Melatonin is a promising cardioprotective agent. Its increase during the night is associated with healthy cardiovascular function. On the other hand, reduced levels of melatonin are related to diseases. Aging and chronodisruptors reduce melatonin levels. Pharmacological supplementation reduces the deleterious effects of cardiovascular risk factors and improves the myocardial response to ischemia/reperfusion injury and other proarrhythmic conditions. The protective mechanisms of melatonin involve its antioxidant properties as well as receptor-mediated actions. Signaling pathways include membrane responses, cytoplasmic modulation of kinases, nuclear receptor interactions, and improvement of mitochondrial functions. This chapter focuses on the electrophysiological and the antiarrhythmic properties of melatonin. The acute and chronic protective mechanisms of melatonin will be analyzed with an emphasis on transmembrane potentials and intercellular communication. An outstanding antifibrillatory effect makes melatonin a novel antiarrhythmic agent worthy of further exploration in the path to clinical applications.
- ventricular fibrillation
- action potential
- connexin 43
- melatonin receptors
“Nothing to do to save his life…” says the Beatles song “Good morning, good morning.” Ironically, cardiovascular mortality and life-threatening arrhythmias show a circadian increase in the mornings, and chronoprotective agents are still missing [1, 2]. This chapter highlights the importance of melatonin as a potential life-saving agent for the darkest nights (of antiarrhythmics drugs) and a brightest tomorrow.
The cardioprotective properties of melatonin are remarkable. Most of the preclinical and clinical studies support the protective actions and the safety profile of this indolamine [3, 4]. In this chapter, we briefly introduce the multitarget and versatile properties of melatonin and general concepts of electrophysiology to appreciate its potential as a promising antiarrhythmic agent. The second and third sections of the chapters focus on acute and chronic melatonin’s antiarrhythmic effects.
1.1 Melatonin properties relevant to heart rhythms
Endogenous and pharmacological increases of melatonin concentrations protect the cardiovascular system [3, 4, 5, 6, 7, 8, 9, 10, 11]. However, the relationships between the cardiovascular and circadian systems are highly complex and should not be interpreted in reductionist ways [5, 12, 13, 14]. Furthermore, our understanding of the pleiotropy of melatonin, a highly preserved molecule of protection, is continuously expanding [3, 4, 5, 6, 7, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]. Therefore, we will focus on melatonin effects on heart rhythms. Additional information regarding melatonin cardiovascular effects can be found elsewhere and include direct actions in the heart, blood vessels, kidney, and other regulatory mechanisms at the nervous, immune, and endocrine systems [11, 25, 26]. Only the electrophysiological information will be extracted from its protective actions against risk factors like hypertension, metabolic syndrome, obesity, inflammation, and pathologies like ischemia/reperfusion injury, infarction, drug-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure [8, 11, 21, 27].
Melatonin is amphipathic and pleiotropic. Melatonin can act on several targets at cell membranes and at intracellular levels in almost any cell [28, 29]. For this electrophysiological analysis, we present the following division of melatonin mechanisms of action:
Improvement of mitochondrial functions
Ion channel modulation
1.1.1 Melatonin as an antioxidant
Melatonin protects against oxidants by several mechanisms. In fact, it has been suggested that one of the main functions of melatonin in all living organisms is to protect them from oxidative stress [30, 31]. Melatonin has a well-characterized and extensively documented antioxidant capacity [31, 32, 33, 34, 35, 36, 37]. Melatonin is a powerful antioxidant, with a potency of up to 10 times greater than vitamin E .
There are oxidants of different chemical nature. They can be free radicals or non-radical reactive species [39, 40]. Free radicals—molecules with an unpaired electron—are unstable, highly reactive, and often trigger chain reactions, which propagate nearby molecular modifications. The most studied oxidants are the reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species. Under physiological conditions, ROS/RNS act as second intracellular messengers modulating signal transduction pathways [40, 41]. A delicate cellular balance between the production and the removal of free radicals maintains low/moderate concentrations. Oxidative stress occurs when oxidants increase above healthy levels and represent a severe risk to the molecular integrity of lipids, proteins, and DNA [39, 40]. Therefore, neutralization of reactive species by scavenger molecules like melatonin is a chemical way of counteracting oxidative stress.
The main agent involved in oxidative damage is superoxide anion, but hydrogen peroxide, hydroxyl radical, nitric oxide (NO), peroxynitrite, and nitroxyl also participate in oxidative stress. The mitochondria are the main source of oxidizing species during oxidative phosphorylation. Oxidants are also the product of the activation of non-mitochondrial enzyme systems such as NADPH oxidase, xanthine oxidase, and nitric oxide synthase [40, 41, 42].
Cells have antioxidants that prevent damage. An antioxidant is any substance that significantly delays or prevents oxidation of lipids, proteins, or DNA . Lipids are often used as target molecules because they are more reactive to oxidants than proteins or DNA. Nonenzymatic antioxidants include reduced glutathione (GSH), vitamins, and melatonin among others. Melatonin is five times more effective than GSH as scavenger of the highly toxic hydroxyl radical . The main antioxidant enzymes are superoxide dismutase (SOD), catalase, thioredoxin, and glutathione peroxidase [40, 41, 42, 43, 44].
Melatonin efficiently prevents oxidative stress. The aromatic indole ring of melatonin reduces and repairs electrophilic radicals acting as generous electron donor. One molecule of melatonin can neutralize up to 10 toxic reagents, including ROS, RNS, and other free radicals [7, 39, 45, 46, 47]. In addition, several metabolites formed when melatonin neutralizes harmful reagents are also antioxidants suggesting that a cascade of reactions increases the efficacy of melatonin [28, 35, 47, 48, 49]. Being a highly lipophilic and hydrophilic compound, melatonin crosses all morphological barriers and acts not only in each cell but also within each subcellular compartment. Additionally, melatonin increases the efficacy of vitamin E, vitamin C, and GSH [33, 50]. Therefore, the elimination of free radicals can be carried out by intracellular interactions independent of any receptor [36, 45, 51].
Melatonin stimulates antioxidant enzymes by acting on membrane, cytoplasmic, and nuclear receptors [39, 43, 52]. Low melatonin concentrations increase the expression or activity of SOD, catalase, and glutathione peroxidase [43, 53].
Ion channels and many other proteins respond to oxidative stress [54, 55, 56, 57, 58]. Amino acid residues are the targets of ROS/RNS. Sulfur atoms like cysteine and methionine, hydroxyl groups from tyrosine, or aromatic rings of histidine, phenylalanine, and tryptophan are vulnerable to reactive species. Those that contain more cysteines are more sensitive to changes because thiol groups (–SH), which exist as thiolates (–S) at physiological pH, tend to react more quickly with ROS/RNS . Many of these proteins are involved in important biological reactions such as oxidative phosphorylation, metabolic regulation, and signal transduction [60, 61]. Oxidative stress can increase late sodium currents through direct Na+ channel modification [62, 63] and result in a prolonged action potential duration and arrhythmogenic triggers known as early-after depolarizations (EAD) . Several reviews describe the redox regulation of calcium channel in cardiac myocytes including the ryanodine receptor calcium, the IP3 receptor, and voltage-dependent L-type calcium channel [65, 66, 67, 68, 69]. ROS and RNS affect the L-type Ca2+ channel Cav1.2 by regulation of cysteine residues. However, calcium channel regulation by redox is controversial with reports of increase and decrease of channel functions . Voltage-gated potassium (Kv) channel, mainly responsible for myocardial repolarization, is sensitive to oxidative stress [58, 70, 71, 72]. Sulfenic acid modification at a conserved cysteine residue of Kv1.5 under prolonged oxidative stress can induce arrhythmia [58, 72].
1.1.2 Melatonin receptors
Melatonin has receptors in the cellular membranes, in the cytoplasm, and in the nucleus. Melatonin membrane receptors express in several regions of the nervous system and in almost all the organs including the heart, arteries, kidneys, liver, gastrointestinal tract, prostate gland, uterus, skin, and eyes . Melatonin activates two subtypes of G-protein-coupled receptors in the plasma membrane, named MT1 and MT2, according to the official IUPHAR nomenclature (previously called Mel1a and Mel1b) . Both receptors have high affinity to melatonin (
Melatonin membrane receptors can exist as monomers, as well as dimers. The MT1 homodimer forms 3- to 4-fold higher proportion than the MT2 homodimer and the MT1/MT2 heterodimer. Nonmammalian vertebrates present a third low-affinity receptor termed Mel1c, and a proposed mammalian homologous is the orphan receptor GPR50 [74, 77, 78, 79]. This orphan lost its properties to directly interact with melatonin but shows an inhibitory interaction with MT1 receptors by forming heterodimers. More recently, other orphans unable to bind melatonin like GPR61, GPR62, and GPR135 showed a similar indirect inhibitory interaction with MT2 receptors . Other G-protein-coupled receptors like the serotonin receptor 5HT2c can interact with melatonin membrane receptors . These interesting interactions of membrane receptors are not further discussed in this chapter but should be considered in future electrophysiological studies with melatonin.
The MT1 and MT2 inhibit adenylate cyclase-protein kinase A-CREB signaling in target cells by pertussis toxin-sensitive Gαi, β, and γ and toxin-insensitive Gq, β, and γ proteins [74, 79]. The MT1 also increases phosphorylation of mitogen-activated protein kinase 1/2 (MAPK) and extracellular signal-regulated kinase 1/2 (ERK), as well as increasing potassium conductance through inwardly rectifying (Kir3.x) channels. The later effect on potassium channels could be relevant to heart electrophysiology since Kir3.x channels are highly expressed in cardiomyocytes and usually coupled to acetylcholine and adenosine membrane receptors . MT2 melatonin receptor activation inhibits both forskolin-stimulated cAMP production and cGMP formation, activates protein kinase C (PKC) in the nervous system, and decreases calcium-dependent dopamine release in the retina. Native functional MT1/MT2 heterodimers in mouse rod photoreceptors mediate melatonin’s enhancement of scotopic light sensitivity through phospholipase C and PKC pathways .
Several compounds interact with MT1 and MT2 receptors, but blocker luzindole is the only with proven myocardial electrophysiological effects . Luzindole and 4P-PDOT competitively block MT1 melatonin receptors at concentrations higher than 300 nM, and both are inverse agonists in systems with constitutively active MT1 receptors [74, 79].
Melatonin interacts with several enzymes and intracellular proteins. The MT3 receptors is a quinone reductase 2 with an affinity in the nanomolar ranges . This enzyme is possibly involved in the regulation of cellular oxidative status, although the exact regulatory action of melatonin remains unclear [84, 85, 86, 87]. Furthermore, the electrophysiological effects of MT3 have not been reported yet.
Melatonin interacts with intracellular proteins such as calmodulin, calreticulin, or tubulin . The low-affinity interaction between melatonin and calmodulin antagonizes the binding of Ca2+ and may be involved in its antioxidant action as well as other electrophysiological signaling processes [89, 90, 91, 92, 93, 94, 95, 96].
Melatonin increases the cytoplasmic levels of the heat shock protein 70 in several tissues including the heart [97, 98, 99, 100, 101, 102]. Further interaction with this chaperon will be described in Section 3 of the chapter.
Melatonin is a ligand for the retinoid-related orphan nuclear hormone receptor family (RZR/ROR) [74, 79]. RZR/RORα is expressed in a variety of organs, whereas RZRβ is specific for the brain and retina . ROR/RZR has been proposed to work in coordination with the plasma membrane receptors MT1/MT2 to regulate gene expression. We suggest a potential interaction with Vitamin D receptor (VDR), which was elegantly confirmed in recent experiments [97, 103].
1.1.3 Melatonin improves mitochondrial functions
Mitochondria are critical for cellular metabolism and energy production. They maintain life but also are gatekeepers of cell death [31, 104]. Mitochondria produce up to 95% of the cellular energy in the form of ATP in aerobic cells . Mitochondrial oxidative phosphorylation uses a system of oxidoreductase protein complexes (complexes I, II, III, and IV) to transfer electrons during ATP production. Deficiencies in the electron transport chain can result in the leakage of electrons and generate ROS/RNS [40, 41, 106, 107]. Oxidative stress decreases respiratory complex activity, impairs electron transport system, and opens the mitochondrial permeability transition pores leading to cell death [104, 106, 108].
Mitochondria are essentials for the protective actions of melatonin [51, 97, 106, 107, 109, 110, 111]. The mechanisms involved include its antioxidant properties and the preservation of complex I and III functions, inhibition of the opening of the permeability transition pores, and the release of cytochrome c. Petrosillo et al. demonstrate that melatonin prevents the opening of the mitochondrial permeability transition pores and its deleterious consequences [51, 110, 112, 113]. We recently reported that melatonin prevents mitochondrial edema, dilation of the ridges, high activity of NADPH oxidase, and apoptosis . Melatonin improves mitofusin-2, which preserves the mitochondrial functional network and prevents apoptosis . The reduction of mitochondrial damage in the heart could be related to the negative regulation of angiotensin II type 1 receptor (AT1) by melatonin . The induction of Hsp70 through melatonin is compatible with an additional mechanism related to Tom 70, a translocase of the outer mitochondrial membrane [97, 115, 116]. The interaction of Hsp70 with Tom 70 initiates mitochondrial import processes . Tom 70 regulates melatonin-induced cardioprotection by preventing mitochondrial deterioration and oxidative stress [97, 115].
Melatonin’s cardioprotection associates with an increase in the number of mitochondria and positive regulation of survival genes such as nicotinamide phosphoribosyl transferase and nicotinamide adenine dinucleotide-dependent deacetylases, called sirtuins . Particularly sirtuin-1 and sirtuin-3 are downstream mediators of the cardioprotective actions of melatonin. Sirtuin-1can modulate fatty acid oxidation, apoptosis, oxidative stress, and autophagy through deacetylation of transduction factors like NF-κB, forkhead box class O, p53, peroxisome proliferator-activated receptor alpha, thioredoxin-1, and Bcl-xL [117, 118, 119, 120, 121]. Sirtuin-3 is a family member that is primarily located in the mitochondria and protects against inflammation and diseases related to oxidative stress. Melatonin elevates sirtuin-3, stimulates superoxide dismutase activity, and suppresses mitochondrial oxidative stress [31, 117, 122, 123]. Additionally, melatonin protects nuclear and mitochondrial DNA [122, 124, 125]. The multiple actions of melatonin provide potent protection against mitochondrial-mediated lesions.
1.1.4 Melatonin modulates ion channels
Melatonin exerts its electrophysiological effects by multiple mechanisms. One of the ways for melatonin to interact is through the modulation of ion channels. Whether we consider its role as a drug or as a biological molecule, it should be taken into account how melatonin has been considered an electrophysiological modulator for many physiological and clinical conditions such as control of circadian rhythms, regulation of arterial blood pressure and heart rate in mammals, sleep processes, and antiaging, among others. Its role in the modulation of several ion channels is crucial to understand the molecular mechanism underlying the electrophysiological properties as an antiarrhythmic.
Melatonin regulates anionic and cationic selective channels by multiple pathways, at different doses and time-dependent responses. It is important to remember the wide spectrum of action this molecule has. For example, results regarding the pathophysiology of lung fibrosis show that volume-regulated anion currents do not respond to acute exposure of cells to melatonin in hypotonic solutions . However, when cells are pre-incubated with melatonin concentrations from 1 to 100 μM for 30–60 min, the anionic currents in response to hypotonicity are blunted in a dose-dependent manner. These time- and dose-dependent responses could support the electrophysiological effect during regional ischemia after 20–30 minutes of melatonin exposure in isolated rat hearts, because during ischemia cardiomyocyte swelling activates anionic currents, and melatonin downregulation of these currents is a potential explanation [127, 128]. Additionally, these MT receptor interactions described in fibroblast deserve further evaluation in myocardial tissue.
From the perspective of the interaction between melatonin and its target, it will be crucial to increase the knowledge about the allosteric contact between melatonin and an ion channel. For example, melatonin blocks the potassium channels (Kv1.3) in a reversible manner through the interaction with different binding sites on the human peripheral blood T lymphocytes . However, the inhibitory effects require high extracellular melatonin in the mM range . Cardiomyocytes do not express this specific potassium channel, but a homologous mechanism can exist for other channels waiting to be reported.
Most of the information regarding the role and effect of melatonin in the organisms has been described in the nervous system. One of the most popular is melatonin-related circadian rhythm. In particular, how melatonin influences circadian phase and electrical activity thanks to the interaction with Kir3.x channels presents them as a therapeutic target for diseases related to circadian disruption and melatonin signaling features . In addition, the effects of melatonin in this pacemaker of circadian rhythm could be due also to its modulation of inwardly rectifying potassium channels (Kir3.1/Kir3.2) via MT1 receptors . Moreover, melatonin is also necessary for circadian regulation of sleep. This effect was described to be driven by the suppression of GABAergic neurons by melatonin in the lateral hypothalamus (crucial function for wakefulness), via interaction with MT1 receptor in order to inactivate hyperpolarization-activated cyclic nucleotide-gated channels .
Melatonin is a potential neuroprotective molecule thanks to its interaction in a mitochondrial pathway involving the closing of permeability transition pore and opening of ATP sensitive potassium channels (KATP) . The opening of KATP contributes to melatonin antiseizure effect . The preventive actions on the permeability transition pore have been reported in myocardial tissue as well [51, 112, 113]. However, opening of KATP channels with high concentrations of melatonin could be proarrhythmic [135, 136].
Melatonin modulates most of the voltage-activated calcium channel subtypes (L, P, Q , N, and R) with different effects [137, 138, 139, 140, 141]. Melatonin inhibits voltage-dependent calcium entry in cultured rat dorsal root ganglia neurons, regulates calcium entry into pineal cells, and has dose-dependent inhibitory effects on free [Ca2+]i in mouse brain cells . Melatonin has no effect on voltage-activated calcium channels in cultured human aortic smooth muscle cells . Melatonin accutelly increase L type calcium currents in chick cardiac membranes [140, 141]. An early study shows that melatonin downregulates voltage-sensitive calcium channels in the heart . These results indicate that melatonin may have differnt acute and chronic implications for normal cardiac physiology and for the pharmacological manipulation of the heart .
Melatonin mediates vasodilation of cerebral arteries through the activation of large-conductance Ca2+-activated K+ (BKCa) channels via both melatonin receptor-dependent and melatonin receptor-independent modes, increasing BKCa channel current density but not the KV channel current density . Small-conductance Ca2+-activated K (SK) channels are also modulated by the action of melatonin . Upregulation of SK channels plays a role in memory loss and indicates that melatonin reverses memory deficits in rats by downregulation of SK1, SK2, and SK3 channels in their hippocampi .
Additional information was brought about KCNQ from the aorta and related with vascular tone, and KCNH2 in the left ventricle was associated with QT duration in rats where melatonin was able to prevent the increase in blood pressure and change KCNQ and KCNH2 gene expression profiles .
Melatonin effects on connexin proteins will be extensively analyzed in the second and third sections of the chapters for its proven relationship with both acute and chronic antiarrhythmic effects of melatonin.
1.2 Electrophysiology and arrhythmias
The heart pumps blood under a synchronized electrical control. Arrhythmias are the electrical problems in the rhythm of the heart. The heartbeats may be faster in the case of tachyarrhythmia and slower in bradyarrhythmia.
Fatal arrhythmic events follow a circadian pattern . Arrhythmogenesis decreases during nighttime when the melatonin levels increase 30 to 70 folds. Life-threatening cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, and sudden cardiac death) are more likely to occur in the morning after waking. Arrhythmias also increase with age and heart diseases [146, 147, 148].
Disturbances in membrane excitability or conduction cause arrhythmias. Excitability manifests as action potentials and involves coordinated ion movements across the cell membrane through ion channels, exchangers, and ATPases . Conduction is the propagation of bioelectrical signal throughout the heart. Action potentials automatically originate at the sinoatrial node, spread to the atria, and, after a small delay in the atrioventricular node, rapidly and synchronously activate the ventricles via the His-Purkinje system. Action potentials propagate from cell to cell using low-resistance pathways known as gap junctions. Connexin proteins assemble into intercellular channels at gap junctions. Connexin 43 (Cx43) is the most abundant connexin in the heart . Gap junctions couple the cells and allow the flow of electrical current and small molecules. The largest accumulation of connexins occurs in a specialized structure at the ends of cardiomyocytes called intercalated discs. Cardiac propagation is anisotropic, particularly more rapid in the longitudinal direction of the cell than in the transverse direction. The lateral borders of the myocytes usually show variable amount gap junctions depending on age or disease.
Cardiovascular diseases are the leading cause of death in the world . Most deaths occur suddenly . Catastrophic sudden death events motivate us to search for causes and possible solutions . This is a great scientific and social health challenge. The approaches of recent years have reduced the burden of cardiovascular disease, but there is still much to improve . A case occurs with arrhythmias. The rhythm disorders motivated emergency interventions, especially during the first hour of the manifestation of coronary heart disease. Cardiopulmonary resuscitation, ambulances, and cardiodefibrillation were response strategies to unexpected events. Unfortunately, they are still unexpected due to the limited understanding of the causes at a level that would allow us to predict, avoid, or control the occurrence of an event . In that sense, the strategies that attempt to determine risks grew in order to establish a more efficient direction of interventions [156, 157]. Today they allow us to expect more lethal events in severely ill people. However, risk factors are still far from being effective and much less efficient. The changes that occur in physiology as a result of exposure to different risk factors would be one of the explanations .
2. Acute antiarrhythmic mechanisms of melatonin
Melatonin acts at multiple electrophysiological levels due to its receptor-dependent and receptor-independent mechanisms. In 1998, the seminal work of Tan et al. highlighted the antiarrhythmic properties of melatonin . During the past two decades, our understanding of the pleiotropic action of melatonin increased significantly.
The antiarrhythmic effect of melatonin was first attributed to its notable antioxidant properties, mainly because melatonin results were better than those obtained with an ascorbic acid at concentration 10–500 times higher . Numerous studies confirmed antiarrhythmic protection and related it to its remarkable antioxidant properties [160, 161, 162, 163, 164, 165, 166, 167].
Our research group corroborated the antiarrhythmic effect of melatonin in isolated hearts of female rats, when administered continuously from the stage prior to the onset of myocardial ischemia . Notably, the antiarrhythmic protection had a dose-dependent response, while the antioxidant capacity was the same for all the doses studied. The preventive effect on the shortening of the action potential that occurs between the 7th and 10th minute of the ischemia was another dose-dependent variable found in our study. This led us to think that the antiarrhythmic mechanism could be due to a lower heterogeneity in the repolarization of myocardial tissue that diminishes the possibility of reentry circuits being formed and maintained. As previously mentioned, the time- and dose-dependent responses could be due to melatonin inhibitory effect against swell-activated anionic currents [126, 127, 128].
We recently showed that melatonin reduces arrhythmias when administered during reperfusion, a useful timing for the clinical context of acute coronary syndromes, because most therapies can only start close to the reperfusion period . Melatonin showed protective mechanisms when administered to isolated hearts of rats fed with fructose and spontaneously hypertensive rats. These animals show greater activity of the enzyme NADPH oxidase, which is one of the main systems for generating free radicals, and, therefore, higher levels of oxidative stress. The antiarrhythmic effect was not affected in the models with greater oxidative stress, and in all groups, it was accompanied by a temporary shortening of the duration of the action potential during the first 3–5 minutes of reperfusion. This result was interpreted as a reduction in the ability to generate early and late postdepolarizations. Self-limited arrhythmic events, such as ventricular extrasystoles, salvos, and even non-sustained ventricular tachycardia, occurred in all experimental groups. The main difference was that the hearts treated with melatonin did not show sustained forms of arrhythmias, either sustained ventricular tachycardia or ventricular fibrillation. These results (potential shortening and absence of sustained arrhythmia) are difficult to reconcile with the mechanisms postulated for reentry circuits.
The same year of our publication of the antiarrhythmic protection of melatonin administered in reperfusion, another group published that melatonin protects against arrhythmias, by increasing the threshold to electrically induce sustained ventricular fibrillation, by increasing the myocardial Cx43 by PKC in hypertensive rats . Melatonin prevented myocardial abnormalities of connexin and improved cardiac conduction.
Based in these interesting results, we tested if melatonin could prevent hypokalemia-induced ventricular fibrillation by Cx43 preservation . The acute administration of melatonin during low potassium perfusion reduced the incidence of ventricular fibrillation and improved the recovery of sinus rhythm in those hearts that, despite being treated with melatonin, developed sustained fibrillation. Protection was mediated by the activation of melatonin receptors and by the prevention of dephosphorylation and lateralization of Cx43.
A brief explanation of the electrophysiological changes induced by hypokalemia will help to appreciate the relevance as antiarrhythmic. Severe hypokalemia induces changes in ventricular repolarization, such as lengthening the QT interval, prominent U waves, fusion of T and U waves associated with and increases risk of arrhythmic death [83, 170, 171]. Our experimental model confirmed the lengthening of the QT interval and correlated with an increase in the duration of the action potential . Melatonin did not prevent the prolongation of the action potential induced by hypokalemia when measured at 90% of repolarization but maintained action potential duration at 50% of repolarization and made the membrane potential more stable, showing less after depolarization. Luzindole blunted both effects of melatonin, suggesting the involvement of melatonin receptor activation in the preservation of membrane potential.
Hypokalemia decreases NaK-ATPase activity and causes an intracellular Ca2+ overload that facilitates the development of delayed postdepolarizations through the transient inward currents [172, 173, 174]. Delayed postdepolarizations are considered triggers of arrhythmias because they can initiate an action potential in isolated cells. However, it is unlikely that an extra action potential can be initiated from a single cell in the tissue due to a mismatch between the current source from the cell and the current sink produced by the surrounding cells . To overcome the source-sink mismatch, there must be a reduced sink through intercellular decoupling or an increase in the source through the synchronization of delayed postdepolarizations between several adjacent cells. Both situations could be assumed based on the results of anisotropic conduction studies and immunofluorescence imaging .
In fact, hypokalemia induces conduction abnormalities, increased amplitude and duration of the P wave, a slight prolongation of the PR interval, atrioventricular block, increased QRS duration, and cardiac arrest [173, 176]. We found all these electrocardiographic disorders during our experimental model of hypokalemia . Melatonin prevented the widening of the QRS and delayed activation of the potential for epicardial action. The latter could be considered as a substitute for conduction velocity in complex tissues such as ventricles, assuming unknown routes from endocardial activation points that indicate the onset of QRS to epicardial myocytes recorded with microelectrodes. These improvements in ventricular conduction were related to Cx43 lateralization and dephosphorylation.
The lateralization of connexins has been detected in chronic atrial fibrillation, cardiac hypertrophy, heart failure, and after myocardial infarction [21, 177, 178, 179]. An increase in the fraction of lateral connexins that form functional channels improves transverse conduction velocity and contributes to the spread of the arrhythmogenic impulse. High side-by-side lateralization can favor conduction blockage due to mismatches between the source and the sink [175, 180]. A unidirectional block can lead to reentry circles that result in tachycardia or ventricular fibrillation . Therefore, the acute lateralization induced by hypokalemia is an important arrhythmogenic factor . It is noteworthy that melatonin prevented acute lateralization of Cx43.
Connexin 43 phosphorylation could lead to better coupling or uncoupling depending on the target amino acid, but dephosphorylation is clearly associated with uncoupling [21, 177, 182]. It is not yet known whether the dephosphorylation of Cx43 during low potassium is the result of increased phosphatase activity and/or an increase in phosphokinase or what are the intracellular mechanisms that prevented dephosphorylation when treated with melatonin. Dramatic reductions in intercellular communication due to the loss of phosphorylated Cx43 and the accumulation of non-phosphorylated Cx43 were previously reported in other experimental models .
Our results could be relevant mainly in those situations in which acute hypokalemia can be anticipated as in dialysis [183, 184]. Both QT interval and the QT dispersion increase after dialysis. We propose that melatonin could make the heart more resistant to arrhythmic events triggered by rapid changes in plasma electrolyte concentrations, regardless of a lack of effects on the ECG. In addition, those dialysis patients also suffer from disorders in the circadian rhythms and low levels of melatonin . However, clinical translations of our results should be done with caution, mainly because we use a high dose of melatonin administered directly to the heart. Based on melatonin’s pharmacokinetics in humans, to achieve a similar concentration in plasma to the one tested
Melatonin has a remarkable antiarrhythmic activity that is carried out based on actions dependent on and independent of receptor activation. To summarize we propose that the antiarrhythmic effect of melatonin is mediated by receptor activation beyond its outstanding antioxidant actions (Figure 1). The shortening of the action potential could be associated with the activation of MT1 melatonin receptors, since they can regulate specific ion channels such as Kir3.1 channel. MT1 and MT2 receptors could indirectly modulate other electrophysiological effects through intracellular signaling such as decreased cyclic adenosine monophosphate, increased phospholipase C, and PKC activation.
3. Chronic antiarrhythmic mechanisms of melatonin
Endogenous melatonin would be an intrinsically protective factor with therapeutic potential [188, 189]. Melatonin is a promising treatment for cardiovascular diseases such as myocardial ischemia/reperfusion injury, hypertension, and heart failure. It has been shown that melatonin levels were reduced in patients with acute myocardial infarction and in patients undergoing primary coronary angioplasty . These findings suggest that melatonin could play an important role in preventing ischemia/reperfusion heart injury. Indeed, reperfusion arrhythmias increase in pinealectomized animals, suggesting a protective role of endogenous physiological melatonin levels [163, 189].
Chronic melatonin supplementation, either in physiological or pharmacological ranges, protects against arrhythmias [8, 21, 97, 163, 169, 189, 191, 192]. Beyond the reported antioxidant properties of melatonin, it reduces severe ventricular arrhythmias by antifibrotic mechanisms, electrical remodeling, direct mitochondrial protection, myocardial Cx43 preservation via PKC signaling, and vitamin D-HSP70/AT1 counterbalance (Figure 2). Its cardioprotective properties persist in relevant cardiovascular risk factor models like hypertensive, obese, and nephropathic rats. The latter is interesting because most of the therapeutic interventions postulated so far fail to be reproduced under risk factor conditions.
A preventive approach would be of great value in the face of unpredictable acute arrhythmic events, especially if the intervention manages to avoid the most severe and potentially lethal arrhythmias such as ventricular tachycardia and fibrillation. Numerous efforts have been made in that direction. In the last quarter of the twentieth century, several antiarrhythmic drugs were tried, but most of them showed a proarrhythmogenic profile or failed to reduce mortality [193, 194, 195, 196]. A time of great progress was appreciated with the introduction of implantable cardiodefibrillators. However, surgical intervention and high cost limit its population efficiency. A strategy to improve the availability of preventive interventions is to select potential beneficiaries based on their risk of serious events. This would compensate for potential side effects and optimize the investment of resources. Other strategies, such as vaccines, are based on achieving the greatest possible scope with the least number of interventions that attenuate the severity of diseases. In the case of arrhythmias, we still have no clear “antiarrhythmic vaccine.” Therefore, risk-oriented strategies would be an acceptable approach.
From a preventive point of view, the pleiotropic protection mechanisms of melatonin could effectively limit the arrhythmic complications associated with hypertension [21, 169]. Arterial hypertension causes vascular deterioration, overloads the heart, and predisposes to a greater number of arrhythmic events. More than five decades ago, it was reported that surgical removal of the pineal gland, a procedure that essentially eliminates circulating levels of melatonin, was followed by a slow but persistent increase in blood pressure in rats . This finding has been confirmed in several subsequent studies . In addition, daily treatment of pinealectomized rats with melatonin attenuated the elevation in blood pressure that accompanies pinealectomy [198, 199]. Potentially related to these experimental findings are those observational studies in humans that document an age-related gradual increase in blood pressure . Of special interest is that the ability of the pineal gland to produce melatonin is compromised during aging so that the levels of melatonin in the blood at night gradually decrease [28, 30, 110]. An implication of these findings is that the loss of melatonin during aging can contribute to gradual hypertension and arrhythmias.
The structural remodeling of the myocardium that follows hypertension (mainly cardiomyocyte hypertrophy and fibrosis) is accompanied by changes in the expression, distribution and function of the ionic channels of the cell membrane and the intercellular channels constituted by Cx43 [21, 191, 200]. Remodeling predisposes to life-threatening ventricular tachycardia and ventricular fibrillation by early or late postdepolarization and reentry. Melatonin prevents changes in ventricular redistribution of Cx43 and reduces arrhythmia inducibility [8, 21, 147, 191].
Another chronodisruptor that increases arrhythmic risk are kidney diseases. Chronic kidney diseases (CKD) alter the nocturnal secretion of melatonin [185, 201]. Melatonin levels correlate negatively with the intrarenal activity of renin-angiotensin II-aldosterone system (RAAS) . Melatonin improves intrarenal RAAS in the 5/6 nephrectomy rat model and reduces blood pressure, oxidative stress, and interstitial fibrosis in the remaining kidneys .
Renal diseases cause cardiovascular and electrolytic remodeling that increases the risk of arrhythmias [204, 205, 206]. Cardiovascular events occur more frequently in patients with chronic kidney disease. Ventricular arrhythmias are particularly prevalent among patients with CKD, even when those patients do not suffer from any electrolyte imbalance . The risk of mortality also increases in patients with CKD who suffer from an acute coronary syndrome . We demonstrated that unilateral ureteral obstruction caused a cardiac remodeling that was accompanied by an increase in reperfusion arrhythmias .
The electrophysiological properties of chronic melatonin deserve attention, due to their relevance for cardiorenal situations with high arrhythmic risk and lack of treatments. We recently confirmed the antifibrotic, antiapoptotic, and antioxidant effects of melatonin and linked them to an HSP 70-VDR/AT1 counterbalance which prevents kidney damage and arrhythmogenic remodeling of the heart .
In renal and myocardial tissue, melatonin increased HSP 70 and VDR and decreased AT1 and fibrosis. Melatonin increases HSP 70 and protects the liver of rats exposed to toluene from cytotoxicity induced by oxidative stress . HSP 70 regulates antioxidant responses to cellular oxidative stress and reduces NADPH oxidase activity and expression . We demonstrated a myocardial increase in HSP 70 in rats treated with melatonin. HSP 70 induces VDR and facilitates intracellular localization of active vitamin D metabolites and transactive VDRs [209, 211, 212]. Nuclear melatonin receptors, as members of retinoid-related orphan receptors, may interact and prevent degradation of VDR [97, 103]. Expression of myocardial VDR links chronic kidney disease with cardiovascular disease due to the reduction in VDR that amplifies the effects of angiotensin . Melatonin decreases renal and myocardial overexpression of AT1 . It is well documented that the AT1 pathway leads to myocardial fibrosis during CKD . As previously suggested, the low expression of AT1 through VDR induction could be a consequence of HSP 70-mediated cellular protection . Angiotensin II exerts a tonic modulation of melatonin synthesis by influencing the activity of tryptophan hydroxylase through AT1 supporting the postulated feedback (or reciprocal regulation) between AT1 and melatonin [97, 202].
Additionally, the mitochondrial dynamics relates to the RAAS. We show that melatonin prevents mitochondrial edema, high activity of NADPH oxidase, and apoptosis. In this sense, the reduction of mitochondrial damage melatonin could be related to the negative regulation of AT1. The induction of HSP 70 through melatonin is compatible with an additional mechanism related to Tom 70. Furthermore, Tom 70 regulates melatonin-induced protection against myocardial infarction [115, 116]. All these data allow us to assume that the induction of HSP 70 by melatonin and the reduction of AT1 are critical components of the cellular stress response.
We attribute the higher vulnerability to ventricular fibrillation during reperfusion in the kidney disease rat model to the prooxidative and profibrotic changes that accompanied the increase in AT1 and the decrease in HSP 70 [97, 209]. Myocardial oxidative stress—particularly in the mitochondria—and fibrosis are well-known proarrhythmic substrates [55, 71]. Free radicals act as triggers for the beginning of arrhythmic events. The persistence of high-frequency rhythms requires reentry circuits . Altered conduction and shortening of the action potential contribute to the complex reentry mechanisms involved in ventricular fibrillation.
Melatonin protection against myocardial remodeling induced by kidney disease is one of the factors that protect against ventricular fibrillation. Chronic melatonin prolongs the action potential duration and hyperpolarizes the cardiomyocytes. These changes are the first report of myocardial action potential modifications by chronic administration of melatonin. Opening of Kir3.x channels by melatonin receptor activation could explain hyperpolarization . The action potential lengthening is harder to explain because melatonin activates currents involved in the action potential repolarization and the only inhibitory effect of melatonin against outward potassium currents was described in neurons [90, 129, 130, 215, 216, 217]. As previously mentioned, the downregulation of volume-activated anionic currents can explain attenuated response to action potential shortening induced by ischemia .
A synthesis of the mechanisms of protection of chronic treatment of melatonin cardiovascular complications is outlined in Figure 2. We focus our attention on the preventive effects of melatonin against the alteration of Cx43, mitochondrial oxidant capacity, and membrane potentials. In addition, modulation of the AT1 and VDR receptors related to the increase of HSP 70 contributes to the cardioprotective effects of melatonin.
Melatonin is the rhythmic protector of healthy heart rhythm and a promising preventive agent against ventricular fibrillation, the most lethal and disorganized heart rhythm. Pleotropic effects of melatonin make it an exceptional acute and chronic antiarrhythmic.
This work was supported by grant by ESC research grant funded by the European Society of Cardiology, by ERC-2014-StG 638284 funded by the European Research Council, by project DPI2016-75458-R funded by MINECO (Spain) and FEDER, and by Reference Group BSICoS T39-17R and project LMP124-18 funded by Gobierno de Aragón and FEDER 2014-2020 “Building Europe from Aragón.”
Conflict of interest
The authors declare no conflict of interest.
Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. European Heart Journal. 2015; 36:2793-2867
Black N, D’Souza A, Wang Y, Piggins H, Dobrzynski H, Morris G, et al. Circadian rhythm of cardiac electrophysiology, arrhythmogenesis, and the underlying mechanisms. Heart Rhythm. 2019; 16:298-307
Baltatu OC, Senar S, Campos LA, Cipolla-Neto J. Cardioprotective melatonin: Translating from proof-of-concept studies to therapeutic use. International Journal of Molecular Sciences. 2019; 20:4342
Zhou H, Ma Q , Zhu P, Ren J, Reiter RJ, Chen Y. Protective role of melatonin in cardiac ischemia-reperfusion injury: From pathogenesis to targeted therapy. Journal of Pineal Research. 2018; 64:e12471
Pliss MG, Kuzmenko NV, Rubanova NS, Tsyrlin VA. Dose-dependent mechanisms of melatonin on the functioning of the cardiovascular system and on the behavior of normotensive rats of different ages. Advances in Gerontology. 2019; 9:327-335
Jiki Z, Lecour S, Nduhirabandi F. Cardiovascular benefits of dietary melatonin: A myth or a reality? Frontiers in Physiology. 2018; 9:528
Favero G, Franceschetti L, Buffoli B, Moghadasian MH, Reiter RJ, Rodella LF, et al. Melatonin: Protection against age-related cardiac pathology. Ageing Research Reviews. 2017; 35:336-349
Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonin and omega-3 fatty acids in female rats. Molecular and Cellular Biochemistry. 2019; 454:191-202
Singhanat K, Apaijai N, Chattipakorn SC, Chattipakorn N. Roles of melatonin and its receptors in cardiac ischemia–reperfusion injury. Cellular and Molecular Life Sciences. 2018; 75:4125-4149
Pandi-Perumal SR, BaHammam AS, Ojike NI, Akinseye OA, Kendzerska T, Buttoo K, et al. Melatonin and human cardiovascular disease. Journal of Cardiovascular Pharmacology and Therapeutics. 2017; 22:122-132
Prado NJ, Ferder L, Manucha W, Diez ER. Anti-inflammatory effects of melatonin in obesity and hypertension. Current Hypertension Reports. 2018; 20:45
Crnko S, Du Pré BC, Sluijter JPG, Van Laake LW. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nature Reviews. Cardiology. 2019; 16:437-447
Rana S, Prabhu SD, Young ME. Chronobiological influence over cardiovascular function. Circulation Research. 2020; 126:258-279
Martino TA, Young ME. Influence of the cardiomyocyte circadian clock on cardiac physiology and pathophysiology. Journal of Biological Rhythms. 2015; 30:183-205
Zhou H, Yue Y, Wang J, Ma Q , Chen Y. Melatonin therapy for diabetic cardiomyopathy: A mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cellular Signalling. 2018; 47:88-100
Yang Y, Sun Y, Yi W, Li Y, Fan C, Xin Z, et al. A review of melatonin as a suitable antioxidant against myocardial ischemia-reperfusion injury and clinical heart diseases. Journal of Pineal Research. 2014; 57:357-366
Sun H, Gusdon AM, Qu S. Effects of melatonin on cardiovascular diseases. Current Opinion in Lipidology. 2016; 27:408-413
Han D, Wang Y, Chen J, Zhang J, Yu P, Zhang R, et al. Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin-conferred cardioprotection against myocardial ischemia/reperfusion injury. Journal of Pineal Research. 2019; 67:e12571
Hsu C-N, Huang L-T, Tain Y-L. Perinatal use of melatonin for offspring health: Focus on cardiovascular and neurological diseases. International Journal of Molecular Sciences. 2019; 20:5681
Li K, Hu F, Xiong W, Wei Q , Liu FF. Network-based transcriptomic analysis reveals novel melatonin-sensitive genes in cardiovascular system. Endocrine. 2019; 64:414-419
Egan Benova T, Szeiffova Bacova B, Viczenczova C, Diez E, Barancik M, Tribulova N. Protection of cardiac cell-to-cell coupling attenuate myocardial remodeling and proarrhythmia induced by hypertension. Physiological Research. 2016; 65(Suppl 1):S29-S42
Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M, et al. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. Journal of Pineal Research. 2017; 63:e12419
Nduhirabandi F, Maarman G, Nduhirabandi F, Maarman GJ. Melatonin in heart failure: A promising therapeutic strategy? Molecules. 2018; 23:1819
Reiter RJ, Tan DX, Paredes SD, Fuentes-Broto L. Beneficial effects of melatonin in cardiovascular disease. Annals of Medicine. 2010; 42:279-285
Pechanova O, Paulis L, Simko F. Peripheral and central effects of melatonin on blood pressure regulation. International Journal of Molecular Sciences. 2014; 15:1792017937
Baltatu OC, Amaral FG, Campos LA, Cipolla-Neto J. Melatonin, mitochondria and hypertension. Cellular and Molecular Life Sciences. 2017; 74:3955-3964
Lahera V, de Las HN, López-Farré A, Manucha W, Ferder L. Role of mitochondrial dysfunction in hypertension and obesity. Current Hypertension Reports. 2017; 19:11
Pandi-Perumal SR. Melatonin: Biological Basis of its Function in Health and Disease. CRC Press; 2005. ISBN 1-58706-244-5
Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin-a pleiotropic, orchestrating regulator molecule. Progress in Neurobiology. 2011; 93:350-384
Poeggeler B, Reiter RJ, Tan D-X, Chen L-D, Manchester LC. Melatonin, hydroxyl radical-mediated oxidative damage, and aging: A hypothesis. Journal of Pineal Research. 1993; 14:151-168
Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: One of evolution’s best ideas. Cellular and Molecular Life Sciences. 2017; 74:3863-3881
Galano A, Tan DX, Reiter RJ. Melatonin as a natural ally against oxidative stress: A physicochemical examination. Journal of Pineal Research. 2011; 51:1-16
Galano A, Reiter RJ. Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection. Journal of Pineal Research. 2018; 65:e12514
Galano A. On the direct scavenging activity of melatonin towards hydroxyl and a series of peroxyl radicals. Physical Chemistry Chemical Physics (PCCP). 2011; 13:7178-7188
Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. Journal of Pineal Research. 2013; 54:245-257
Manchester LC, Coto-Montes A, Boga JA, Andersen LPH, Zhou Z, Galano A, et al. Melatonin: An ancient molecule that makes oxygen metabolically tolerable. Journal of Pineal Research. 2015; 59:403-419
Reiter RJ, Tan DX, Galano A. Melatonin: Exceeding expectations. Physiology. 2014; 9:325-333
Reiter RJ, Tan DX. Melatonin: A novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovascular Research. 2003; 58:10-19
Reiter RJ, Mayo JC, Tan D-X, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: Under promises but over delivers. Journal of Pineal Research. 2016; 61:253-278
Forman HJ. Redox signaling: An evolution from free radicals to aging. Free Radical Biology & Medicine. 2016; 97:398-407
Dröge W. Free radicals in the physiological control of cell function. Physiological Reviews. 2002; 82:47-95
Radi R. Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine. Proceedings of the National Academy of Sciences of the United States of America. 2018; 115:5839-5848
Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, et al. Regulation of antioxidant enzymes: A significant role for melatonin. Journal of Pineal Research. 2004; 36:1-9
Afanas’Ev I. ROS and RNS signaling in heart disorders: Could antioxidant treatment be successful? Oxidative Medicine and Cellular Longevity. 2011; 2011:1-13
Yang Y, Sun Y, Yi W, Li Y, Fan C, Xin Z, et al. A review of melatonin as a suitable antioxidant against myocardial ischemia-reperfusion injury and clinical heart diseases. Journal of Pineal Research. 2014; 57:357-366
Brazão V, Santello FH, Colato RP, Mazotti TT, Tazinafo LF, MPA T, et al. Melatonin: Antioxidant and modulatory properties in age-related changes during Trypanosoma cruziinfection. Journal of Pineal Research. 2017; 63:e12409
Tan D-X, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? Journal of Pineal Research. 2007; 42:28-42
Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, et al. The changing biological roles of melatonin during evolution: From an antioxidant to signals of darkness, sexual selection and fitness. Biological Reviews. 2010; 85:607-623
Tengattini S, Reiter RJ, Tan DX, Terron MP, Rodella LF, Rezzani R. Cardiovascular diseases: Protective effects of melatonin. Journal of Pineal Research. 2008; 44:16-25
Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Saiz MM, Aldea-Perona A, de la Torre JM, Garcia-Camarero T, et al. Cardioprotection with melatonin in the acute myocardial infarction: Awaiting results of MARIA trial? International Journal of Cardiology. 2015; 182:54-55
Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. The American Journal of Physiology-Heart and Circulatory Physiology. 2009; 297:H1487-H1493
Yeung HM, Hung MW, Lau CF, Fung ML. Cardioprotective effects of melatonin against myocardial injuries induced by chronic intermittent hypoxia in rats. Journal of Pineal Research 2015; 58:12-25
Yanar K, Simsek B, Çakatay U. Integration of melatonin related redox homeostasis, aging, and circadian rhythm. Rejuvenation Research. 2019; 22:409-419
Sovari AA. Cellular and molecular mechanisms of arrhythmia by oxidative stress. Cardiology Research and Practice. 2016; 2016:1-7
Yang KC, Kyle JW, Makielski JC, Dudley SC. Mechanisms of sudden cardiac death: Oxidants and metabolism. Circulation Research. 2015; 116:1937-1955
Zhou L, Cortassa S, Wei AC, Aon MA, Winslow RL, O’Rourke B. Modeling cardiac action potential shortening driven by oxidative stress-induced mitochondrial oscillations in guinea pig cardiomyocytes. Biophysical Journal. 2009; 97:1843-1852
Akbarali HI. Oxidative stress and ion channels. In Systems Biology of Free Radicals and Antioxidants; Springer-Verlag Berlin Heidelberg, 2012; pp. 355-373; ISBN 9783642300189
Bhuyan R, Chakraborti S. Oxidative stress and modulation of cardiac Kv1.5 channel. In: Oxidative Stress in Heart Diseases. Singapore: Springer; 2019. pp. 191-203
Poole LB. The basics of thiols and cysteines in redox biology and chemistry. Free Radical Biology & Medicine. 2015; 80:148-157
Chouchani ET, James AM, Methner C, Pell VR, Prime TA, Erickson BK, et al. Identification and quantification of protein S -nitrosation by nitrite in the mouse heart during ischemia. The Journal of Biological Chemistry. 2017; 292:14486-14495
Smith BC, Marletta MA. Mechanisms of S-nitrosothiol formation and selectivity in nitric oxide signaling. Current Opinion in Chemical Biology. 2012; 16:498-506
Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. The Journal of Physiology. 1997; 500:631-642
Ma JH, Luo AT, Zhang PH. Effect of hydrogen peroxide on persistent sodium current in Guinea pig ventricular myocytes. Acta Pharmacologica Sinica. 2005; 26:828-834
Light PE, Wallace CHR, Dyck JRB. Constitutively active adenosine monophosphate-activated protein kinase regulates voltage-gated sodium channels in ventricular myocytes. Circulation. 2003; 107:1962-1965
Mazzocchi G, Sommese L, Palomeque J, Felice JI, Di Carlo MN, Fainstein D, et al. Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814. The Journal of Physiology. 2016; 594:3005-3030
Bogeski I, Kappl R, Kummerow C, Gulaboski R, Hoth M, Niemeyer BA. Redox regulation of calcium ion channels: Chemical and physiological aspects. Cell Calcium. 2011; 50:407-423
Bogeski I, Niemeyer BA. Redox regulation of ion channels. Antioxidants & Redox Signaling. 2014; 21:859-862
Zima AV, Blatter LA. Redox regulation of cardiac calcium channels and transporters. Cardiovascular Research. 2006; 71:310-321
Sag CM, Wagner S, Maier LS. Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radical Biology & Medicine. 2013; 63:338-349
Yang K-C, Kyle JW, Makielski JC, Dudley SC. Mechanisms of sudden cardiac death. Circulation Research. 2015; 116:1937-1955
Jeong E-M, Liu M, Sturdy M, Gao G, Varghese ST, Sovari AA, et al. Metabolic stress, reactive oxygen species, and arrhythmia. Journal of Molecular and Cellular Cardiology. 2012; 52:454-463
Svoboda LK, Reddie KG, Zhang L, Vesely ED, Williams ES, Schumacher SM, et al. Redox-sensitive sulfenic acid modification regulates surface expression of the cardiovascular voltage-gated potassium channel Kv1.5. Circulation Research. 2012; 111:842-853
Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: Distribution and functions. Molecular and Cellular Endocrinology. 2012; 351:152-166
Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, et al. Update on melatonin receptors: IUPHAR review 20. British Journal of Pharmacology. 2016; 173:2702-2725
Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang XP, et al. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature. 2019; 569:284-288
Johansson LC, Stauch B, McCorvy JD, Han GW, Patel N, Huang XP, et al. XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity. Nature. 2019; 569:289-292
Benleulmi-Chaachoua A, Chen L, Sokolina K, Wong V, Jurisica I, Emerit MB, et al. Protein interactome mining defines melatonin MT1 receptors as integral component of presynaptic protein complexes of neurons. Journal of Pineal Research. 2016; 60:95-108
Jockers R, Maurice P, Boutin JA, Delagrange P. Melatonin receptors, heterodimerization, signal transduction and binding sites: What’s new? British Journal of Pharmacology. 2008; 154:1182-1195
Cecon E, Oishi A, Jockers R. Melatonin receptors: Molecular pharmacology and signalling in the context of system bias. British Journal of Pharmacology. 2018; 175:3263-3280
Oishi A, Karamitri A, Gerbier R, Lahuna O, Ahmad R, Jockers R. Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT 2 receptor reciprocally modulate their signaling functions. Scientific Reports. 2017; 7:8990
Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: Their structure, function, and physiological roles. Physiological Reviews. 2010; 90:291-366
Baba K, Benleulmi-Chaachoua A, Journé AS, Kamal M, Guillaume JL, Dussaud S, et al. Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Science Signaling. 2013; 6:ra89-ra89
Prado NJ, Egan Beňová T, Diez ER, Knezl V, Lipták B, Ponce Zumino AZ, et al. Melatonin receptor activation protects against low potassium-induced ventricular fibrillation by preserving action potentials and connexin-43 topology in isolated rat hearts. Journal of Pineal Research. 2019; 67:e12605
Boutin JA, Ferry G. Is there sufficient evidence that the melatonin binding site MT3 is quinone reductase 2? The Journal of Pharmacology and Experimental Therapeutics. 2019; 368:59-65
Zhang HM, Zhang Y. Melatonin: A well-documented antioxidant with conditional pro-oxidant actions. Journal of Pineal Research. 2014; 57:131-146
Boutin JA, Marcheteau E, Hennig P, Moulharat N, Berger S, Delagrange P, et al. MT3/QR2 melatonin binding site does not use melatonin as a substrate or a co-substrate. Journal of Pineal Research. 2008; 45:524-531
Mailliet F, Ferry G, Vella F, Berger S, Cogé F, Chomarat P, et al. Characterization of the melatoninergic MT3 binding site on the NRH:Quinone oxidoreductase 2 enzyme. Biochemical Pharmacology. 2005; 71:74-88
Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJMM, Zisapel N, et al. Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways. Progress in Neurobiology. 2008; 85:335-353
Gonano LA, Sepúlveda M, Rico Y, Kaetzel M, Valverde CA, Dedman J, et al. Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias. Circulation: Arrhythmia and Electrophysiology. 2011; 4:947-957
Squecco R, Tani A, Zecchi-Orlandini S, Formigli L, Francini F. Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium. European Journal of Pharmacology. 2015; 758:40-52
Wong R, Steenbergen C, Murphy E. Mitochondrial permeability transition pore and calcium handling. In: Mitochondrial Bioenergetics. Methods in Molecular Biology (Methods and Protocols). Humana Press. 2012; 810. ISBN 978-1-61779-381-3
Valverde CA, Kornyeyev D, Mattiazzi AR, Escobar AL. Reperfusion after ichemia causes cytosolic calcium overload due to rapid calcium release from the sarcoplasmic reticulum. Biophysical Journal. 2009; 96:550a
Yeung HM, Hung MW, Fung ML. Melatonin ameliorates calcium homeostasis in myocardial and ischemia-reperfusion injury in chronically hypoxic rats. Journal of Pineal Research. 2008; 45:373-382
Valverde CA, Mattiazzi A, Escobar AL. Camkii exacerbates calcium waves during reperfusion of ischemic heart. Biophysical Journal. 2014; 106:322a
Baumeister P, Quinn TA. Altered calcium handling and ventricular arrhythmias in acute ischemia. Clinical Medicine Insights: Cardiology. 2016; 10s1:CMC.S39706
ter Keurs HEDJ, Boyden PA. Calcium and Arrhythmogenesis. Physiological Reviews. 2007; 87:457-506
Prado NJ, Casarotto M, Calvo JP, Mazzei L, Ponce Zumino AZ, García IM, et al. Antiarrhythmic effect linked to melatonin cardiorenal protection involves AT 1 reduction and Hsp70-VDR increase. Journal of Pineal Research. 2018; 65:e12513
Xu W, Cai S-YY, Zhang Y, Wang Y, Ahammed GJ, Xia X-JJ, et al. Melatonin enhances thermotolerance by promoting cellular protein protection in tomato plants. Journal of Pineal Research. 2016; 61:457-469
Rezzani R, Rodella LF, Bonomini F, Tengattini S, Bianchi R, Reiter RJ. Beneficial effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are receptor mediated. Journal of Pineal Research. 2006; 41:288-295
Tas U, Ogeturk M, Kuloglu T, Sapmaz HI, Kocaman N, Zararsiz I, et al. HSP70 immune reactivity and TUNEL positivity in the liver of toluene-inhaled and melatonin-treated rats. Toxicology and Industrial Health. 2013; 29:514-522
Yoon YM, Kim HJ, Lee JH, Lee SH. Melatonin enhances mitophagy by upregulating expression of heat shock 70 kDa protein 1 L in human mesenchymal stem cells under oxidative stress. International Journal of Molecular Sciences. 2019; 20:4545
Motawi TK, Ahmed SA, A Hamed M, El-Maraghy SA, M Aziz W. Melatonin and/or rowatinex attenuate streptozotocin-induced diabetic renal injury in rats. Journal of Biomedical Research. 2019; 33:113-121
Fang N, Hu C, Sun W, Xu Y, Gu Y, Wu L, et al. Identification of a novel melatonin-binding nuclear receptor: Vitamin D receptor. Journal of Pineal Research. 2020; 68:e12618
Morciano G, Giorgi C, Bonora M, Punzetti S, Pavasini R, Wieckowski MR, et al. Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury. Journal of Molecular and Cellular Cardiology. 2015; 78:142-153
Hacışevki A, Baba B. An overview of melatonin as an antioxidant molecule: a biochemical approach. In: Melatonin—Molecular Biology, Clinical and Pharmaceutical Approaches. Rijeka: IntechOpen; 2018
Ganie SA, Dar TA, Bhat AH, Dar KB, Anees S, Zargar MA, et al. Melatonin: A potential anti-oxidant therapeutic agent for mitochondrial dysfunctions and related disorders. Rejuvenation Research. 2016; 19:21-40
Das N, Mandala A, Naaz S, Giri S, Jain M, Bandyopadhyay D, et al. Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. Journal of Pineal Research. 2017; 62:e12404
Donato AJ, Morgan RG, Walker AE, Lesniewski LA. Cellular and molecular biology of aging endothelial cells. Journal of Molecular and Cellular Cardiology. 2015; 89:122-135
Xu S, Pi H, Zhang L, Zhang N, Li YM, Zhang H, et al. Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria. Journal of Pineal Research. 2016; 60:291-302
Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Mitochondrial bioenergetics decay in aging: Beneficial effect of melatonin. Cellular and Molecular Life Sciences. 2017; 74:3897-3911
Ma Z, Xin Z, Di W, Yan X, Li X, Reiter RJ, et al. Melatonin and mitochondrial function during ischemia/reperfusion injury. Cellular and Molecular Life Sciences. 2017; 74:3989-3998
Petrosillo G, Di Venosa N, Pistolese M, Casanova G, Tiravanti E, Colantuono G, et al. Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: Role of cardiolipin. The FASEB Journal. 2006; 20:269-276
Petrosillo G, Moro N, Paradies V, Ruggiero FM, Paradies G. Increased susceptibility to Ca2+-induced permeability transition and to cytochrome c release in rat heart mitochondria with aging: Effect of melatonin. Journal of Pineal Research. 2010; 45:340-346
Kang JW, Hong JM, Lee SM. Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis. Journal of Pineal Research. 2016; 60:383-393
Pei HF, Hou JN, Wei FP, Xue Q , Zhang F, Peng CF, et al. Melatonin attenuates postmyocardial infarction injury via increasing Tom70 expression. Journal of Pineal Research. 2017; 62:e12371
Fan ACY, Young JC. Function of cytosolic chaperones in Tom70-mediated mitochondrial import. Protein and Peptide Letters. 2011; 18:122-131
Lochner A, Marais E, Huisamen B. Melatonin and cardioprotection against ischaemia/reperfusion injury: What’s new? A review. Journal of Pineal Research. 2018; 65:e12490
Matsushima S, Sadoshima J. The role of sirtuins in cardiac disease. The American Journal of Physiology-Heart and Circulatory Physiology. 2015; 309:H1375-H1389
D’Onofrio N, Servillo L, Balestrieri ML. SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection. Antioxidants & Redox Signaling. 2018; 28:711-732
Yu L, Sun Y, Cheng L, Jin Z, Yang Y, Zhai M, et al. Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: Role of SIRT1. Journal of Pineal Research. 2014; 57:228-238
Yu L, Liang H, Dong X, Zhao G, Jin Z, Zhai M, et al. Reduced silent information regulator 1 signaling exacerbates myocardial ischemia-reperfusion injury in type 2 diabetic rats and the protective effect of melatonin. Journal of Pineal Research. 2015; 59:376-390
Mayo JC, Sainz RM, González Menéndez P, Cepas V, Tan DX, Reiter RJ. Melatonin and sirtuins: A “not-so unexpected” relationship. Journal of Pineal Research. 2017; 62:e12391
Yu L, Gong B, Duan W, Fan C, Zhang J, Li Z, et al. Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: Role of AMPK-PGC-1α-SIRT3 signaling. Scientific Reports. 2017; 7:41337
Chua S, Lee F-YY, Chiang H-JJ, Chen K-HH, Lu H-II, Chen Y-TTY-LL, et al. The cardioprotective effect of melatonin and exendin-4 treatment in a rat model of cardiorenal syndrome. Journal of Pineal Research. 2016; 61:438-456
Majidinia M, Sadeghpour A, Mehrzadi S, Reiter RJ, Khatami N, Yousefi B. Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways. Journal of Pineal Research. 2017; 63:e12416
Ben SI, Mies F, Naeije R, Shlyonsky V. Melatonin down-regulates volume-sensitive chloride channels in fibroblasts. Pflügers Archiv: European Journal of Physiology. 2012; 464:273-285
Diez ER, Prados LV, Carrión A, Ponce ZAZ, Miatello RM. A novel electrophysiologic effect of melatonin on ischemia/reperfusion-induced arrhythmias in isolated rat hearts. Journal of Pineal Research. 2009; 46:155-160
Diez ER, Prado NJ, Carrión AM, Petrich ER, Ponce Zumino AZ, Miatello RM. Electrophysiological effects of tamoxifen: Mechanism of protection against reperfusion arrhythmias in isolated rat hearts. Journal of Cardiovascular Pharmacology. 2013; 62:184-191
Varga Z, Panyi G, Péter M, Pieri C, Csécsei G, Damjanovich S, et al. Multiple binding sites for melatonin on Kv1.3. Biophysical Journal. 2001; 80:1280-1297
Hablitz LM, Molzof HE, Abrahamsson KE, Cooper JM, Prosser RA, Gamble KL. GIRK channels mediate the nonphotic effects of exogenous melatonin. The Journal of Neuroscience. 2015; 35:14957-14965
Nelson CS, Marino JL, Allen CN. Melatonin receptors activate heteromeric G-protein coupled Kir3 channels. Neuroreport. 1996; 7:717-720
Huang Y, Li Y, Leng Z. Melatonin inhibits GABAergic neurons in the hypothalamus consistent with a reduction in wakefulness. Neuroreport. 2020; 31:92-98
Waseem M, Tabassum H, Parvez S. Melatonin modulates permeability transition pore and 5-hydroxydecanoate induced KATP channel inhibition in isolated brain mitochondria. Mitochondrion. 2016; 31:1-8
Mohammadi F, Shakiba S, Mehrzadi S, Afshari K, Rahimnia AH, Dehpour AR. Anticonvulsant effect of melatonin through ATP-sensitive channels in mice. Fundamental & Clinical Pharmacology. 2020; 34:148-155
Brown DA, Aon MA, Frasier CR, Sloan RC, Maloney AH, Anderson EJ, et al. Cardiac arrhythmias induced by glutathione oxidation can be inhibited by preventing mitochondrial depolarization. Journal of Molecular and Cellular Cardiology. 2010; 48:673-679
Nakaya H. Role of ATP-sensitive K+ channels in cardiac arrhythmias. Journal of Cardiovascular Pharmacology and Therapeutics. 2014; 19:237-243
Ayar A, Martin DJ, Ozcan M, Kelestimur H. Melatonin inhibits high voltage activated calcium currents in cultured rat dorsal root ganglion neurones. Neuroscience Letters. 2001; 313:73-77
Choi TY, Kwon JE, Durrance ES, Jo SH, Choi SY, Kim KT. Melatonin inhibits voltage-sensitive Ca2+ channel-mediated neurotransmitter release. Brain Research. 2014; 1557:34-42
Escames G, Macías M, León J, García J, Khaldy H, Martín M, et al. Calcium-dependent effects of melatonin inhibition of glutamatergic response in rat striatum. Journal of Neuroendocrinology. 2001; 13:459-466
Mei YA, Lee PPN, Wei H, Zhang ZH, Pang SF. Melatonin and its analogs potentiate the nifedipine-sensitive high-voltage-activated calcium current in the chick embryonic heart cells. Journal of Pineal Research. 2001; 30:13-21
Mück AO, Seeger H, Bartsch C, Lippert TH. Does melatonin affect calcium influx in human aortic smooth muscle cells and estradiol-mediated calcium antagonism? Journal of Pineal Research. 1996; 20:145-147
Chen LD, Kumar P, Reiter RJ, Tan DX, Chamber JP, Manchester LC, et al. Melatonin reduces 3H-nitrendipine binding in the heart. Proceedings of the Society for Experimental Biology and Medicine. 1994; 207:34-37
Xu Z, Wu Y, Zhang Y, Zhang H, Shi L. Melatonin activates BKCa channels in cerebral artery myocytes via both direct and MT receptor/PKC-mediated pathway. European Journal of Pharmacology. 2019; 842:177-188
Al Dera H, Alassiri M, Eleawa SM, AlKhateeb MA, Hussein AM, Dallak M, et al. Melatonin improves memory deficits in rats with cerebral hypoperfusion, possibly, through decreasing the expression of small-conductance Ca2+-activated K+ channels. Neurochemical Research. 2019; 44:1851-1868
Ovali MA, Uzun M. The effects of melatonin administration on KCNQ and KCNH2 gene expressions and QTc interval in pinealectomised rats. Cellular and Molecular Biology. 2017; 63:45-50
Arntz HR, Willich SN, Oeff M, Brüggemann T, Stern R, Heinzmann A, et al. Circadian variation of sudden cardiac death reflects age-related variability in ventricular fibrillation. Circulation. 1993; 88:2284-2289
Tribulova N, Szeiffova Bacova B, Benova T, Viczenczova C. Can we protect from malignant arrhythmias by modulation of cardiac cell-to-cell coupling? Journal of Electrocardiology. 2015; 48:434-440
Babiker F, Al-Jarallah A, Al-Awadi M. Effects of cardiac hypertrophy, diabetes, aging, and pregnancy on the Cardioprotective effects of Postconditioning in male and female rats. Cardiology Research and Practice. 2019; 2019:3403959
Carro J, Pueyo E, Rodríguez Matas JF. A response surface optimization approach to adjust ionic current conductances of cardiac electrophysiological models. Application to the study of potassium level changes. PLoS One. 2018; 13:e0204411
Johnson R, Camelliti P. Role of non-Myocyte gap junctions and Connexin Hemichannels in cardiovascular health and disease: Novel therapeutic targets? International Journal of Molecular Sciences. 2018; 19:866
Pk W, Whelton PK, Carey RM, Aronow WS, Ovbiagele B, Casey DE, et al. Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. Journal of American College of Cardiology. 2017; 283
Steinberg C, Laksman ZWM, Krahn AD. Sudden cardiac death: A reappraisal. Trends in Cardiovascular Medicine. 2016; 26:709-719
Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal. 2018; 39:119-177
Roth GA, Huffman MD, Moran AE, Feigin V, Mensah GA, Naghavi M, et al. Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation. 2015; 132:1667-1678
Ambale-Venkatesh B, Yang X, Wu CO, Liu K, Hundley WG, McClelland R, et al. Cardiovascular event prediction by machine learning. Circulation Research. 2017; 121:1092-1101
Adabag AS, Luepker RV, Roger VL, Gersh BJ. Sudden cardiac death: Epidemiology and risk factors. Nature Reviews. Cardiology. 2010; 7:216-225
Li Y, Nantsupawat T, Tholakanahalli V, Adabag S, Wang Z, Benditt DG, et al. Characteristics and periodicity of sustained ventricular tachyarrhythmia events in a population of military veterans with implantable cardioverter defibrillator. Journal of Interventional Cardiac Electrophysiology. 2019. DOI: 10.1007/s10840-019-00569-0. [Epub ahead of print]
Tang PT, Shenasa M, Boyle NG. Ventricular arrhythmias and sudden cardiac death. Cardiac Electrophysiology Clinics. 2017; 9:693-708
Tan D-X, Manchester LC, Reiter RJ, Qi W, Kim SJ, El-Sokkary GH. Ischemia/reperfusion-induced arrhythmias in the isolated rat heart: Prevention by melatonin. Journal of Pineal Research. 1998; 25:184-191
Lagneux C, Joyeux M, Demenge P, Ribuot C, Godin-Ribuot D. Protective effects of melatonin against ischemia-reperfusion injury in the isolated rat heart. Life Sciences. 2000; 66:503-509
Szárszoi O, Asemu G, Vaněček J, Ošt’ádal B, Kolář F. Effects of melatonin on ischemia and reperfusion injury of the rat heart. Cardiovascular Drugs and Therapy. 2001; 15:251-257
Kaneko S, Okumura K, Numaguchi Y, Matsui H, Murase K, Mokuno S, et al. Melatonin scavenges hydroxyl radical and protects isolated rat hearts from ischemic reperfusion injury. Life Sciences. 2000; 67:101-112
Lee YM, Chen HR, Hsiao G, Sheu JR, Wang JJ, Yen MH. Protective effects of melatonin on myocardial ischemia/reperfusion injury in vivo. Journal of Pineal Research. 2002; 33:72-80
Bertuglia S, Reiter RJ. Melatonin reduces ventricular arrhythmias and preserves capillary perfusion during ischemia-reperfusion events in cardiomyopathic hamsters. Journal of Pineal Research. 2007; 42:55-63
Važan R, Pancza D, Béder I, Styk J. Ischemia-reperfusion injury—Antiarrhythmic effect of melatonin associated with reduced recovering of contractility. General Physiology and Biophysics. 2005; 24:355-359
Vazan R, Ravingerova T. Protective effect of melatonin against myocardial injury induced by epinephrine. Journal of Physiology and Biochemistry. 2015; 71:43-49
Dobsak P, Siegelova J, Eicher JC, Jancik J, Svacinova H, Vasku J, et al. Melatonin protects against ischemia-reperfusion injury and inhibits apoptosis in isolated working rat heart. Pathophysiology. 2003; 9:179-187
Diez ER, Renna NF, Prado NJ, Lembo C, Ponce Zumino AZ, Vazquez-Prieto M, et al. Melatonin, given at the time of reperfusion, prevents ventricular arrhythmias in isolated hearts from fructose-fed rats and spontaneously hypertensive rats. Journal of Pineal Research. 2013; 55:166-173
Benova T, Viczenczova C, Radosinska J, Bacova B, Knezl V, Dosenko V, et al. Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythmias. Canadian Journal of Physiology and Pharmacology. 2013; 91:633-639
Lee S, Kang E, Yoo KD, Choi Y, Kim DK, Joo KW, et al. Lower serum potassium associated with increased mortality in dialysis patients: A nationwide prospective observational cohort study in Korea. PLoS One. 2017; 12:e0171842
Pun PH, Goldstein BA, Gallis JA, Middleton JP, Svetkey LP. Serum potassium levels and risk of sudden cardiac death among patients with chronic kidney disease and significant coronary artery disease. Kidney International Reports. 2017; 2:1122-1131
Osadchii OE. Electrophysiological determinants of arrhythmic susceptibility upon endocardial and epicardial pacing in Guinea-pig heart. Acta Physiologica. 2012; 205:494-506
Osadchii OE. Impact of hypokalemia on electromechanical window, excitation wavelength and repolarization gradients in guinea-pig and rabbit hearts. PLoS One. 2014; 9:e105599
Osadchii OE. Effects of antiarrhythmics and hypokalemia on the rate adaptation of cardiac repolarization. Scandinavian Cardiovascular Journal. 2018; 52:218-226
Xie Y, Sato D, Garfinkel A, Qu Z, Weiss JN. So little source, so much sink: Requirements for after depolarizations to propagate in tissue. Biophysical Journal. 2010; 99:1408-1415
Osadchii OE. Mechanisms of hypokalemia-induced ventricular arrhythmogenicity. Fundamental & Clinical Pharmacology. 2010; 24:547-559
Ek-Vitorín J, Pontifex T, Burt J, Ek-Vitorín JF, Pontifex TK, Burt JM. Cx43 channel gating and permeation: Multiple phosphorylation-dependent roles of the carboxyl terminus. International Journal of Molecular Sciences. 2018; 19:1659
Palatinus JA, O’Quinn MP, Barker RJ, Harris BS, Jourdan J, Gourdie RG. ZO-1 determines adherens and gap junction localization at intercalated disks. The American Journal of Physiology: Heart and Circulatory Physiology. 2011; 300:H583-H594
Iyyathurai J, Himpens B, Bultynck G, D’hondt C. Calcium wave propagation triggered by local mechanical stimulation as a method for studying gap junctions and hemichannels. Methods in Molecular Biology (Clifton, NJ). 2016; 1437:203-211
Dhein S, Seidel T, Salameh A, Jozwiak J, Hagen A, Kostelka M, et al. Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias. Frontiers in Physiology. 2014; 5:424
Xie Y, Garfinkel A, Camelliti P, Kohl P, Weiss JN, Qu Z. Effects of fibroblast-myocyte coupling on cardiac conduction and vulnerability to reentry: A computational study. Heart Rhythm. 2009; 6:1641-1649
Remo BF, Qu J, Volpicelli FM, Giovannone S, Shin D, Lader J, et al. Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias. Circulation Research. 2011; 108:1459-1466
Hoppe LK, Muhlack DC, Koenig W, Carr PR, Brenner H, Schöttker B. Association of abnormal serum potassium levels with arrhythmias and cardiovascular mortality: A systematic review and meta-analysis of observational studies. Cardiovascular Drugs and Therapy. 2018; 32:197-212
Trenor B, Cardona K, Romero L, Gomez JF, Saiz J, Rajamani S, et al. Pro-arrhythmic effects of low plasma [K+] in human ventricle: An illustrated review. Trends in Cardiovascular Medicine. 2018; 28:233-242
Ishigaki S, Ohashi N, Isobe S, Tsuji N, Iwakura T, Ono M, et al. Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease. Clinical and Experimental Nephrology. 2016; 20:878-884
Zetner D, Andersen L, Rosenberg J. Pharmacokinetics of alternative administration routes of melatonin: A systematic review. Drug Research (Stuttgart). 2015; 66:169-173
Andersen LPH, Gögenur I, Rosenberg J, Reiter RJ. The safety of melatonin in humans. Clinical Drug Investigation. 2016; 36:169-175
Gul-Kahraman K, Yilmaz-Bozoglan M, Sahna E. Physiological and pharmacological effects of melatonin on remote ischemic perconditioning after myocardial ischemia-reperfusion injury in rats: Role of Cybb, Fas, NfκB, Irisin signaling pathway. Journal of Pineal Research. 2019; 67:e12589
Sahna E, Olmez E, Acet A. Effects of physiological and pharmacological concentrations of melatonin on ischemia-reperfusion arrhythmias in rats: Can the incidence of sudden cardiac death be reduced? Journal of Pineal Research. 2002; 32:194-198
Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ. Circadian variation in acute myocardial infarction size: Likely involvement of the melatonin and suprachiasmatic nuclei. International Journal of Cardiology. 2017; 235:191
Nagibin V, Egan Benova T, Viczenczova C, Szeiffova Bacova B, Dovinova I, Barancik M, et al. Ageing related down-regulation of myocardial connexin-43 and up-regulation of MMP-2 may predict propensity to atrial fibrillation in experimental animals. Physiological Research. 2016; 65(Suppl 1):S91-S100
Sedova KA, Bernikova OG, Cuprova JI, Ivanova AD, Kutaeva GA, Pliss MG, et al. Association between antiarrhythmic, electrophysiological, and Antioxidative effects of melatonin in ischemia/reperfusion. International Journal of Molecular Sciences. 2019; 20:6331
Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, et al. AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A report of the American College of Cardiology/American Heart Association task force on clinical practice Gui. Heart Rhythm. 2017; 15:e190-e252
Li J, Hu D, Song X, Han T, Gao Y, Xing Y. The role of biologically active ingredients from natural drug treatments for arrhythmias in different mechanisms. BioMed Research International. 2017; 2017:1-10
Al-Gobari M, Al-Aqeel S, Gueyffier F, Burnand B. Effectiveness of drug interventions to prevent sudden cardiac death in patients with heart failure and reduced ejection fraction: An overview of systematic reviews. BMJ Open. 2018; 8:e021108
Erath JW, Hohnloser SH. Drugs to prevent sudden cardiac death. International Journal of Cardiology. 2017; 237:22-24
Zanoboni A, Zanoboni-Muciaccia W. Experimental hypertension in pinealectomized rats. Life Sciences. 1967; 6:2327-2331
Holmes SW, Sugden D. Proceedings: The effect of melatonin on pinealectomy-induced hypertension in the rat. British Journal of Pharmacology. 1976; 56:360P-361P
De Farias TDSM, De Oliveira AC, Andreotti S, Do Amaral FG, Chimin P, De Proença ARA, et al. Pinealectomy interferes with the circadian clock genes expression in white adipose tissue. Journal of Pineal Research. 2015; 58:251-261
Simko F, Pechanova O. Remodelling of the heart and vessels in experimental hypertension: Advances in protection. Journal of Hypertension. 2010; 28(Suppl 1):S1-S6
Russcher M, Koch B, Nagtegaal E, van der Putten K, ter Wee P, Gaillard C. The role of melatonin treatment in chronic kidney disease. Frontiers in Bioscience (Landmark Ed). 2012; 17:2644-2656
Campos LA, Cipolla-Neto J, Amaral FG, Michelini LC, Bader M, Baltatu OC. The angiotensin-melatonin Axis. International Journal of Hypertension. 2013; 2013:1-7
Ishigaki S, Ohashi N, Matsuyama T, Isobe S, Tsuji N, Iwakura T, et al. Melatonin ameliorates intrarenal renin–angiotensin system in a 5/6 nephrectomy rat model. Clinical and Experimental Nephrology. 2018; 22:539-549
Franczyk-Skóra B, Gluba-Brzózka A, Wranicz JK, Banach M, Olszewski R, Rysz J. Sudden cardiac death in CKD patients. International Urology and Nephrology. 2015; 47:971-982
Pun PH. The interplay between CKD, sudden cardiac death, and ventricular arrhythmias. Advances in Chronic Kidney Disease. 2014; 21:480-488
Bonato FOB, Canziani MEF, Bonato FOB, Canziani MEF. Ventricular arrhythmia in chronic kidney disease patients. Jornal Brasileiro de Nefrologia. 2017; 39:186-195
Bonato FOB, Watanabe R, Lemos MM, Cassiolato JL, Wolf M, Canziani MEF. Asymptomatic ventricular arrhythmia and clinical outcomes in chronic kidney disease: A pilot study. The Journal CardioRenal Medicine. 2016; 7:66-73
Reddan DN, Szczech L, Bhapkar MV, Moliterno DJ, Califf RM, Ohman EM, et al. Renal function, concomitant medication use and outcomes following acute coronary syndromes. Nephrology, Dialysis, Transplantation. 2005; 20:2105-2112
Diez ER, Altamirano LB, García IM, Mazzei L, Prado NJ, Fornes MW, et al. Heart remodeling and ischemia–reperfusion arrhythmias linked to myocardial vitamin D receptors deficiency in obstructive nephropathy are reversed by Paricalcitol. Journal of Cardiovascular Pharmacology and Therapeutics. 2015; 20:211-220
Mazzei L, Docherty NG, Manucha W. Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy. Cell Stress & Chaperones. 2015; 20:893-906
Lutz W, Kohno K, Kumar R. The role of heat shock protein 70 in vitamin D receptor function. Biochemical and Biophysical Research Communications. 2001; 282:1211-1219
Ferder M, Inserra F, Manucha W, Ferder L. The world pandemic of vitamin D deficiency could possibly be explained by cellular inflammatory response activity induced by the renin-angiotensin system. The American Journal of Physiology-Cell Physiology. 2013; 304:C1027-C1039
García IM, Altamirano L, Mazzei L, Fornés M, Cuello-Carrión FD, Ferder L, et al. Vitamin D receptor-modulated Hsp70/AT1 expression may protect the kidneys of SHRs at the structural and functional levels. Cell Stress & Chaperones. 2014; 19:479-491
McElwee SK, Velasco A, Doppalapudi H. Mechanisms of sudden cardiac death. Journal of Nuclear Cardiology. 2016; 23:1368-1379
van den Top M, Buijs RM, Ruijter JM, Delagrange P, Spanswick D, Hermes ML. Melatonin generates an outward potassium current in rat suprachiasmatic nucleus neurones in vitro independent of their circadian rhythm. Neuroscience. 2001; 107:99-108
Hou S-W, Zheng P, Sun F-Y. Melatonin inhibits outward delayed rectifier potassium currents in hippocampal CA1 pyramidal neuron via intracellular indole-related domains. Journal of Pineal Research. 2004; 36:242-249
Yang XF, Miao Y, Ping Y, Wu HJ, Yang XL, Wang Z. Melatonin inhibits tetraethylammonium-sensitive potassium channels of rod ON type bipolar cells via MT2 receptors in rat retina. Neuroscience. 2011; 173:19-29