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Acute L-Citrulline Supplementation Increases Nitric Oxide Bioavailability but Not Inspiratory Muscle Oxygenation and Respiratory Performance.
Theodorou, AA, Zinelis, PT, Malliou, VJ, Chatzinikolaou, PN, Margaritelis, NV, Mandalidis, D, Geladas, ND, Paschalis, V
Nutrients. 2021;(10)
Abstract
The present study aimed to investigate whether acute L-citrulline supplementation would affect inspiratory muscle oxygenation and respiratory performance. Twelve healthy males received 6 g of L-citrulline or placebo in a double-blind crossover design. Pulmonary function (i.e., forced expired volume in 1 s, forced vital capacity and their ratio), maximal inspiratory pressure (MIP), fractional exhaled nitric oxide (NO•), and sternocleidomastoid muscle oxygenation were measured at baseline, one hour post supplementation, and after an incremental resistive breathing protocol to task failure of the respiratory muscles. The resistive breathing task consisted of 30 inspirations at 70% and 80% of MIP followed by continuous inspirations at 90% of MIP until task failure. Sternocleidomastoid muscle oxygenation was assessed using near-infrared spectroscopy. One-hour post-L-citrulline supplementation, exhaled NO• was significantly increased (19.2%; p < 0.05), and this increase was preserved until the end of the resistive breathing (16.4%; p < 0.05). In contrast, no difference was observed in the placebo condition. Pulmonary function and MIP were not affected by the L-citrulline supplementation. During resistive breathing, sternocleidomastoid muscle oxygenation was significantly reduced, with no difference noted between the two supplementation conditions. In conclusion, a single ingestion of 6 g L-citrulline increased NO• bioavailability but not the respiratory performance and inspiratory muscle oxygenation.
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Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia.
Nader, E, Romana, M, Guillot, N, Fort, R, Stauffer, E, Lemonne, N, Garnier, Y, Skinner, SC, Etienne-Julan, M, Robert, M, et al
Frontiers in immunology. 2020;:551441
Abstract
Chronic hemolysis, enhanced oxidative stress, and decreased nitric oxide (NO) bioavailability promote vasculopathy in sickle cell anemia (SCA). Oxidative stress and NO are known to modulate eryptosis in healthy red blood cells (RBCs); however, their role in SCA eryptosis and their impact on the genesis of RBC-derived microparticles (RBC-MPs) remains poorly described. RBC-MPs could play a role in vascular dysfunction in SCA. The aims of this study were to evaluate the roles of oxidative stress and NO in eryptosis and RBC-MPs release, and to determine whether RBC-MPs could be involved in vascular dysfunction in SCA. Markers of eryptosis and oxidative stress, plasma RBC-MPs concentration and arterial stiffness were compared between SCA and healthy (AA) individuals. In-vitro experiments were performed to test: 1) the effects of oxidative stress (antioxidant: n-acetylcysteine (NAC); pro-oxidant: cumene hydroperoxide) and NO (NO donor: sodium nitroprusside (SNP); NO-synthase inhibitor (L-NIO)) on eryptosis, RBC deformability and RBC-MP genesis; 2) the effects of SCA/AA-RBC-MPs on human aortic endothelial cell (HAEC) inflammatory phenotype and TLR4 pathway. Eryptosis, RBC-MPs, oxidative stress and arterial stiffness were increased in SCA. NAC increased RBC deformability and decreased eryptosis and RBC-MPs release, while cumene did the opposite. SNP increased RBC deformability and limited eryptosis, but had no effect on RBC-MPs. L-NIO did not affect these parameters. Arterial stiffness was correlated with RBC-MPs concentration in SCA. RBC-MPs isolated directly from SCA blood increased adhesion molecules expression and the production of cytokines by HAEC compared to those isolated from AA blood. TLR4 inhibition alleviated these effects. Our data show that oxidative stress could promote eryptosis and the release of RBC-MPs that are potentially involved in macrovascular dysfunction in SCA.
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Hypertension is associated with blunted NO-mediated leg vasodilator responsiveness that is reversed by high-intensity training in postmenopausal women.
Gunnarsson, TP, Ehlers, TS, Baasch-Skytte, T, Lund, AP, Tamariz-Ellemann, A, Gliemann, L, Nyberg, M, Bangsbo, J
American journal of physiology. Regulatory, integrative and comparative physiology. 2020;(6):R712-R723
Abstract
The menopausal transition is associated with increased prevalence of hypertension, and in time, postmenopausal women (PMW) will exhibit a cardiovascular disease risk score similar to male counterparts. Hypertension is associated with vascular dysfunction, but whether hypertensive (HYP) PMW have blunted nitric oxide (NO)-mediated leg vasodilator responsiveness and whether this is reversible by high-intensity training (HIT) is unknown. To address these questions, we examined the leg vascular conductance (LVC) in response to femoral infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) and skeletal muscle markers of oxidative stress and NO bioavailability before and after HIT in PMW [12.9 ± 6.0 (means ± SD) years since last menstrual cycle]. We hypothesized that ACh- and SNP-induced LVC responsiveness was reduced in hypertensive compared with normotensive (NORM) PMW and that 10 wk of HIT would reverse the blunted LVC response and decrease blood pressure (BP). Nine hypertensive (HYP (clinical systolic/diastolic BP, 149 ± 11/91 ± 83 mmHg) and eight normotensive (NORM (122 ± 13/75 ± 8 mmHg) PMW completed 10 wk of biweekly small-sided floorball training (4-5 × 3-5 min interspersed by 1-3-min rest periods). Before training, the SNP-induced change in LVC was lower (P < 0.05) in HYP compared with in NORM. With training, the ACh- and SNP-induced change in LVC at maximal infusion rates, i.e., 100 and 6 µg·min-1·kg leg mass-1, respectively, improved (P < 0.05) in HYP only. Furthermore, training decreased (P < 0.05) clinical systolic/diastolic BP (-15 ± 11/-9 ± 7 mmHg) in HYP and systolic BP (-10 ± 9 mmHg) in NORM. Thus, the SNP-mediated LVC responsiveness was blunted in HYP PMW and reversed by a period of HIT that was associated with a marked decrease in clinical BP.
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FCER2 T2206C variant associated with FENO levels in asthmatic children using inhaled corticosteroids: The PACMAN study.
Karimi, L, Vijverberg, SJH, Farzan, N, Ghanbari, M, Verhamme, KMC, Maitland-van der Zee, AH
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(11):1429-1436
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Abstract
BACKGROUND The FCER2 gene, via encoding of the CD23 receptor, plays an important role in the regulation of IgE responses. A genetic variant of the FCER2 gene (T2206C) was previously shown to be associated with IgE levels in asthmatic children. IgE sensitization has also been linked to increased levels of fractional exhaled nitric oxide (FENO). OBJECTIVE To investigate whether the FCER2 T2206C variant influences FENO levels in asthmatic children with a reported use of inhaled corticosteroids (ICS). METHODS This cross-sectional study involved 593 asthmatic children with a reported use of ICS, availability of FENO measurements and genotyping data on the FCER2 T2206C variant (rs28364072). An additive genetic model was assumed, and the association between the FCER2 T2206C variant and the log-transformed (ln) FENO levels was evaluated using linear regression analysis, adjusted for age, sex, adapted British Thoracic Society (BTS) treatment steps and atopy. RESULTS The mean age of the population was 9.1 ± 2.2 years, and the median of FENO levels was 13.0 ppb with an interquartile range (IQR) of (8.0-27.5 ppb). The minor allele (G) frequency of rs28364072 was 29.6%, and each extra copy of the G allele was significantly associated with a lower level of the geometric mean of FENO (log scale, β = -0.12, 95% CI: -0.23, -0.02). CONCLUSION AND CLINICAL RELEVANCE Our results showed that the FCER2 T2206C variant was significantly associated with lower FENO levels in carriers of the G allele. Nevertheless, this SNP contributed little to the variability in FENO levels in this patient population. Our findings contribute to the present knowledge on FENO in asthmatic children; however, future replication studies are required to establish the role of this gene in relation to FENO.
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Exhaled breath NOx levels in a middle-aged adults population-based study: reference values and association with the smoking status.
Chérot-Kornobis, N, Hulo, S, Giovannelli, J, de Broucker, V, Matran, R, Amouyel, P, Sobaszek, A, Dauchet, L, Edmé, JL
Respiratory medicine. 2018;:134-140
Abstract
BACKGROUND Biomarkers in exhaled breath condensate (EBC) are potentially sensitive indicators of early biochemical changes in airways following exposure to pneumotoxic substances, particularly in susceptible subjects. NOx are the stable end products of the nitrite-nitrate-NO oxidative stress pathway and can be used to monitor airway inflammatory diseases, especially in asthma. Nevertheless, population-based surveys are needed to better interpret EBC NOx levels in clinical studies. The aim of this study was to establish reference values of EBC NOx in a large group of middle-aged, healthy adults of a sample of the general population with particular focus on the smoking status. METHODS The EBC NOx levels were analysed from 2872 subjects among the ELISABET population-based cross sectional study including a representative sample of men and women aged from 40 to 66 years olds conducted in northern France, which included comprehensive questionnaires by interview and spirometry data. Healthy participants were defined as participants with no self-reported respiratory disease. RESULTS For the healthy subjects (n = 1251), the median NOx concentration (IQR) was equal to 7.2 μM (3.12) and concentrations of NOx in EBC did not differ significantly according to smoking status. The upper fifth percentile (95%) (ULN) of NOx concentrations among healthy subjects was equal to 13.6 μM, ranging from 12.7 μM (smokers) to 14.4 μM (ex smokers). Among subjects with EBC NOx values higher than the ULN and compared with subjects that had EBC NOx values lower than the ULN, we found a significant higher proportion of subjects with current asthma (10.5% vs 6.5%) or with chronic bronchitis symptoms (7.6% vs 3.3%). CONCLUSION This population-based study has provided the distribution and the upper limit reference value of a nitrosative stress biomarker (NOx) in EBC of middle aged, healthy adults. EBC NOx levels were not associated with smoking status.
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Association between Plasma Endothelin-1, Transforming Growth Factor-β, Fibroblast Growth Factor, and Nitric Oxide Levels and Liver Injury in Hematopoietic Stem Cell Transplantation Recipients with Persistent Iron Overload after Transplantation.
Akı, ŞZ, Suyanı, E, Cengiz, M, Özenirler, S, Elbeğ, Ş, Paşaoğlu, H, Sucak, GT
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2015;(5):948-53
Abstract
Graft-versus-host disease, iron overload, and infections are the major causes of liver dysfunction in allogeneic hematopoietic stem cell transplantation (AHSCT) recipients. We investigated the relationship between serum iron parameters and the levels of transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), endothelin-1 (ET-1), and nitric oxide (NO) as predictors of chronic liver injury in 54 AHSCT recipients who survived at least a year after transplantation. Serum samples from patients were obtained for the evaluation of ET-1, TGF-β, FGF, NO, and nontransferrin bound iron at the first year follow-up visit using commercially available ELISA kits. Patients were categorized depending on serum ferritin and transferrin saturation levels. The parameters were compared between the groups, and survival analysis was also performed. Most of the AHSCT recipients (81.5%) were in complete remission during the study. After a median follow-up time of 73 months (range, 13 to 109 months), 72.2% of the patients were alive. Mean serum levels of ET-1, NO, TGF-β, and FGF were 81.54 ± 21.62 μmol/mL, 31.82 ± 26.42 μmol/mL, 2.56 ± 0.77 ng/mL, and 50.31 ± 32.69 pg/mL, respectively. Nineteen patients (35.2% of the cohort) had serum ferritin levels higher than 1000 ng/mL. Mean serum levels of ET-1, NO, TGF-β, and FGF were similar in patients with serum ferritin levels below or above 1000 ng/mL (P > .05). Serum ferritin levels were positively correlated with serum alanine aminotransferase (r = .284, P = .042) and γ-glutamyl transferase (r = .271, P = .05) levels and were negatively correlated with serum albumin levels (r = .295, P = .034). There was a significant positive correlation between serum transferrin saturation and alanine aminotransferase levels (r = .305, P = .03). Serum ET-1 level was positively correlated with alkaline phosphatase levels (r = .304, P = .026). In univariate Cox regression analysis serum levels of iron parameters, ET-1, NO, TGF-β, and FGF did not have an impact on overall survival (P > .05). The probability of progression-free survival was also similar in patients with ferritin levels above or below 1000 ng/mL (P = .275). The probability of survival was similar in patients with transferrin saturation ≥70% and <70% (P > .05). Serum iron parameters showed a positive correlation with liver injury. However, there was no correlation between fibrogenic cytokines and liver transaminases. Our results suggest that iron overload at least with the current levels of ferritin might have a relatively benign course. Prospective randomized trials will guide the actual role of iron chelation in the post-transplantation setting.
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Regulation of 5-oxo-ETE synthesis by nitric oxide in human polymorphonuclear leucocytes upon their interaction with zymosan and Salmonella typhimurium.
Viryasova, GM, Galkina, SI, Gaponova, TV, Romanova, JM, Sud'ina, GF
Bioscience reports. 2014;(3)
Abstract
In the present study we have presented data on the regulation of LT (leukotriene) and 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) syntheses in human neutrophils upon interaction with OZ (opsonized zymosan) or Salmonella typhimurium. Priming of neutrophils with PMA (phorbol 12-myristate 13-acetate) and LPS (lipopolysaccharide) elicits 5-oxo-ETE formation in neutrophils exposed to OZ, and the addition of AA (arachidonic acid) significantly increases 5-oxo-ETE synthesis. We found that NO (nitric oxide)-releasing compounds induce 5-oxo-ETE synthesis in neutrophils treated with OZ or S. typhimurium. Exposure of neutrophils to zymosan or bacteria in the presence of the NO donor DEA NONOate (1,1-diethyl-2-hydroxy-2-nitroso-hydrazine sodium) considerably increased the conversion of endogenously formed 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) to 5-oxo-ETE. To our knowledge, this study is the first to demonstrate that NO is a potent regulator of 5-oxo-ETE synthesis in human polymorphonuclear leucocytes exposed to Salmonella typhimurium and zymosan.
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Reduction of death rate due to acute myocardial infarction in subjects with cancers through systemic restoration of impaired nitric oxide.
Ghosh, R, Ray, U, Jana, P, Bhattacharya, R, Banerjee, D, Sinha, A
PloS one. 2014;(2):e88639
Abstract
INTRODUCTION Excessive aggregation of platelets at the site of plaque rupture on the coronary artery led to the formation of thrombus which is reported to precipitate acute myocardial infarction (AMI). Nitric oxide (NO) has been reported to inhibit platelet aggregation and induce thrombolysis through the in situ formation of plasmin. As the plasma NO level in AMI patients from two different ethnic groups was reduced to 0 µM (median) compared to 4.0 µM (median) in normal controls, the effect of restoration of the NO level to normal ranges on the rate of death due to AMI was determined. METHODS AND RESULTS The restoration of plasma NO level was achieved by a sticking small cotton pad (10×25 mm) containing 0.28 mmol sodium nitroprusside (SNP) in 0.9% NaCl to the abdominal skin of the participants using non-toxic adhesive tape which was reported to normalize the plasma NO level. The participants (8,283) were volunteers in an independent study who had different kinds of cancers and did not wish to use any conventional therapy for their condition but opted to receive SNP "pad" for their condition for 3 years. The use of SNP "pad" which normalized (≈4.0 µM) the plasma NO level that in consequence reduced the death rate due to AMI, among the participants, was found to be significantly reduced compared to the death due to AMI in normal population. CONCLUSION Our data suggested that the use of SNP "pad" significantly reduced the death due to AMI. TRIAL REGISTRATION www.ctri.nic.in CTRI/2013/12/004236.
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Angiotensin II receptor blockade reduces salt sensitivity of blood pressure through restoration of renal nitric oxide synthesis in patients with diabetic nephropathy.
Imanishi, M, Okada, N, Konishi, Y, Morikawa, T, Maeda, I, Kitabayashi, C, Masada, M, Shirahashi, N, Wilcox, CS, Nishiyama, A
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2013;(1):67-73
Abstract
INTRODUCTION We have previously demonstrated the increased salt sensitivity of blood pressure (BP) in diabetic patients with early nephropathy. Here, we examined the effects of an angiotensin II receptor blocker (ARB) on salt sensitivity and renal oxidative stress or nitric oxide (NO) in those patients. PATIENTS AND METHODS Type 2 diabetic patients with (n = 6) and without (n = 6) microalbuminuria were studied on a high-salt diet for one week and on a salt-restricted diet for one week. The study was repeated in the patients with microalbuminuria during treatment with an ARB, valsartan (80 mg/day). Salt sensitivity was assessed from the BP/sodium excretion curve. Urinary excretion rates of NOx, 8-hydroxy-2-deoxyguanosine as a marker of oxidative stress, and plasma tetrahydrobiopterin as a cofactor for NO synthase were measured. RESULTS Compared with diabetic patients without microalbuminuria, patients with microalbuminuria showed greater salt sensitivity and lower urinary excretion of NOx. In the patients with microalbuminuria, treatment with valsartan reduced salt sensitivity in association with increased NOx excretion, reduced 8-hydroxy-2,-deoxyguanosine excretion, and increased plasma tetrahydrobiopterin levels. CONCLUSIONS These data support the hypothesis that ARBs reduce the salt sensitivity of BP by decreasing renal oxidative stress and restoring NO activity in diabetic patients with microalbuminuria.
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Insulin-mediated activation of the L-arginine nitric oxide pathway in man, and its impairment in diabetes.
Rajapakse, NW, Chong, AL, Zhang, WZ, Kaye, DM
PloS one. 2013;(5):e61840
Abstract
AIMS/HYPOTHESIS Impaired L-arginine transport has been reported in cardiovascular diseases, providing a possible mechanism for reduced nitric oxide (NO) production. Given that cardiovascular diseases are also associated with insulin resistance, and insulin is known to induce vasodilation via a NO-dependent pathway, we hypothesised that abnormal insulin modulation of L-arginine transport may contribute to vascular dysfunction in diabetes. METHODS Forearm blood flow (FBF) responses to insulin and sodium nitroprusside (SNP) were measured in control and type 2 diabetic volunteers using venous occlusion plethysmography. Effects of intra-arterial insulin on the forearm veno-arterial flux of arginine and related amino acids were determined by HPLC. The effect of locally delivered insulin on arginine transport was assessed during an intra-arterial infusion of [4,5-(3)H] L-arginine. RESULTS In controls, intrabrachial infusion of 5 mUnits/min insulin lead to a progressive rise in FBF (p<0.001) while this was not evident in diabetics. In support of this observation, we observed a concomitant, significant increase in the flux of N-hydroxy-L-arginine (the NO precursor) in controls (baseline vs. 60 mins insulin: 16.2±12.2 vs. 33.0±13.1 nmol/100 ml tissue/min; p<0.01), whilst no increase was observed in diabetics. Moreover, insulin augmented the clearance of [(3)H]L-arginine from the forearm circulation in controls (baseline vs insulin: 123±22 vs. 150±28 ml/min; p<0.05) but not in diabetics. CONCLUSION These findings suggest that insulin resistance may contribute substantially to the onset and development of cardiovascular disease in type 2 diabetics via abnormal insulin-mediated regulation of L-arginine transport.