Melatonin for a Healthy Heart Rhythm [chapter]

Natalia Jorgelina Prado, Margarita Segovia-Roldan, Emiliano Raúl Diez, Esther Pueyo
2020 Melatonin [Working Title]  
Melatonin is a promising cardioprotective agent. Its increase during the night is associated with healthy cardiovascular function. On the other hand, reduced levels of melatonin are related to diseases. Aging and chronodisruptors reduce melatonin levels. Pharmacological supplementation reduces the deleterious effects of cardiovascular risk factors and improves the myocardial response to ischemia/ reperfusion injury and other proarrhythmic conditions. The protective mechanisms of melatonin
more » ... of melatonin involve its antioxidant properties as well as receptor-mediated actions. Signaling pathways include membrane responses, cytoplasmic modulation of kinases, nuclear receptor interactions, and improvement of mitochondrial functions. This chapter focuses on the electrophysiological and the antiarrhythmic properties of melatonin. The acute and chronic protective mechanisms of melatonin will be analyzed with an emphasis on transmembrane potentials and intercellular communication. An outstanding antifibrillatory effect makes melatonin a novel antiarrhythmic agent worthy of further exploration in the path to clinical applications. Melatonin for a Healthy Heart Rhythm DOI: Cells have antioxidants that prevent damage. An antioxidant is any substance that significantly delays or prevents oxidation of lipids, proteins, or DNA [40]. Lipids are often used as target molecules because they are more reactive to oxidants than proteins or DNA. Nonenzymatic antioxidants include reduced glutathione (GSH), vitamins, and melatonin among others. Melatonin is five times more effective than GSH as scavenger of the highly toxic hydroxyl radical [34]. The main antioxidant enzymes are superoxide dismutase (SOD), catalase, thioredoxin, and glutathione peroxidase [40][41][42][43][44]. Melatonin efficiently prevents oxidative stress. The aromatic indole ring of melatonin reduces and repairs electrophilic radicals acting as generous electron donor. One molecule of melatonin can neutralize up to 10 toxic reagents, including ROS, RNS, and other free radicals [7, 39,[45][46][47]. In addition, several metabolites formed when melatonin neutralizes harmful reagents are also antioxidants suggesting that a cascade of reactions increases the efficacy of melatonin [28, 35,[47][48][49]. Being a highly lipophilic and hydrophilic compound, melatonin crosses all morphological barriers and acts not only in each cell but also within each subcellular compartment. Additionally, melatonin increases the efficacy of vitamin E, vitamin C, and GSH [33, 50]. Therefore, the elimination of free radicals can be carried out by intracellular interactions independent of any receptor [36, 45, 51]. Melatonin stimulates antioxidant enzymes by acting on membrane, cytoplasmic, and nuclear receptors [39, 43, 52]. Low melatonin concentrations increase the expression or activity of SOD, catalase, and glutathione peroxidase [43, 53]. Ion channels and many other proteins respond to oxidative stress [54][55][56][57][58]. Amino acid residues are the targets of ROS/RNS. Sulfur atoms like cysteine and methionine, hydroxyl groups from tyrosine, or aromatic rings of histidine, phenylalanine, and tryptophan are vulnerable to reactive species. Those that contain more cysteines are more sensitive to changes because thiol groups (-SH), which exist as thiolates (-S) at physiological pH, tend to react more quickly with ROS/RNS [59]. Many of these proteins are involved in important biological reactions such as oxidative phosphorylation, metabolic regulation, and signal transduction [60, 61]. Oxidative stress can increase late sodium currents through direct Na + channel modification [62, 63] and result in a prolonged action potential duration and arrhythmogenic triggers known as early-after depolarizations (EAD) [64]. Several reviews describe the redox regulation of calcium channel in cardiac myocytes including the ryanodine receptor calcium, the IP3 receptor, and voltage-dependent L-type calcium channel [65] [66] [67] [68] [69] . ROS and RNS affect the L-type Ca 2+ channel Cav1.2 by regulation of cysteine residues. However, calcium channel regulation by redox is controversial with reports of increase and decrease of channel functions [66] . Voltage-gated potassium (Kv) channel, mainly responsible for myocardial repolarization, is sensitive to oxidative stress [58, [70] [71] [72] . Sulfenic acid modification at a conserved cysteine residue of Kv1.5 under prolonged oxidative stress can induce arrhythmia [58, 72] .
doi:10.5772/intechopen.91447 fatcat:7m4cewiflzfj5idbcnspsl2tyu