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Randomised, double-blind, placebo-controlled clinical trial investigating the effects of inorganic nitrate in hypertension-induced target organ damage: protocol of the NITRATE-TOD study in the UK.
Lau, CWZ, Hamers, AJP, Rathod, KS, Shabbir, A, Cooper, J, Primus, CP, Davies, C, Mathur, A, Moon, JC, Kapil, V, et al
BMJ open. 2020;(1):e034399
Abstract
INTRODUCTION Arterial stiffness and left ventricular (LV) hypertrophy are the key markers of hypertensive target organ damage (TOD) associated with increased cardiovascular morbidity and mortality. We have previously shown that dietary inorganic nitrate supplementation lowers blood pressure (BP) in hypertension, however, whether this approach might also improve markers of hypertensive TOD is unknown. In this study, we will investigate whether daily dietary inorganic nitrate administration reduces LV mass and improves measures of arterial stiffness. METHODS AND DESIGN NITRATE-TOD is a double-blind, randomised, single-centre, placebo-controlled phase II trial aiming to enrol 160 patients with suboptimal BP control on one or more antihypertensives. Patients will be randomised to receive 4 months once daily dose of either nitrate-rich beetroot juice or nitrate-deplete beetroot juice (placebo). The primary outcomes are reduction in LV mass and reduction in pulse wave velocity (PWV) and central BP.The study has a power of 95% for detecting a 9 g LV mass change by cardiovascular MRI (~6% change for a mildly hypertrophied heart of 150 g). For PWV, we have a power of >95% for detecting a 0.6 m/s absolute change. For central systolic BP, we have a>90% power to detect a 5.8 mm Hg difference in central systolic BP.Secondary end points include change in ultrasound flow-mediated dilation, change in plasma nitrate and nitrite concentration and change in BP. ETHICS AND DISSEMINATION The study was approved by the London-City and East Research Ethics Committee (10/H0703/98). Trial results will be published according to the Consolidated Standards of Reporting Trials statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT03088514.
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Potential Benefits of Nitrate Supplementation on Antioxidant Defense System and Blood Pressure Responses after Exercise Performance.
Menezes, EF, Peixoto, LG, Teixeira, RR, Justino, AB, Puga, GM, Espindola, FS
Oxidative medicine and cellular longevity. 2019;:7218936
Abstract
Nitrate (NO3 -) supplementation is associated with exercise performance, oxygen uptake, blood flow, and blood pressure improvement, and it can act as an antioxidant agent. This study evaluated the effects of sodium nitrate supplementation on oxidative stress markers and blood pressure responses after aerobic exercise performance in physically active males. Fourteen subjects aged 22 ± 3 years and with a BMI of 23 ± 1 kg/m2 were submitted to four exercise tests in intervals of 5 days. Nitrate supplementation (NO session) and placebo supplementation (PL session) were acute (AC) and over a period of 5 days (FD) in random order with a crossover design. Saliva was collected at basal (0'); 60 min after supplementation (60'); immediately after exercise (90'); and 15, 30, and 60 min after the test (105', 120', and 150'). The NO session had higher concentrations (P < 0.05) of salivary nitrite in both AC and FD treatments when compared with the PL session. There was a reduction in systolic blood pressure (SBP) only after FD in the NO session. Furthermore, uric acid and total antioxidant capacity (FRAP) salivary concentrations increased, while SOD activity and TBARS levels decreased after FD but not after AC in the NO session. The results suggest that nitrate supplemented over a period of 5 days reduced SBP and indirectly acted as an antioxidant in healthy nonsedentary young men.
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Dietary nitrate does not reduce oxygen cost of exercise or improve muscle mitochondrial function in patients with mitochondrial myopathy.
Nabben, M, Schmitz, JPJ, Ciapaite, J, le Clercq, CMP, van Riel, NA, Haak, HR, Nicolay, K, de Coo, IFM, Smeets, H, Praet, SF, et al
American journal of physiology. Regulatory, integrative and comparative physiology. 2017;(5):R689-R701
Abstract
Muscle weakness and exercise intolerance negatively affect the quality of life of patients with mitochondrial myopathy. Short-term dietary nitrate supplementation has been shown to improve exercise performance and reduce oxygen cost of exercise in healthy humans and trained athletes. We investigated whether 1 wk of dietary inorganic nitrate supplementation decreases the oxygen cost of exercise and improves mitochondrial function in patients with mitochondrial myopathy. Ten patients with mitochondrial myopathy (40 ± 5 yr, maximal whole body oxygen uptake = 21.2 ± 3.2 ml·min-1·kg body wt-1, maximal work load = 122 ± 26 W) received 8.5 mg·kg body wt-1·day-1 inorganic nitrate (~7 mmol) for 8 days. Whole body oxygen consumption at 50% of the maximal work load, in vivo skeletal muscle oxidative capacity (evaluated from postexercise phosphocreatine recovery using 31P-magnetic resonance spectroscopy), and ex vivo mitochondrial oxidative capacity in permeabilized skinned muscle fibers (measured with high-resolution respirometry) were determined before and after nitrate supplementation. Despite a sixfold increase in plasma nitrate levels, nitrate supplementation did not affect whole body oxygen cost during submaximal exercise. Additionally, no beneficial effects of nitrate were found on in vivo or ex vivo muscle mitochondrial oxidative capacity. This is the first time that the therapeutic potential of dietary nitrate for patients with mitochondrial myopathy was evaluated. We conclude that 1 wk of dietary nitrate supplementation does not reduce oxygen cost of exercise or improve mitochondrial function in the group of patients tested.
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Dietary nitrate supplementation: effects on plasma nitrite and pulmonary O2 uptake dynamics during exercise in hypoxia and normoxia.
Kelly, J, Vanhatalo, A, Bailey, SJ, Wylie, LJ, Tucker, C, List, S, Winyard, PG, Jones, AM
American journal of physiology. Regulatory, integrative and comparative physiology. 2014;(7):R920-30
Abstract
We investigated the effects of dietary nitrate (NO3 (-)) supplementation on the concentration of plasma nitrite ([NO2 (-)]), oxygen uptake (V̇o2) kinetics, and exercise tolerance in normoxia (N) and hypoxia (H). In a double-blind, crossover study, 12 healthy subjects completed cycle exercise tests, twice in N (20.9% O2) and twice in H (13.1% O2). Subjects ingested either 140 ml/day of NO3 (-)-rich beetroot juice (8.4 mmol NO3; BR) or NO3 (-)-depleted beetroot juice (PL) for 3 days prior to moderate-intensity and severe-intensity exercise tests in H and N. Preexercise plasma [NO2 (-)] was significantly elevated in H-BR and N-BR compared with H-PL (P < 0.01) and N-PL (P < 0.01). The rate of decline in plasma [NO2 (-)] was greater during severe-intensity exercise in H-BR [-30 ± 22 nM/min, 95% confidence interval (CI); -44, -16] compared with H-PL (-7 ± 10 nM/min, 95% CI; -13, -1; P < 0.01) and in N-BR (-26 ± 19 nM/min, 95% CI; -38, -14) compared with N-PL (-1 ± 6 nM/min, 95% CI; -5, 2; P < 0.01). During moderate-intensity exercise, steady-state pulmonary V̇o2 was lower in H-BR (1.91 ± 0.28 l/min, 95% CI; 1.77, 2.13) compared with H-PL (2.05 ± 0.25 l/min, 95% CI; 1.93, 2.26; P = 0.02), and V̇o2 kinetics was faster in H-BR (τ: 24 ± 13 s, 95% CI; 15, 32) compared with H-PL (31 ± 11 s, 95% CI; 23, 38; P = 0.04). NO3 (-) supplementation had no significant effect on V̇o2 kinetics during severe-intensity exercise in hypoxia, or during moderate-intensity or severe-intensity exercise in normoxia. Tolerance to severe-intensity exercise was improved by NO3 (-) in hypoxia (H-PL: 197 ± 28; 95% CI; 173, 220 vs. H-BR: 214 ± 43 s, 95% CI; 177, 249; P = 0.04) but not normoxia. The metabolism of NO2 (-) during exercise is altered by NO3 (-) supplementation, exercise, and to a lesser extent, hypoxia. In hypoxia, NO3 (-) supplementation enhances V̇o2 kinetics during moderate-intensity exercise and improves severe-intensity exercise tolerance. These findings may have important implications for individuals exercising at altitude.
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Effects of CPAP on nitrate and norepinephrine levels in severe and mild-moderate sleep apnea.
Pinto, P, Bárbara, C, Montserrat, JM, Patarrão, RS, Guarino, MP, Carmo, MM, Macedo, MP, Martinho, C, Dias, R, Gomes, MJ
BMC pulmonary medicine. 2013;:13
Abstract
BACKGROUND Reduced plasma nitrate (NO(x)) levels and increased urinary norepinephrine (U-NE) levels have been described in severe obstructive sleep apnea (OSA), and are reverted by continuous positive airway pressure (CPAP). The effect of CPAP on these biomarkers in mild-moderate OSA is not well understood. The aim of this study was to compare NO(x) and U-NE levels and blood pressure (BP) between male patients with mild-moderate and severe OSA and determine the impact of 1 month of CPAP therapy on these parameters. METHODS We undertook a prospective study of 67 consecutive OSA patients (36 mild-moderate, 31 severe). Measurements of plasma NO(x) at 11 pm, 4 am and 7 am, 24-h U-NE and ambulatory BP were obtained at baseline and after 1 month of CPAP. RESULTS At baseline, NO(x) levels showed a significant decrease during the night in both groups (p < 0.001). U-NE level and BP were significantly higher in the severe OSA group. After 1 month of CPAP, there was a significant increase in NO(x) levels and a reduction in U-NE level and BP only in patients with severe OSA. CONCLUSIONS One month of CPAP results in significant improvements in NO(x) levels, 24-h U-NE level and BP in patients with severe OSA, but not in patients with mild-moderate OSA. TRIAL REGISTRATION ClinicalTrials.gov: NCT01769807.
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Inhaled nitric oxide therapy increases blood nitrite, nitrate, and s-nitrosohemoglobin concentrations in infants with pulmonary hypertension.
Ibrahim, YI, Ninnis, JR, Hopper, AO, Deming, DD, Zhang, AX, Herring, JL, Sowers, LC, McMahon, TJ, Power, GG, Blood, AB
The Journal of pediatrics. 2012;(2):245-51
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Abstract
OBJECTIVE To measure the circulating concentrations of nitric oxide (NO) adducts with NO bioactivity after inhaled NO (iNO) therapy in infants with pulmonary hypertension. STUDY DESIGN In this single center study, 5 sequential blood samples were collected from infants with pulmonary hypertension before, during, and after therapy with iNO (n = 17). Samples were collected from a control group of hospitalized infants without pulmonary hypertension (n = 16) and from healthy adults for comparison (n = 12). RESULTS After beginning iNO (20 ppm) whole blood nitrite levels increased approximately two-fold within 2 hours (P<.01). Whole blood nitrate levels increased to 4-fold higher than baseline during treatment with 20 ppm iNO (P<.01). S-nitrosohemoglobin increased measurably after beginning iNO (P<.01), whereas iron nitrosyl hemoglobin and total hemoglobin-bound NO-species compounds did not change. CONCLUSION Treatment of pulmonary hypertensive infants with iNO results in increases in levels of nitrite, nitrate, and S-nitrosohemoglobin in circulating blood. We speculate that these compounds may be carriers of NO bioactivity throughout the body and account for peripheral effects of iNO in the brain, heart, and other organs.
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Estrogen therapy increases plasma concentrations of nitric oxide metabolites in postmenopausal women but increases flow-mediated vasodilation only in younger women.
López-Jaramillo, P, Díaz, LA, Pardo, A, Parra, G, Jaimes, H, Chaudhuri, G
Fertility and sterility. 2004;(6):1550-5
Abstract
OBJECTIVE To evaluate the effect of estrogen therapy (ET) on endothelial nitric oxide (NO) production and in flow-mediated vasodilation (FMV). DESIGN Randomized, crossover, double-blind, placebo-controlled study. SETTING Healthy postmenopausal women in an academic research environment. PATIENT(S): Forty postmenopausal women between 45 and 72 years of age. INTERVENTION(S): Women received ET or placebo during two periods of 12 weeks that were separated by 2 weeks of washout. MAIN OUTCOME MEASURE(S): Flow-mediated vasodilation, nitrite and nitrate, lipid profile, creatinine, and glucose were measured at weeks 12 and 24. Student's t or Wilcoxon tests were used for comparative analyses, and kappa test and limit analysis determined variability. RESULT(S): After placebo treatment, nitrate and nitrite mean concentration was 8.28 +/- 1.17 mmol/L; it increased to 62.6 +/- 12.82 mmol/L after ET. Percentage FMV was 18.8 +/- 2.58 after the placebo period and did not change after ET (20.1 +/- 1.92) in the whole sample, but in the subgroup (n = 15) of younger women (45-50 years of age), percentage FMV increased from 13.6 +/- 3.6 after the placebo period to 22.2 +/- 3.5 after ET. CONCLUSION(S): An increase in plasma concentrations of nitrite and nitrate after ET was observed in all the women studied, but the improvement in FMV was observed only in the younger ones. These age-related differences in FMV in response to ET must be further investigated.
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Decreasing resistance in the maternal uterine and peripheral arterial system is apparently unrelated to plasma and urinary levels of nitrite/nitrate and cyclic-guanosinmonophosohate during the course of normal pregnancies.
Schiessl, B, Strasburger, CJ, Bidlingmaier, M, Spannagl, M, Ugele, B, Kainer, F
Journal of perinatal medicine. 2003;(4):281-6
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Abstract
AIMS: The aim of the presented study was to clarify the relationship between the pulsatility index of the uterine arteries and the maternal cubital artery and peripheral concentrations of the metabolites of nitric oxide (NO) and its second messenger cyclic guanosinmonophophate (cGMP) during the normal course of pregnancy and postpartum. METHODS 49 uncomplicated pregnancies were investigated every 4-6 weeks until delivery, 29 of them were additionally investigated postpartum. Paralleling each Doppler sonographic investigation maternal blood and urine samples were taken. The measurements of nitrite/nitrate and cGMP were performed with a colorimetric and radio immuno assay. We demonstrate a significant decrease of the PI of the uterine arteries and of the cubital artery with inverse correlation to advancing gestational age. RESULTS The concentrations of nitrite/nitrate and cGMP remain stable during gestation and do not correlate to the PI of the uterine and cubital artery. Postpartum a re-increase in the uterine and peripheral resistance can be shown. The concentrations of urinary cGMP and nitrite/nitrate as well as plasma cGMP remain unchanged, whereas plasma nitrite/nitrate decreases postpartum. CONCLUSIONS The status of NO biosyntheses in normal pregnancy remains controversial. We hypothesize further systemically acting mediators which contribute to the decreasing vascular resistance.