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Hypotensive effects of melatonin in rats: Focus on the model, measurement, application, and main mechanisms
Abstract
The hypotensive effects of melatonin are based on a negative correlation between melatonin levels and blood pressure in humans. However, there is a positive correlation in nocturnal animals that are often used as experimental models in cardiovascular research, and the hypotensive effects and mechanism of melatonin action are often investigated in rats and mice. In rats, the hypotensive effects of melatonin have been studied in normotensive and spontaneously or experimentally induced hypertensive strains. In experimental animals, blood pressure is often measured indirectly during the light (passive) phase of the day by tail-cuff plethysmography, which has limitations regarding data quality and animal well-being compared to telemetry. Melatonin is administered to rats in drinking water, subcutaneously, intraperitoneally, or microinjected into specific brain areas at different times. Experimental data show that the hypotensive effects of melatonin depend on the experimental animal model, blood pressure measurement technique, and the route, time and duration of melatonin administration. The hypotensive effects of melatonin may be mediated through specific membrane G-coupled receptors located in the heart and arteries. Due to melatonin’s lipophilic nature, its potential hypotensive effects can interfere with various regulatory mechanisms, such as nitric oxide and reactive oxygen species production and activation of the autonomic nervous and circadian systems. Based on the research conducted on rats, the cardiovascular effects of melatonin are modulatory, delayed, and indirect. Does melatonin have blood pressure-lowering effects, and are nocturnal animals suitable for testing the hypotensive effects of melatonin? The hypotensive effects of melatonin depend on the experimental animal model, blood pressure measurement method, route, time and duration of melatonin administration.
... MLT is directly engaged, through immediate actions, in the regulation of the anticipated BP dipping that happens nightly in humans, in addition to controlling daily BP rhythm . [43][44][45] . ...
... There have been studies showing that non-dippers' nocturnal MLT release is suppressed in hypertensive patients. 45,64,65 CONCLUSION Endogenous MLT would be a naturally cardioprotective agent with therapeutic promise. MLT rhythmicity seems to have essential roles in many CV activities as an antioxidant, an antiinflammatory agent, a chronobiotic and perhaps as an epigenetic regulator. ...
Melatonin (MLT) "N-acetyl-5-methoxytryptamine"; a pineal hormone; has a diurnal variation and may be necessary for the suprachiasmatic nucleus (SCN) and peripheral tissue's molecular circadian clocks to be synchronized, has powerful receptor-dependent and receptor-independent effects on a number of cardiovascular (CV) variables, including endothelial cells function, thrombus formation, blood pressure (BP), and heart rate (HR). MLT possesses antioxidative, anti-inflammatory, chronobiotic, and perhaps epigenetics regulatory characteristics. Low blood concentrations of MLT have been found in persons who have coronary artery disease (CAD), arterial hypertension (HT), and congestive cardiac failure. The physiological function of endogenous MLT and its circadian rhythm in the human CV system is reviewed in this article.
... MЕЛ також належить вирішальна роль в епігенетичній регуляції АТ у дорослих, яка програмується під час внутрішньоутробного і/або неонатального розвитку [6]. MЕЛ, на додаток до контролю добового ритму АТ, безпосередньо бере участь у регуляції зменшення показників АТ вночі [34]. ...
Melatonin has several impacts on the cardiovascular system, including the potential to reduce blood pressure in addition to its role in regulating sleep. It has the ability to decrease adrenergic system activity and indirectly enhance endothelial function. Melatonin can provide antihypertensive effects by stimulating own receptors in the central nervous system and peripheral arteries. In addition, melatonin is a potential treatment for patients with hypertension, including the “night-peaker” category. However, the results of only a few randomized trials suggest that melatonin supplements are effective in the treatment of hypertension. Melatonin can lower blood pressure due to vasodilatation, direct blocking of Ca2+ channels and increased production of nitric oxide in the endothelium; antioxidant properties; suppression of the sympathetic nervous system, reduction of norepinephrine production, as well as activation of the parasympathetic nervous system. Because the drug is usually taken at bedtime, it may increase the duration and quality of sleep and therefore lower blood pressure during sleep. Low endogenous melatonin secretion during sleep may be associated with elevated nocturnal blood pressure and comorbid cardiovascular diseases. In addition, melatonin exhibits an excellent safety profile. Consequently, larger-scale, longer-term studies with higher patient heterogeneity, biomarker identification, and idiosyncrasies related to melatonin use are required. The aim of this narrative review is to analyze the peculiarities of the mechanisms of action, as well as the effect of exogenous melatonin on blood pressure parameters in the experiment and clinic. The search was conducted in Scopus, Science Direct (from Elsevier), and PubMed, including the MEDLINE databases. The key words used were “melatonin,” “blood pressure”, “hypertension”, “obesity”, “metabolic syndrome”. We manually searched the bibliography of publications to find study results that the online search did not yield.
... For example, in the case of European perch, under laboratory conditions, already 1 lx during the dark phase significantly reduced the secretion of melatonin [9], in contrast to an experiment in the natural environment, when one month of 15 lx ALAN did not change the melatonin levels in perch [10]. ALAN generally decreases melatonin in both diurnal and nocturnal animals; therefore, its involvement in cardiovascular regulation is questionable (reviewed in: [15]). ...
Artificial light at night (ALAN) affects most of the population. Through the retinohypothalamic tract, ALAN modulates the activity of the central circadian oscillator and, consequently, various physiological systems, including the cardiovascular one. We summarised the current knowledge about the effects of ALAN on the cardiovascular system in diurnal and nocturnal animals. Based on published data, ALAN reduces the day-night variability of the blood pressure and heart rate in diurnal and nocturnal animals by increasing the nocturnal values of cardiovascular variables in diurnal animals and decreasing them in nocturnal animals. The effects of ALAN on the cardiovascular system are mainly transmitted through the autonomic nervous system. ALAN is also considered a stress-inducing factor, as glucocorticoid and glucose level changes indicate. Moreover, in nocturnal rats, ALAN increases the pressure response to load. In addition, ALAN induces molecular changes in the heart and blood vessels. Changes in the cardiovascular system significantly depend on the duration of ALAN exposure. To some extent, alterations in physical activity can explain the changes observed in the cardiovascular system after ALAN exposure. Although ALAN acts differently on nocturnal and diurnal animals, we can conclude that both exhibit a weakened circadian coordination among physiological systems, which increases the risk of future cardiovascular complications and reduces the ability to anticipate stress.
... Melatonin is a potent antioxidant [35] and anti-inflammatory factor [36]. It also has an impact on energy metabolism [37] and on the cardiovascular system [38]. ...
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The brain is one of the organs involved in sepsis, and sepsis-induced brain injury manifests as sepsis-associated encephalopathy (SAE). SAE may be present in up to 70% of septic patients. SAE has a very wide spectrum of clinical symptoms, ranging from mild behavioral changes through cognitive disorders to disorders of consciousness and coma. The presence of SAE increases mortality in the population of septic patients and may lead to chronic cognitive dysfunction in sepsis survivors. Therefore, therapeutic interventions with neuroprotective effects in sepsis are needed. Melatonin, a neurohormone responsible for the control of circadian rhythms, exerts many beneficial physiological effects. Its anti-inflammatory and antioxidant properties are well described. It is considered a potential therapeutic factor in sepsis, with positive results from studies on animal models and with encouraging results from the first human clinical trials. With its antioxidant and anti-inflammatory potential, it may also exert a neuroprotective effect in sepsis-associated encephalopathy. The review presents data on melatonin as a potential drug in SAE in the wider context of the pathophysiology of SAE and the specific actions of the pineal neurohormone.
... The available data indicate that the melatoninergic system may interact with the RAAS: (1) Angiotensin II and melatonin seem to have opposite roles in cardiovascular pathophysiology. While Ang II increases BP and pathologic remodeling of a hypertensive and failing heart [188], melatonin has been shown to reduce BP in hypertensive patients [111,174,189,190] and in a number of animal models of hypertension [101,112,173,191,192] and to exert antifibrotic effects in hypertensive [101,[193][194][195][196][197] and failing heart [198] and in kidney [52,199], similar to the ACE inhibitor captopril [52,[193][194][195][196]199]. ...
Anxiety disorders are the most common mental diseases. Anxiety and the associated physical symptoms may disturb social and occupational life and increase the risk of somatic diseases. The pathophysiology of anxiety development is complex and involves alterations in stress hormone production, neurosignaling pathways or free radical production. The various manifestations of anxiety, its complex pathophysiological background and the side effects of available treatments underlie the quest for constantly seeking therapies for these conditions. Melatonin, an indolamine produced in the pineal gland and released into the blood on a nightly basis, has been demonstrated to exert anxiolytic action in animal experiments and different clinical conditions. This hormone influences a number of physiological actions either via specific melatonin receptors or by receptor-independent pleiotropic effects. The underlying pathomechanism of melatonin’s benefit in anxiety may reside in its sympatholytic action, interaction with the renin–angiotensin and glucocorticoid systems, modulation of interneuronal signaling and its extraordinary antioxidant and radical scavenging nature. Of importance, the concentration of this indolamine is significantly higher in cerebrospinal fluid than in the blood. Thus, ensuring sufficient melatonin production by reducing light pollution, which suppresses melatonin levels, may represent an endogenous neuroprotective and anxiolytic treatment. Since melatonin is freely available, economically undemanding and has limited side effects, it may be considered an additional or alternative treatment for various conditions associated with anxiety.
Melatonin (5-methoxy-N-acetyltryptamine) is an indoleamine compound that plays a critical role in the regulation of circadian rhythms. While melatonin is primarily synthesized from the amino acid tryptophan in the pineal gland of the brain, it can also be produced locally in various tissues, such as the skin and intestines. Melatonin’s effects in target tissues can be mediated through receptor-dependent mechanisms. Additionally, melatonin exerts various actions via receptor-independent pathways. In biological systems, melatonin and its endogenous metabolites often produce similar effects. While injuries are common in daily life, promoting optimal wound healing is essential for patient well-being and healthcare outcomes. Beyond regulating circadian rhythms as a neuroendocrine hormone, melatonin may enhance wound healing through (1) potent antioxidant properties, (2) anti-inflammatory actions, (3) infection control, (4) regulation of vascular reactivity and angiogenesis, (5) analgesic (pain-relieving) effects, and (6) anti-pruritic (anti-itch) effects. This review aims to provide a comprehensive overview of scientific studies that demonstrate melatonin’s potential roles in supporting effective wound healing.
Melatonin, a signaling hormone with pleiotropic biofunctions, has shown health benefits. Trimethylamine-N-oxide (TMAO) and asymmetric dimethylarginine (ADMA) are uremic toxins involved in the development of hypertension. TMAO originates from trimethylamine (TMA), a gut microbial product. ADMA is an endogenous nitric oxide (NO) synthase inhibitor. We examined whether melatonin therapy could prevent hypertension and kidney disease by mediating gut microbiota-derived metabolites and the NO pathway using an adenine-induced chronic kidney disease (CKD) young rat model. Six-week-old young Sprague Dawley rats of both sexes were fed a regular diet (C group), a diet supplemented with 0.5% adenine (CKD group), or adenine plus 0.01% melatonin in their drinking water (CKD + M group) for three weeks (N = 8/group). Adenine-fed rats developed renal dysfunction, hypertension, renal hypertrophy and increased uremic toxin levels of TMAO and ADMA. Melatonin therapy prevented hypertension in both sexes and attenuated kidney injury in males. Melatonin reversed the changes to the plasma TMAO-to-TMA ratio induced by CKD in both sexes. Besides, the protective effects of melatonin were associated with restoration of gut microbiota alterations, including increased α-diversity, and enhancement of the abundance of the phylum Proteobacteria and the genus Roseburia in male rats. Melatonin therapy also partially prevented the increases in ADMA in male CKD rats. Melatonin sex-specifically protected young rats against hypertension and kidney injury induced by CKD. The results of this study contribute toward a greater understanding of the interaction between melatonin, gut microbiota-derived metabolites, and the NO pathway that is behind CKD, which will help to prevent CKD-related disorders in children.
Reactive oxygen species (ROS) are subcellular messengers in signal transductions pathways with both beneficial and deleterious roles. ROS are generated as a by-product of mitochondrial respiration or metabolism or by specific enzymes such as superoxide dismutases, glutathione peroxidase, catalase, peroxiredoxins, and myeloperoxidases. Under physiological conditions, the low levels of ROS production are equivalent to their detoxification, playing a major role in cellular signaling and function. In pathological situations, particularly atherosclerosis or hypertension, the release of ROS exceeds endogenous antioxidant capacity, leading to cell death. At cardiovascular levels, oxidative stress is highly implicated in myocardial infarction, ischemia/reperfusion, or heart failure. Here, we will first detail the physiological role of low ROS production in the heart and the vessels. Indeed, ROS are able to regulate multiple cardiovascular functions, such as cell proliferation, migration, and death. Second, we will investigate the implication of oxidative stress in cardiovascular diseases. Then, we will focus on ROS produced by NAPDH oxidase or during endothelial or mitochondrial dysfunction. Given the importance of oxidative stress at the cardiovascular level, antioxidant therapies could be a real benefit. In the last part of this review, we will detail the new therapeutic strategies potentially involved in cardiovascular protection and currently under study.
Melatonin is released by the pineal gland and can modulate cardiovascular system function via the G protein-coupled melatonin receptors MT1 and MT2. Most vessels are surrounded by perivascular adipose tissue (PVAT), which affects their contractility. The aim of our study was to evaluate mRNA and protein expression of MT1 and MT2 in the mesenteric artery (MA) and associated PVAT of male rats by RT-PCR and Western blot. Receptor localization was further studied by immunofluorescence microscopy. Effects of melatonin on neurogenic contractions were explored in isolated superior MA ex vivo by measurement of isometric contractile tension. MT1, but not MT2, was present in MA, and MT1 was localized mainly in vascular smooth muscle. Moreover, we proved the presence of MT1, but not MT2 receptors, in MA-associated PVAT. In isolated superior MA with intact PVAT, neuro-adrenergic contractile responses were significantly smaller when compared to arteries with removed PVAT. Pre-treatment with melatonin of PVAT-stripped arterial rings enhanced neurogenic contractions, while the potentiating effect of melatonin was not detected in preparations with preserved PVAT. We hypothesize that melatonin can stimulate the release of PVAT-derived relaxing factor(s) via MT1, which can override the direct pro-contractile effect of melatonin on vascular smooth muscle. Our results suggest that melatonin is involved in the control of vascular tone in a complex way, which is vessel specific and can reflect a sum of action on different layers of the vessel wall and surrounding PVAT.
It has been documented that constant light exposure exerts complicated cardiovascular effects. However, a mounting collection of conflicting results did not make it any easier for researchers and physicians to consider the role of light on cardiovascular function. This study was designed to investigate how constant light exposure (24 h light/day) influences the cardiac function in normal and heart-failure (HF) rats. In normal rats, two groups of SD rats were accustomed in 12 h light/12 h dark (LD) or 24 h light (constant light, CL) for 4 weeks. In HF rats which was induced by myocardial infarction (MI) was let recover in LD for 4 weeks. Interestingly, compared with rats in LD environment (ejection fraction, EF%: 93.64 ± 2.02 in LD, 14.62 ± 1.53 in HF-LD), constant light (2 weeks) weakened the cardiac function in normal and HF rats (EF%: 79.42 ± 2.91 in CL, 11.50 ± 1.08 in HF-CL). The levels of renal sympathetic nerve activity and c-fos expression in the rostral ventrolateral medulla (RVLM), a key region controlling sympathetic outflow, were significantly increased in normal and HF rats after constant light (RSNA, Max%: 8.64 ± 0.48 in LD, 20.02 ± 1.24 in CL, 20.10 ± 1.16 in HF-LD, 26.82 ± 1.69 in HF-CL). In conclusion, it is suggested that constant light exposure exerts detrimental cardiovascular effects, which may be associated with the RVLM-related sympathetic hyperactivity.
Obesity is a worldwide epidemic disease that induces important structural and functional changes to the heart and predisposes a patient to devastating cardiac complications. Sirtuin1 (SIRT1) has been found to have roles in regulating cardiac function, but whether it can help in cardioprotection is not clear. The aim of the present study was to determine whether melatonin, by modulating SIRT1 and in turn mitochondria signaling, may alleviate obesity-induced cardiac injuries. We investigated 10 lean control mice and 10 leptin-deficient obese mice (ob/ob) orally supplemented with melatonin for 8 weeks, as well as equal numbers of age-matched lean and ob/ob mice that did not receive melatonin. Hearts were evaluated using multiple parameters, including biometric values, morphology, SIRT1 activity and expression of markers of mitochondria biogenesis, oxidative stress, and inflammation. We observed that ob/ob mice experienced significant heart hypertrophy, infiltration by inflammatory cells, reduced SIRT1 activity, altered mitochondrial signaling and oxidative balance, and overexpression of inflammatory markers. Notably, melatonin supplementation in ob/ob mice reverted these obesogenic heart alterations. Melatonin prevented heart remodeling caused by obesity through SIRT1 activation, which, together with mitochondrial pathways, reduced oxidative stress and inflammation.
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The purpose of the work on normotensive rats of different age groups (3, 15, and 22 months) is to study the synchronism between the functioning of the cardiovascular system and the locomotor activity of animals in open field tests by a single injection of exogenous melatonin in different doses (1 and 10 mg/kg). The studies show a unidirectional dose-dependent effect of exogenous melatonin on the locomotor activity of rats of different ages and an age-dependent effect of melatonin on the parameters of the cardiovascular system. The results show the possible desynchronization between the circadian rhythms of locomotor activity and the functioning of the cardiovascular system with aging, which can lead to a discrepancy between hemodynamic parameters and the level of locomotor activity.
Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin-conferred cardioprotection remains unclear. In this study, we employed both loss-of-function and gain-of-function approaches to reveal the answer. Mice (wild-type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild-type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R-initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2-silenced heart, but not the MT1 subtype. Furthermore, AAV9-mediated cardiomyocyte-specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.
This study investigated whether continuous light exposure (CLE) results in behavioural disturbances in rats and whether melatonin can modify these potential changes. Four groups of 3-month-old Wistar rats were treated as follows for six weeks: control, melatonin, CLE, and CLE with melatonin. CLE increased systolic blood pressure and melatonin reduced it. No changes in behavioural patterns by CLE were observed. In the controls, melatonin reduced both exploration and locomotion but these parameters remained uninfluenced in the CLE. We conclude that melatonin exerted a different impact on behaviour in controls and in the CLE group.
Consumption of food high in fructose and salt is associated with the epidemic of hypertension. Hypertension can originate from early life. Melatonin, a pleiotropic hormone, regulates blood pressure. We examined whether maternal melatonin therapy can prevent maternal high-fructose combined with post-weaning high-salt diet-induced programmed hypertension in adult offspring. Pregnant Sprague-Dawley rats received either a normal diet (ND) or a 60% fructose diet (HF) during pregnancy and the lactation period. Male offspring were on either the ND or a high-salt diet (HS, 1% NaCl) from weaning to 12 weeks of age and were assigned to five groups (n = 8/group): ND/ND, HF/ND, ND/HS, HF/HS, and HF/HS+melatonin. Melatonin (0.01% in drinking water) was administered during pregnancy and lactation. We observed that maternal HF combined with post-weaning HS diets induced hypertension in male adult offspring, which was attenuated by maternal melatonin therapy. The beneficial effects of maternal melatonin therapy on HF/HS-induced hypertension related to regulating several nutrient-sensing signals, including Sirt1, Sirt4, Prkaa2, Prkab2, Pparg, and Ppargc1a. Additionally, melatonin increased protein levels of mammalian targets of rapamycin (mTOR), decreased plasma asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine levels, and increased the l-arginine-to-ADMA ratio. The reprogramming effects by which maternal melatonin therapy protects against hypertension of developmental origin awaits further elucidation.
The melatonin receptor subfamily is composed of three members, MT1 and MT2, which are binding to melatonin, and GPR50, which shows high sequence homology to MT1 and MT2 but does not bind to melatonin or any other known ligand. An interesting feature of these receptors is their capacity to form homo- and heteromers between each other and also with other GPCRs. The following heteromers have been described: MT1/MT2, MT1/GPR50, and heteromers composed of MT2 and the serotonin 5-HT2c receptor or the orphan GPR61, GPR62, and GPR135 receptors. These heteromers represent novel pharmacological entities as they exhibit functional properties that are different from those of the corresponding homomers. Formation of several of these heteromers has been confirmed in tissues. MT2/5-HT2c heteromers are targeted by the clinically relevant antidepressant agomelatine, and MT1/MT2 heteromers regulate nocturnal retinal light sensitivity. Here, we resume our current knowledge on melatonin receptor heteromerization and discuss how it contributes to the diversification of the function of melatonin receptors.
The renin-angiotensin-aldosterone system (RAAS) is a dominant player in several cardiovascular pathologies. This study investigated whether alterations induced by l-NAME, (NLG)-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, and the protective effect of melatonin are associated with changes in the RAAS. Four groups of 3-month-old male Wistar rats (n = 10) were treated as follows for four weeks: untreated controls, rats treated with melatonin (10 mg/kg/day), rats treated with l-NAME (40 mg/kg/day), and rats treated with l-NAME + melatonin. l-NAME administration led to hypertension and left ventricular (LV) fibrosis in terms of enhancement of soluble, insoluble and total collagen concentration and content. Melatonin reduced systolic blood pressure enhancement and lowered the concentration and content of insoluble and total collagen in the LV. The serum concentration of angiotensin (Ang) 1–8 (Ang II) and its downstream metabolites were reduced in the l-NAME group and remained unaltered by melatonin. The serum aldosterone level and its ratio to Ang II (AA2-ratio) were increased in the l-NAME group without being modified by melatonin. We conclude that l-NAME-hypertension is associated with reduced level of Ang II and its downstream metabolites and increased aldosterone concentration and AA2-ratio. Melatonin exerts its protective effect in l-NAME-induced hypertension without affecting RAAS.
Melatonin, due to its multiple means and mechanisms of action, plays a fundamental role in the regulation of the organismal physiology by fine tunning several functions. The cardiovascular system is an important site of action as melatonin regulates blood pressure both by central and peripheral interventions, in addition to its relation with the renin–angiotensin system. Besides, the systemic management of several processes, melatonin acts on mitochondria regulation to maintain a healthy cardiovascular system. Hypertension affects target organs in different ways and cellular energy metabolism is frequently involved due to mitochondrial alterations that include a rise in reactive oxygen species production and an ATP synthesis decrease. The discussion that follows shows the role played by melatonin in the regulation of mitochondrial physiology in several levels of the cardiovascular system, including brain, heart, kidney, blood vessels and, particularly, regulating the renin–angiotensin system. This discussion shows the putative importance of using melatonin as a therapeutic tool involving its antioxidant potential and its action on mitochondrial physiology in the cardiovascular system.
Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with NG-nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction.
Melatonin, synthesized primarily by the pineal gland, is a neuroendocrine hormone with high membrane permeability. The vascular effects of melatonin, including vasoconstriction and vasodilation, have been demonstrated in numerous studies. However, the mechanisms underlying these effects are not fully understood. Large-conductance Ca2+-activated K+ (BKCa) channels are expressed broadly on smooth muscle cells and play an important role in vascular tone regulation. The present study explored the mechanisms of myocyte BKCa channels and endothelial factors underlying the action of melatonin on the mesenteric arteries (MAs). Vascular contractility and patch-clamp studies were performed on myocytes of MAs from Wistar rats. Melatonin induced significant vasodilation on MAs. In the presence of Nω-nitro-L-arginine methyl ester (L-NAME), an potent endothelial oxide synthase (eNOS) inhibitor, melatonin elicited concentration-dependent relaxation, with lowered pIC50. The effect of melatonin was significantly attenuated in the presence of BKCa channel blocker Iberiotoxin or MT1/MT2 receptor antagonist Luzindole in both (+) L-NAME and (-) L-NAME groups. In the (+) L-NAME group, Iberiotoxin caused a parallel rightward shift of the melatonin concentration-relaxation curve, with pIC50 lower than that of Luzindole. Both inside-out and cell-attached patch clamp recordings showed that melatonin significantly increased the open probability, mean open time, and voltage sensitivity of BKCa channels. In a cell-attached patch clamp configuration, the melatonin-induced enhancement of BKCa channel activity was significantly suppressed by Luzindole. These findings indicate that in addition to the activation of eNOS, melatonin-induced vasorelaxation of MAs is partially attributable to its direct (passing through the cell membrane) and indirect (via MT1/MT2 receptors) activation of the BKCa channels on mesenteric arterial myocytes.
Background
Reliable measurement of blood pressure in conscious mice is essential in cardiovascular research. Telemetry, the “gold‐standard” technique, is invasive and expensive and therefore tail‐cuff, a noninvasive alternative, is widely used. However, tail‐cuff requires handling and restraint during measurement, which may cause stress affecting blood pressure and undermining reliability of the results.
Methods and Results
C57Bl/6J mice were implanted with radio‐telemetry probes to investigate the effects of the steps of the tail‐cuff technique on central blood pressure, heart rate, and temperature. This included comparison of handling techniques, operator's sex, habituation, and influence of hypertension induced by angiotensin II. Direct comparison of measurements obtained by telemetry and tail‐cuff were made in the same mouse. The results revealed significant increases in central blood pressure, heart rate, and core body temperature from baseline following handling interventions without significant difference among the different handling technique, habituation, or sex of the investigator. Restraint induced the largest and sustained increase in cardiovascular parameters and temperature. The tail‐cuff readings significantly underestimated those from simultaneous telemetry recordings; however, “nonsimultaneous” telemetry, obtained in undisturbed mice, were similar to tail‐cuff readings obtained in undisturbed mice on the same day.
Conclusions
This study reveals that the tail‐cuff technique underestimates the core blood pressure changes that occur simultaneously during the restraint and measurement phases. However, the measurements between the 2 techniques are similar when tail‐cuff readings are compared with telemetry readings in the nondisturbed mice. The differences between the simultaneous recordings by the 2 techniques should be recognized by researchers.
Melatonin is a hormone secreted from the pineal gland and has different cardiovascular effects. KCNQ genes expressed in aorta related with vascu- lar tone and KCNH2 gene characterised in left ventricle associated with QT duration. The aim of this study was to investigate the effects of melatonin on the regulation of the blood pressure and the relationships between the expressions of aorta KCNQ1-5, left ventricle KCNH2 genes and the QTc interval. For that purpose, 42 male adult Sprague-Dawley rats were devided into six groups; SHAM, SHAM+L-NAME, PLT, PLT+L-NAME, PLT+MEL and PLT+L-NAME+MEL. Pinealectomy operation was applied in PLT groups. L-NAME was added in drinking water (40 mg/kg/day) and melatonin was given subcutanously (5 mg/kg/day). The blood pressure, heart rate (HR) and QTc interval values were recorded on 0, 1st, 7th, 14th and 21st days of experiment. Left ventricle and thoracic aorta samples were obtained to investigate the changes of gene expression levels of KCNQ1-5 and KCNH2, respectively. The increased blood pressure and HR were observed in SHAM+L-NAME, PLT, and PLT+L-NAME groups compared to MEL and SHAM groups (p < 0.05). On the other hand, the long QTc interval was recorded in PLT and all L-NAME groups compared to others (p < 0.05). The decreases in KCNH2 gene expression levels were observed in groups have QTc prolongation. In conclusion, PLT operation could cause an increasing in blood pressure, HR and QTc duration, melatonin was able to prevent these increasings and could change KCNQ and KCNH2 gene expresion profiles. Further molecular studies are required to evaluate these effects.
As in humans, young, female, spontaneously hypertensive rats (SHR) have a lower blood pressure than male SHR. In male, normotensive rats (WKY), α2- and β1+2-adrenoceptors (AR) reciprocally controlled catecholamine release and vascular smooth muscle tension. This interaction was malfunctioning in male SHR. The present study analyzed if a favorable shift in the α2/β1+2AR interaction may represent an antihypertensive protection in females. Female SHR (early hypertension, 12–14 weeks) and age-matched WKY were infused with tyramine (15 min) to stimulate norepinephrine (NE) release through the reuptake transporter, consequently preventing reuptake. Presynaptic control of vesicular release was therefore reflected as differences in overflow to plasma. The released NE increased total peripheral vascular resistance (TPR). The results showed that β1>2AR facilitated tyramine-stimulated NE release in both strains, also in the presence of α2AR-antagonist (L-659,066). βAR-antagonist (atenolol-β1, ICI-118551-β2, nadolol-β1+2) had no effect on the increased secretion of epinephrine after L-659,066 in WKY, but β1>2AR-antagonist augmented the L-659,066-induced increase in the secretion of epinephrine in SHR. Nadolol increased the TPR response to tyramine with a greater effect in WKY than SHR, whereas β1or2-selective antagonists did not. One βAR-subtype may therefore substitute for the other. When both β1+2AR were blocked, α2AR-antagonist still reduced the TPR response in WKY but not SHR. Thus, α2/β1+2AR reciprocally controlled catecholamine release, with a particular negative β1AR-influence on α2AR-auto-inhibition of epinephrine secretion in SHR. Moreover, in these female rats, β1/2AR-independent α2AR-mediated vasoconstriction was seen in WKY but not SHR, but β1/2AR-mediated vasodilation downregulated adrenergic vasoconstriction, not only in WKY but also in SHR.
Background
Phenylhydrazine (PHE) in experimental animal models has been widely reported to cause haemolytic anaemia, via the induction of oxidative stress and thus causing deleterious cardiovascular complications. Hence, this study was designed to evaluate the possible modulatory role of melatonin (MLT) or vitamin C when co-administered with PHE.
Methods
Anaemia was established with PHE administration. MLT or vitamin C was co-administered with PHE. Haematological parameters, markers of oxidative stress, enzymic and non-enzymic antioxidants, blood pressure and electrocardiograms were assessed.
Results
PHE administration led to a significant (p<0.05) increase in malondialdehyde (MDA), and hydrogen peroxide (H
Conclusions
Hence, MLT and vitamin C could be employed as therapeutic targets in various cardiovascular diseases and its complications.
Cardiovascular diseases including hypertension are often associated with behavioural alterations. The aim of this study was to show, whether ivabradine, the blocker of If-channel in sinoatrial node, is able to modify the behaviour of rats in L-nitro-arginine methyl ester (L-NAME)-induced hypertension and to compare the effect of ivabradine with captopril and melatonin. 12-week-old male Wistar rats were divided into the following groups: controls, ivabradine (10 mg/kg/24 h), L-NAME (40 mg/kg/24 h), L-NAME + ivabradine, L-NAME + captopril (100 mg/kg/24 h), L-NAME + melatonin (10 mg/kg/24 h). Systolic blood pressure (SBP) and heart rate (HR) were measured by tail-cuff method once a week. The behaviour of rats was investigated during 23-hours in the phenotyper after four weeks of the treatment. Chronic administration of L-NAME induced hypertension without a change in HR. All tested substances partly prevented the increase of SBP, while ivabradine and melatonin also reduced HR. Ivabradine, captopril and melatonin reduced daily food intake, slightly decreased daily water intake and attenuated body weight gain. In L-NAME group, locomotor activity was enhanced by ivabradine, whereas exploratory behaviour was increased by melatonin and captopril. In conclusion, ivabradine, besides its potentially protective hemodynamic actions, does not seem to exert any disturbing effects on behaviour in L-NAME-induced hypertension in rats, while some of its effects were similar to captopril or melatonin. It is suggested that ivabradine used in cardiovascular indications is harmless regarding the effect on behaviour.
We aimed to explore the effects of melatonin and n-3 polyunsaturated fatty acids (PUFA) supplementation on plasma and aortic nitric oxide (NO) levels in isoproterenol (Iso) affected spontaneously hypertensive (SHR) and Wistar rats. Untreated control rats were compared with Iso injected (118 mg/kg, s.c.) rats, and Iso injected plus supplemented with melatonin (10 mg/kg, p.o.) or PUFA (1.68 g/kg, p.o.) for two months. Plasma and aortic basal, L-NAME inhibited, adrenaline and acetylcholine stimulated NO were determined using Griess method. Plasma NO levels were lower in SHR versus Wistar rats. Iso decreased NO in Wistar while not in SHR. PUFA but not melatonin intake of Iso treated SHR increased plasma NO along with a decrease in systolic blood pressure. Basal aortic NO level was higher in SHR than Wistar rats and not altered by Iso. Intake of melatonin increased but PUFA decreased basal NO levels in Wistar+Iso and did not affect in SHR+Iso rats. Acetylcholine and adrenaline induced aortic NO release was significantly increased in Wistar+Iso but not SHR+Iso group. Melatonin intake increased Ach induced aortic NO in Wistar+Iso and SHR+Iso groups, whereas there was no effect of PUFA intake. Findings suggest that PUFA modulates plasma and melatonin aortic NO levels of isoproterenol affected rats in a strain-dependent manner.
Purpose of review:
Melatonin is a neuroendocrine hormone synthesized primarily by the pineal gland. Numerous studies have suggested that melatonin plays an important role in various cardiovascular diseases. In this article, recent progress regarding melatonin's effects on cardiovascular diseases is reviewed.
Recent findings:
In the past year, studies have focused on the mechanism of protection of melatonin on cardiovascular diseases, including myocardial ischemia-reperfusion injury, myocardial hypoxia-reoxygenation injury, pulmonary hypertension, hypertension, atherosclerosis, valvular heart diseases, and other cardiovascular diseases.
Summary:
Studies have demonstrated that melatonin has significant effects on ischemia-reperfusion injury, myocardial chronic intermittent hypoxia injury, pulmonary hypertension, hypertension, valvular heart diseases, vascular diseases, and lipid metabolism. As an inexpensive and well tolerated drug, melatonin may be a new therapeutic option for cardiovascular disease.
The aim of the present study was to investigate the protective effects of melatonin (MLT) on hypertension-induced renal injury and identify its mechanism of action. Twenty-four healthy male Wistar rats were divided into a sham control group (n=8), which was subjected to sham operation and received vehicle treatment (physiological saline intraperitoneally at 0.1 ml/100 g), a vehicle group (n=8), which was subjected to occlusion of the left renal artery and vehicle treatment, and the MLT group (n=8), which was subjected to occlusion of the left renal artery and treated with MLT (10 mg/kg/day). Pathological features of the renal tissues were determined using hematoxylin and eosin staining and Masson staining. Urine protein, serum creatinine (Scr), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical analysis was performed to determine the expression of heme oxygenase‑1 (HO‑1), intercellular adhesion molecule‑1 (ICAM‑1), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Furthermore, reverse transcription polymerase chain reaction was conducted to determine the mRNA expression of HO‑1, ICAM‑1, eNOS and iNOS. A marked decrease in blood pressure was noticed in the MLT group at week 4 compared with that of the vehicle group (P<0.01). Furthermore, MLT treatment attenuated the infiltration of inflammatory cells and oedema/atrophy of renal tubules. MLT attenuated hypertension-induced increases in urine protein excretion, serum creatinine and MDA as well as decreases in SOD activity in renal tissues. Furthermore, MLT attenuated hypertension-induced increases in iNOS and ICAM‑1 as well as decreases in eNOS and HO‑1 expression at the mRNA and protein level. In conclusion, the results of the present study indicated that MLT had protective roles in hypertension‑induced renal injury. Its mechanism of action is, at least in part, associated with the inhibition of oxidative stress.
Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the eNOS gene resulting in decreased vascular eNOS expression and NOx synthesis. Melatonin is involved in epigenetic regulation and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-week old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P=0.008 vs. control) and mean arterial blood pressure increased (109.5±3.8 vs. 104.0±4.7 mm Hg, P=0.002 ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P<0.001 vs. control) and decreased plasma nitric oxide concentration (10.1±11.1 vs. 29.5±8.0 µM (P<0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P=0.005, vs. ART+vehicle), normalized nitric oxide plasma concentration (23.1±14.6 µM, P=0.002, vs. ART+vehicle) and mesentery-artery responsiveness to acetylcholine (P<0.008 vs. ART+vehicle) and prevented arterial hypertension (104.6±3.4 mmHg, P<0.003 vs. ART+vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.
Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis in vivo that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically-instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by in vivo fetal treatment with the NO clamp. Melatonin modulates the fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
The suprachiasmatic nucleus (SCN) is the master circadian pacemaker. The pineal hormone melatonin is involved in the regulation of circadian phase. As a part of the circadian system, its synthesis and secretion is under SCN control. On the other hand, melatonin feeds back on the SCN to regulate its function. Melatonin has two specific windows of time at which it regulates SCN function, namely dusk and dawn. It has been suggested that melatonin exerts its effect on the SCN during that specific window of time via one or both of its specific receptors, MT1 or MT2. The hypothesis that the density of these receptors varies across the circadian cycle was tested. Using immunohistochemistry with receptor-specific antibodies, the localization and distribution of melatonin receptors MT1 and MT2 was studied in the SCN at different Zeitgeber times (ZT): ZT 11–13 (dusk), 23–01 (dawn), 5–7 (mid-day), and 17–19 (midnight). Our results show that MT1 receptor density significantly increased at dusk relative to dawn and midnight (p<0.01 and p<0.001 respectively). Although MT1 receptors were widespread in the SCN and parts of the optic chiasm at dusk, they were restricted to the SCN during the mid-day period. MT2 receptors were not detected in the SCN. Thus, we find that melatonin receptor MT1 density and distribution varies with circadian time. This creates a time window during which melatonin can affect the operation of the SCN. We also find that melatonin regulates SCN function via MT1 receptors with a minimal role for MT2.
Context:
Melatonin, a pineal hormone and a potent antioxidant, has important roles in metabolic regulation.
Objective:
This study investigated serum asymmetric dimethylarginine (ADMA), homocysteine (Hcy), nitric oxide (NO) levels, known to be reliable markers of cardiovascular diseases, and determined possible protective effects of melatonin in fructose-fed rats.
Materials and methods:
Sprague-Dawley rats were divided into four groups: control, fructose, melatonin, and fructose plus melatonin. Metabolic syndrome was induced in rats by 20% (w/v) fructose solution in tap water, and melatonin was administered at the dose of 20 mg/kg bw per day by oral gavage. After 8 weeks, serum lipids, glucose, insulin, ADMA, Hcy, and NOx (the stable end products of NO) levels were quantified.
Results:
Fructose administration caused a statistically significant increase in systolic blood pressure (SBP), serum insulin, triglycerides, and very low-density lipoprotein (VLDL)-cholesterol levels compared with the control group and the metabolic syndrome model was successfully demonstrated. In comparison with the control group, fructose caused a significant increase in serum ADMA, Hcy, and NOx levels. Melatonin counteracted the changes in SBP, serum ADMA, and Hcy levels found in rats both alone and administered with fructose.
Discussion and conclusion:
These results show that high fructose consumption leads to elevated SBP, atherogenic lipid profile, increased serum ADMA, and Hcy levels and melatonin treatment has beneficial effects on these biochemical parameters in rats. Melatonin might be beneficial for the prevention and/or treatment of the cardiovascular complications of metabolic syndrome not only by reducing the well-known risk factors of the disease but also by diminishing blood ADMA and Hcy levels.
Anabolic-androgenic steroids (AAS) are nominated for clinical use to promote protein synthesis in many therapeutic conditions. However, the indiscriminate use of AAS is related to hazardous cardiac disturbances and oxidative stress. We designed a study to investigate whether prolonged treatment with high doses of stanozolol modifies the activities of some antioxidant enzymes in the heart in sedentary and trained rats and whether this treatment causes alterations of cardiovascular parameters. In addition, the effectiveness of melatonin as an antioxidant and as a modulator of the cardiovascular side effects of stanozolol (STA) treatment was analyzed.
Thirty male Wistar rats were divided into the following six groups: sedentary (S), stanozolol sedentary (SS), stanozolol-melatonin sedentary (SMS), trained (T), stanozolol trained (ST) and stanozolol-melatonin trained (SMT). The stanozolol-treatment rats received 5 mg.kg(-1) by subcutaneous injection before each exercise session (5 d.wk(-1), i.e., 25 mg.kg(-1).wk(-1)), while control groups received only saline solution injection. The melatonin-treatment groups received intraperitoneal injections of melatonin (10 mg.kg(-1)), 5 d.wk(-1) for 6 wk. Electrocardiography, blood pressure and antioxidant enzyme activity measurements were performed at the end of the experimental period for cardiac function and molecular assessment.
This is the first time that the in vivo effects of melatonin treatment on stanozolol-induced cardiovascular side effects have been studied. Stanozolol induced bradycardia and significantly increased cardiac superoxide dismutase and catalase activities. Trained stanozolol-treated rats experienced an increase in blood pressure and relative heart weight, and they developed left cardiac axis deviation. Although melatonin did not prevent cardiac hypertrophy in exercised stanozolol-treated animals, it maintained blood pressure and cardiac catalase activity, and it prevented stanozolol-induced cardiac electrical axis deviation.
In conclusion, under our experimental conditions, chronic stanozolol administration induced mild cardiovascular side effects that were partly attenuated by melatonin treatment. However, these results showed that the combination of melatonin and exercise could minimize the stanozolol side effects in the cardiovascular system.
Exposure of rats to continuous light attenuates melatonin production and results in hypertension development. This study investigated whether hypertension induced by continuous light (24 hours/day) exposure induces heart and aorta remodelling and if these alterations are prevented by melatonin or angiotensin converting enzyme inhibitor captopril. Four groups of 3-month-old male Wistar rats (10 per group) were treated as follows for six weeks: untreated controls, exposed to continuous light, light-exposed, and treated with either captopril (100 mg/kg/day) or melatonin (10 mg/kg/day). Exposure to continuous light led to hypertension, left ventricular (LV) hypertrophy and fibrosis, and enhancement of the oxidative load in the LV and aorta. Increase in systolic blood pressure by continuous light exposure was prevented completely by captopril and partially by melatonin. Both captopril and melatonin reduced the wall thickness and cross-sectional area of the aorta and reduced the level of oxidative stress. However, only captopril reduced LV hypertrophy development and only melatonin reduced LV hydroxyproline concentration in insoluble and total collagen in rats exposed to continuous light. In conclusion, captopril prevented LV hypertrophy development in the continuous light-induced hypertension model, while only melatonin significantly reduced fibrosis. This antifibrotic action of melatonin may be protective in hypertensive heart disease.
Background
Fetal chronic hypoxia is associated with blood flow redistribution and oxidative damage in the brain, leading to increased perinatal morbimortality. Melatonin reduces oxidative stress, improves vascular function, and has neuroprotective effects.
Objectives
This study aimed to determine the effects of an oral melatonin treatment to pregnant ewes at high-altitude, on the cerebrovascular function of their neonates.
Study design
Ten high-altitude pregnant sheep received either vehicle or melatonin (10 mg/d) during the last third of gestation until delivery. Postnatal daily hemodynamic measurements were recorded from lambs until 12 days old. In addition, lambs were submitted to a graded oxygenation protocol to assess cerebrovascular responses. Subsequently, lambs were euthanized, and middle cerebral arteries (MCA) were collected for vascular function, protein levels, and morphostructural analyses.
Results
Antenatal treatment doubled plasma levels of melatonin in pregnant ewes. Melatonin increased carotid flow and decreased carotid vascular resistance in the lambs by the end of the first week. Furthermore, melatonin increased MCA's maximal vasoconstrictor and vasodilator responses, associated with nitric oxide-dependent and independent mechanisms.
Conclusions
An oral treatment with melatonin during pregnancy promotes postnatal cerebral perfusion in chronically hypoxic neonates. Melatonin is a potential treatment for cerebrovascular dysfunction due to perinatal chronic hypoxia.
Cardiovascular (CV) health is often expressed by changes in heart rate and blood pressure, the physiological record of which may be affected by moving, anaesthesia, handling, time of day and many other factors in rodents. Telemetry measurement minimises these modulations and enables more accurate physiological recording of heart rate and blood pressure than non-invasive methods. Measurement of arterial blood pressure by telemetry requires implanting a catheter tip into the artery. Telemetry enables us to sample physiological parameters with a high frequency continuously for several months. By measuring the pressure in the artery using telemetry, we can visualize pressure changes over a heart cycle as the pressure wave. From the pressure wave, we can subtract systolic, diastolic, mean and pulse pressure. From the beat-to-beat interval (pressure wave) and the RR' interval (electrocardiogram), we can derive the heart rate. From beat-to-beat variability, we can evaluate the autonomic nervous system's activity and spontaneous baroreflex sensitivity and their impact on CV activity. On a long-term scale, circadian variability of CV parameters is evident. Circadian variability is the result of the circadian system's activity, which synchronises and organises many activities in the body, such as autonomic and reflex modulation of the CV system and its response to load over the day. In the presented review, we aimed to discuss telemetry devices, their types, implantation, set-up, limitations, short-term and long-term variability of heart rate and blood pressure in CV research. Data collection by telemetry should be, despite some limitations, standard in modern experimental CV research.
Decreased secretion of melatonin was reported to be associated with an enhanced risk of hypertension and diabetes. However, the effect of melatonin on gestational hypertension (GH) and the underlying mechanism remain unclear. A GH mouse model was established via electrical stimulation. The hypertensive phenotypes were indicated by systolic blood pressure (SBP) and urinary protein levels. Uterine artery (UtA) endothelial function was detected by relaxation, peak systolic velocity (PSV), end-diastolic velocity (EDV), resistance index (RI) and pulsatility index (PI). Protein expression levels were determined using immunochemistry and Western blots. Pregnancy outcomes were indicated by the fetal live ratio, fetal weight and placental weight. Melatonin supplementation ameliorated hypertensive phenotypes in the mice with GH and enhanced UtA endothelial response to acetylcholine. The BKCa potassium channel was involved in the effect of melatonin on UtA endothelial function, and melatonin promoted BKCa potassium channel expression and function in UtAs. Finally, melatonin improved pregnancy outcomes in pregnant mice. In conclusion, melatonin ameliorates hypertension in hypertensive pregnant mice and suppresses hypertension-induced decreases in Ca²⁺-activated K⁺ channels in uterine arteries.
Prenatal hypoxia (PH) has negative consequences on the cardiovascular system in adulthood and can affect the responses to additional insults later in life. We explored the effects of PH imposed during embryonic day 20 (10.5% O 2 for 12 h) on circadian rhythms of systolic blood pressure (BP) and heart rate (HR) in mature male rat offspring measured by telemetry. We evaluated: (1) stability of BP and HR changes after PH; (2) circadian variability of BP and HR after 2 and 5 weeks of exposure to artificial light at night (ALAN; 1–2 lx); and (3) response of BP and HR to norepinephrine. PH increased BP in the dark (134 ± 2 mmHg vs. control 127 ± 2 mmHg; p = 0.05) and marginally in the light (125 ± 1 mmHg vs. control 120 ± 2 mmHg) phase of the day but not HR. The effect of PH was highly repeatable between 21- and 27-week-old PH male offspring. Two weeks of ALAN decreased the circadian variability of HR ( p < 0.05) and BP more in control than PH rats. After 5 weeks of ALAN, the circadian variability of HR and BP were damped compared to LD and did not differ between control and PH rats ( p < 0.05). Responses of BP and HR to norepinephrine did not differ between control and PH rats. Hypoxia at the end of the embryonic period increases BP and affects the functioning of the cardiovascular system in mature male offspring. ALAN in adulthood decreased the circadian variability of cardiovascular parameters, more in control than PH rats.
Preeclampsia is a life-threatening multiorgan systemic disease with manifestations including gestational hypertension, oxidative stress, and vascular dysfunction. We aimed to evaluate the therapeutic effects of melatonin on an L-NAME (NLG-nitro-l-arginine methyl ester)-induced rat preeclampsia model. During gestation, L-NAME was added to drinking water at 50 mg/kg/day from gestation day (GD) 8. Rats received the combination of L-NAME with melatonin (10 mg/kg/day), or aspirin (1.5 mg/kg/day), and rats that received only L-NAME or no treatments were used as controls. Aspirin was mixed with rodent chow and melatonin was administered intraperitoneally. Blood pressure and urine protein content were monitored every 3 days. On GD19, blood samples were collected for biochemical analysis. Compared to untreated L-NAME rats, melatonin led to markedly lowered blood pressure and urine protein content, and recovery in the fetus alive ratio, fetal weight, and the fetal weight/placental weight ratio. Compared to untreated L-NAME rats, plasma antioxidant capacity and plasma malondialdehyde were increased and decreased by melatonin, respectively, in L-NAME rats. Melatonin treatment also reduced sFlt-1, increased PlGF, and decreased the sFlt-1/PlGF ratio. In the placenta, melatonin also reduced sFlt-1 levels and increased Nrf2, PlGF, and HO-1 levels. We have demonstrated in a rat model of preeclampsia that melatonin exerts significant protective effects through lowering blood pressure and reducing oxidative stress.
Background: Hypertension is a cardiovascular syndrome with the highest morbidity and mortality worldwide. Hypertension caused by various stress factors is called stress-induced hypertension (SIH). The rostral ventrolateral medulla (RVLM) "neuroinflammatory-sympathetic overactivation" is involved in SIH formation. Melatonin has anti-inflammatory, anti-oxidant and blood pressure lowering effects. The present study is to explore the antihypertensive effects and mechanism of central melatonin which based on microglia derived neuroinflammation. Methods: Stress-induced hypertension (SIH) was induced by electric foot-shock stressors with noise interventions in rats. Melatonin (0.01，0.1，1 mmol/L) was administered to RVLM and then blood pressure (BP) and serum norepinephrine (NE) were monitored to reflect sympathetic vasomotor activity in SIH rats. Excitatory neurotransmitter (Glutamate) and inhibitory neurotransmitter [γ-aminobutyric acid (GABA)] were measured using ELISA kits. Markers of microglia M1 polarization (CD86) and pro-inflammatory cytokines (PICs (IL-1β, TNF-α)) expression in the RVLM were measured by RT-qPCR. Results: (1) Stress-induced increase in blood pressure and serum NE concentration; RVLM microinjection melatonin attenuated the elevation of blood pressure and increase of plasma NE in SIH rats in a dose-dependent manner. (2) The expression of CD86, PICs (IL-1β, TNF-α) and c-fos were increased in SIH rats; RVLM injection melatonin attenuated RVLM neuroinflammation and its effect is concentration-dependent. (3). Stress-induced increase in glutamate concentration in RVLM; RVLM injection melatonin reduced glutamate level and increased GABA level in SIH rats in a concentration-dependent manner. Conclusion: RVLM injection of melatonin inhibits M1 polarization and has anti-hypertensive effects. Melatonin reduces M1 polarization in microglia might be a novel target and a new strategy for anti-stress induced-hypertension.
Some seasonally-breeding animals are more aggressive during the short, "winter-like" days (SD) of the non-breeding season, despite gonadal regression and reduced circulating androgen levels. While the mechanisms underlying SD increases in aggression are not well understood, previous work from our lab suggests that pineal melatonin (MEL) and the adrenal androgen dehydroepiandrosterone (DHEA) are important in facilitating non-breeding aggression in Siberian hamsters (Phodopus sungorus). To characterize the role of MEL in modulating seasonal transitions in aggressive behavior, we housed male hamsters in long days (LD) or SD, treated them with timed MEL (M) or saline injections, and measured aggression after 3, 6, and 9 weeks. Furthermore, to assess whether MEL mediates seasonal shifts in gonadal and adrenal androgen synthesis, serum testosterone (T) and DHEA concentrations were quantified 36 h before and immediately following an aggressive encounter. LD-M and SD males exhibited similar physiological and behavioral responses to treatment. Specifically, both LD-M and SD males displayed higher levels of aggression than LD males and reduced circulating DHEA and T in response to an aggressive encounter, whereas LD males elevated circulating androgens. Interestingly, LD and SD males exhibited distinct relationships between circulating androgens and aggressive behavior, in which changes in serum T following an aggressive interaction (∆T) were negatively correlated with aggression in LD males, while ∆DHEA was positively correlated with aggression in SD males. Collectively, these findings suggest that SD males transition from synthesis to metabolism of circulating androgens following an aggressive encounter, a mechanism that is modulated by MEL.
Sympathetic overactivation contributes to the pathogenesis of both experimental and human hypertension. We have previously reported that oxidative stress in sympathetic premotor neurons leads to arterial baroreflex dysfunction and increased sympathetic drive to the kidneys in an experimental model of neurogenic hypertension. In this study, we hypothesized that melatonin, a potent antioxidant, may be protective in the brainstem regions involved in the tonic and reflex control of blood pressure (BP) in renovascular hypertensive rats. Neurogenic hypertension was induced by placing a silver clip (gap of 0.2 mm) around the left renal artery, and after 5 weeks of renal clip placement, the rats were treated orally with melatonin (30 mg/kg/day) by gavage for 15 days. At the end of melatonin treatment, we evaluated baseline mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), and the baroreflex control of heart rate (HR) and rSNA. Reactive oxygen species (ROS) were detected within the brainstem regions by dihydroethidium staining. Melatonin treatment effectively reduced baseline MAP and sympathoexcitation to the ischemic kidney in renovascular hypertensive rats. The baroreflex control of HR and rSNA were improved after melatonin treatment in the hypertensive group. Moreover, there was a preferential decrease in ROS within the rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS). Therefore, our study indicates that melatonin is effective in reducing renal sympathetic overactivity associated with decreased ROS in brainstem regions that regulate BP in an experimental model of neurogenic hypertension.
Aims:
Cardiovascular parameters exhibit significant 24-h variability, which is coordinated by the suprachiasmatic nucleus (SCN), and light/dark cycles control SCN activity. We aimed to study the effects of light at night (ALAN; 1-2 lx) on cardiovascular system control in normotensive rats.
Main methods:
Heart rate (HR) and blood pressure (BP) were measured by telemetry during five weeks of ALAN exposure. From beat-to-beat telemetry data, we evaluated spontaneous baroreflex sensitivity (sBRS). After 2 (A2) and 5 (A5) weeks of ALAN, plasma melatonin concentrations and the response of BP and HR to norepinephrine administration were measured. The expression of endothelial nitric oxide synthase (eNOS) and endothelin-1 was determined in the aorta. Spontaneous exploratory behaviour was evaluated in an open-field test.
Key findings:
ALAN significantly suppressed the 24-h variability in the HR, BP, and sBRS after A2, although the parameters were partially restored after A5. The daily variability in the BP response to norepinephrine was reduced after A2 and restored after A5. ALAN increased the BP response to norepinephrine compared to the control after A5. Increased eNOS expression was found in arteries after A2 but not A5. Endothelin-1 expression was not affected by ALAN. Plasma melatonin levels were suppressed after A2 and A5. Spontaneous exploratory behaviour was reduced.
Significance:
ALAN decreased plasma melatonin and the 24-h variability in the haemodynamic parameters and increased the BP response to norepinephrine. A low intensity ALAN can suppress circadian control of the cardiovascular system with negative consequences on the anticipation of a load.
This study compares the recommendations of the most recent American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Society of Hypertension (ESH) blood pressure guidelines. Both guidelines represent updates of previous guidelines and reinforce previous concepts of prevention regarding elevated blood pressure. Specifically, a low-sodium diet, exercise, body weight reduction, low to moderate alcohol intake, and adequate potassium intake are emphasized. Overall, both guidelines agree on the proper method of blood pressure measurement, the use of home blood pressure and ambulatory monitoring, and restricted use of beta-blockers as first-line therapy. The major disagreements are with the level of blood pressure defining hypertension, flexibility in identifying blood pressure targets for treatment, and the use of initial combination therapy. Although initial single-pill combination therapy is strongly recommended in both guidelines, the ESC/ESH guideline recommends it as initial therapy in patients at ≥140/90 mm Hg. The ACC/AHA guideline recommends its use in patients >20/10 mm Hg above blood pressure goal. Thus, the only real disagreement is that the ACC/AHA guidelines maintain that all people with blood pressure >130/80 mm Hg have hypertension, and blood pressure should be lowered to <130/80 mm Hg in all. In contrast, the ESC/ESH guidelines state that hypertension is defined as >140/90 mm Hg, with the goal being a level <140/90 mm Hg for all targeting to <130/80 mm Hg only in those at high cardiovascular risk, but always considering individual tolerability of the proposed goal.
The current systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the potential effect of melatonin supplementation on blood pressure in patients with metabolic disorders. The following databases were searched until June 2018: PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Two reviewers independently assessed the eligibility of retrieved studies, extracted data from included trials, and evaluated the risk of bias of included studies. Statistical heterogeneity was tested using Cochran’s Q test and I-square (I2) statistic. Data were pooled using random-effect models and standardized mean difference (SMD) was considered as the effect size. Eight RCTs, out of 743 potential citations, were eligible to be included in the current meta-analysis. The pooled findings indicated a significant reduction in systolic (SBP) (SMD = −0.87; 95% CI, −1.36, −0.38; P = 0.001; I2: 84.3) and diastolic blood pressure (DBP) (SMD = −0.85; 95% CI, −1.20, −0.51; P = 0.001; I2: 68.7) following melatonin supplementation in individuals with metabolic disorders. In summary, the current meta-analysis demonstrated that melatonin supplementation significantly decreased SBP and DBP in patients with metabolic disorders. Additional prospective studies are recommended using higher supplementation doses and longer intervention periods to confirm our findings.
The pineal hormone melatonin is a neuroendocrine hormone with high membrane permeability that is involved in regulation of circadian rhythm of several biological functions. Large-conductance Ca²⁺-activated K⁺ (BKCa) channels are abundantly expressed in vascular smooth muscle cells and play an important role in vascular tone regulation. We investigated the mechanisms through which myocyte BKCa channels mediate effects of melatonin on cerebral arteries (CAs). Arterial contractility measurements showed that melatonin alone did not change vascular tone in CAs; however, it induced concentration-dependent vasodilation of phenylephrine-induced contraction in CAs. In the presence of the potent endothelial oxide synthase inhibitor, Nω-nitro-L-arginine methyl ester, melatonin-elicited relaxation was significantly inhibited by iberiotoxin (BKCa channel blocker). Melatonin significantly increased BKCa currents but not voltage-gated K⁺ (KV) currents in whole-cell recordings. Melatonin decreased the amplitude of Ca²⁺ sparks and spontaneous transient outward currents (STOCs), however, a significant increase in open probability of BKCa channels was observed in both inside-out and cell-attached patch-clamp recordings. This melatonin-induced enhancement of BKCa channel activity was significantly suppressed by luzindole (melatonin MT1/MT2 receptor inhibitor), U73122 (phospholipase C (PLC) inhibitor), and Ro31–8220 (protein kinase C (PKC) inhibitor). Melatonin had no significant effects on sarcoplasmic reticulum release of Ca²⁺. These findings indicate that melatonin-induced vasorelaxation of CAs is partially attributable to direct (passing through the cell membrane) and indirect (via melatonin MT1/MT2 receptors-PLC-PKC pathway) activation of BKCa channels on CA myocytes.
Like it or not, your two suprachiasmatic nuclei (SCN) govern your life: from when you wake up and fall asleep, to when you feel hungry or can best concentrate. Each is composed of approximately 10,000 tightly interconnected neurons, and the pair sit astride the mid-line third ventricle of the hypothalamus, immediately dorsal to the optic chiasm (Figure 1A). Together, they constitute the master circadian clock of the mammalian brain. They generate an internal representation of solar time that is conveyed to every cell in our body and in this way they co-ordinate the daily cycles of physiology and behaviour that adapt us to the twenty-four hour world. The temporary discomfort associated with jetlag is a reminder of the importance of this daily programme, but there is growing recognition that its chronic disruption carries a cost for health of far greater scale. In this primer, we shall briefly review the historical identification of the SCN as the master circadian clock, and then discuss it on three different levels: the cell-autonomous SCN, the SCN as a cellular network and, finally, the SCN as circadian orchestrator. We shall focus on the intrinsic electrical and transcriptional properties of the SCN and how these properties are thought to form an input to, and an output from, its intrinsic cellular clockwork. Second, we shall describe the anatomical arrangement of the SCN, how its sub-regions are delineated by different neuropeptides, and how SCN neurons communicate with each other via these neuropeptides and the neurotransmitter γ-aminobutyric acid (GABA). Finally, we shall discuss how the SCN functions as a circadian oscillator that dictates behaviour, and how intersectional genetic approaches are being used to try to unravel the specific contributions to pacemaking of specific SCN cell populations.
The objective for the present study is to investigate the effects of melatonin (MEL) on systolic blood pressure (SBP), some biochemical parameters; serum (malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH), nitric oxide (NO)) in NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) treated rats. The male albino rats divided into five groups treated for 4 weeks: Group 1: Control rats. Group 2: L-NAME (35 mg/100 ml drinking water). Group 3: L-NAME (35 mg/100 ml drinking water) + melatonin (30 mg/Kg diet). Group 4: L-NAME (35 mg/100 ml drinking water) + melatonin (60 mg/Kg diet). Group 5: L-NAME (35 mg/100 ml drinking water) + melatonin (120 mg/Kg diet). A significant elevation in SBP and serum MDA were detected in L-NAME treated rats. Co-administration of melatonin with L-NAME prevented increasing in SBP and serum level of MDA in a dose dependent manner. On the other hand serum levels of SOD and GSH were decreased in response to L-NAME treatment, while, co-treatment with melatonin increased SOD and GSH in a dose dependent manner. The decrease serum NO level in response to L-NAME was significantly increased by melatonin but its level was decreased by increasing melatonin doses. In conclusion: L-NAME induced hypertension model was associated with decreased NO level, interestingly; melatonin increased serum NO in L-NAME treatments, but with increasing dose of MEL, NO level was decreased. Furthermore; MEL through its antioxidant properties reduced oxidative stress and prevented lipid peroxidation.
In mammals, the rhythmic secretion of melatonin from the pineal gland is driven by the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The robust nightly peak of melatonin secretion is an output signal of the circadian clock and is supposed to deliver the circadian message to the whole of the organism. Since the circadian system regulates many behavioral and physiological processes, its disruption by external (shift-work, jet-lag) or internal desynchronization (blindness, aging) causes many different health problems. Externally applied melatonin is used in humans as a chronobiotic drug to treat desynchronization and circadian disorders, and the success of these treatments does, at first glance, underline the supposed pivotal role of melatonin in the synchronization of the circadian system. On the other hand, pinealectomy in experimental animals and humans does not abolish their rhythms of rest and activity. Furthermore, mice with deficient melatoninergic systems neither display overt defects in their rhythmic behavior nor do they show obvious signs of disease susceptibility, let alone premature mortality. During the last years, our laboratory has investigated several mouse stains with intact or compromised internal melatonin signaling systems in order to better understand the physiological role of the melatoninergic system. These and other investigations which will be reviewed in the present contribution confirm the synchronizing effect of endogenous melatonin and the melatoninergic system. However, these effects are subtle. Thus melatonin does not appear as the master of internal synchronization, but as one component in a cocktail of synchronizing agents.
Melatonin, a multitasking indolamine, seems to be involved in a variety of physiological and metabolic processes via both receptor-mediated and receptor-independent mechanisms. The aim of our study was to find out whether melatonin can affect blood pressure (BP), nitric oxide synthase (NOS) activity, eNOS and nNOS protein expressions in rats with metabolic syndrome (SHR/cp). Rats were divided into four groups: 6-week-old male WKY andSHR/cp and age-matched WKY and SHR/cp treated with melatonin (10 mg/kg/day) for 3 weeks. BP was measured by tailcuff plethysmography. NOS activity, eNOS and nNOS protein expressions were determined in the heart, aorta, brain cortex and cerebellum. MT1 receptors were analyzed in the brain cortex and cerebellum. In SHR/cp rats, BP was decreased after melatonin treatment. In the same group, melatonin did not affect NOS activity and eNOS protein expression in the heart and aorta, while it increased both parameters in the brain cortex and cerebellum. Interestingly, melatonin elevated MT1 protein expression in the cerebellum. Neuronal NOS protein expression was not changed within the groups. In conclusion, increased NOS activity/eNOS upregulation in particular brain regions may contribute partially to BP decrease in SHR/cp rats after melatonin treatment. Participation of MT1 receptors in this melatonin action may be supposed. © 2016 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
Circadian rhythms have evolved to anticipate and adapt animals to the constraints of the earth’s 24-hour light cycle1. Although the molecular processes that establish periodicity in clock neurons of the suprachiasmatic nucleus (SCN) are well understood, the mechanisms by which axonal projections from the central clock drive behavioural rhythms are unknown2, 3, 4. Here we show that the sleep period in mice (Zeitgeber time, ZT0–12) is preceded by an increase in water intake promoted entirely by the central clock, and not motivated by physiological need. Mice denied this surge experienced significant dehydration near the end of the sleep period, indicating that this water intake contributes to the maintenance of overnight hydromineral balance. Furthermore, this effect relies specifically on the activity of SCN vasopressin (VP) neurons that project to thirst neurons in the OVLT (organum vasculosum lamina terminalis), where VP is released as a neurotransmitter. SCN VP neurons become electrically active during the anticipatory period (ZT21.5–23.5), and depolarize and excite OVLT neurons through the activation of postsynaptic VP V1a receptors and downstream non-selective cation channels. Optogenetic induction of VP release before the anticipatory period (basal period; ZT19.5–21.5) excited OVLT neurons and prompted a surge in water intake. Conversely, optogenetic inhibition of VP release during the anticipatory period inhibited the firing of OVLT neurons and prevented the corresponding increase in water intake. Our findings reveal the existence of anticipatory thirst, and demonstrate this behaviour to be driven by excitatory peptidergic neurotransmission mediated by VP release from central clock neurons.
Disturbances in regular circadian oscillations can have negative effects on cardiovascular function, but epidemiological data are inconclusive and new data from animal experiments elucidating critical biological mechanisms are needed. To evaluate the consequences of chronic phase shifts of the light/dark (LD) cycle on hormonal and cardiovascular rhythms, two experiments were performed. In Experiment 1, male rats were exposed to either a regular 12:12 LD cycle (CONT) or rotating 8-h phase-delay shifts of LD every second day (SHIFT) for 10 weeks. During this period, blood pressure (BP) was monitored weekly, and daily rhythms of melatonin, corticosterone, leptin and testosterone were evaluated at the end of the experiment. In Experiment 2, female rats were exposed to the identical shifted LD schedule for 12 weeks, and daily rhythms of BP, heart rate (HR) and locomotor activity were recorded using telemetry. Preserved melatonin rhythms were found in the pineal gland, plasma, heart and kidney of SHIFT rats with damped amplitude in the plasma and heart, suggesting that the central oscillator can adapt to chronic phase-delay shifts. In contrast, daily rhythms of corticosterone, testosterone and leptin were eliminated in SHIFT rats. Exposure to phase shifts did not lead to increased body weight and elevated BP. However, a shifted LD schedule substantially decreased the amplitude and suppressed the circadian power of the daily rhythms of BP and HR, implying weakened circadian control of physiological and behavioural processes. The results demonstrate that endocrine and cardiovascular rhythms can differentially adapt to chronic phase-delay shifts, promoting internal desynchronization between central and peripheral oscillators, which in combination with other negative environmental stimuli may result in negative health effects.
Decreased oxygenation during pregnancy and early periods of ontogeny can affect normal body development and result in diseases in adulthood. The aim of this study was to use the model of prenatal intermittent hypoxia (PIH) and evaluate the effects of short-term hypoxia at the end of gestation on blood pressure (BP) control in adulthood. Wistar rats were exposed daily to PIH for 4 h during gestational day 19 and 20. In adult male rats, heart rate (HR), systolic BP and pulse pressure (PP) were acquired by radiotelemetry during 1 week. On the basis of HR variability and BP variability, sympathovagal balance (LF/HF) and spontaneous baroreflex sensitivity (sBRS) were evaluated. Systolic BP and PP were significantly elevated in PIH rats in comparison with control rats during the light and dark phase of the day, while LF/HF increased only during the light phase of the day. In contrast, sBRS tended to decrease only during the dark phase in PIH rats. In all measured and calculated parameters, significant circadian rhythms were present and were not affected by PIH. In conclusion, our data suggest that short intermittent hypoxia at the end of gestation can increase BP and PP via significant changes in LF/HF, which occur especially during the passive phase of the day. Results suggest that minor changes in the autonomous nervous system activity induced by environmental conditions during the perinatal period may contribute to development of hypertension in adulthood.Hypertension Research advance online publication, 25 February 2016; doi:10.1038/hr.2016.21.
Melatonin, a potent antioxidant molecule plays a role in blood pressure regulation. We hypothesized that melatonin may generate a protective effect in a high salt diet (HSD) rodent model mediated by decreasing renal oxidative stress. Dahl salt sensitive rats were divided into 3 groups according to diet: normal chow [control; HSD; HSD with melatonin (30/mg/kg/day) placed in their water (HSD+Mel) over an 8- week period. Blood pressure was measured by the tail cuff method. Kidney injury was evaluated by 24H urine protein excretion. Glomerular injury index (GII) (fibrotic glomeruli/100 glomeruli) was evaluated from a Masson's trichrom stained section. Kidney oxidative stress was determined by superoxide production via dihydroethidium staining. Expression of oxidative stress related genes was measured by RT-qPCR. Melatonin had no effect on blood pressure increase induced by HSD and attenuated proteinuria induced by HSD (HSD- 50.7±12, HSD+Mel- 22.3±4.3, controls- 6.5±1.0 gram protein/gram creatinine, p<0.001). HSD induced glomerular damage was significantly diminished by melatonin (GII in HSD -24±6, HSD+Mel-3.6±0.8, controls- 0.8±0.5. p<0.05). Superoxide production was significantly higher in kidneys of HSD fed rats than the controls (99±9 vs. 60±7 relative fluorescent units (RFU)/μm(2) , respectively, p<0.05). Melatonin also decreased superoxide production (74±5 RFU/μm(2) , p<0.05). The expression of kidney iNOS and p67(phox) mRNA was significantly higher in HSD than in the controls and HSD+Mel rats. Treatment with melatonin eliminated the deleterious effect of HSD in the kidneys of Dahl salt sensitive rats. The beneficial effect of melatonin is not mediated by lowering BP but by a direct anti-oxidative effect. This article is protected by copyright. All rights reserved.
The influences of severe heat stroke (HS) on cardiovascular function during recovery are incompletely understood. We hypothesized that HS would elicit a HR increase persisting through 24h of recovery due to hemodynamic, thermoregulatory and inflammatory events necessitating tachycardia to support mean arterial pressure (MAP). Core temperature (Tc), HR and MAP were measured via radiotelemetry in conscious male Fischer 344 rats (n=22; 282.4 ± 3.5g) during exposure to 37°C ambient temperature (Ta) until a Tc,Max of 42.0°C, and during recovery at 20°C Ta through 24h. Rats were divided into MILD, MODERATE and SEVERE groups based on pathophysiology. HS rats exhibited hysteresis relative to Tcwith HR higher for a given Tc during recovery compared to heating (p<0.0001). "Reverse" hysteresis occurred in MAP with pressure during cooling lower than heating per degree Tc (p<0.0001). MILD HS rats showed tachycardia (p<0.01 vs CON) through 8h of recovery, elevated MAP (p< 0.05 vs CON) for the initial 5h of recovery with sustained hyperthermia (p<0.05 vs CON) through 24h. MODERATE HS rats showed significant tachycardia (p<0.01 vs CON), normal MAP (p>0.05 vs CON) and rebound hyperthermia from 4-24h post-HS (p<0.05 vs CON). SEVERE HS rats showed tachycardia (p<0.05 vs CON), hypotension (p<0.01 vs CON) and hypothermia for 24h (p<0.05 vs CON). SEVERE HS rats showed 14- and 12-fold increase in heart and liver iNOS expression, respectively. Hypotension and hypothermia in SEVERE HS rats was consistent with iNOS-mediated systemic vasodilation. These findings provide mechanistic insight into hemodynamic and thermoregulatory impairments during 24h of HS recovery.
Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
