Melatonin in cardiovascular disease

Abstract

This editorial refers to “Cardiovascular effects of melatonin receptor agonists”. The hormone melatonin is synthesized primarily in the pineal gland, retina, several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Based on the data available, the last 18 years indicate that melatonin influences multiple factors of the cardiovascular function. Multiple evidences reveal that the rhythmicity of melatonin has a crucial role in a variety of cardiovascular pathophysiological processes including anti-inflammatory, antioxidant, anti-hypertensive and possibly as an antilipidemic function. Melatonin receptors receive and transduce melatonin's message to influence daily and seasonal rhythms of physiology. The melatonin message is translated through the interaction between the melatonin receptors (MT1 and MT2) and its coupling to G proteins, which are potential therapeutic targets in disorders ranging from insomnia, circadian sleep disorders, depression and cardiovascular diseases. Based on the data available, melatonin seems to have cardioprotective properties via its direct free radical scavenger activity. Melatonin efficiently interacts with several reactive oxygen species (receptor-independent actions). Collectively, these protective actions of melatonin may have potential clinical applicability for individuals with cardiovascular disease.

Keywords::

• agomelatine
• cardiac pathophysiology
• cardiovascular disease
• circadin
• melatonin receptor
• ramelteon

1. Protective effects of melatonin

Cardiovascular disease is the leading cause of morbidity and mortality in the Western World and, according to the World Health Organisation, it will be the major cause of death in the world by the year 2020 [1]. Ischemia/Reperfusion, atherosclerosis and hypertension are some of the most important processes where free radicals impact on cardiac physiology. About this, it has recently been revealed that melatonin possesses various pleiotropic effects on cardiovascular system (Figure 1) [2].

Figure 1. Pleiotropic effects of the melatonin on cardiovascular system.

Reactive oxygen species (ROS) play an important role in the pathogenesis of cardiac ischemia/reperfusion injury. One of the main sources of ROS in cardiomyocytes during ischemia and early reperfusion may be a disturbance of the electron transport chain in mitochondria [3]. The fundamental processes underlying the development of vascular disease, such as atherosclerosis, set their origins in an initial insult to the vessel wall. The alteration may appear from mechanical disruption or it can result from biological causes, such as hypercholesterolemia, diabetes and an excess of free radicals.

There is a general agreement that ROS play a vital role in the pathogenesis of coronary atherosclerosis and its complications [4]. Hypertension is recognized as a multi-factorial situation resulting from the effect of a combination of environmental and genetic factors. Furthermore, the increased oxidative stress has also been described in human models of hypertension [5]. The importance of ROS in the development and maintenance of hypertension has been recognized for some time [6]. Cardiac adaptation in response to intrinsic or external stress involves a complex process of chamber remodeling and myocyte molecular modifications [7]. In this context, in a human study has been demonstrated a relationship between melatonin and the LV remodeling [8].

Hydrogen transfer and electron transfer have been identified as the main mechanisms determining the free radical-scavenging activity of melatonin. However, there are other mechanisms, such as the radical adduct formation, which have non-negligible contributions to the overall free radical-scavenging activity of melatonin [9]. It has been shown that melatonin reacts with a wide variety of radicals at high rates. Some of them are radical hydroxyl, radical peroxy trichloromethyl, radical alkoxyl and radical azide. On the contrary, there seems to be a general agreement on the modest efficiency of melatonin as antioxidant for detoxifying other radicals such as lypoperoxyl, peroxyl and radical anion. In any case, based on all the gathered data, it can be concluded, without hesitation, that melatonin efficiently protects against oxidative stress through a variety of mechanisms [9].

The discovery of melatonin as a direct free radical scavenger and as an indirect antioxidant via its stimulatory actions on antioxidative enzymes has greatly increased interest in the potential cardioprotective properties of this indoleamine. Several comprehensive reviews have summarized this topic in more detail [2,10-13].

The administration of melatonin, at pharmacological doses, has been reported to reduce blood pressure as a consequence of various mechanisms including a direct hypothalamic effect, a lowering of catecholamine levels, relaxation of the smooth muscle wall and, most importantly, as a result of its antioxidant properties [2]. However, individuals who lack a nightime blood melatonin rise do not drop their blood pressure at night. So, physiological levels of melatonin are also involved in blood pressure regulation [14].

Studies in animals have confirmed the ameliorative effects of melatonin on abnormal function and cardiac tissue destruction resulting from ischemia-reperfusion after the administration of pharmacologic doses of melatonin prior to ischemia and/or during reperfusion [15].

2. Melatonin receptors as therapeutic targets

In a variety of physiological responses, melatonin acts through its receptor binding sites as membrane and nuclear. Two mammalian receptor subtypes have been cloned and designated as MT₁ and MT₂ [10]. These receptors have been identified in human coronary arteries from pathological samples and also from healthy controls. Animal studies suggest that melatonin has dual effects on the vasculature, depending on the specific receptor type activated, with vasoconstriction occurring after MT₁-activation and vasorelaxation after MT₂-activation [12]. The problem here is that direct free radical scavenging properties (much of melatonin's antioxidant activity) is not related to these receptors; rather, it is a direct interaction of melatonin with radical species, that is, it is receptor-independent. In fact, recently it has been demonstrated that MT1 and MT2 receptors have nothing to do with protecting the brain from ischemia-reperfusion injury [16]. This is very likely the same for ischemia-reperfusion injury in any organ, including the heart.

Melatonin receptor agonists currently on the market are all MT1/MT2-nonselective melatonin receptor agonists. These agonists are: Agomelatine, Ramelteon and Circadin (prolonged-release melatonin formulation) [17]. These are indicated for a number of conditions ranging from insomnia and circadian entrainment to depression and seasonal affective disorder. Until the present time, there is no indication of these agonists for the treatment of cardiovascular diseases. Moreover, these agonists provide no protection against free radical damage produced in the cardiovascular diseases [17].

The availability of melatonin receptor ligands with well-defined pharmacological properties and selectivity, advances in the molecular biology of the melatonin receptors, the discovery of novel cellular and signaling mechanisms transducing effector responses, have increased our understanding of the role of melatonin and its receptors in the modulation of circadian, endocrine, immune and cardiovascular function [17,18]. A unique feature of the melatonin message that must always be taken into account is that it is time-dependent along of day. Effects of melatonin and melatonin-related drugs are affected by time of day and duration of exposure, probably because of changes in the diurnal sensitivity and/or efficacy of MT₁ and MT₂ melatonin receptors [17].

In conclusion, the identification of novel targets for the treatment of disorders involving alterations in the melatonin system should provide new opportunities for therapeutic targets. Discovery of specific and selective agonists for the MT₁ and MT₂ melatonin receptors would provide additional tools for the study of melatonin function and the design of novel therapeutics.

Declaration of interest

The author states no conflicts of interest and has received no payment in preparation of this manuscript. This work was supported within the framework of one research project (FUNCIS 1-II/2006).

Acknowledgments

I thank P Abreu-Gonzalez for his invaluable comments during the preparation of this editorial. I thank I Abreu-Afonso for technical assistance in the preparation of the manuscript.

Notes