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1.
Effects of dietary sports supplements on metabolite accumulation, vasodilation and cellular swelling in relation to muscle hypertrophy: A focus on "secondary" physiological determinants.
Cholewa, J, Trexler, E, Lima-Soares, F, de Araújo Pessôa, K, Sousa-Silva, R, Santos, AM, Zhi, X, Nicastro, H, Cabido, CET, de Freitas, MC, et al
Nutrition (Burbank, Los Angeles County, Calif.). 2019;:241-251
Abstract
Increased blood flow via vasodilation, metabolite production, and venous pooling contribute to the hyperemia and cellular swelling experienced during resistance training. It has been suggested that these effects play a role in hypertrophic adaptations. Over the past 2 decades, sport supplement products have been marketed to promote exercise hyperemia and intracellular fluid storage, thereby enhancing hypertrophy via acute swelling of myocytes. The three main classes of supplements hypothesized to promote exercise-induced hyperemia include vasodilators, such as nitric oxide precursor supplements; anaerobic energy system ergogenic aids that increase metabolite production, such as β-alanine and creatine; and organic osmolytes, such as creatine and betaine. Previous studies indicated that these dietary supplements are able to improve muscle performance and thus enhance muscle hypertrophy; however, recent evidences also point to these three classes of supplements affecting "secondary" physiological determinants of muscle mass accretion such as vasodilation, metabolite accumulation, and muscle cellular swelling. Although we recognize that the literature is relatively scarce regarding these topics, a better comprehension and discussion of these determinants can lead to increased knowledge and might guide further research regarding the proposed mechanisms of action of the identified compounds. In this case, increased knowledge may contribute to the development of improved efficacy, new products, or direct new research to specifically investigate those secondary effects. The aim of this review was to bring into focus new perspectives associated with secondary physiological effects induced by supplementation and to determine their relevance.
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2.
SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses.
Filippatos, TD, Liontos, A, Papakitsou, I, Elisaf, MS
Postgraduate medicine. 2019;(2):82-88
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. The aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors' cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors (i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); (ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), (iii) favor the production of ketones, which can act as a 'superfuel' in the cardiac and renal tissue (the 'thrifty substrate' hypothesis), (iv) improve many metabolic variables (the metabolic effects hypothesis), (v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), (vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), (vii) directly decrease the activity of the upregulated in heart failure Na+-H+ exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis). Additionally, some SGLT2 inhibitors exhibit also SGLT1 inhibitory action possibly resulting in an attenuation of oxidative stress in ischemic myocardium (the SGLT1 inhibition hypothesis). Thus, many mechanisms have been suggested (and possibly act cumulatively) for the cardioprotective effects of SGLT2 inhibitors.
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3.
Microvascular Vasodilator Plasticity After Acute Exercise.
Robinson, AT, Fancher, IS, Mahmoud, AM, Phillips, SA
Exercise and sport sciences reviews. 2018;(1):48-55
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Abstract
Endothelium-dependent vasodilation is reduced after acute exercise or after high intraluminal pressure in isolated arterioles from sedentary adults but not in arterioles from regular exercisers. The preserved vasodilation in arterioles from exercisers is hydrogen peroxide (H2O2) dependent, whereas resting dilation is nitric oxide (NO) dependent. We hypothesize chronic exercise elicits adaptations allowing for maintained vasodilation when NO bioavailability is reduced.
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High-Density Lipoproteins: Effects on Vascular Function and Role in the Immune Response.
Haghikia, A, Landmesser, U
Cardiology clinics. 2018;(2):317-327
Abstract
The focus in studies of high-density lipoproteins was on their capacity to remove excess cholesterol and deliver it to the liver. Other functions and vascular effects have been described. Clinical trials and translational/genetic studies have led to a refined understanding of the role of high-density lipoprotein; it is likely not a causal cardiovascular risk factor. In healthy subjects, it limits lipid oxidation, protects endothelial cell functions/integrity, and exerts antiinflammatory/antiapoptotic effects. In patients with coronary disease or diabetes, it undergoes modifications/remodeling, resulting in dysfunctional high-density lipoprotein. We summarize recent findings about the regulation of its function and discuss the clinical implications.
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How is the human umbilical artery regulated?
Lorigo, M, Mariana, M, Feiteiro, J, Cairrao, E
The journal of obstetrics and gynaecology research. 2018;(7):1193-1201
Abstract
The purpose of this review is to present an update of the main mechanisms involved in the physiological regulation of contraction and relaxation of the human umbilical artery (HUA) smooth muscle cells. A literature review was performed based on the analysis of papers available on PubMed. The most important and relevant studies regarding the regulation of the HUA are presented in this article. The vascular smooth muscle is a highly specialized structure, whose main function is to regulate the vascular tonus. This is controlled by a balance between the cellular signaling pathways that mediate contraction and relaxation. The cells responsible for the contractile property of this muscle are the smooth muscle cells (SMC), and an excellent source of these cells is the HUA, involved in fetoplacental circulation. Since the umbilical blood vessels are not innervated, the HUA tonus is modulated by vasoactive substances that regulate the contractile process. The main vasoactive substances that induce contraction are serotonin, histamine, thromboxane, bradykinin, endothelin 1 and prostaglandin F2α, that are linked to the activation of proteins Gq and Gi/0 . On the other hand, the main vasorelaxation mechanisms are the activation of adenyl and guanil cyclases, potassium channels and the inhibition of calcium channels. The SMC from the HUA allow the study of different cellular mechanisms and their functions. Therefore, these cells are an important tool to study the mechanisms regulating the contractility of this artery, allowing to detect potential therapeutic targets to treat HUA disorders (gestational hypertension and pre-eclampsia).
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Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators.
Fiorucci, S, Zampella, A, Cirino, G, Bucci, M, Distrutti, E
American journal of physiology. Heart and circulatory physiology. 2017;(1):H21-H32
Abstract
Bile acids are end products of cholesterol metabolism generated in the liver and released in the intestine. Primary and secondary bile acids are the result of the symbiotic relation between the host and intestinal microbiota. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals that exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid-activated receptors, GPBAR1 (also known as TGR5) and the farnesosid-X-receptor (FXR), have also been detected in the vascular system and their activation mediates the vasodilatory effects of bile acids in the systemic and splanchnic circulation. GPBAR1, is a G protein-coupled receptor, that is preferentially activated by lithocholic acid (LCA) a secondary bile acid. GPBAR1 is expressed in endothelial cells and liver sinusoidal cells (LSECs) and responds to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-γ-lyase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSECs is due to genomic and nongenomic effects, involves protein phosphorylation, and leads to release of H2S. Despite that species-specific effects have been described, vasodilation caused by GPBAR1 ligands in the liver microcirculation and aortic rings is abrogated by inhibition of CSE but not by eNOS inhibitor. Vasodilation caused by GPBAR1 (and FXR) ligands also involves large conductance calcium-activated potassium channels likely acting downstream to H2S. The identification of GPBAR1 as a vasodilatory receptor is of relevance in the treatment of complex disorders including metabolic syndrome-associated diseases, liver steatohepatitis, and portal hypertension.
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Vascular hyperpolarization in human physiology and cardiovascular risk conditions and disease.
Schinzari, F, Tesauro, M, Cardillo, C
Acta physiologica (Oxford, England). 2017;(1):124-137
Abstract
Hyperpolarization causing smooth muscle relaxation contributes to the maintenance of vascular homeostasis, particularly in small-calibre arteries and arterioles. It may also become a compensatory vasodilator mechanism upregulated in states with impaired nitric oxide (NO) availability. Bioassay of vascular hyperpolarization in the human circulation has been hampered by the complexity of mechanisms involved and the limited availability of investigational tools. Firm evidence, however, supports the notion that hyperpolarization participates in the regulation of resting vasodilator tone and vascular reactivity in healthy subjects. In addition, an enhanced endothelium-derived hyperpolarization contributes to both resting and agonist-stimulated vasodilation in a variety of cardiovascular risk conditions and disease. Thus, hyperpolarization mediated by epoxyeicosatrienoic acids (EETs) and H2 O2 has been observed in coronary arterioles of patients with coronary artery disease. Similarly, ouabain-sensitive and EETs-mediated hyperpolarization has been observed to compensate for NO deficiency in patients with essential hypertension. Moreover, in non-hypertensive patients with multiple cardiovascular risk factors and in hypercholesterolaemia, KCa channel-mediated vasodilation appears to be activated. A novel paradigm establishes that perivascular adipose tissue (PVAT) is an additional regulator of vascular tone/function and endothelium is not the only agent in vascular hyperpolarization. Indeed, some PVAT-derived relaxing substances, such as adiponectin and angiotensin 1-7, may exert anticontractile and vasodilator actions by the opening of KCa channels in smooth muscle cells. Conversely, PVAT-derived factors impair coronary vasodilation via differential inhibition of some K+ channels. In view of adipose tissue abnormalities occurring in human obesity, changes in PVAT-dependent hyperpolarization may be relevant for vascular dysfunction also in this condition.
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Heteroreceptors Modulating CGRP Release at Neurovascular Junction: Potential Therapeutic Implications on Some Vascular-Related Diseases.
González-Hernández, A, Marichal-Cancino, BA, Lozano-Cuenca, J, López-Canales, JS, Muñoz-Islas, E, Ramírez-Rosas, MB, Villalón, CM
BioMed research international. 2016;:2056786
Abstract
Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide belonging to the calcitonin gene peptide superfamily. CGRP is a potent vasodilator with potential therapeutic usefulness for treating vascular-related disease. This peptide is primarily located on C- and Aδ-fibers, which have extensive perivascular presence and a dual sensory-efferent function. Although CGRP has two major isoforms (α-CGRP and β-CGRP), the α-CGRP is the isoform related to vascular actions. Release of CGRP from afferent perivascular nerve terminals has been shown to result in vasodilatation, an effect mediated by at least one receptor (the CGRP receptor). This receptor is an atypical G-protein coupled receptor (GPCR) composed of three functional proteins: (i) the calcitonin receptor-like receptor (CRLR; a seven-transmembrane protein), (ii) the activity-modifying protein type 1 (RAMP1), and (iii) a receptor component protein (RCP). Although under physiological conditions, CGRP seems not to play an important role in vascular tone regulation, this peptide has been strongly related as a key player in migraine and other vascular-related disorders (e.g., hypertension and preeclampsia). The present review aims at providing an overview on the role of sensory fibers and CGRP release on the modulation of vascular tone.
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Eating and arterial endothelial function: a meta-analysis of the acute effects of meal consumption on flow-mediated dilation.
Thom, NJ, Early, AR, Hunt, BE, Harris, RA, Herring, MP
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2016;(11):1080-1090
Abstract
Given that endothelial dysfunction precedes atherosclerotic cardiovascular disease, exploring the parameters that modify postprandial flow-mediated dilation (FMD) is important for public health. The objectives of the study are to estimate the population effect of meal ingestion on FMD and to determine how the effect varied based on patient characteristics and modifiable methodological features. Articles published before June 2015 were located using MEDLINE, PubMed and Web of Science. One hundred fifty-four effects were derived from 78 articles involving 2,548 subjects were selected. Included articles required measurement of FMD in adults before and after meal ingestion. Effects were analysed using an unstandardized mean gain random effects model, and significant moderators were analysed using meta-regression. Meal consumption significantly reduced FMD by a heterogeneous mean effect size delta (Δ) of -2.03 (95% CI: [-2.28, -1.77]), an ~2% reduction in FMD. FMD reductions were larger among normal weight individuals, males, those with a cardio-metabolic disorder, those with elevated baseline FMD, and individuals with impaired glucose tolerance at baseline. Macronutrient meal ingestion significantly reduced FMD, an effect that was moderated by body mass index, sex and two-way interactions between disease status and both baseline FMD and baseline blood glucose levels.
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Influence of beta-blockers on endothelial function: A meta-analysis of randomized controlled trials.
Peller, M, Ozierański, K, Balsam, P, Grabowski, M, Filipiak, KJ, Opolski, G
Cardiology journal. 2015;(6):708-16
Abstract
BACKGROUND Endothelial dysfunction (ED) frequently precedes cardiovascular diseases (CVD) and is a well-established risk factor of major adverse cardiac events. Beta-blockers are the fundamental drugs used in CVD treatment. METHODS A systematic literature search for randomized controlled trials investigating influence of beta-blockers on endothelial function assessed by flow-mediated dilation (FMD) was performed in the PubMed and Cochrane Databases. RESULTS Sixteen full-text studies involving a total of 1,273 patients were included in the final analysis. The mean age of participating patients ranged from 44.9 to 63.2 years, the follow-up duration from 1 to 12 months. The comparison of FMD change between the beta-blockers and placebo groups showed a statistically significant effect of beta-blockers on endothelial function (mean difference [MD] 0.83; 95% confidence interval [CI] 0.11-1.55; p = 0.02). Third generation beta-blockers improved FMD in a statistically significant manner compared with second generation beta-blockers (MD 1.65; 95% CI 0.17-3.11; p = 0.03). Beta-blockers gave an FMD change similar to that obtained with angiotensin receptor blockers (ARB), calcium channel blockers (CCB) or hydrochlorothiazide. The FMD value in the beta-blocker group was significantly lower compared with the group treated with angiotensin converting enzyme inhibitors (ACEI) (MD -0.79; 95% CI -1.37-(-0.21); p = 0.008) and higher than in the ivabradine group (1.6 ± 3.61 vs -0.3 ± 1.66; p = 0.02). CONCLUSIONS Beta-blockers improve the endothelial function compared with placebo. More-over, third generation beta-blockers improve FMD values significantly better than the second generation ones. Beta-blockers had similar effect on endothelial function as did ARB, CCB or diuretics. However, the beneficial effect of beta-blockers was lower when confronted with ACEI.