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Abstract Background Exacerbated oxidative stress is thought to be a mediator of arterial hypertension. It has been postulated that creatine (Cr) could act as an antioxidant agent preventing increased oxidative stress. The aim of this study was to investigate the effects of nine weeks of Cr or placebo supplementation on oxidative stress and cardiovascular parameters in spontaneously hypertensive rats (SHR). Findings Lipid hydroperoxidation, one important oxidative stress marker, remained unchanged in the coronary artery (Cr: 12.6 ± 1.5 vs. Pl: 12.2 ± 1.7 nmol·mg-1; p = 0.87), heart (Cr: 11.5 ± 1.8 vs. Pl: 14.6 ± 1.1 nmol·mg-1; p = 0.15), plasma (Cr: 67.7 ± 9.1 vs. Pl: 56.0 ± 3.2 nmol·mg-1; p = 0.19), plantaris (Cr: 10.0 ± 0.8 vs. Pl: 9.0 ± 0.8 nmol·mg-1; p = 0.40), and EDL muscle (Cr: 14.9 ± 1.4 vs. Pl: 17.2 ± 1.5 nmol·mg-1; p = 0.30). Additionally, Cr supplementation affected neither arterial blood pressure nor heart structure in SHR (p > 0.05). Conclusions Using a well-known experimental model of systemic arterial hypertension, this study did not confirm the possible therapeutic effects of Cr supplementation on oxidative stress and cardiovascular dysfunction associated with arterial hypertension.

Abstract Background In Brazil, heart failure leads to approximately 25,000 deaths per year. Abnormal calcium handling is a hallmark of heart failure and changes in genes encoding for proteins involved in the re-uptake of calcium might harbor mutations leading to inherited cardiomyopathies. Phospholamban (PLN) plays a prime role in cardiac contractility and relaxation and mutations in the gene encoding PLN have been associated with dilated cardiomyopathy. In this study, our objective was to determine the presence of the -36A>C alteration in PLN gene in a Brazilian population of individuals with HF and to test whether this alteration is associated with heart failure or with a worse prognosis of patients with HF. Methods We genotyped a cohort of 881 patients with HF and 1259 individuals from a cohort of individuals from the general population for the alteration -36A>C in the PLN gene. Allele and genotype frequencies were compared between groups (patients and control). In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotypic groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the -36A>C were compared regarding mortality incidence in HF patients. Results No significant association was found between the study polymorphism and HF in our population. In addition, no association between PLN -36A>C polymorphism and demographic, clinical and functional characteristics and mortality incidence in this sample of HF patients was observed. Conclusion Our data do not support a role for the PLN -36A>C alteration in modulating the heart failure phenotype, including its clinical course, in humans.

New Findings What is the central question of this study? Knockout mice lacking both α2A- and α2C-adrenergic receptors (α2A/α2C-ARKO) provide a model for understanding the mechanisms underlying the deleterious effects of sympathetic hyperactivity on the cardiovascular system. The purpose of this study was to compare the effects of sympathetic hyperactivity on the vascular reactivity of large and small arteries from α2A/α2C-ARKO mice and to evaluate the role of nitric oxide and oxidative stress., What is the main finding and its importance? We show that sympathetic hyperactivity alters vascular reactivity only in small arteries. Uncoupling endothelial nitric oxide synthase may be a significant source of superoxide anion and reduced NO bioavailability in small arteries from α2A/α2C-ARKO mice, increasing the contractile tone., Knockout mice lacking both α2A- and α2C-adrenergic receptors (α2A/α2C-ARKO) provide a model for understanding the mechanisms underlying the deleterious effects of sympathetic hyperactivity on the cardiovascular system. Thus, in the present study we investigated the vascular reactivity of large and small arteries of α2A/α2C-ARKO mice. Aorta and mesenteric small arteries (MSAs) from 7-month-old male α2A/α2C-ARKO mice and congenic C57BL6/J mice (wild-type, WT) were studied. In the aorta, noradrenaline- and serotonin-induced contraction was similar between groups, but in MSAs there was an increase in agonist-induced contraction in α2A/α2C-ARKO compared with WT. The l-NAME effect was reduced in MSAs of α2A/α2C-ARKO mice compared with WT mice, as was basal NO evaluated by a 4,5-diaminofluorescein diacetate probe. Increased total endothelial nitric oxide synthase (eNOS) protein expression was observed in MSAs from α2A/α2C-ARKO mice, while the dimer/monomer ratio of eNOS was decreased. Mesenteric small arteries from α2A/α2C-ARKO mice showed an increase in ethidium bromide-positive nuclei, indicating oxidative stress, which was attenuated by incubation with l-NAME. The sympathetic hyperactivity present in α2A/α2C-ARKO mice alters vascular reactivity only in certain types of arteries. Moreover, after chronic sympathetic hyperactivity, uncoupling eNOS may be a significant source of superoxide anion and reduced NO bioavailability in small vessels, increasing the contractile tone. [ABSTRACT FROM AUTHOR]

Three types of beta adrenergic receptors (ARβ1-3) mediate the sympathetic activation of brown adipose tissue (BAT), the key thermogenic site for mice which is also present in adult humans. In this study, we evaluated adaptive thermogenesis and metabolic profile of a mouse with Arβ2 knockout (ARβ2KO). At room temperature, ARβ2KO mice have normal core temperature and, upon acute cold exposure (4 8C for 4 h), ARβ2KO mice accelerate energy expenditure normally and attempt to maintain body temperature. ARβ2KO mice also exhibited normal interscapular BAT thermal profiles during a 30-min infusion of norepinephrine or dobutamine, possibly due to marked elevation of interscapular BAT (iBAT) and of Arβ1, and Arβ3 mRNA levels. In addition, ARβ2KO mice exhibit similar body weight, adiposity, fasting plasma glucose, cholesterol, and triglycerides when compared with WT controls, but exhibit marked fasting hyperinsulinemia and elevation in hepatic Pepck (Pck1) mRNA levels. The animals were fed a high-fat diet (40% fat) for 6 weeks, ARβ2KO mice doubled their caloric intake, accelerated energy expenditure, and induced Ucp1 expression in a manner similar to WT controls, exhibiting a similar body weight gain and increase in the size of white adipocytes to the WT controls. However, ARβ2KO mice maintain fasting hyperglycemia as compared with WT controls despite very elevated insulin levels, but similar degrees of liver steatosis and hyperlipidemia. In conclusion, inactivation of the ARβ2KO pathway preserves cold- and diet-induced adaptive thermogenesis but disrupts glucose homeostasis possibly by accelerating hepatic glucose production and insulin secretion. Feeding on a high-fat diet worsens the metabolic imbalance, with significant fasting hyperglycemia but similar liver structure and lipid profile to the WT controls. [ABSTRACT FROM AUTHOR]

Beta2-adrenergic receptor ( B2 AR) signaling is known to impair Th1-cell differentiation and function in a c AMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-γ. CD4+ Foxp3+ Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3+ Treg cells express functional B2 AR. B2 AR activation in Treg cells leads to increased intracellular c AMP levels and to protein kinase A ( PKA)-dependent CREB phosphorylation. We also found that signaling via B2 AR enhances the in vitro suppressive activity of Treg cells. B2 AR-mediated increase in Treg-cell suppressive function was associated with decreased IL-2 m RNA levels in responder CD4+ T cells and improved Treg-cell-induced conversion of CD4+ Foxp3− cells into Foxp3+ induced Treg cells. Moreover, B2 AR signaling increased CTLA-4 expression in Treg cells in a PKA-dependent way. Finally, we found that PKA inhibition totally prevented the B2 AR-mediated increase in Treg-cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through B2 AR signaling. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) is predominantly regulated by the sympathetic nervous system (SNS) and the adrenergic receptor signaling pathway. Knowing that a mouse with triple &bgr;-receptor knockout (KO) is cold intolerant and obese, we evaluated the independent role played by the &bgr;1 isoform in energy homeostasis. First, the 30 min i.v. infusion of norepinephrine (NE) or the &bgr;1 selective agonist dobutamine (DB) resulted in similar interscapular BAT (iBAT) thermal response in WT mice. Secondly, mice with targeted disruption of the &bgr;1 gene (KO of &bgr;1 adrenergic receptor (&bgr;1KO)) developed hypothermia during cold exposure and exhibited decreased iBAT thermal response to NE or DB infusion. Thirdly, when placed on a high-fat diet (HFD; 40% fat) for 5 weeks, &bgr;1KO mice were more susceptible to obesity than WT controls and failed to develop diet-induced thermogenesis as assessed by BAT Ucp1 mRNA levels and oxygen consumption. Furthermore, &bgr;1KO mice exhibited fasting hyperglycemia and more intense glucose intolerance, hypercholesterolemia, and hypertriglyceridemia when placed on the HFD, developing marked non-alcoholic steatohepatitis. In conclusion, the &bgr;1 signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis. [ABSTRACT FROM AUTHOR]

This case report assessed quality of life, activities of daily living, motor symptoms, functional ability, neuromuscular parameters and mRNA expression of selected genes related to muscle protein synthesis and degradation in a patient with Multiple System Atrophy (MSA). The patient underwent resistance training with instability devices (i.e., bosu, dyna disk, balance disk, Swiss ball) for six months twice a week. After the six months training, the patient's left and right quadriceps muscle cross-sectional area and leg press one-repetition maximum increased 6.4%, 6.8%, and 40%, respectively; the patient's timed up and go, sit to stand, dynamic balance, and activities of daily living improved 33.3%, 28.6%, 42.3%, and 40.1%, respectively; the patient's severity of motor symptoms and risk of falls decreased 32% and 128.1%, respectively. Most of the subscales of quality of life demonstrated improvements as well, varying from 13.0% to 100.0%. mRNA expression of mechanogrowth factor and mammalian target of rapamycin increased 12.7-fold and 1.5- fold, respectively. This case report describes likely the first nonpharmacological therapeutic tool that might be able to decrease the severity of motor symptoms and risk of falls, and to improve functional ability, neuromuscular parameters, and quality of the life in a patient with MSA. [ABSTRACT FROM AUTHOR]

Aim: To summarize current knowledge, gaps, quality of the evidence and show main results related to the role of the autonomic nervous system in lung cancer., Methods: Studies were identified through electronic databases (PubMed, Scopus, Embase and Cochrane Library) in October 2023, and a descriptive analysis was performed. Twenty-four studies were included, and most were observational., Results: Our data indicated an increased expression of β-2-adrenergic receptors in lung cancer, which was associated with poor prognosis. However, the use of β-blockers as an add-on to standard treatment promoted enhanced overall survival, recurrence-free survival and reduced metastasis occurrence., Conclusion: Although the results herein seem promising, future research using high-quality prospective clinical trials is required to draw directions to guide clinical interventions., Competing Interests: Competing interests disclosure The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties., (© 2024 Future Medicine Ltd.)

Heart failure (HF) is characterized by decreased exercise capacity, attributable to neurocirculatory and skeletal muscle factors. Cardiac resynchronization therapy (CRT) and exercise training have each been shown to decrease muscle sympathetic nerve activity (MSNA) and increase exercise capacity in patients with HF. We hypothesized that exercise training in the setting of CRT would further reduce MSNA and vasoconstriction and would increase Ca 2+ -handling gene expression in skeletal muscle in patients with chronic systolic HF. Thirty patients with HF, ejection fraction <35% and CRT for 1 mo, were randomized into two groups: exercise-trained (ET, n = 14) and untrained (NoET, n = 16) groups. The following parameters were compared at baseline and after 4 mo in each group: V̇o 2 peak , MSNA (microneurography), forearm blood flow, and Ca 2+ -handling gene expression in vastus lateralis muscle. After 4 mo, exercise duration and V̇o 2 peak were significantly increased in the ET group (P = 0.04 and P = 0.01, respectively), but not in the NoET group. MSNA was significantly reduced in the ET (P = 0.001), but not in NoET, group. Similarly, forearm vascular conductance significantly increased in the ET (P = 0.0004), but not in the NoET, group. The expression of the Na + /Ca 2+ exchanger (P = 0.01) was increased, and ryanodine receptor expression was preserved in ET compared with NoET. In conclusion, the exercise training in the setting of CRT improves exercise tolerance and neurovascular control and alters Ca 2+ -handling gene expression in the skeletal muscle of patients with systolic HF. These findings highlight the importance of including exercise training in the treatment of patients with HF even following CRT., (Copyright © 2016 the American Physiological Society.)

Beta2-adrenergic receptor (B2AR) signaling is known to impair Th1-cell differentiation and function in a cAMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-γ. CD4(+) Foxp3(+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3(+) Treg cells express functional B2AR. B2AR activation in Treg cells leads to increased intracellular cAMP levels and to protein kinase A (PKA)-dependent CREB phosphorylation. We also found that signaling via B2AR enhances the in vitro suppressive activity of Treg cells. B2AR-mediated increase in Treg-cell suppressive function was associated with decreased IL-2 mRNA levels in responder CD4(+) T cells and improved Treg-cell-induced conversion of CD4(+) Foxp3(-) cells into Foxp3(+) induced Treg cells. Moreover, B2AR signaling increased CTLA-4 expression in Treg cells in a PKA-dependent way. Finally, we found that PKA inhibition totally prevented the B2AR-mediated increase in Treg-cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through B2AR signaling., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We hypothesized that the muscle vasodilatation during mental stress and exercise would vary among humans who are polymorphic at alleles 16 and 27 of the beta(2)-adrenoceptors. From 216 preselected volunteers, we studied 64 healthy, middle-aged normotensive women selected to represent three genotypes: homozygous for the alleles Arg(16) and Gln(27) (Arg(16)/Gln(27), n = 34), Gly(16) and Gln(27) (Gly(16)/Gln(27), n = 20), and Gly(16) and Glu(27) (Gly(16)/Glu(27), n = 10). Forearm blood flow (plethysmography) and muscle sympathetic nerve activity (microneurography) were recorded during 3-min Stroop color-word test and 3-min handgrip isometric exercise (30% maximal voluntary contraction). Baseline muscle sympathetic nerve activity, forearm vascular conductance, mean blood pressure, and heart rate were not different among groups. During mental stress, the peak forearm vascular conductance responses were greater in Gly(16)/Glu(27) group than in Gly(16)/Gln(27) and Arg(16)/Gln(27) groups (1.79 +/- 0.66 vs. 0.70 +/- 0.11 and 0.58 +/- 0.12 units, P = 0.03). Similar results were found during exercise (0.80 +/- 0.25 vs. 0.28 +/- 0.08 and 0.31 +/- 0.08 units, P = 0.02). Further analysis in a subset of subjects showed that brachial intra-arterial propranolol infusion abolished the difference in vasodilatory response between Gly(16)/Glu(27) (n = 6) and Arg(16)/Gln(27) (n = 7) groups during mental stress (0.33 +/- 0.20 vs. 0.46 +/- 0.21 units, P = 0.50) and exercise (0.08 +/- 0.06 vs. 0.03 +/- 0.03 units, P = 0.21). Plasma epinephrine concentration in Arg(16)/Gln(27) and Gly(16)/Glu(27) groups was similar. In conclusion, women who are homozygous for Gly(16)/Glu(27) of the beta(2)-adrenoceptors have augmented muscle vasodilatory responsiveness to mental stress and exercise.