Melatonin interactions with blood pressure and vascular function during l-NAME-induced hypertension

Paulis, Ludovít; Pecháňová, Oľga; Zicha, Josef; Barta, Andrej; Gardlík, Roman; Celec, Peter; Kuneš, Jaroslav; Šimko, Fedor

doi:10.1111/j.1600-079x.2009.00732.x

Cited by 48 publications

(37 citation statements)

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“…26 However, in our experiment compound 21 was given together with L-NAME. The inhibition of NO synthase by L-NAME is difficult to counterbalance, 24 and the effects observed in our study are most likely NO independent and might relate to the direct antiproteosynthetic and antiproliferative properties of AT 2 R per se. 18,19 Most pathological parameters in our study were only partly restored by AT 2 R stimulation, suggesting that effects coupled to the AT 2 R are partly NO dependent and partly NO independent.…”

Section: Discussionmentioning

confidence: 93%

“…AT 2 R was already reported to exert antiproliferative, anti-inflammatory, and cardioprotective effects that at least partly counterbalance the effects of AT 1 R stimulation. 16 -21 In vivo inhibition of NO synthase by treating animals with N -nitro-L-arginine-methyl ester (L-NAME) provides a wellestablished model of hypertension, [22][23][24] vascular wall remodeling, 25,26 and PWV increase. 27,28 Using this model, we aimed to investigate the effects of long-term direct AT 2 R stimulation by the novel nonpeptide AT 2 R agonist, compound 21, on aortic remodeling and PWV in L-NAME-treated rats.…”

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confidence: 99%

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Direct Angiotensin II Type 2 Receptor Stimulation in N ^ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension

et al. 2012

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Abstract-Pulse wave velocity (PWV), a direct marker of arterial stiffness, is an independent cardiovascular risk factor.Although the angiotensin II type 1 receptor blockade belongs to major antihypertensive and cardioprotective therapies, less is known about the effects of long-term stimulation of the angiotensin II type 2 receptor. Previously, compound 21, a selective nonpeptide angiotensin II type 2 receptor agonist improved the outcome of myocardial infarction in rats along with anti-inflammatory properties. We investigated whether compound 21 alone or in combination with angiotensin II type 1 receptor blockade by olmesartan medoxomil could prevent PWV increase and aortic remodeling in N -nitro-L-argininemethyl ester (L-NAME)-induced hypertension. Male adult Wistar rats (nϭ65) were randomly assigned to control, L-NAME, L-NAMEϩcompound-21, L-NAMEϩolmesartan, and L-NAMEϩolmesartanϩcompound-21 groups and treated for 6 weeks. We observed that L-NAME hypertension was accompanied by enhanced PWV, increased wall thickness, and stiffness of the aorta, along with elevated hydroxyproline concentration. Olmesartan completely prevented hypertension, PWV and wall thickness increase, and the increase of aortic stiffness and partly prevented hydroxyproline accumulation. Compound 21 partly prevented all of these alterations, yet without concomitant prevention of blood pressure rise. Although the combination therapy with olmesartan and compound 21 led to blood pressure levels, PWV, and wall thickness comparable to olmesartan-alone-treated rats, only in the combination group was complete prevention of increased hydroxyproline deposition achieved, resulting in even more pronounced stiffness reduction. We conclude that chronic angiotensin II type 2 receptor stimulation prevented aortic stiffening and collagen accumulation without preventing hypertension in rats with inhibited NO synthase. These effects were additive to angiotensin II type 1 receptor blockade, yet without additional blood pressurelowering effect, and they seem to be NO and blood pressure independent. Key Words: L-NAME Ⅲ vascular remodeling Ⅲ arterial stiffness Ⅲ pulse wave velocity Ⅲ renin-angiotensin system Ⅲ hypertension A rterial hypertension is a highly prevalent and still insufficiently controlled medical condition leading to severe cardiovascular complications. 1,2 One of the main contributors to the cardiovascular risk in these patients is the associated target organ damage. Augmented pulse wave velocity (PWV), which is considered to be the best and direct marker of arterial stiffness, 3 is regarded as an indicator of subclinical organ damage by current European guidelines for hypertension treatment. 4 The effects of current antihypertensive treatment on PWV have been investigated with various outcomes. The angiotensin II type 1 receptor (AT 1 R) antagonists, together with angiotensin-converting enzyme inhibitors, belong to the gold standard cardioprotective therapies. 5,6 In a study on 113 hypertensives, 2-to 3-year treatment with candesartan produced a l...

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Section: Discussionmentioning

confidence: 93%

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confidence: 99%

Direct Angiotensin II Type 2 Receptor Stimulation in N ^ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension

et al. 2012

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“…[26] partly prevented the development of hypertension [25] and pathological heart remodelling [26]. (3) Melatonin treatment prevented the development or induced the reversion of hypertension and left ventricular fibrosis also in L-NAME-induced hypertension [27,28] and in spontaneously hypertensive rats (SHR) [29,30].…”

Section: The Protective Role Of Melatonin Against Heart and Vessel Rementioning

confidence: 99%

Remodelling of the heart and vessels in experimental hypertension: advances in protection

Šimko

Pecháňová

2010

Journal of Hypertension

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Left ventricular hypertrophy (LVH), despite its adaptive nature, increases cardiovascular morbidity and mortality. Novel approaches for protection against pathological heart remodelling are presented in this supplement. Melatonin diminishes myocardial fibrosis in rats exposed to continuous light and N-nitro-L-arginine-methyl ester (L-NAME) treatment and reduces production of endothelium-derived constricting factors in L-NAME-induced hypertension. Melatonin, because of its extraordinary antioxidant and scavenging properties, benefits for endothelium and sympatholytic action, may prove to be a useful protective drug against heart remodelling. In hypertension induced by relative aldosteronism, the correction of macro and micronutrient dyshomeostasis appears to act beneficially within pathological myocardial remodelling. Alterations in the signal cascade of pathological myocardial growth, including humoral stimuli, receptors, intracellular messengers or transcriptional factors, may be favourably modified at different levels. Inhibition of nuclear factor kappa B (NF-kappaB) potentiates hypertension development, enhances oxidative load, increases the cross-sectional area of the aorta and reduces nitric oxide (NO) synthase activity in L-NAME hypertension. It is suggested that NF-kappaB may play a protective rather than a deleterious role in the haemodynamically overloaded circulation. Compound 21, a recently developed peptide angiotensin II type 2 (AT2) receptor agonist, offers a novel approach in investigating the role of AT2 receptors in the protection of the hypertensive heart. A novel NO donor, L-419, with its intrinsic protection of NO, improves the entire NO signalling cascade and thus favourably influencing the response of the left ventricle to haemodynamic overload. LVH prevention or regression should be considered a therapeutic success only when, along with hypertrophied mass reduction, an improvement of the heart structure, function, metabolism and electrical stability is achieved.

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“…The drugs were suspended in the formed gel after cooling. Melatonin was protected against light exposure [17]. Insulin kits were obtained from Biosource, Europe S.A. Total cholesterol, triglyceride, HDL cholesterol and LDL cholesterol kits were brought from Bio Merieux, France.…”

Section: Methodsmentioning

confidence: 99%

“…Rats were fed a high fructose diet for ten weeks then received melatonin at dose of 10 mg/kg/ day orally for six weeks [17].…”

Section: High Fructose Diet Rats Treated With Melatonin Groupmentioning

confidence: 99%

Effects of Combination of Carvedilol and Melatonin on Induced Metabolic Syndrome in Rats

Malak¹

2014

Biochem Physiol

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Background: The prevalence of metabolic syndrome is increasing and it is considered one of the main threats to human health worldwide. Fructose feeding induces hyper-insulinemia, insulin resistance and hyper-triglyceridemia. The main objective of the present study is to evaluate the pharmacological effects of the single and combined administration of carvedilol and melatonin on fructose-induced metabolic syndrome in rats.

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Melatonin interactions with blood pressure and vascular function during l-NAME-induced hypertension

Cited by 48 publications

References 42 publications

Direct Angiotensin II Type 2 Receptor Stimulation in N ^ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension

Direct Angiotensin II Type 2 Receptor Stimulation in N ^ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension

Remodelling of the heart and vessels in experimental hypertension: advances in protection

Effects of Combination of Carvedilol and Melatonin on Induced Metabolic Syndrome in Rats

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Melatonin interactions with blood pressure and vascular function during l-NAME-induced hypertension

Cited by 48 publications

References 42 publications

Direct Angiotensin II Type 2 Receptor Stimulation in N ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension

Direct Angiotensin II Type 2 Receptor Stimulation in N ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension

Remodelling of the heart and vessels in experimental hypertension: advances in protection

Effects of Combination of Carvedilol and Melatonin on Induced Metabolic Syndrome in Rats

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Direct Angiotensin II Type 2 Receptor Stimulation in N ^ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension

Direct Angiotensin II Type 2 Receptor Stimulation in N ^ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension