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Cardiovascular Research 58 (2003) 10–19
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Review
Melatonin: a novel protective agent against oxidative injury of the
ischemic / reperfused heart
Russel J. Reiter*, Dun-Xian Tan
Department of Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7762, San Antonio,
TX 78229 -3900, USA
Received 3 September 2002; accepted 25 November 2002
Abstract
Keywords: Cardiomyopathy; free radicals; Ischemia; Reperfusion
1. Introduction
In the United States and other economically well-developed countries of the world, cardiovascular disease is a
major cause of disability and mortality [1]. In these
countries, conditions relating to the heart and adnexa
account for almost half the deaths that occur each year.
Furthermore, the costs of cardiovascular-related treatments
including emergency room visits, by-pass surgery, cardiac
catheterizations and stent placements have placed a major
*Corresponding author. Tel.: 11-210-567-3859; fax: 11-210-5676948.
E-mail address: [email protected] (R.J. Reiter).
financial burden on the health care system and on many
families. Ischemic heart disease is particularly debilitating
with an estimated 1.5 million myocardial infarctions being
reported annually in the US resulting in roughly 200 000
deaths. Unfortunately, significant reductions in these numbers seem unlikely considering the health status of many
individuals. The American Heart Association estimates up
to 50% of US inhabitants have elevated serum cholesterol
with associated coronary artery disease [2] and in excess of
50% of the population is over weight, a factor that taxes
the heart excessively.
A reduction in coronary blood flow due to atherosTime for primary review 20 days.
0008-6363 / 03 / $ – see front matter  2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.
doi:10.1016 / S0008-6363(02)00827-1
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This brief review summarizes the recently obtained evidence which illustrates the beneficial effects of the endogenously produced
antioxidant, melatonin, in reducing tissue damage and reversing cardiac pathophysiology in models of experimental ischemia / reperfusion.
The report also describes the actions of other antioxidants, especially vitamin E and antioxidative enzymes, in altering the degree of
ischemia / reperfusion damage in the heart. Based on the data available, melatonin seems to have advantages over other antioxidants tested
in terms of ameliorating the hypoxia and reoxygenation-induced damage. While the bulk of the studies that have used melatonin to
overcome cardiac injury following transient arterial occlusion and subsequent reperfusion have used pharmacological doses to achieve
protection, two recent reports have further shown that merely reducing endogenous circulating concentrations of melatonin (by surgical
removal of a source of melatonin, i.e. the pineal gland) exaggerates the degree of injury and reduces survival of animals as a result of
induced ischemia / reperfusion of the heart. These findings are consistent with observations in other organs where the loss of physiological
concentrations of melatonin results in increased oxidative damage during hypoxia and reoxygenation. These findings have implications for
the elderly since in the aged endogenous levels of melatonin are naturally reduced thereby possibly predisposing them to more severe
cardiac damage during a heart attack. To date, the bulk of the studies relating to the protective actions of melatonin in reducing cardiac
ischemia / reperfusion injury have used the rat as the experimental model. Considering the high efficacy of melatonin in limiting
ischemia / reperfusion damage as well as melatonin’s low toxicity, the studies should be expanded to include other species and models of
cardiac ischemia / reperfusion. The results of these investigations would help to clarify the potential importance of the use of melatonin in
situations of oxidative damage to the heart in humans.
 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.
R. J. Reiter, D.-X. Tan / Cardiovascular Research 58 (2003) 10–19
clerotic plaques or vasospasm can be sufficiently prolonged to result in severe damage to the myocardium
which leads to cellular injury and eventually to cellular
death due to apoptosis and / or necrosis. Loss of this vital
tissue ultimately leads to compromised cardiac function
thereby jeopardizing the overall health of the individual
and possibly leading to death. A number of treatment
options have been exploited to reduce cardiac damage
resulting from an ischemic episode. Some of these include
the use of thrombolytic agents (e.g. tissue plasminogen
activator and streptokinase) to dissolve clots and percutaneous transluminal balloon angioplasty; these procedures
are essential to prevent long-term deprivation of oxygenated blood to the heart which would lead to tissue loss;
however, the re-instatement of blood flow, i.e. reperfusion,
is not without significant negative consequences and
cellular damage [3,4]. Thus, when oxygenated blood reenters previously hypoxic cardiac tissue it initiates a
cascade of events that, paradoxically, results in further
cellular and tissue damage [5–8]. This tissue destruction is
referred to as reperfusion injury.
The combination of ischemia / reperfusion (I / R) causes
11
numerous and complex reactions in tissues (Fig. 1) which
culminate in the mutilation of essential molecules and
organelles in a number of cells including components of
the coronary endothelium and myocardium with the recruitment of circulating blood elements, e.g. leukocytes
and platelets. During the transient ischemia and the period
of reperfusion many cells generate by-products of oxygen
that are toxic to the heart. Indeed, the partially reducedoxygen metabolites, referred to as reactive oxygen species
(ROS) are accepted as accounting for much of the cardiac
damage that occurs during I / R injury [9,10].
2. Use of melatonin to reduce cardiac I / R damage
Several recent publications present evidence that a
newly discovered antioxidant, melatonin, has significant
protective actions against the cardiac damage and altered
physiology that occurs during I / R injury. These actions
were apparent even when melatonin was given as a single
acute dose. In light of the observations that melatonin
reduced molecular damage and cellular loss in other organs
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Fig. 1. As illustrated in this simplified figure, the events that lead to molecular damage and cell death during I / R injury are extremely complex. These
processes clearly include free radical generation and ancillary events which eventually cause damage to key macromolecules. Considering the numerous
intracellular actions of melatonin as a direct free radical scavenger, as an indirect antioxidant due to its ability to stimulate antioxidative enzymes, and its
effect on mitochondrial electron transport and oxidative phosphorylation, this indole has proven effective in reducing molecular damage and cell death in
models of rat I / R injury.
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R. J. Reiter, D.-X. Tan / Cardiovascular Research 58 (2003) 10–19
with melatonin (1 or 10 mg / kg i.p.) or 5-MCA-NAT (10
mg / kg i.p.) 30 min before the hearts were perfused using
the Langendorff method. In terms of both the physiological
parameters and infarct size, the authors reported that
melatonin or 5-MCA-NAT provided ‘spectacular protection’ against I / R injuries. Considering the large amount of
experimental evidence implicating free radicals in cardiac
arrhythmias during hypoxia / reoxygenation [14], Lagneux
et al. [13] surmised that melatonin’s free radical scavenging activity accounted for its ability to restore cardiac
function. However, since the role of free radicals in
determining infarct size is somewhat less clear [15], the
authors were more cautious in assuming that the reduction
in the size of the lesion was exclusively related to the
indole’s antioxidant properties.
Additional confirmations of the ameliorative effects of
melatonin on abnormal function and cardiac tissue destruction after I / R have been provided by Szarszoi et al. [16],
Lee et al. [17] and Sahna and co-workers [18,19]. In the
first of these reports, melatonin given in pharmacological
doses (as in the studies reported above) prior to ischemia
and / or during reperfusion reduced the incidence of reperfusion-induced ventricular fibrillation and decreased the
arrhythmia score [16]. This protective action of melatonin
was presumed to be related to its free radical scavenging
activity.
Lee et al. [17] performed the first in vivo study in which
melatonin was tested for its ability to protect the heart
when its blood supply is transiently interrupted. Using a
bolus i.v. injection of either 0.5, 1.0 or 5.0 mg / kg before
left coronary artery occlusion, melatonin markedly suppressed ventricular tachycardia and fibrillation and also
reduced the total number of PVCs (Fig. 2). Additional
studies showed that melatonin also significantly reduced
O ?2
production and lowered myloperoxidase activity (an
2
index of neutrophil infiltration) during I / R. Finally, while
eight of nine rats with an ischemic / reperfused heart died,
none of the animals (10 of 10) treated with either 1 or 5
mg / kg melatonin succumbed. The authors of this report
describe the actions of melatonin as being ‘pronounced’
and presumed its beneficial actions related to both its
ability to reduce neutrophil infiltration into the ischemic /
reperfused tissue and due to the antioxidant properties of
the indole.
Heretofore, the studies documenting the protective role
of melatonin in the hypoxic / reperfused heart used pharmacological doses of the indole. Sahna and co-workers
[18,19] were the first to examine whether endogenous,
physiological concentrations of melatonin would change
the outcome of such studies. In this case, rats were
surgically pinealectomized to reduce endogenous levels of
melatonin and, 2 months later, they, along with pinealintact controls, were used in studies of cardiac I / R injury.
When the left coronary artery was occluded for 7 min
followed by 7 min of reperfusion, the degree of cardiac
arrhythmias was significantly greater in the heart of the
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during transient interruption of blood flow followed by
reperfusion, Tan et al. [11] examined its effect on these
responses at the level of the heart. Using a Langendorff rat
heart preparation, a ligature was placed around the descending coronary artery for 10 min; this was estimated to
have reduced total coronary flow by in excess of 25%. The
ischemic episode was followed by a 10 min reperfusion
period during which most hearts (80 and 90%, respectively) exhibited premature ventricular contractions (PVC)
and / or ventricular fibrillation (VF). When melatonin was
infused throughout the period of the occlusion and after
reopening of the coronary artery, it highly significantly
reduced both the PVC and VF. The arrhythmias in this
study were defined in accordance with the guidelines of the
Lamberth Conventions. The concentration of melatonin in
the perfusate was either 1, 10 or 50 mM. Anticipating that
melatonin’s effects in this study were likely related to its
antioxidant action, as a positive control Tan et al. [11]
infused another free radical scavenger, i.e. vitamin C, in a
separate group of hearts. At a concentration of 500 mM
(i.e. up to 500 times the concentration of melatonin),
ascorbate was significantly less effective than melatonin in
preventing the cardiac arrhythmias in this model of I / R.
Additional investigations confirming the beneficial effects of melatonin on the physiology and morphology of
the hypoxic / reoxygenated heart followed shortly. Kaneko
et al. [12] also used isolated rat hearts that were subjected
to 30 min ischemia and 30 min perfusion. The concentration of melatonin in the perfusion medium in this
study was 100 mM. Again, the duration of ventricular
tachycardia and VF were significantly reduced by
melatonin relative to the durations of these arrhythmias in
control hearts. Additionally, melatonin significantly restored the function of the left ventricule (LV), i.e. the LV
developed pressure, 1dp / dt and 2dp / dt (63.0, 60.3 and
59.4%) compared to values of 30.2, 29.7 and 31.5%,
respectively, in the diluent-infused hearts. Kaneko et al.
[12] further extended their studies by measuring ?OH
generation (by estimating levels of 2,3-dihydroxybenzoic
acid after salicylate administration) and observed
melatonin highly significantly reduced the amount of this
metabolite in the perfusate. At the conclusion of the
reperfusion period, the hearts were collected and the levels
of lipid peroxidation products were measured in the
tissues. For this endpoint, melatonin again highly significantly reduced the levels of oxidized lipids in the heart.
These findings clearly documented the beneficial effects of
melatonin when it is used during I / R of the heart and the
results are consistent with melatonin’s protective actions as
a free radical scavenger.
Essentially simultaneously, Lagneux et al. [13] published their findings in which both melatonin and an
analogue, 5-methoxy-carbonylamino-N-acetyl tryptamine
(5-MCA-NAT), were compared in terms of their efficacies
in reducing both the abnormal cardiac physiology and
infarct volume after I / R. In this case, rats were treated
R. J. Reiter, D.-X. Tan / Cardiovascular Research 58 (2003) 10–19
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Fig. 2. Cardiac arrhythmias during induced ischemia (left) and reperfusion (right) of the rat heart and their reduction following the administration of
melatonin. PVC, premature ventricular contraction; VT, ventricular tachycardia; VF, ventricular fibrillation; I / R, ischemia / reperfusion. * P,0.05 verses
I / R only.
pinealectomized rats compared to the controls. Even more
importantly, the incidence of mortality was 63% in rats
lacking their pineal gland compared to only 25% in the
pineal-intact rats after I / R induction. These findings
suggest that endogenous melatonin levels are protective of
the heart during episodes of hypoxia and reoxygenation. A
follow-up study by the same group [56] showed that
infarct size was also exaggerated in the ischemia-reperfused heart when rats were deficient in physiological levels
of melatonin due to pinealectomy. This is consistent with
previously published findings in reference to the brain
where a reduction in endogenous melatonin levels, due to
pinealectomy, also exaggerated neural injury after an
episode of I / R.
The results showing increased I / R-induced cardiac
damage after a reduction in physiological levels of
melatonin have implications for the elderly inasmuch as in
old individuals endogenous levels of melatonin may be
significantly lower than in young individuals [20]. The
findings illustrating a potential role for physiological levels
of melatonin in abating cardiac damage during I / R also is
interesting in light of several studies showing that humans
with cardiovascular disease have noticeably lower circulating melatonin levels [21–24] than do age-matched subjects
without significant cardiovascular deterioration. Similarly,
patients suffering with cardiac syndrome X have an
attenuated nocturnal rise in serum melatonin levels relative
to that of age-matched individuals with no cardiac pathology [25]. It remains unknown, however, whether the
reduced endogenous melatonin levels in patients with
cardiovascular disease is a cause, an effect or even related
to the compromised cardiovascular function.
All of the studies summarized above in which
melatonin, either physiologically or pharmacologically,
was found to be protective of both the function and
morphology of the I / R heart used the rat as the experimen-
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R. J. Reiter, D.-X. Tan / Cardiovascular Research 58 (2003) 10–19
the cardiomyocytes. The reports that have investigated the
efficacy of melatonin as a cardiac protector during I / R
injury are summarized in Table 1.
To further emphasize the efficacy of melatonin in
reducing I / R damage, the reader is reminded that not only
in the heart, but in other organs as well, melatonin has a
highly favorable effect in reducing tissue damage that
follows transient episodes of hypoxia and reoxygenation.
Thus, in the in vivo brain (including the spinal cord)
[29–32], liver [33], kidney [34], gastrointestinal tract [35],
lung [36] and placenta [37] the amount of tissue damage
and the severity of compromised function after I / R were
shown to be reduced when melatonin was employed as an
ameliorative agent. Furthermore, the damage inflicted by
other agents that induce high oxidative stress is reduced
when melatonin is exogenously administered [38–41].
Subsequent to the publication of the reports illustrating
the potential utility of melatonin in the treatment of I / R,
Duncker and Verdouw [27] posed the question as to
whether melatonin has a future as a cardioprotective agent.
The authors of the current review feel that this is a
reasonable likelihood, not only in terms of protecting
against I / R injury but also against cardiotoxicity induced
by a variety of drugs [42]. For example, there is a
significant amount of literature regarding the beneficial
actions of melatonin at the level of heart in animals treated
with chemotherapeutic drugs which often have significant
toxicity in cardiac tissue which results in serious cardiomyopathy often leading to congestive heart failure [42–
45].
The data that have accumulated to date surely justify
more extensive studies using melatonin in other models
(and species) of cardiac I / R injury and, if successful, tests
in humans as well. Melatonin is an uncommonly safe,
stable and inexpensive molecule. For example, numerous
studies have shown that melatonin, given to humans in
huge pharmacological doses, e.g. 1 g daily for a month
[46] or in smaller amounts for varying treatment periods
[47–50], are without measurable side effects. The same
holds for animal studies. Thus, giving female rats 200 mg
melatonin per kg body weight (the equivalent of an
average-weight human consuming 14 g melatonin daily)
throughout pregnancy caused no maternal or fetal toxicity
[51].
3. Mechanisms of melatonin’s protective actions in
the heart
It is well accepted that O 2 -derived reactants can cause
contractile dysfunction of the myocardium and certainly
reperfusion of the heart with oxygenated blood after a
period of ischemia causes oxidative damage in the reperfused tissue [52]. These toxic O 2 -based reactants along
with RNS (Fig. 3) are widely believed to play a significant
role in cardiopathophysiology after I / R [9,10].
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tal model. The only other species that has been tested in
similar studies is the rabbit. In this report [26], rabbits
underwent coronary artery occlusion and reperfusion and,
when melatonin was given at a dose of either 10 or 50
mg / kg i.v., it did not change the hemodynamic parameters
of the I / R heart nor did it alter infarct volume. Melatonin
also did not aggravate any of the parameters tested and the
authors concluded that it was a safe drug with no apparent
side effects on the cardiovascular system. Considering the
numerous reports documenting the high efficacy of
melatonin in reducing abnormal cardiac physiology, infarct
volume and mortality in rats subjected to cardiac I / R, the
results obtained in this rabbit study would seem to be
unusual. In evaluating this study, Duncker and Verdouw
[27] point out that the rabbit heart lacks xanthine oxidase
which may account for the failure of the antioxidant
melatonin to reduce cardiac malfunction during I / R in this
species. It would seem judicious that melatonin administration be reassessed in the rabbit I / R model and certainly in
other species that are considered surrogates for human
heart attack. This seems especially important given
melatonin’s highly protective effects in models of cardiac
I / R in the rat.
The doses of melatonin used in the aforementioned
studies certainly caused blood concentrations of the indole
to exceed the physiological levels that normally occur in
the species used; therefore, the doses used were unquestionably pharmacological. On the other hand, pharmacological doses of any effective antioxidant would have to be
given to reduce the massive cardiac damage that occurs
during ischemia / reperfusion injury. Indeed, the reason the
oxidative damage occurs in these situations is that the
physiological levels of all antioxidants combined, i.e.
glutathione, vitamins C and E, uric acid, etc., are insufficient to prevent the tissue destruction associated with
such an extreme oxidative stress.
A thorough in vitro analysis of melatonin’s actions at
the level of the hypoxic / reoxygenated cardiomyocytes has
been performed by Salie et al. [28]. For this study, adult rat
cardiomyocytes were isolated and grown in culture and
chemical hypoxia was induced by the addition of 1.5 mM
KCN and 20 mM deoxyglucose to the superfusion fluid.
Cells were preloaded with either tetramethylrhodamine
(TMRM) in combination with either dichlorodihydrofluorescein (DCDHF), dihydrorhodamine 123 (DHR) or fluo
3 to determine the effects of melatonin, using confocal
laser scanning microscopy, on H 2 O 2 levels, ROS concentrations and Ca 21 levels, respectively. Chemical hypoxia caused marked morphological changes of the cardiomyocytes and significantly increased H 2 O 2 , ROS and
[Ca 21 ] i accumulation. Melatonin, at a concentration of
either 50 or 100 mM, significantly reduced these changes
(except for DCDHF fluorescence). These findings, as with
the in vivo results summarized above, strongly implicate
the antioxidant properties of melatonin in its protective
effects against hypoxia / reoxygenation injury at the level of
R. J. Reiter, D.-X. Tan / Cardiovascular Research 58 (2003) 10–19
15
Table 1
Publications in which pharmacological or physiological levels of melatonin have been used to protect the heart from ischemia / reperfusion (I / R) injury
Duration
of I / R (min)
Actions of melatonin
Reference
Langendorff
model (rat)
10 / 10
Reduced premature ventricular
contraction and fibrillation
[11]
Langendorff
model (rat)
30 / 30
Reduced ventricular tachycardia
and fibrillation; restored left ventricular
function; reduced lipid peroxidation,
lowered ?OH generation
[12]
Langendorff
model (rat)
5 / 30
Reduced reperfusion arrhythmias,
reduced infarct volume
[13]
Langendorff
model (rat)
20 / 40
Reduced ventricular fibrillation,
improved arrhythmia score
[16]
In situ heart
(rat)
45 / 60
Reduced ventricular tachycardia
and fibrillation, lowered total
ventricular contractions, reduced
O ?2
and MPO activity, lowered
2
infarct volume, increased survival
[17]
In situ heart
(rat)
7/7
Reduced ventricular fibrillation,
lowered mortality
[18] a
In situ heart
(rat)
3 / 120
Reduced infarct volume
[19] a
In situ heart
(rabbit)
30 / 180
No improvement of cardiac function,
no reduction in infarct volume
[26] b
Cardiomyocytes
in culture (rat)
12.5 or
27.5 / 1.5
Reduced morphological damage,
lowered reactive oxygen
generation, reduced [Ca 21 ] i
[28]
21
?OH, hydroxyl radical; O ?2
] i , intracellular calcium levels.
2 , superoxide anion radical; MPO, myloperoxidase activity; [Ca
a
In these reports, previously pinealectomized rats exhibited greater cardiac malfunction and damage as a result of I / R injury; these results suggest that
physiological (endogenous) levels of melatonin protect the heart during I / R.
b
This is the only study on I / R and the potential of melatonin as a pharmacological protector that did not use the rat heart.
That melatonin directly detoxifies O 2 -based free radicals
and related reactants is well documented [53–56]. For
example, melatonin is highly effective scavenger of the
?OH as shown using a variety of techniques by many
different authors [57–59]; this is important because of the
highly toxic nature of this reactant. Furthermore, some
products of melatonin’s interaction with O 2 -based reactants have been identified and two of them, i.e. cyclic
3-hydroxymelatonin
[60]
and
N-acetyl-5-methoxykynuramine (AFMK) [61,62], are also effective free
radical scavengers [55,56]. This cascade of reactions
greatly increases the effective concentrations of melatonin
and may account, in part, for the high efficacy of this
antioxidant in protecting against I / R injury at the level of
the heart. Furthermore, the chief hepatic metabolite of
melatonin, namely, 6-hydroxymelatonin, is also reportedly
an effective free radial scavenger [63]. Thus, even when
melatonin itself is metabolically converted to 6-hydroxymelatonin before it can function in the direct detoxification
of a radical(s), its major hepatic metabolic product may be
capable of doing so.
Besides O 2 -based reactants, nitrogen-derived species
(Fig. 3), most noteably the ONOO 2 and peroxynitrous
acid (ONOOH) are likely involved in cardiomyocyte
damage during I / R injury. Melatonin also has been shown
to neutralize these non-radical, but nevertheless toxic,
species [64,65] and, additionally, melatonin probably
reduces ONOO 2 [which occurs when nitric oxide (NO?)
couples with O ?2
2 ] by directly scavenging NO? [66,67]
and / or by inhibiting its formation by suppressing the
activity of its rate limiting enzyme, nitric oxide synthase.
In I / R, NO? is generally considered to contribute to the
resulting molecular damage, but under some other conditions inhibition of nitric oxide synthase may result in
detrimental effects.
While melatonin’s (and its metabolites) functions as a
free radical scavenger, including its ability to apparently
directly detoxify H 2 O 2 [68], may be important relative to
its protective effects against injury due to hypoxia / reoxygenation, it is unlikely that this is the sole means of its
beneficial effects. Not specifically during cardiac I / R
injury but in other cases of high oxidative stress, melatonin
has been shown to promote the metabolism of O 2 -based
reactants to innocuous or less toxic substances. For example, melatonin stimulates gene expression and activities of
the superoxide dismutases, important antioxidative en-
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Model
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R. J. Reiter, D.-X. Tan / Cardiovascular Research 58 (2003) 10–19
zymes which dismutase O ?2
to H 2 O 2 (Fig. 3) [69].
2
Thereafter, the two enzymes assigned the function of
metabolizing H 2 O 2 , i.e. catalase and glutathione peroxidase (GPx), and thereby reducing the formation of the
devastatingly toxic ?OH, have been shown to be stimulated
by melatonin as well [70,71]. These indirect antioxidative
actions of melatonin could certainly magnify its protective
actions in the heart under conditions of high oxidative
stress. Also of significance is a report by Urata et al. [72]
who have shown that melatonin increases the levels of
glutathione, an important intracellular antioxidant, by
stimulating
its
rate-limiting
enzyme,
gammaglutamylcysteine synthase.
Besides directly neutralizing and indirectly detoxifying
oxygen and nitrogen-based reactants, melatonin may also
act at the level of the mitochondrial respiratory chain to
reduce electron leakage and, therefore, free radical generation [73,74]. While melatonin’s actions at the level of the
mitochondria is a rather recent area of investigative
interest, the ability of the indole to reduce electron leakage
is inferred from its stimulatory action on the activities of
complex I and complex IV, its promotion of ATP production [73], and its action in reducing oxidative damage
to mitochondrial DNA. It is anticipated that research
related to the mitochondrial actions of melatonin will
flourish in the next several years and the information
garnered will clarify how the functions of melatonin at the
mitochondrial level may be beneficial to the heart generally and during I / R injury specifically.
Another important component of I / R injury is the
recruitment of activated leukocytes to the injured tissue
(Fig. 1) [75]. Once at their target, these cells generate
inflammatory mediators, e.g. leukotriene B 4 , platelet-activating factor, etc., and they also lead to the activation of
oxidant-sensitive nuclear transcription factors, in particular
nuclear factor kappa B (NFkB); these agents, combined
with the generation of free radicals by the leukocytes,
induce inflammatory mediators by endothelial cells and / or
mast cells which cause the mobilization of adhesion
molecules (selectins and ICAM). As a consequence,
leukocytes adhere to the endothelium which leads to a
cascade of events that contribute to cardiac damage.
Melatonin, due to its ability to reduce the expression of the
adhesion molecules, P-selectin and ICAM [76], as well as
the suppression of NFkB translocation into the nucleus
[77] may be helpful in reducing cardiac injury during I / R.
Although the specific details of the mechanisms involved in the melatonin’s ability to reduce oxidative
damage at the level of the heart (and other tissues) during
hypoxia and especially during reperfusion remain to be
clarified, studies to date almost uniformly confirm the
beneficial effects of the indole under these conditions.
Clearly, melatonin has at its disposal numerous means by
which it may limit cardiac damage during I / R (Table 2),
but which of these functions plays the dominant role in its
protective actions is uncertain at this time. Beyond the
actions of melatonin described, Duncker and Verdouw [27]
summarize still other effects of melatonin which may be
beneficial to cardiovascular physiology in general and
cardiac function in particular.
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Fig. 3. Oxygen and nitrogen-based reactants which are generated in abundance during ischemia / reperfusion inflict massive damage to molecules and
cellular organelles. SOD, superoxide dismutase; GPx, glutathione peroxidase; GRd, glutathione reductase; NOS, nitric oxide synthase.
R. J. Reiter, D.-X. Tan / Cardiovascular Research 58 (2003) 10–19
Table 2
Effects of melatonin that potentially contribute to its ability of protect the
cardiovascular system from oxidative injury
Actions
References
Scavengers of oxygen-based reactants
Scavenges nitrogen-based reactants
Cascade actions whereby melatonin
metabolites also function of scavengers
Stimulates antioxidative enzymes
Inhibits a proxidative enzyme
Increases glutathione levels
Stabilizes cellular membranes
Increases the efficiency of oxidative
phosphorylation
Reduces leukocyte recruitment and adhesion
molecule expression
Reduces homocysteine-induced damage
[53–58]
[64,65,78]
[55,61,63]
[70,79]
[71]
[72]
[80,81]
[73,74]
[35,76]
[82,83]
4. Concluding remarks
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In this brief review we have summarized the data
describing the protective actions of an endogenously
produced molecule, melatonin (and its metabolites), on
myocardial damage that accompanies a transient interruption and re-establishment of blood flow to the heart. While
melatonin’s beneficial actions are thus far convincing, by
far the bulk of the studies have been directed to a single
species, the rat. Extension of these findings to other
commonly used experimental models of heart attack is
essential for advancement of this potentially important
molecule as a cardioprotective agent. The importance of
these studies is emphasized by the fact that melatonin,
given either acutely or chronically at pharmacological
doses, is virtually without toxicity [46,49–51]. Additionally, when given orally it is rapidly absorbed and it is also
safe and easy to administer intravenously. Furthermore,
exogenously administered melatonin does not interfere
with its endogenous production. It is known that melatonin
levels in the serum correlate with the total antioxidant
status of this fluid in both the rat and human [79,84,85]. Its
ability to protect the heart does not only derive from
studies documenting its beneficial actions during I / R
injury, but also the data showing it is equally protective of
the heart against drugs, especially cancer chemotherapeutic
agents, that normally cause cardiomyopathy [41–44]. In
view of the large amount of positive data that has already
accumulated, additional studies in this field should be of
high priority.
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