The term ‘melatonin’ stems from the Greek word ‘melas’, which means ‘dark’, and the Greek word ‘tonos’. The hormone of darkness, chemically known as N-acetyl-5-methoxytryptamine, is a pleiotropic molecule found in all organisms in the animal kingdom 1. Melatonin entered the arena of medicine in 1958, when it was isolated and used in the field of dermatology 2. It is secreted by the pineal gland of mammals in varying levels throughout the day with maximum production only in complete darkness 3,4. Moreover, it is found in cells, bone marrow, thymus, gastrointestinal tract, skin, and eyes 5.
Melatonin is a ubiquitous hormone reported to be correlated with a variety of functions such as sleep disturbances, circadian rhythm regulation, anti-inflammatory, antioxidant 3,6,7, antineoplastic 3,8,9, antidepressive 10,11, and vasodilatory action through its receptors [melatonin type 1 (MT1) and melatonin type 2 (MT2)]. These receptors are situated in human coronary arteries, aorta, and left-ventricular tissue 12,13. The beneficial effect of this indoleamine on various systems and on cardiac physiology, and its role in the reduction of blood pressure (BP) have been investigated previously 14. However, much more research will be necessary before its action is fully delineated.
The role of melatonin in noncardiovascular disease
Melatonin plays a significant role in the function of the circadian rhythm, which is responsible for the maintenance of the daily sleep/wake cycle and the regulation of various systems such as endocrine, immune, cardiovascular and metabolic systems 4,10. The pacemaker of the circadian rhythm is located in the suprahiasmatic nucleus; however, it is worth stressing that peripheral oscillators are found in peripheral organs such as the heart 15–17.
Melatonin has successfully been used in situations in which the biological clock is disturbed, for example, in jet-lag syndrome, insomnia, or night shift work 15,18. Furthermore, an analogue of melatonin called agomelatine has antidepressant anxiolytic functions and lacks side effects associated with widely used antidepressants 10,11. Melatonin was found to be effective in the symptomatic treatment of Alzheimer’s disease and cognitive impairment syndrome 19, and plays a role in delaying the progression of Alzheimer’s disease 3. Melatonin’s antineoplastic ability stems from a combination of its antioxidant, antimitotic, and antiangiogenic properties 3,8. It has also been reported that this pleiotropic molecule has a beneficial effect on tinnitus 20, septic shock 5,21, immune diseases such as rheumatoid arthritis 3,22, and bone diseases 23. Melatonin has been implicated in protection from various associations and complications of diabetes including obesity, fatty liver, renal dysfunction, and neuropathy 6,7,24,25. However, a full review on these effects is beyond the scope of this article.
Melatonin’s noncardiovascular actions are illustrated in Fig. 1.
Role of melatonin in the cardiovascular system
The human cardiovascular system seems to be regulated by diurnal variations, which influence a number of components of its physiology such as heart rate, BP, endothelial function, and fibrinolytic activity, according to Dominguez-Rodriguez et al. 24. This notion is also reinforced by the fact that many cardiac events such as myocardial infarction, ventricular arrhythmias, cardiac arrest, or sudden death follow a circadian pattern, as some of them show a preference for early morning hours. Even platelet aggregability exhibits a circadian rhythm, reaching a peak in the morning 15,24.
According to Kazuomi and colleagues, the disruption of circadian rhythm caused by insomnia, sleep deprivation, or shift working leads to a reduction in melatonin levels. This in turn causes dysfunction of the autonomic nervous system – which enhances salt sensitivity and hypertension – and an increase in aldosterone, which in turn participates in the development of cardiovascular disease. However, more studies are needed for confirmation of this hypothesis 26.
Melatonin’s role in modulating the risk of cardiovascular events is noteworthy. Patients with coronary artery disease and high levels of low-density lipoprotein cholesterol are found to have low levels of melatonin 24. This hormone has been shown to suppress the formation of cholesterol and low-density lipoprotein by 38 and 42%, respectively. In contrast, human and animal studies have shown that it has an enhancing effect on the formation of high-density lipoprotein 14,24,25,27.
Melatonin has been reported to be linked to a large number of cardiovascular related functions such as regulation of BP (arterial in both humans and animals and renovascular in rats), modulation of inflammatory factors that contribute to cardiovascular diseases, and protection of myocytes against ischemia and reperfusion injury (in animal studies), mainly because of its antioxidant action 14,24,28,29.
Rodella and colleagues demonstrated through experimental studies that this versatile molecule, acting as an antioxidant and free-radical scavenger, is involved in the process of ageing. Given the fact that endothelial ageing contributes to cardiovascular disease, it can become a modulator of atherosclerosis 30. Ageing related alterations of the cardiovascular system of mice and rats can be beneficially modulated by melatonin 27,31.
The circadian pattern of blood pressure
BP exhibits fluctuations during the day according to a circadian pattern: an increase in the morning is followed by high levels throughout the active day and a reduction by 10–20% during sleep 26,32. The contribution of the rise in melatonin levels to the low levels of BP encountered during sleep has been examined in several studies. The conclusion that may be reached is that this multifunctional hormone has an antihypertensive effect at night and early in the morning, stressing the higher risk of cardiovascular events at this time of the day 14,25.
Nondippers, that is patients who show less than 10% drop in their BP levels during the night, are characterized by chronodisruption and lower melatonin levels 17,33,34. The effectiveness of a single morning dose of antihypertensive treatment is disputable 32. Several mechanisms are implicated in the pathogenesis of nondippers/risers: increased salt sensitivity, excessive salt consumption, dysfunction of the autonomic nervous system, and an abnormality in melatonin secretion 26. On the basis of the observation that modulation of circadian rhythm could ameliorate hypertension in nondippers, melatonin was used in the study by Rechcinski et al. 33 to transfer 35% of the patients from the ‘nondipper’ category to the ‘dipper’ category, thereby reducing the risk of cardiovascular events in them. However, an overwhelming reduction in BP (>20%) was observed in three patients, raising the risk of cardiovascular implications.
Enjuanes-Grau and colleagues presented an innovative cohort study, in which the participants observed were young medical residents on duty, to study the differences in BP and melatonin levels on an on-call working day compared with an ordinary working day. Both melatonin and BP lost their circadian patterns (no significant BP drop during the night on-call). The researchers propose the possibility of increased cardiovascular risk among physicians during on-call working days 35.
The Ambulatory Blood Pressure Monitoring and Cardiovascular Events study, involving 3000 hypertensive patients, revealed the positive effects of chronotherapy on treatment of hypertension 32,36. In this study, benefits such as BP control and a reduction in cardiovascular events were observed on dosing with antihypertensive drugs at bedtime. A disruption in the circadian rhythm has been postulated as partly responsible for this pathological situation 32. Melatonin emerges as a potent antihypertensive factor according to a plethora of experimental evidence. Unremitted light exposure in rats results in the reduction of melatonin secretion, vasoconstriction, and hypertension 32.
Role of melatonin in hypertension
Emerging evidence from animal studies suggests that melatonin contributes to the reduction of cardiac hypertrophy – by free-radical scavenging – and therefore to the incidence of heart failure 14. It reduces left-ventricular remodeling 32 due to hypertension probably through its ameliorative effect on the nocturnal BP 1. Many studies on humans and animals have reported the effectiveness of melatonin in the regulation of BP not only through direct action but also through cardioprotection against drug-mediated cardiotoxicity (Table 1). Suppressed levels of this indoleamine are found in hypertensive patients 37. It is of considerable interest that pinealectomy causes a continuous increase in BP 29. Complementary to these findings is the connection between a gradual drop in the levels of melatonin during senescence and the rise in BP 14.
According to Reiter et al. 1, melatonin was found to notably reduce the mean arterial BP by 21 mmHg and the heart rate by 33–51 beats/min in spontaneously hypertensive rats, but it did not have a reductive effect on the heart weight – possibly related to the dose of melatonin used in this study. In another animal study, systemic BP was reduced by 25% on treatment with melatonin, but the ventricular weight : body weight ratio was not altered. However, emphasis should be laid on the fact that melatonin depressed the levels of hydoxyproline in the left ventricle. Hydoxyproline is a component of fibrotic tissue. It is evident that the antifibrotic property of melatonin is triggered 1. Echocardiographically, melatonin had a positive effect on the pathological remodeling and functioning of the left ventricle. It is referred to protect against cardiac enlargement due to hyperthyroidism or chronic oxygen deprivation in rats 1,29.
In a study conducted by Kozirog et al. 25, it was demonstrated that patients with metabolic syndrome showed a reduction by a mean of 12.3 mmHg in systolic and 6.5 mmHg in diastolic BP when treated with 5 mg of melatonin 2 h before bedtime.
Moreover, renovascular hypertension, which develops mainly through oxidative procedures, can also be reduced significantly using melatonin instead of placebo in rats 14. Animal studies have shown that protection of cardiac function as well as amelioration of oxidative damage in other target organs of hypertension (brain and kidneys) can be accomplished using this indoleamine 28.
It is worth mentioning that Lee et al. 38, in an attempt to investigate the effect of antenatal, postpartum, and postweaning supplementation of melatonin on BP of spontaneously hypertensive rats (SHR), reached the conclusion that this ubiquitous hormone has a depressive impact on the rise in BP in the offspring of SHR, but does not modulate their tendency to develop hypertension. On the basis of the findings of the study by Tain et al. 34, who suggested the use of melatonin as a prehypertensive tool, melatonin prevents hypertension in young SHR by restoring nitric oxide (NO). Rezzani et al. 39 studied the beneficial properties of melatonin – anti-inflammatory, antioxidant and apoptotic properties – that contribute to the reduction of hypertension in SHR and the regression of vascular remodeling. On the contrary, melatonin did not have the same effect on the BP of TGR (mRen2)27 rats, in which hypertension is mainly attributed to the increased activation of the renin–angiotensin–aldosterone system 17.
A notable study conducted by Forman et al. 40 highlights morning levels of melatonin as an independent factor in the incidence of hypertension in women and reveals that its deficiency may be pathophysiologically related to the development of hypertension. They suggested a possible correlation between melatonin levels, sleep disordered breathing (obstructive sleep apnea), and hypertension. Nevertheless, they recognized the need for studies on a larger cohort to establish melatonin as an independent risk factor for hypertension.
Melatonin’s hypotensive action was examined alone and in combination with other antihypertensive drugs such as angiotensin converting enzyme inhibitors, moxonidine (centrally acting antihypertensive drug), and capozide (diuretic+captopril) 22. The indoleamine enhanced the hypotensive effect of the above drugs and, in addition, restored circadian hemodynamic rhythms in combination with moxonidine in hypertensive patients. Despite this, it should be noted that the addition of melatonin to nifedipine resulted in an increase in BP by about 6.5 mmHg and in the heart rate by about 3.9 beats/min 33. In a study on 43 patients, aged 44–69 years, with coronary heart disease, stable angina, and hypertension, it was observed that the use of melatonin caused an optimum decrease in BP during day and night 22.
Ramelteon, a highly selective agonist of melatonin receptors (MT1, MT2), was examined in the study by Oxenkrug et al. 37 to determine its hypotensive effect on rats. The findings support the conclusion that ramelteon is effective in reducing age-associated systolic BP (14 mmHg). Another finding of this study is that ramelteon also attenuated age-associated weight gain in SHR. This evidence places it as a potent measure against hypertension mainly in its early stages 37.
This remarkable pleiotropic molecule also provides cardioprotection against toxicity induced by anthracycline, doxorubicin, daunorubicin, and epirubicin in animals, as described by Reiter and Tan 29.
Effect of melatonin on nocturnal blood pressure
Another area of interest in our experimental investigation was nocturnal BP and the impact of the hormone of darkness on it. The nocturnal rise in melatonin levels in humans is associated with the physiological nocturnal dip in BP 1. According to Grossman and colleagues, melatonin reduced systolic BP at night by 6.1 mmHg and diastolic BP by 3.51 mmHg, as assessed in clinical trials. The researchers stressed the fact that this decrease was achieved using controlled-release melatonin, as fast-release melatonin had no effect 41,42. The latter, that is the different formulations of melatonin used in various studies, is hypothesized to be the reason for the distinctions in the outcomes observed 41.
Melatonin has a half-life of 40–50 min; hence, the dosage in hypertensive patients is not sufficient throughout the night when fast-release melatonin is used 41. A double-blinded study on 16 men with essential hypertension receiving melatonin for 3 weeks, 1 h before sleep, revealed a reduction in nocturnal systolic and diastolic BP by 6 and 4 mmHg, respectively 29. According to Zeman et al. 17, the optimum effect of melatonin is observed when it is administered at the beginning of the night.
Mechanisms of blood pressure modification
The regulation of BP by the action of melatonin is thought to be mediated by various mechanisms, which include receptor mediated and receptor independent actions 32,43. Both MT1 and MT2 receptors are present in vascular smooth-muscle cells, whereas MT2 is present in endothelial cells as well 43. The activation of melatonin receptors results in a decrease in cyclic AMP and in phospatidylino-inositol-4,5-biphosphate hydrolysis, which leads to the inhibition of vasodilatation or vasoconstriction 43. The activation of the MT2 receptor on endothelial cells can lead to an increase in cytosolic Ca2+ levels 43 and consequently to in an increase in NO levels, which leads to vasodilatation 25,32,43. Melatonin acts as an antioxidant 44 directly by scavenging hydroxyl, peroxyl, superoxide, and NO free radicals and indirectly by stimulating antioxidant enzymes 3,43. Other mechanisms include interaction with calmodulin, inhibition of Ca2+ channels, and calcium pump stimulation in cardiomyocytes 43 (Fig. 2). Studies on humans have revealed the suppressive effect of oral melatonin on sympathetic tone 45, probably through modulation of cardiac autonomic activity by the circadian pacemaker, the suprahiasmatic nucleus 45, and through attenuation of sympathetic activity in response to orthostatic stress after receiving 3 mg of melatonin 46. Experimental and human studies also showed that administration of melatonin also reduced catecholamines 14,25,47.
According to Paulis et al. 48, the hypotensive action of melatonin is mainly attributed to the enhancement of the NO pathway, as observed in L-NAME-induced hypertension. Nevertheless, melatonin through its antioxidative ability and its cumulative effect with the endothelium-derived hyperpolarizing factor mildly reduces BP 48. L-NAME hypertension results in higher levels of pineal melatonin without a similar effect on the levels of plasma or tissue melatonin, probably because of its use against oxidative stress 13. According to Grossini et al. 12, intracoronary administration of melatonin in anesthetized pigs leads to an increase in coronary blood flow and cardiac contractility mediated by MT1 and MT2 receptors, NO release, and β-adrenoreceptors.
The treatment of healthy young women and men with melatonin was associated with relaxation of carotid and axillary arteries 40. Moreover, melatonin has a negative influence on the vasoactive action of norepinephrine and phenylephrine 40. A different mechanism by which melatonin exerts its antihypertensive action was proposed by Li and colleagues. They demonstrated that melatonin enhances the depressive effect of γ-aminobutyric acid on BP in rats with stress-induced hypertension. γ-Aminobutyric acid is a stress-inhibitory neurotransmitter, which reduces the activity of angiotensin II 49.
Mechanisms proposed for the ameliorating effect of melatonin on nocturnal hypertension include sympathetic inhibition, antioxidant action, and release of endothelium factors that probably suppress arterial restenosis and thrombosis 41. Melatonin was also found to decrease carotid–femoral pulse-wave velocity, a marker of aortic stiffness, in healthy young men 41.
Mounting evidence suggests a potential role for melatonin in the treatment of hypertension. Many studies support the notion that melatonin, acting through diverse mechanisms, has a noteworthy ameliorative effect on BP and cardiovascular pathology. However, more research is required to quantify the safety and efficacy of melatonin in the prevention of hypertension-related cardiovascular disease.
Conflicts of interest
There are no conflicts of interest.
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