.x channels, and melatonin receptor activation shortens the action potential duration [23,47]. However, we recently showed that melatonin-induced changes on myocardial repolarization were associated with melatonin antioxidative properties but not with its antiarrhythmic actions [15,48,49].…”

“…Cardiac electrograms and transmembrane action potentials from left ventricle epicardial cells were obtained from isolated rat hearts, as previously described [15,23].…”

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

“…Bro-Jeppesen et al reported baseline plasma IL-6 and IL-10 levels were significantly higher in non-survivors compared with survivors [11,12]. Melatonin, an anti-oxidant and anti-inflammatory agent, improves neurological outcomes and preserves hippocampal mitochondrial function in cardiac arrest [36], which may be associated with its protection against inflammation [22,[37][38][39], myocardial ischemia-reperfusion injury [40][41][42][43], ventricular fibrillation [44], cardiac hypertrophy [45], dilated cardiomyopathy [46], and mitochondria-related disorders [47,48]. As neutralization of IL-17 rescues neuroinflammation [49], melatonin may contribute to the complex role of IL-17 signaling in ROSC [50].…”

Plasma Adipokines in Patients Resuscitated from Cardiac Arrest: Difference of Visfatin between Survivors and Nonsurvivors

“…Cardiac disease is still a worldwide health issue [26][27][28][29]. Notably, obesity contributes critically in the pathophysiology of cardiovascular diseases; however, there is an obesity paradox in cardiac arrest patients [21].…”