Melatonin and Human Cardiovascular Disease

Abstract

The possible therapeutic role of melatonin in the pathophysiology of coronary artery disorder (CAD) is increasingly being recognized. In humans, exogenous melatonin has been shown to decrease nocturnal hypertension, improve systolic and diastolic blood pressure, reduce the pulsatility index in the internal carotid artery, decrease platelet aggregation and reduce serum catecholamine levels. Low circulating levels of melatonin are reported in individuals with CAD, arterial hypertension and congestive heart failure. This review assesses current literature on the cardiovascular effects of melatonin in humans. It can be concluded that melatonin deserves to be considered in clinical trials evaluating novel therapeutic interventions for cardiovascular disorders.

Full text

Review Article
Melatonin and Human
Cardiovascular Disease
Seithikurippu R. Pandi-Perumal, MSc
1
, Ahmed S. BaHammam, MD, FACP
1
,
Nwakile I. Ojike, MD, MS
2
, Oluwaseun A. Akinseye, MD
3,4
, Tetyana Kendzerska, MD, PhD
5
,
Kenneth Buttoo, MD, FRCP(C)
6
, Perundurai S. Dhandapany, MSc, PhD
7,8,9,10
,
Gregory M. Brown, MD, PhD
11
, and Daniel P. Cardinali, MD, PhD
12
Abstract
The possible therapeutic role of melatonin in the pathophysiology of coronary artery disorder (CAD) is increasingly being
recognized. In humans, exogenous melatonin has been shown to decrease nocturnal hypertension, improve systolic and diastolic
blood pressure, reduce the pulsatility index in the internal carotid artery, decrease platelet aggregation, and reduce serum
catecholamine levels. Low circulating levels of melatonin are reported in individuals with CAD, arterial hypertension, and con-
gestive heart failure. This review assesses current literature on the cardiovascular effects of melatonin in humans. It can be
concluded that melatonin deserves to be considered in clinical trials evaluating novel therapeutic interventions for cardiovascular
disorders.
Keywords
blood pressure, cardioprotection, cardiovascular disorders, coronary artery disease, hypertension, platelets, melatonin
Background
Cardiovascular diseases (CVD) are the leading cause of death
globally, with estimated 17.5 million deaths in 2012, representing
31%of all global deaths.
1
In the United States, about 1 in every
4 deaths is attributed to CVD with a direct cost of US$312.6
billion in the year 2011.
2
Although there is a documented
improvement in mortality rate from CVD, the overall impact
such as survival with disability, dependency, and cost of care has
significantly increased in the past decades.
3
There has equally
been an extensive improvement in the knowledge and understand-
ing of the pathophysiology of CVDs over the last years with
advances in pharmacological and procedural interventions.
1
Department of Medicine, College of Medicine, The University Sleep Disorders Center, King Saud University, Riyadh, Saudi Arabia
2
Division of Health and Behavior, Department of Population Health, New York University Medical Center, Center for Healthful Behavior Change, New York,
NY, USA
3
Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, NY, USA
4
CUNY School of Public Health at Brooklyn College, New York, NY, USA
5
Institute for Clinical Evaluative Sciences, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada
6
Sleep Disorders Center, Ajax, Ontario, Canada
7
The Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
8
Department of Medicine, Oregon Health and Science University, Portland, OR, USA
9
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
10
Centre for Cardiovascular Biology and Disease, Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, India
11
Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada
12
BIOMED-UCA-CONICET and Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Cato
´lica Argentina, Buenos Aires,
Argentina
Manuscript submitted: February 25, 2016; accepted: May 31, 2016.
Corresponding Authors:
Ahmed S. BaHammam, University Sleep Disorders Centre, College of Medicine, King Saud University, Box 225503, Riyadh 11324, Saudi Arabia.
Email: ashammam2@gmail.com
Daniel P. Cardinali, BIOMED-UCA-CONICET and Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Cato
´lica Argentina,
1107 Buenos Aires, Argentina.
Email: danielcardinali@fibertel.com.ar
Journal of Cardiovascular
Pharmacology and Therapeutics
2017, Vol. 22(2) 122-132
ªThe Author(s) 2016
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1074248416660622
journals.sagepub.com/home/cpt

The focus of this review article is on the therapeutic poten-
tial of melatonin in CVDs. Melatonin (IUPAC name: N-[2-(5-
methoxy-1H-indol-3-yl) ethyl] acetamide) is a natural methoxy-
indole first described as a pineal hormone and later shown to
bepresent in most mammalian and nonmammalian cells.
4
Its
effect is thought to be mediated through both receptor-
mediated and receptor-independent mechanisms. The
receptor-mediated actions of melatonin comprise of membrane
melatonergic receptors (MT1 and MT2) located throughout the
vascular system including the heart (cardiomyocytes, left ven-
tricle, and coronary arteries).
5,6
Melatonin may also be the
natural ligand for the retinoid-related orphan nuclear hormone
receptor family (RZR/ROR).
7
The MT1 melatonergic receptors mediate arterial vasocon-
striction, inhibit neuronal firing and cell proliferation in cancer
cells, and modulate reproductive and metabolic functions.
8,9
Activation of MT2 melatonergic induces vasodilation, phase
shift circadian rhythms of neuronal firing in the suprachias-
matic nucleus, enhances immune responses, and inhibits dopa-
mine release in retina and leukocyte rolling in arterial beds. The
receptor-independent mechanism of action of melatonin is
achieved through its antioxidant and mitochondrial-protecting
effects.
7
Melatonin has been shown to decrease nocturnal hyperten-
sion,
10
reduce the pulsatility index in the internal carotid artery,
decrease platelet aggregation,
11,12
and reduce serum catecho-
lamine levels.
13
Moreover, decreased melatonin levels were
reported in various pathological conditions including hyperten-
sion with nondipper pattern,
14
congestive heart failure
(CHF),
15
ischemic heart disease,
16
or in patients after acute
myocardial infarction.
17
Figure 1 presents the functional pleio-
tropy of melatonin.
This article provides a review of current literature on the
cardiovascular effects of melatonin in humans. Medical litera-
ture was identified by searching databases including (MED-
LINE, EMBASE), bibliographies from published literature,
and clinical trial registries/databases. Searches were last
updated on August 10, 2015.
Basic Aspects of Melatonin Physiology
Relevant to Cardiovascular Physiopathology
By using specific melatonin antibodies, the presence of mela-
tonin has been verified in multiple extrapineal tissues such as
the brain, retina, lens, cochlea, Harderian gland, airway epithe-
lium, gastrointestinal tract, liver, kidney, thyroid, pancreas,
thymus, spleen, immune system cells, skin, carotid body, repro-
ductive tract, and endothelial cells.
18
For further details, the
reader is referred to a review by Acun
˜a-Castroviejo et al.
18
Whether melatonin is produced in those tissues is a matter of
debate because melatonin’s amphiphilicity would allow an
easy entry from circulation in most cases.
19
However, in some
tissues, melatonin concentrations exceed those in the blood.
20
Although the enzymatic machinery to produce melatonin is
foundinmostoftheselocations,
18
circulating melatonin in
mammals is derived exclusively from the pineal gland.
Melatonin effects on the vasculature depend on the specific
receptor type activated. Animal studies reveal that vasocon-
striction is mediated through MT1 activation and vasorelaxa-
tion through MT2 activation, with the likely mechanism of
action being via the modulation of the noradrenergic and/or
nitric oxide (NO) effect.
21
Melatonin is metabolized in the liver to 6-sulfatoxymelato-
nin (aMT6s), which is subsequently excreted in urine.
22
Mel-
atonin that is produced outside the pineal gland generally does
not reach the circulation, for example, in case of the gastro-
intestinal tract, melatonin goes through a high presystemic
hepatic elimination rate and therefore does not exert systemic
effects.
23
Reactive oxygen and nitrogen species are significant con-
tributors to cardiac damage during ischemia–reperfusion injury
after an acute coronary syndrome. The reported lower serum
level of melatonin in this group of individuals (Table 1) wor-
sens the possibility of further cardiac damage from ischemia–
reperfusion injury because melatonin has been described as a
direct free radical scavenger that protects against reactive oxy-
gen and nitrogen species with high efficacy.
30
Melatonin also
indirectly stimulates antioxidative enzymes such as superoxide
dismutase, glutathione peroxidase, glutathione reductase, and
glucose-6-phosphate dehydrogenase, thereby lowering mole-
cular damage under conditions of elevated oxidative stress such
as acute coronary syndrome.
30
Because of its highly lipophilic properties, melatonin
crosses all cell membranes and easily reaches subcellular com-
partments, including mitochondria and nuclei, where it may
accumulate in high amounts.
18,31
Melatonin counteracts lipid
peroxidation
32
and DNA damage.
33
In particular, melatonin
preserves normal mitochondrial function by reducing and pre-
venting mitochondrial oxidative stress, thus curtailing subse-
quent apoptotic events and cell death.
18,31
Not only is
melatonin itself a direct free radical scavenger but also meta-
bolites that are formed during these interactions like N1-acetyl-
N2-formyl-5-methoxykynuramine, which is deformylated to
N1-acetyl-5-methoxykynuramine, and cyclic 3-hydroxymela-
tonin are also free radical scavengers.
34
Thus, a cascade of
metabolites of melatonin may contribute to the efficacy of the
parent molecule to protect against oxidative stress.
7
A major
question to the view that antioxidants exert their health-
protective effects by 1-electron reactions with free radicals has
been raised by Forman et al.
35
By kinetic constraints, in vivo
scavenging of radicals may be ineffective in antioxidant
defense. Instead, enzymatic removal of nonradical electro-
philes, such as hydroperoxides, in 2-electron redox reactions
could be the major antioxidant mechanism.
35
Indeed, the con-
cept of radical avoidance was proposed to attempt to explain
the protective effects of melatonin at the level of radical gen-
eration rather than detoxification of radicals already formed.
36
If melatonin is capable of decreasing the processes leading to
enhanced radical formation, this might be achieved by low
concentrations of the methoxyindole. The isoforms of
NAD(P)H oxidases (Nox) and the mitochondria should be
mentioned as main sources of free radicals. Moreover, reactive
Pandi-Perumal et al 123

nitrogen species can secondarily give rise to the formation of
reactive oxygen species (ROS), both in and outside mitochon-
dria, so that levels of oxidants can be considerably decreased
by limitation of NO formation. Melatonin downregulates NO
synthesis and inhibits ROS formation in microglia exposed to
amyloid-b1-42 by preventing the phosphorylation of the p47
Nox subunit.
37
Melatonin is also very effective to attenuate
mitochondrial-free radical formation. Therefore, radical avoid-
ance by melatonin must be recognized as a highly complex
phenomenon, which comprises the integrative, orchestrating
role of this molecule with its numerous actions at different
levels. It should be noted that concentrations of melatonin may
be sufficient for relevant direct scavenging in melatonin-
synthesizing organs, especially pineal gland and Harderian
gland. Whether accumulation in mitochondria leads to effec-
tive concentrations may be debated but is uncertain.
Melatonin displays a significant anti-inflammatory action
and reduces the serum levels of oxidized low-density
Figure 1. Functional pleiotropy of melatonin.
124 Journal of Cardiovascular Pharmacology and Therapeutics 22(2)

Table 1. Reduction of Melatonin Secretion in Patients with CVD.
Study Design Population Characteristics, Sample Size Melatonin Measurement Results Ref.
Observational
cross-
sectional
study
15 patients with coronary heart disease
(CHD), 10 healthy controls
Serum melatonin concentrations
were measured by
radioimmunoassay at night
(02:00 hours) and afternoon
(14:00 hours)
Melatonin was significantly lower in the
patients with CHD than in healthy
controls (median 7.8 [interquartile
range 6.5-11.8] vs 36.2 [32.2-42.5] pg/
mL, P< .0001). Melatonin was
undetectable in the afternoon
16
Observational
cross-
sectional
study
48 male patients with severe CHD, 24 of
them were taking b-blockers daily in
therapeutic dosages. 18 age-matched
healthy men served as controls
6-sulfatoxymelatonin (aMT6s) was
measured by radioimmunoassay
(RIA) in overnight urine
Night time urinary aMT6s levels were
significantly lower in patients with
CHD than in the control group
(F¼16.8, P< .001) b-adrenoceptor
blocker treatment had no significant
influence in these patients (F¼0.052)
24
Observational
cross-
sectional
study
24 healthy participants; 32 patients with
chronic, stable, coronary disease; 27
patients with unstable angina
Nocturnal excretion of aMT6s in
urine collected from 18:00 to
06:00 hours. aMT6s was
measured by a specific RIA
Urinary aMT6s was significantly lower in
patients with unstable angina than in
healthy participants or in patients with
stable angina. It correlated negatively
with age in healthy participants, but
not in patients with coronary disease.
aMT6s in patients treated with
b-adrenoceptor blockers did not differ
significantly from patients with
coronary disease not receiving
b-blockers.
25
Observational
cross-
sectional
study
33 hospitalized patients with congestive
heart failure (CHF) versus 146 healthy
ambulatory controls
Nocturnal excretion of aMT6s in
urine collected from 18:00 to
06:00 hours. aMT6s was
measured by a specific RIA
aMT6s levels were lower in patients with
CHF than controls (median 2.6 mgvs
6.02 mg, P< .0001). This decrease was
observed regardless of b-adrenergic
blocker treatment. There were no
significant differences in urinary aMT6s
levels between patients with chronic
and acute CHF. A significant decrease
in aMT6s excretion occurred with age
15
Observational
cross-
sectional
study
16 elderly patients with essential
hypertension, patients were defined as
either dippers (DIP, n ¼8) or
nondippers (NDIP, n ¼8) according
to the nocturnal change in the mean
arterial pressure
aMT6s was determined by ELISA in
2 separate urine collections, 1 in
the daytime and 1 during the
night
Daily aMT6s excretion was comparable
in DIP (3.28 +0.87 mg/12 hours) and
NDIP (2.31 +0.68 mg/12 hours; P¼
.39). Although DIP presented the
physiological nocturnal increase in
urinary aMT6s (8.19 +1.68 mg/12
hours), this surge of melatonin
production was missing in NDIP
14
Observational
cross-
sectional
study
16 patients with angiographically
documented CAD versus 9 healthy
controls
Blood samples were collected
every 2 hours between 22:00 and
08:00 hours. Melatonin levels
were measured by RIA
Patients with CAD secreted less
nocturnal melatonin at 02:00, 04:00,
and 08:00 hours than control
participants (P¼.014, P¼.04, and
P¼.025, respectively). Peak and delta
melatonin (peak-lowest melatonin)
were significantly lower in patients
with CAD (P¼.006 and P¼.002,
respectively). Peak time of melatonin
secretion was observed earlier in
patients with CAD
26
Observational
cross-
sectional
study
190 patients with primary hypertension
exhibiting a dipping and nondipping BP
profile (88 men and 102 women)
Plasma melatonin was measured at
the middle of the daytime and
nighttime by RIA
When patients were divided into dippers
and nondippers on the basis of mean
arterial or diastolic BP, a lower ratio of
night/day melatonin concentration
was found in nondippers than in
dippers. There was a blunted night/day
difference in plasma melatonin
concentrations in patients with
hypertension with the nondipping
profile in diastolic BP
27
(continued)
Pandi-Perumal et al 125

lipoprotein (LDL) responsible for atherogenic vascular forma-
tions.
38,39
Indeed, oxidized LDL participates in the initiation
and progression of atherosclerosis and contributes to endothe-
lial dysfunction and plaque destabilization through multiple
mechanisms.
40
In vitro melatonin was found to inhibit oxida-
tive LDL modification,
41
a process that may translate in
reduced formation of atherogenic plaques in vivo. Melatonin
also decreases the formation of cholesterol and reduces LDL
accumulation in freshly isolated human mononuclear leuko-
cyte.
42
However, not all studies have reported the LDL-
lowering effect of melatonin.
43
Cyclophilin A is a ubiquitously expressed protein that has
been highlighted as a major secreted oxidative stress-induced
factor in atherosclerosis. In a study evaluating the role of cyclo-
philin A in the early phase of atherosclerosis, the atheroprotec-
tive effect of melatonin was assessed.
44
Cyclophilin A
expression increased and modulated inflammatory cell adhe-
sion and interleukin 6 expression inducing vascular smooth
muscle cell migration and inflammatory cell extravasation. All
these effects were prevented by melatonin, indicating that mel-
atonin treatment may represent a new atheroprotective
approach that contributes to reducing the early phase of
atherosclerosis.
45
Melatonin inhibits several physiological processes in human
platelets including the aggregation phenomenon, the release of
ATP and serotonin (indexes of the platelet secretory mechan-
ism), and the production of thromboxane B2.
11,12
In an experimental study with an isolated perfused heart
model in which the anterior descending coronary artery was
temporarily ligated, infusion of melatonin (1-250 mmol/L) dur-
ing the ischemic and reperfusion episodes prevented the occur-
rence of arrhythmias including premature ventricular
contraction and ventricular fibrillation, which have been shown
to occur on reperfusion without the infusion of melatonin.
46
Protective effects of melatonin shortly after coronary artery
ligation and in the absence of ischemia reperfusion were also
reported.
47
In a recent study using genetically engineered mice,
it was demonstrated that nuclear melatonin receptor RORa
may serve as an endogenous defender against ischemia reper-
fusion injury and may mediate the beneficial effect of melato-
nin on myocardial ischemia and reperfusion injury.
48
Likewise,
the ex vivo pretreatment with melatonin improved survival and
function of adipose tissue–derived mesenchymal stem cells in
vitro and in vivo, and by using a rat model of myocardial
infarction, it was found that melatonin pretreatment enhanced
the viability of engrafted stem cells and promoted their ther-
apeutic potency.
49
In view of these experimental and observa-
tional cross-sectional studies, melatonin might exert a
cytoprotective effect at the level of human heart.
Melatonin Levels in CVDs
Individuals with elevated LDL/cholesterol levels have been
reported to have low circulating levels of melatonin,
50
and low
melatonin levels have been reported in patients with CAD
(Table 1). In an observational cross-sectional study of 15 indi-
viduals with CAD versus 10 healthy participants, melatonin
was significantly lower in the patients with CAD than in the
healthy controls.
16
This is consistent with analysis of data from
another observational cross-sectional study, which reported
that nighttime urinary aMT6s levels were significantly lower
in patients with CAD than in the control group.
24
Significantly
lower urinary aMT6s levels were reported in patients with
unstable angina or in patients with stable angina.
25
Yaprak
Table 1. (continued)
Study Design Population Characteristics, Sample Size Melatonin Measurement Results Ref.
Observational
cross-
sectional
study
180 consecutive patients with a first
ST-segment elevation myocardial
infarction who underwent primary
percutaneous coronary intervention
within 6 hours from onset of
symptoms
Intraplatelet melatonin levels were
measured in platelet-rich plasma
using an enzymatic immunoassay
procedure
Patients with angiographic no-reflow had
lower intraplatelet melatonin levels
compared to patients without no-
reflow (12.32 +3.64 vs 18.62 +3.88
ng/100 000 platelets, P< .0001). After
adjusting by potential confounders,
binary logistic regression analysis
indicated that intraplatelet melatonin
levels were the only significant
predictor of angiographic no-reflow
(odds ratio 1.58, P< .0001)
28
Observational
longitudinal
study
554 young women without baseline
hypertension
First morning urine melatonin
levels
During 8 years of follow-up, a total of
125 women developed hypertension.
The relative risk for incident
hypertension among women in the
highest quartile of urinary melatonin
(>27.0 ng per mg creatinine)
compared to the lowest quartile
(<10.1 ng per mg creatinine) was 0.49
(95% CI, 0.28-0.85; P< .001)
29
Abbreviations: BP, blood pressure; ELISA, enzyme-linked immunosorbent assay.
126 Journal of Cardiovascular Pharmacology and Therapeutics 22(2)

et al reported that patients with CAD secreted less nocturnal
melatonin at 02:00, 04:00, and 08:00 hours than controls .
26
In
another related study of 180 consecutive patients with a first
ST-segment elevation myocardial infarction who underwent
percutaneous coronary intervention within 6 hours from onset
of symptoms, patients with angiographic no-reflow had lower
intraplatelet melatonin levels compared to patients without no-
reflow.
28
Intraplatelet melatonin levels were the only signifi-
cant predictor of angiographic no-reflow after adjusting for
potential confounders.
Low urinary aMT6s excretion was reported in CHF, a
decrease that was observed regardless of b-adrenergic blocker.
There were no significant differences in the low urinary aMT6s
levels between patients with chronic and acute CHF.
15
Concerning patients with hypertension, there were reports
indicating the suppression of nocturnal melatonin secretion in
nondippers,
14,27
and in an observational longitudinal study of
554 young women without baseline hypertension, the relative
risk for incident hypertension among women in the highest
quartile of urinary melatonin was about half that in the lowest
quartile.
29
Melatonin Effects on Arterial Blood Pressure
in Humans
Numerous pharmacological and nonpharmacological proce-
dures have been used in the treatment of hypertension; how-
ever, the percentage of individuals with uncontrolled
hypertension still remains unacceptably high.
51
The effects of melatonin on cardiovascular function in
healthy participants are significant (Table 2). Melatonin in
comparison to placebo was able to reduce blood pressure
(BP), vascular reactivity, the pulsatility index in the internal
carotid artery, and circulating catecholamines in healthy parti-
cipants.
13,52,53
In another related study comparing postmeno-
pausal women with and without hormone replacement therapy
(HRT), melatonin reduced internal carotid artery pulsatility
index, systolic and diastolic BP, and increased the NO level
in HRT-treated women only, suggesting that several effects of
melatonin may be modulated by gonadal steroids.
54
As shown
by power spectral analysis of heart rate variability and BP
monitoring, melatonin administration increased cardiac vagal
tone and reduced plasma norepinephrine and dopamine levels
in the supine position in awake healthy volunteers.
55
Although BP was reduced significantly, heart rate and burst
rate of muscle sympathetic nerve activity (MSNA) did not
change significantly after melatonin.
56
However, in another
study examining the sympathetic nerve responses to ortho-
static stress, the increase in MSNA was smaller in the
melatonin-treated group.
57
Blunted decline in the physiological BP’s nocturnal fall, the
nondipper pattern, is associated with hypertension-induced
organ damage such as left ventricular hypertrophy, microalbu-
minuria, reduced arterial compliance, and worse prognosis in
terms of cardiovascular events.
58
As shown in Table 3, mela-
tonin treatment can be useful in this kind of patients.
A double-blind, placebo-controlled study demonstrated that
melatonin given orally (2.5 mg/d) for 3 weeks to patients with
essential hypertension significantly reduced both systolic and
diastolic BP.
60
Nondipper hypertensives have also been found
to have a missing surge of melatonin production at nighttime
compared to hypertensives who had an appropriate reduction in
BP at nighttime (Table 1).
14,27
In a meta-analysis performed on the effect of melatonin on
nocturnal BP, the combination of controlled-release melatonin
and antihypertensive treatment was found effective and safe in
ameliorating nocturnal hypertension, whereas fast-release mel-
atonin was not.
61
The data differed from a former report indi-
cating that the evening administration of melatonin induced an
increase of BP and heart rate in patients with hypertension well
controlled by nifedipine.
59
These discrepancies underline the
necessity of further studies on the matter.
It has been suggested that the reduction in nocturnal BP by
repeated melatonin intake at night is attributable to its curing
effect on the circadian output of the suprachiasmatic nucleus.
64
The normalization of circadian pacemaker function in the reg-
ulation of BP by melatonin treatment has thus been proposed as
a potential strategy for the treatment of essential hypertension.
The vasoregulatory actions of melatonin are complex and
may involve both central and peripheral mechanisms.
65,66
The
responses elicited by the activation of MT1 (vasoconstriction)
and MT2 (vasodilation) are dependent on circadian time, dura-
tion, and mode of exposure to endogenous or exogenous mel-
atonin, as well as of functional receptor sensitivity.
Potential Use of Melatonin in Pulmonary
Hypertension
Oxidative stress has been proposed as one of the major
mechanisms leading to the development of pulmonary hyper-
tension.
67,68
Therefore, it is reasonable to explore the effect of
antioxidant therapy in pulmonary hypertension. As discussed
above, melatonin has a potent antioxidant activity, which can
reduce antioxidant damage in cardiovascular tissues.
Three recent animal studies have suggested that melatonin
may be beneficial in hypoxic pulmonary hypertension. In one
study performed in newborn sheep gestated, born, and raised at
3600 m, melatonin reduced pulmonary artery pressure and
resistance for the first 3 days of treatment and significantly
improved the vasodilator function of small pulmonary arteries,
reduced pulmonary oxidative stress markers, and increased
enzymatic and nonenzymatic antioxidant capacity.
69
In another study performed in Sprague Dawley rats exposed
to intermittent chronic hypoxia for 4 weeks to induce hypoxic
pulmonary hypertension,
70
melatonin administration attenu-
ated the elevation of right ventricular pressure and reduced the
pulmonary vascular structure remodeling. In line with these
findings, a third study assessed the effect of melatonin as a
curative or preventive therapy of pulmonary hypertension in
Long Evans rats in which pulmonary hypertension had been
induced by injecting monocrotaline. Melatonin was adminis-
tered 5 days prior to or 14 days after the injection of
Pandi-Perumal et al 127

Table 2. Effects of Melatonin on Cardiovascular Function in Healthy Humans.
Study Design Population Experiment Results Ref.
Placebo-controlled
study
12 young women Melatonin 1 mg oral tablet between
14:30 and 17:30 hours, 90 minutes
before investigation
The administration of melatonin
significantly reduced BP, the
pulsatility index in the internal
carotid artery, and catecholamines
levels
52
Placebo-controlled
study
17 young, healthy, early follicular-
phase women
Melatonin 1 mg oral tablet between
14:30 and 17:30 hours, 90 minutes
before investigation
The administration of melatonin
significantly reduced BP, the
pulsatility index in the internal carotid
artery, and catecholamines levels
53
Randomized,
double-blind,
placebo-
controlled study
14 normal healthy young men Melatonin 1 mg oral tablet between
14:30 and 17:30 hours, 90 minutes
before investigation
The administration of melatonin
significantly reduced BP, the
pulsatility index in the internal
carotid artery, and catecholamines
levels. The effect of melatonin on
pulsatility index was related to
baseline values, being greater in
men with higher baseline values
13
Randomized,
double-blind
placebo-
controlled study
23 postmenopausal women of which
12 were on the estrogenic phase
and 11 were under hormone
replacement therapy (HRT) and
with continuous transdermal
estradiol plus cyclic
medroxyprogesterone acetate
Melatonin 1 mg oral tablet between
14:30 and 17:30 hours, 90 minutes
before investigation
In untreated postmenopausal women,
melatonin treatment was
ineffective, while in HRT-treated
women, studied during the
estrogenic phase, melatonin
reduced, within 90 minutes,
systolic (8.1 +9.9 mm Hg;
P¼.054), diastolic (5.0 +7.0
mm Hg; P¼.049), and mean
(6.0 +6.6 mm Hg; P¼.037)
BP. Norepinephrine but not
epinephrine levels were also
reduced. Similarly, resistance to
blood flow in the internal carotid
artery was decreased by melatonin
54
Placebo-controlled
study
26 healthy men Melatonin (2 mg). Power spectral
analysis of heart rate variability
(HRV) and BP monitoring were
recorded in the supine position
before and 60 minutes after
melatonin administration and in the
standing position 60 minutes after
administration. Plasma
catecholamine levels were also
measured
Compared with placebo, melatonin
administration increased R-R
interval, the square root of the
mean of the squared differences
between adjacent normal R-R
intervals, melatonin decreased the
low-frequency to high-frequency
ratio and BP in the supine position
(P< .01). Plasma norepinephrine
and dopamine levels in the supine
position after melatonin
administration were significantly
lower than in placebo
55
Observational
study
5 healthy male participants 3 mg of melatonin was given and the
BP, heart rate, and muscle
sympathetic nerve activity (MSNA)
were recorded continuously for
80 minutes
BP was reduced significantly, while
heart rate and burst rate of MSNA
did not change significantly
56
Placebo-controlled
study
11 healthy participants 50 minutes after receiving a 3 mg
tablet of melatonin or placebo (in
different days) sympathetic nerve
responses to orthostatic stress
(MSNA), arterial BP, heart rate,
forearm blood flow, and thoracic
impedance were measured
During the placebo trial, MSNA
increasedby 33% +8% and 251% +
70% during 10 and 40 mm Hg,
respectively, but increased by only
8% +7% and 111% +35% during
10 and 40 mm Hg with
melatonin, respectively (P<.01).
Arterial BP and forearm vascular
resistance responses to orthostatic
stress were unchanged by melatonin
57
Abbreviations: BP, blood pressure.
128 Journal of Cardiovascular Pharmacology and Therapeutics 22(2)

Table 3. Effect of Melatonin in Patients with Hypertension.
Study Design Population Experiment Results Ref.
Double-blind
crossover
study
47 outpatients with mild-to-moderate
essential hypertension taking
nifedipine 30 or 60 mg as a
monotherapy at 08:30 hours for at
least 3 months
Melatonin 5 mg at 22:30 hours. A
24-hour noninvasive ambulatory
blood pressure (BP) monitoring
was recorded from each patient
The evening administration of
melatonin increased BP and heart
rate (HR) throughout the 24-hour
period (Delta SBP ¼þ6.5 mm Hg,
P< .001; Delta DBP ¼þ4.9 mm
Hg, P< .01; Delta HR ¼þ3.9
beats/minute, P< .01). The increase
in DBP as well as HR was
particularly evident during the
morning and the afternoon hours
59
Double-blind,
placebo-
controlled,
crossover
study
16 men with untreated essential
hypertension
2.5 mg of oral melatonin given as a
single and repeated (daily for 3
weeks) dose 1 hour before sleep.
24-hour ambulatory blood
pressure and actigraphic estimates
of sleep quality
Repeated melatonin intake reduced
systolic and diastolic blood
pressure during sleep by 6 and 4
mm Hg, respectively. Heart rate
was not affected. A single dose of
melatonin had no effect on blood
pressure. Repeated doses of
melatonin also improved sleep
P<.05
60
Randomized,
double-blind,
placebo-
controlled
study
38 patients with treated hypertension
(22 males) with confirmed
nocturnal hypertension (mean
nighttime systolic BP >125 mm Hg),
according to repeated 24-hour
ambulatory blood pressure
monitoring
Controlled-release melatonin 2 mg or
placebo 2 hours before bedtime for
4 weeks. 24-hour ambulatory blood
pressure monitoring
Melatonin treatment reduced
nocturnal systolic BP significantly
from 136 +9 to 130 +10 mm Hg
(P¼.011), and diastolic BP from 72
+11 to 69 +9mmHg(P¼.002),
whereas placebo had no effect on
nocturnal BP. The reduction in
nocturnal systolic BP was
significantly greater with melatonin
than with placebo (P¼.01), and
was most prominent between 2:00
AM and 5:00 AM (P¼.002)
61
Combined
analysis of
controlled
clinical trials
Post hoc analysis of pooled
antihypertensive drug-treated
subpopulations from 4 randomized,
double-blind trials
Prolonged-release melatonin (PRM; 2
mg) for 3 weeks or 28 weeks.
Measured the efficacy (by Leeds
Sleep Evaluation Questionnaire
scores of quality of sleep and
alertness and behavioral integrity,
sleep latency, and Clinical Global
Impression of Improvement) and
safety of PRM for primary insomnia
in patients aged 55 years and older
who were treated with
antihypertensive drugs
Compared to placebo, PRM had
significantly improved quality of
sleep and behavior following
awakening (P< .0008). Sleep
latency (P¼.02) and CGI-I
(P¼.0003) also improved
significantly. No differences were
observed between PRM and
placebo groups in daytime blood
pressure at baseline and treatment
phases. The rate of adverse events
normalized per 100 patient-weeks
was lower for PRM (3.66) than for
placebo (8.53)
62
Randomized,
double-blind,
placebo-
controlled,
parallel-group
design
16 patients with hypertension
(age 45-64 years; 9 women) treated
with the b-blockers atenolol or
metoprolol
Melatonin 2.5 mg nightly for 3 weeks.
Sleep quality measured by
polysomnography
Melatonin supplementation for 3
weeks significantly increased total
sleep time (þ36 minutes; P¼.046),
increased sleep efficiency (þ7.6%;
P¼.046), decreased sleep onset
latency to Stage 2 (14 minutes;
P¼.001), increased Stage 2 sleep
(þ41 minutes; P¼.037) when
compared to placebo. The sleep
onset latency remained significantly
shortened on the night after
discontinuation of melatonin
administration (25 minutes;
P¼.001), suggesting a carry-over
effect
63
Pandi-Perumal et al 129

monocrotaline. The study showed that both curative and pre-
ventive treatment improved right ventricular functional and
plasma oxidative stress parameters and reduced cardiac inter-
stitial fibrosis.
71
Therefore, melatonin seems to confer beneficial effects in
pulmonary hypertension via antioxidant, anti-inflammatory,
and antiproliferative mechanisms. Clinical investigation of the
effects of melatonin on right ventricle hemodynamic function
in patients with pulmonary hypertension is warranted.
Melatonin Dose and Safety
The majority of clinical trials on the therapeutic usefulness of
melatonin in different fields of medicine have shown very low
toxicity of melatonin over a wide range of doses.
72
Doses of
melatonin that considerably exceed those used in cardiovascu-
lar disorders have been found to be safe. In the treatment of
amyotrophic lateral sclerosis, patients received either 60 mg/d
orally for up to 13 months
73
or enteral doses of 300 mg/d for up
to2years.
74
In a phase 1 dose escalation study in healthy
volunteers to assess the tolerability and pharmacokinetics of
20, 30, 50, and 100 mg oral doses of melatonin, no adverse
effects after oral melatonin, other than mild transient drowsi-
ness with no effects on sleeping patterns, were seen.
75
There-
fore, further clinical trials using dosages of melatonin in the
range of 50 to 100 mg/d appear to be reasonable and are war-
ranted. The priorities for populations, outcomes, and durations
of these studies must be defined.
Conclusion
The possible therapeutic role of melatonin in CVDs is increas-
ingly apparent, especially with potential benefits in the reduc-
tion of ischemia–reperfusion injury and decreasing nocturnal
BP. The data suggest that preserving endogenous melatonin
levels, or the use of melatonin supplements, may be beneficial
in CVDs.
Melatonin is available in pharmacologically pure form, is
relatively inexpensive, is absorbed when administered via any
route, and its toxicity is remarkably low. Considering that
CVDs are the leading cause of death globally,
1
the fact that
melatonin has been found to be cardioprotective and possess
low toxicity could have important clinical implications. There-
fore, more extensive, large-size clinical trials are needed to
evaluate melatonin’s efficacy as a novel therapeutic interven-
tion in CVDs.
Author Contributions
Seithikurippu R. Pandi-Perumal, Ahmed S. BaHammam, Gregory
M. Brown, and Daniel P. Cardinali contributed to conception, drafted
the manuscript, critically revised the manuscript, gave final approval,
and agree to be accountable for all aspects of work ensuring integrity
and accuracy. Nwakile I. Ojike, Oluwaseun A. Akinseye, Tetyana
Kendzerska, Kenneth Buttoo, and Perundurai S. Dhandapany drafted
the manuscript, critically revised the manuscript, gave final approval,
and agree to be accountable for all aspects of work ensuring integrity
and accuracy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: This work
was supported by a grant from the Agencia Nacional de Promocio´n
Cientı´fica y Tecnolo´gica, Argentina (PICT 2012, 0984).
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