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Chapter
Melatonin for a Healthy Heart
Rhythm
Natalia JorgelinaPrado, MargaritaSegovia-Roldan,
EmilianoRaúlDiez and EstherPueyo
Abstract
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 mecha-
nisms of melatonin involve its antioxidant properties as well as receptor-mediated
actions. Signaling pathways include membrane responses, cytoplasmic modula-
tion 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 intercel-
lular communication. An outstanding antifibrillatory effect makes melatonin a
novel antiarrhythmic agent worthy of further exploration in the path to clinical
applications.
Keywords: melatonin, arrhythmias, ventricular fibrillation, action potential,
connexin 43, melatonin receptors
. Introduction
“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 melatonins antiarrhythmic
effects.
Melatonin
. Melatonin properties relevant to heart rhythms
Endogenous and pharmacological increases of melatonin concentrations protect
the cardiovascular system [3–11]. However, the relationships between the cardio-
vascular and circadian systems are highly complex and should not be interpreted in
reductionist ways [5, 1214]. Furthermore, our understanding of the pleiotropy of
melatonin, a highly preserved molecule of protection, is continuously expanding
[3–7, 10, 1524]. 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, inflam-
mation, 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:
a. Antioxidant
b. Receptor activation
c. Improvement of mitochondrial functions
d. 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 [31–37]. Melatonin is a powerful
antioxidant, with a potency of up to 10 times greater than vitamin E [38].
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, pro-
teins, 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 [40–42].
Melatonin for a Healthy Heart Rhythm
DOI: hp://dx.doi.org/10.5772/intechopen.91447
Cells have antioxidants that prevent damage. An antioxidant is any substance
that significantly delays or prevents oxidation of lipids, proteins, or DNA [40].
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 [34]. The main
antioxidant enzymes are superoxide dismutase (SOD), catalase, thioredoxin, and
glutathione peroxidase [4044].
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, 4547]. In addition, several metabolites
formed when melatonin neutralizes harmful reagents are also antioxidants suggest-
ing that a cascade of reactions increases the efficacy of melatonin [28, 35, 4749].
Being a highly lipophilic and hydrophilic compound, melatonin crosses all mor-
phological 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, cytoplas-
mic, 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 [5458]. 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 [59]. Many of these
proteins are involved in important biological reactions such as oxidative phosphory-
lation, 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) [64]. 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 [6569].
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 [66]. Voltage-gated potassium (Kv)
channel, mainly responsible for myocardial repolarization, is sensitive to oxidative
stress [58, 7072]. Sulfenic acid modification at a conserved cysteine residue of
Kv1.5 under prolonged oxidative stress can induce arrhythmia [58, 72].
.. 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, gas-
trointestinal tract, prostate gland, uterus, skin, and eyes [73]. 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) [74]. Both receptors have high affinity to melatonin (Kd ~ 0.1 pM). In
2019, Stauch and Johansson reported the crystal structures of the human MT1 and
MT2 and set a solid base concerning ligand recognition for both receptors [75, 76].
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, 7779]. 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 [80]. Other G-protein-coupled receptors like the serotonin receptor
5HT2c can interact with melatonin membrane receptors [79]. 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 [81]. 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 melatonins enhance-
ment of scotopic light sensitivity through phospholipase C and PKC pathways [82].
Several compounds interact with MT1 and MT2 receptors, but blocker luzindole
is the only with proven myocardial electrophysiological effects [83]. 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 [84].
This enzyme is possibly involved in the regulation of cellular oxidative status,
although the exact regulatory action of melatonin remains unclear [8487].
Furthermore, the electrophysiological effects of MT3 have not been reported yet.
Melatonin interacts with intracellular proteins such as calmodulin, calreticulin,
or tubulin [88]. 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 [89–96].
Melatonin increases the cytoplasmic levels of the heat shock protein 70in several
tissues including the heart [97102]. 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 [33]. 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].
.. 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
Melatonin for a Healthy Heart Rhythm
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produce up to 95% of the cellular energy in the form of ATP in aerobic cells
[105]. 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, 109111]. 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 permeabil-
ity 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 [97]. Melatonin improves mitofusin-2,
which preserves the mitochondrial functional network and prevents apoptosis
[114]. The reduction of mitochondrial damage in the heart could be related to the
negative regulation of angiotensin II type 1 receptor (AT1) by melatonin [97]. 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 pro-
cesses [116]. Tom 70 regulates melatonin-induced cardioprotection by preventing
mitochondrial deterioration and oxidative stress [97, 115].
Melatonins cardioprotection associates with an increase in the number of mito-
chondria and positive regulation of survival genes such as nicotinamide phosphori-
bosyl transferase and nicotinamide adenine dinucleotide-dependent deacetylases,
called sirtuins [117]. 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 [117–121]. Sirtuin-3 is a family
member that is primarily located in the mitochondria and protects against inflam-
mation and diseases related to oxidative stress. Melatonin elevates sirtuin-3, stimu-
lates 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.
.. 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
Melatonin
currents do not respond to acute exposure of cells to melatonin in hypotonic solu-
tions [126]. However, when cells are pre-incubated with melatonin concentrations
from 1 to 100μM for 30–60min, the anionic currents in response to hypotonic-
ity 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 down-
regulation 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 [129]. However, the inhibitory effects
require high extracellular melatonin in the mM range [129]. 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 [130]. 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 [131]. 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 [132].
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) [133]. The opening of KATP
contributes to melatonin antiseizure effect [134]. 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 melato-
nin could be proarrhythmic [135, 136].
Melatonin modulates most of the voltage-activated calcium channel subtypes
(L, P, Q , N, and R) with different effects [137–141]. 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 [137]. Melatonin has no effect on voltage-activated
calcium channels in cultured human aortic smooth muscle cells [141]. Melatonin
accutelly increase L type calcium currents in chick cardiac membranes [140, 141].
An early study shows that melatonin downregulates voltage-sensitive calcium chan-
nels in the heart [142]. These results indicate that melatonin may have differnt acute
and chronic implications for normal cardiac physiology and for the pharmacological
manipulation of the heart [142].
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 [143]. Small-conductance
Melatonin for a Healthy Heart Rhythm
DOI: hp://dx.doi.org/10.5772/intechopen.91447
Ca2+-activated K (SK) channels are also modulated by the action of melatonin
[144]. 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 [144].
Additional information was brought about KCNQ from the aorta and related
with vascular tone, and KCNH2in the left ventricle was associated with QT dura-
tion in rats where melatonin was able to prevent the increase in blood pressure and
change KCNQ and KCNH2 gene expression profiles [145].
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.
. 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 [2]. 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 [146148].
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 [149].
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 [150]. Gap junctions couple the cells and allow the
flow of electrical current and small molecules. The largest accumulation of connex-
ins 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 [151].
Most deaths occur suddenly [152]. Catastrophic sudden death events motivate
us to search for causes and possible solutions [153]. 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 [154]. 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 pre-
dict, avoid, or control the occurrence of an event [155]. 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 differ-
ent risk factors would be one of the explanations [158].
Melatonin
. 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 [159]. 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 antiox-
idant properties, mainly because melatonin results were better than those obtained
with an ascorbic acid at concentration 10–500 times higher [159]. Numerous studies
confirmed antiarrhythmic protection and related it to its remarkable antioxidant
properties [160167].
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 [127]. 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 previ-
ously mentioned, the time- and dose-dependent responses could be due to melatonin
inhibitory effect against swell-activated anionic currents [126128].
We recently showed that melatonin reduces arrhythmias when administered
during reperfusion, a useful timing for the clinical context of acute coronary syn-
dromes, because most therapies can only start close to the reperfusion period [168].
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 postdepolariza-
tions. 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 sus-
tained forms of arrhythmias, either sustained ventricular tachycardia or ventricular
fibrillation. These results (potential shortening and absence of sustained arrhyth-
mia) 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 hyperten-
sive rats [169]. 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 [83]. 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 fibrilla-
tion. Protection was mediated by the activation of melatonin receptors and by the
prevention of dephosphorylation and lateralization of Cx43.
Melatonin for a Healthy Heart Rhythm
DOI: hp://dx.doi.org/10.5772/intechopen.91447
A brief explanation of the electrophysiological changes induced by hypokale-
mia 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 lengthen-
ing of the QT interval and correlated with an increase in the duration of the action
potential [83]. 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 poten-
tial 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 [172174]. 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 [175]. 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 [83].
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 [83].
Melatonin prevented the widening of the QRS and delayed activation of the poten-
tial for epicardial action. The latter could be considered as a substitute for conduc-
tion 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, 177179]. 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 mis-
matches between the source and the sink [175, 180]. A unidirectional block can lead
to reentry circles that result in tachycardia or ventricular fibrillation [181]. Therefore,
the acute lateralization induced by hypokalemia is an important arrhythmogenic
factor [83]. 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 [177].
Our results could be relevant mainly in those situations in which acute hypo-
kalemia 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
Melatonin

more resistant to arrhythmic events triggered by rapid changes in plasma electro-
lyte 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 [185]. 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 melatonins pharmacokinetics in humans, to achieve a similar
concentration in plasma to the one tested ex vivo, a dose 10 times higher the highest
intravenous dose tested until now should be administered [186, 187].
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 ). 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.
. Chronic antiarrhythmic mechanisms of melatonin
Endogenous melatonin would be an intrinsically protective factor with thera-
peutic 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
[190]. 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 pharmacologi-
cal ranges, protects against arrhythmias [8, 21, 97, 163, 169, 189, 191, 192]. Beyond
the reported antioxidant properties of melatonin, it reduces severe ventricular
Figure 1.
Acute antiarrhythmic mechanisms of melatonin. The red arrows indicate stimulation, and the interrupted blue
lines indicate blockage.

Melatonin for a Healthy Heart Rhythm
DOI: hp://dx.doi.org/10.5772/intechopen.91447
arrhythmias by antifibrotic mechanisms, electrical remodeling, direct mitochon-
drial protection, myocardial Cx43 preservation via PKC signaling, and vitamin
D-HSP70/AT1 counterbalance (Figure ). Its cardioprotective properties persist in
relevant cardiovascular risk factor models like hypertensive, obese, and nephro-
pathic 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 proar-
rhythmogenic profile or failed to reduce mortality [193196]. 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 attenu-
ate the severity of diseases. In the case of arrhythmias, we still have no clear “antiar-
rhythmic 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, over-
loads 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 [197]. This finding has
been confirmed in several subsequent studies [11]. In addition, daily treatment of
pinealectomized rats with melatonin attenuated the elevation in blood pressure
Figure 2.
Antiarrhythmic mechanisms of chronic melatonin administration. Extracellular lines represent reduced fibrosis
after melatonin treatment. The red arrows indicate stimulation and blue ones show blockage. The green arrow
marks direct mitochondrial protection.
Melatonin

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 [7]. 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 expres-
sion, 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) [202]. Melatonin improves intrarenal
RAAS in the 5/6 nephrectomy rat model and reduces blood pressure, oxidative
stress, and interstitial fibrosis in the remaining kidneys [203].
Renal diseases cause cardiovascular and electrolytic remodeling that increases
the risk of arrhythmias [204206]. 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 [207]. The risk of mortality also increases in patients with
CKD who suffer from an acute coronary syndrome [208]. We demonstrated that
unilateral ureteral obstruction caused a cardiac remodeling that was accompanied
by an increase in reperfusion arrhythmias [209].
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 [97].
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 [100]. HSP 70
regulates antioxidant responses to cellular oxidative stress and reduces NADPH oxi-
dase activity and expression [210]. 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 [212]. Melatonin decreases renal
and myocardial overexpression of AT1 [97]. It is well documented that the AT1
pathway leads to myocardial fibrosis during CKD [97]. As previously suggested,
the low expression of AT1 through VDR induction could be a consequence of HSP
70-mediated cellular protection [213]. 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

Melatonin for a Healthy Heart Rhythm
DOI: hp://dx.doi.org/10.5772/intechopen.91447
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 melato-
nin 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 melato-
nin and the reduction of AT1 are critical components of the cellular stress response.
We attribute the higher vulnerability to ventricular fibrillation during reperfu-
sion 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 [214]. 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 [131]. 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, 215217]. As previously
mentioned, the downregulation of volume-activated anionic currents can explain
attenuated response to action potential shortening induced by ischemia [126].
A synthesis of the mechanisms of protection of chronic treatment of melatonin
cardiovascular complications is outlined in Figure . 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.
. Conclusions
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.
Acknowledgements
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.
Melatonin

Author details
Natalia JorgelinaPrado1,2, MargaritaSegovia-Roldan2, Emiliano RaúlDiez1,2*
andEstherPueyo1,2
1 Medical Faculty, CONICET, IMBECU, National University of Cuyo, Mendoza,
Argentina
2 I3A, Universidad de Zaragoza, IIS Aragón and CIBER-BBN, Zaragoza, Spain
*Address all correspondence to: diez.emiliano@fcm.uncu.edu.ar
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

Melatonin for a Healthy Heart Rhythm
DOI: hp://dx.doi.org/10.5772/intechopen.91447
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