Inorganic nitrate benefits contrast-induced nephropathy after coronary angiography for acute coronary syndromes: the NITRATE-CIN trial.

BACKGROUND AND AIMS: Contrast-induced nephropathy (CIN), also known as contrast-associated acute kidney injury (CA-AKI) underlies a significant proportion of the morbidity and mortality following coronary angiographic procedures in high-risk patients and remains a significant unmet need. In pre-clinical studies inorganic nitrate, which is chemically reduced in vivo to nitric oxide, is renoprotective but this observation is yet to be translated clinically. In this study, the efficacy of inorganic nitrate in the prevention of CIN in high-risk patients presenting with acute coronary syndromes (ACS) is reported. METHODS: NITRATE-CIN is a double-blind, randomized, single-centre, placebo-controlled trial assessing efficacy of inorganic nitrate in CIN prevention in at-risk patients presenting with ACS. Patients were randomized 1:1 to once daily potassium nitrate (12 mmol) or placebo (potassium chloride) capsules for 5 days. The primary endpoint was CIN (KDIGO criteria). Secondary outcomes included kidney function [estimated glomerular filtration rate (eGFR)] at 3 months, rates of procedural myocardial infarction, and major adverse cardiac events (MACE) at 12 months. This study is registered with ClinicalTrials.gov: NCT03627130. RESULTS: Over 3 years, 640 patients were randomized with a median follow-up of 1.0 years, 319 received inorganic nitrate with 321 received placebo. The mean age of trial participants was 71.0 years, with 73.3% male and 75.2% Caucasian; 45.9% had diabetes, 56.0% had chronic kidney disease (eGFR <60 mL/min) and the mean Mehran score of the population was 10. Inorganic nitrate treatment significantly reduced CIN rates (9.1%) vs. placebo (30.5%, P < .001). This difference persisted after adjustment for baseline creatinine and diabetes status (odds ratio 0.21, 95% confidence interval 0.13-0.34). Secondary outcomes were improved with inorganic nitrate, with lower rates of procedural myocardial infarction (2.7% vs. 12.5%, P = .003), improved 3-month renal function (between-group change in eGFR 5.17, 95% CI 2.94-7.39) and reduced 1-year MACE (9.1% vs. 18.1%, P = .001) vs. placebo. CONCLUSIONS: In patients at risk of renal injury undergoing coronary angiography for ACS, a short (5 day) course of once-daily inorganic nitrate reduced CIN, improved kidney outcomes at 3 months, and MACE events at 1 year compared to placebo.

Increased nitrate intake from beetroot juice over 4 weeks affects nitrate metabolism, but not vascular function or blood pressure in older adults with hypertension.

The decline in vascular function and increase in blood pressure with aging contribute to an increased cardiovascular disease risk. In this randomized placebo-controlled crossover study, we evaluated whether previously reported cardiovascular benefits of plant-derived inorganic nitrate via nitric oxide (NO) translate into improved vascular function and blood pressure-lowering in 15 men and women (age range: 56-71 years) with treated hypertension. We investigated the effects of a single ∼400 mg-dose at 3 hours post-ingestion (3H POST) and the daily consumption of 2 × âˆ¼400 mg of nitrate through nitrate-rich compared with nitrate-depleted (placebo) beetroot juice over 4 weeks (4WK POST). Measurements included nitrate and nitrite in plasma and saliva; endothelial-dependent and -independent forearm blood flow (FBF) responses to acetylcholine (FBFACh) and glyceryltrinitrate (FBFGTN); and clinic-, home- and 24-hour ambulatory blood pressure. Compared to placebo, plasma and salivary nitrate and nitrite increased at 3H and 4WK POST following nitrate treatment (P < 0.01), suggesting a functioning nitrate-nitrite-NO pathway in the participants of this study. There were no differences between treatments in FBFACh and FBFGTN-area under the curve (AUC) ratios [AUC ratios after (3H POST, 4WK POST) compared with before (PRE) the intervention], or 24-hour ambulatory blood pressure or home blood pressure measures (P > 0.05). These findings do not support the hypothesis that an increased intake of dietary nitrate exerts sustained beneficial effects on FBF or blood pressure in hypertensive older adults, providing important information on the efficacy of nitrate-based interventions for healthy vascular aging. This study was registered under ClinicialTrials.gov (NCT04584372).

Influence of acute dietary nitrate supplementation on oxygen delivery/consumption and limit of tolerance during progressive forearm exercise in men: a randomized crossover trial.

Beetroot juice (BRJ) supplementation increases nitric oxide bioavailability with hypoxia and acidosis, characteristics of high-intensity exercise. We investigated whether BRJ improved forearm oxygen delivery:demand matching in an intensity-dependent manner. Healthy men (21 ± 2.5 years) participated in a randomized crossover trial between October 2017 and May 2018 (Queen's University, Kingston, ON, Canada). Participants completed a forearm incremental exercise test to limit of tolerance (IET-LOT) 2.5 h post placebo (PL) versus BRJ (2 completed PL/BRJ vs. 9 completed BRJ/PL) within a 2-week period. Data are presented as mean ± standard deviation. There was a significant main effect of drink (PL < BRJ; P = 0.042, ηp2 = 0.385) and drink × intensity interaction for arteriovenous oxygen difference (PL < BRJ; P = 0.03; ηp2= 0.197; 20%-50% and 90% LOT). BRJ did not influence oxygen delivery (P = 0.893, ηp2 = 0.002), forearm blood flow (P = 0.589, ηp2 = 0.03) (forearm vascular conductance (P = 0.262, ηp2 = 0.124), mean arterial pressure (P = 0.254,ηp2 = 0.128)), oxygen consumption (P = 0.194, ηp2 = 0.179) or LOT (P = 0.432, d = 0.247). In healthy men, BRJ did not improve forearm oxygen delivery (vasodilatory or pressor response) during IET-LOT. Increased arteriovenous oxygen difference at submaximal intensities did not significantly influence oxygen consumption or performance across the entire range of forearm exercise intensities. This study adds to the growing body of evidence that BRJ does not influence small muscle mass blood flow in humans regardless of exercise intensity.

Effectiveness of Nitrate Intake on Recovery from Exercise-Related Fatigue: A Systematic Review.

BACKGROUND: Recovery between efforts is critical to achieving optimal physical and sports performance. In this sense, many nutritional supplements that have been proven to improve recovery and physical and physiological performance are widely used. Supplements such as nitrates (NO3-), including organic foods such as beets, promote muscle recovery and relieve fatigue. This study aimed to comprehensively summarise the available literature on the effect of NO3- consumption on exercise-related fatigue and muscle damage. METHODS: A systematic search was carried out based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) using electronic databases (e.g., PubMed, Scopus, and Web of Science). From a total of 1634 studies identified, 15 studies were included in this review. RESULTS: Based on the review, NO3- intake provokes physiological and metabolic responses that could potentially boost exercise-related recovery. NO3- could improve recovery indicators related to strength, pain, inflammation, and muscle damage. CONCLUSIONS: Despite the relative proven effectiveness of NO3- on recovery after aerobic and anaerobic efforts, based on the heterogeneity of the procedures (e.g., dosage, chronic vs. acute intake, participants' characteristics, variables and outcomes), it could be premature to suggest its extended use in sports.

Time course of human skeletal muscle nitrate and nitrite concentration changes following dietary nitrate ingestion.

Dietary nitrate (NO3-) ingestion can be beneficial for health and exercise performance. Recently, based on animal and limited human studies, a skeletal muscle NO3- reservoir has been suggested to be important in whole body nitric oxide (NO) homeostasis. The purpose of this study was to determine the time course of changes in human skeletal muscle NO3- concentration ([NO3-]) following the ingestion of dietary NO3-. Sixteen participants were allocated to either an experimental group (NIT: n = 11) which consumed a bolus of ∼1300 mg (12.8 mmol) potassium nitrate (KNO3), or a placebo group (PLA: n = 5) which consumed a bolus of potassium chloride (KCl). Biological samples (muscle (vastus lateralis), blood, saliva and urine) were collected shortly before NIT or PLA ingestion and at intervals over the course of the subsequent 24 h. At baseline, no differences were observed for muscle [NO3-] and [NO2-] between NIT and PLA (P > 0.05). In PLA, there were no changes in muscle [NO3-] or [NO2-] over time. In NIT, muscle [NO3-] was significantly elevated above baseline (54 ± 29 nmol/g) at 0.5 h, reached a peak at 3 h (181 ± 128 nmol/g), and was not different to baseline from 9 h onwards (P > 0.05). Muscle [NO2-] did not change significantly over time. Following ingestion of a bolus of dietary NO3-, skeletal muscle [NO3-] increases rapidly, reaches a peak at ∼3 h and subsequently declines towards baseline values. Following dietary NO3- ingestion, human m. vastus lateralis [NO3-] expressed a slightly delayed pharmacokinetic profile compared to plasma [NO3-].

Efficacy and safety of nitrate supplementation on exercise tolerance in chronic obstructive pulmonary disease: A systematic review and meta-analysis.

BACKGROUND: Exercise intolerance was prevalent in people with chronic obstructive pulmonary disease (COPD) and had a detrimental effect on the quality of life. We aimed to evaluate the efficacy and safety of nitrate supplementation in exercise tolerance of people with COPD. METHODS: We searched medical databases including Cochrane Library, EMBASE, and PubMed from inception to October 2020 for randomized control trials in treating COPD with nitrate supplementation. RESULTS: Nine trials were identified. Compared with placebo, nitrate supplementation has no significant effect on the following variables: exercise endurance time (standard mean difference [SMD]: 0.06; 95% confidence interval [CI]: -0.39 to 0.52; P = .79), exercise capacity (SMD: 0.30; 95% CI: -0.21 to 0.80; P = .25), oxygen consumption (SMD: -0.04; 95% CI: -0.33 to 0.25; P = .80), resting systolic blood pressure (MD: -2.84; 95% CI: -8.46 to 2.78; P = .32), systolic blood pressure after exercise (MD: -4.66; 95% CI -15.66 to 6.34; P = .41), resting diastolic blood pressure (MD: 0.89; 95% CI: -4.41 to 6.19; P = .74), diastolic blood pressure after exercise (MD: -0.21; 95% CI: -5.51 to 5.10; P = .94), heart rate (MD: -2.52; 95% CI: -7.76 to 2.73; P = .35), and arterial oxygen saturation (MD: -0.44; 95% CI: -2.38 to 1.49; P = .65). No severe adverse effects from nitrate supplementation were reported in the included trails. CONCLUSION: Current evidence suggests that nitrate supplementation may be safe but ineffective for improving exercise tolerance in people with COPD.

The Effect of Beetroot Ingestion on High-Intensity Interval Training: A Systematic Review and Meta-Analysis.

Dietary nitrate supplementation has shown promising ergogenic effects on endurance exercise. However, at present there is no systematic analysis evaluating the effects of acute or chronic nitrate supplementation on performance measures during high-intensity interval training (HIIT) and sprint interval training (SIT). The main aim of this systematic review and meta-analysis was to evaluate the evidence for supplementation of dietary beetroot-a common source of nitrate-to improve peak and mean power output during HIIT and SIT. A systematic literature search was carried out following PRISMA guidelines and the PICOS framework within the following databases: PubMed, ProQuest, ScienceDirect, and SPORTDiscus. Search terms used were: ((nitrate OR nitrite OR beetroot) AND (HIIT or high intensity or sprint interval or SIT) AND (performance)). A total of 17 studies were included and reviewed independently. Seven studies applied an acute supplementation strategy and ten studies applied chronic supplementation. The standardised mean difference for mean power output showed an overall trivial, non-significant effect in favour of placebo (Hedges' g = -0.05, 95% CI -0.32 to 0.21, Z = 0.39, p = 0.69). The standardised mean difference for peak power output showed a trivial, non-significant effect in favour of the beetroot juice intervention (Hedges' g = 0.08, 95% CI -0.14 to 0.30, Z = 0.72, p = 0.47). The present meta-analysis showed trivial statistical heterogeneity in power output, but the variation in the exercise protocols, nitrate dosage, type of beetroot products, supplementation strategy, and duration among studies restricted a firm conclusion of the effect of beetroot supplementation on HIIT performance. Our findings suggest that beetroot supplementation offers no significant improvement to peak or mean power output during HIIT or SIT. Future research could further examine the ergogenic potential by optimising the beetroot supplementation strategy in terms of dosage, timing, and type of beetroot product. The potential combined effect of other ingredients in the beetroot products should not be undermined. Finally, a chronic supplementation protocol with a higher beetroot dosage (>12.9 mmol/day for 6 days) is recommended for future HIIT and SIT study.

Effect of dietary nitrate on human muscle power: a systematic review and individual participant data meta-analysis.

BACKGROUND: Previous narrative reviews have concluded that dietary nitrate (NO3-) improves maximal neuromuscular power in humans. This conclusion, however, was based on a limited number of studies, and no attempt has been made to quantify the exact magnitude of this beneficial effect. Such information would help ensure adequate statistical power in future studies and could help place the effects of dietary NO3- on various aspects of exercise performance (i.e., endurance vs. strength vs. power) in better context. We therefore undertook a systematic review and individual participant data meta-analysis to quantify the effects of NO3- supplementation on human muscle power. METHODS: The literature was searched using a strategy developed by a health sciences librarian. Data sources included Medline Ovid, Embase, SPORTDiscus, Scopus, Clinicaltrials.gov , and Google Scholar. Studies were included if they used a randomized, double-blind, placebo-controlled, crossover experimental design to measure the effects of dietary NO3- on maximal power during exercise in the non-fatigued state and the within-subject correlation could be determined from data in the published manuscript or obtained from the authors. RESULTS: Nineteen studies of a total of 268 participants (218 men, 50 women) met the criteria for inclusion. The overall effect size (ES; Hedge's g) calculated using a fixed effects model was 0.42 (95% confidence interval (CI) 0.29, 0.56; p = 6.310 × 10- 11). There was limited heterogeneity between studies (i.e., I2 = 22.79%, H2 = 1.30, p = 0.3460). The ES estimated using a random effects model was therefore similar (i.e., 0.45, 95% CI 0.30, 0.61; p = 1.064 × 10- 9). Sub-group analyses revealed no significant differences due to subject age, sex, or test modality (i.e., small vs. large muscle mass exercise). However, the ES in studies using an acute dose (i.e., 0.54, 95% CI 0.37, 0.71; p = 6.774 × 10- 12) was greater (p = 0.0211) than in studies using a multiple dose regimen (i.e., 0.22, 95% CI 0.01, 0.43; p = 0.003630). CONCLUSIONS: Acute or chronic dietary NO3- intake significantly increases maximal muscle power in humans. The magnitude of this effect-on average, ~ 5%-is likely to be of considerable practical and clinical importance.

Dietary nitrate supplementation prevents radiotherapy-induced xerostomia.

Management of salivary gland hypofunction caused by irradiation (IR) therapy for head and neck cancer remains lack of effective treatments. Salivary glands, especially the parotid gland, actively uptake dietary nitrate and secrete it into saliva. Here, we investigated the effect of dietary nitrate on the prevention and treatment of IR-induced parotid gland hypofunction in miniature pigs, and elucidated the underlying mechanism in human parotid gland cells. We found that nitrate administration prevented IR-induced parotid gland damage in a dose-dependent manner, by maintaining the function of irradiated parotid gland tissue. Nitrate could increase sialin expression, a nitrate transporter expressed in the parotid gland, making the nitrate-sialin feedback loop that facilitates nitrate influx into cells for maintaining cell proliferation and inhibiting apoptosis. Furthermore, nitrate enhanced cell proliferation via the epidermal growth factor receptor (EGFR)-protein kinase B (AKT)-mitogen-activated protein kinase (MAPK) signaling pathway in irradiated parotid gland tissue. Collectively, nitrate effectively prevented IR-induced xerostomia via the EGFR-AKT-MAPK signaling pathway. Dietary nitrate supplementation may provide a novel, safe, and effective way to resolve IR-induced xerostomia.

Head and neck cancers are commonly treated using radiotherapy, where a beam of high-energy radiation is targeted at the tumour. This often severely damages the surrounding salivary glands, leading to chronic dry mouth and impairing a patient's sense of taste, nutrient intake, speech and immune system. Despite this significant impact on quality of life, there is no effective treatment yet for this side effect. In the body, salivary glands are one of the primary users of a compound known as nitrate, which is commonly found in the diet. In the glands, it is ushered into cells thanks to a protein known as sialin. The nutrient supports the activity and maintenance of the glands, before it is released in the saliva. Feng, Wu et al. therefore decided to test whether nitrate could offer protection during neck and head radiotherapy. The experiments used miniature pigs, which have similar salivary glands to humans. The animals that received sodium nitrate before and after exposure to radiation preserved up to 85% of their saliva production. By comparison, without any additional nitrate, saliva production fell to 20% of pre-radiation levels. To understand how this protective effect emerged, Feng, Wu et al. added nitrate to cells from a human salivary gland known as the parotid. This led to the cells producing more sialin, creating a feedback loop which increases the amount of nitrate in the salivary glands. Further examination then showed that the compound promotes growth of cells and reduce their death. These findings therefore suggest that clinical studies may be worthwhile to test if nitrate could be used to prevent dry mouth in head and neck cancer patients who undergo radiotherapy.

Effect of diabetic kidney disease on therapeutic strategies for coronary artery disease: ten year follow-up.

BACKGROUND: The best treatment for coronary artery disease (CAD) in patients with type 2 diabetes (DM2) and chronic kidney disease is unknown. METHODS: This retrospective study included MASS registry patients with DM2 and multivessel CAD, stratified by kidney function. Primary endpoint was combined of mortality, myocardial infarction, or additional revascularization. RESULTS: Median follow-up was 9.5 years. Primary endpoint occurrences among strata 1 and 2 were 53.4% and 40.7%, respectively (P=.020). Mortality rates were 37.4% and 24.6% in strata 1 and 2, respectively (P<.001). We observed a lower rate of major adverse cardiovascular events (MACE) (P=.027 for stratum 1 and P<.001 for stratum 2) and additional revascularization (P=.001 for stratum 1 and P<.001 for stratum 2) for those in the surgical group. In a multivariate analysis, eGFR was an independent predictor of MACE (P=.034) and mortality (P=.020). CONCLUSIONS: Among subjects with DM2 and CAD the presence of lower eGFR rate was associated with higher rates of MACE and mortality, irrespective of treatment choice. CABG was associated with lower rates of MACE in both renal function strata. eGFR was an independent predictor of MACE and mortality in a 10-year follow-up.

Effects of inorganic nitrate on ischaemia-reperfusion injury after coronary artery bypass surgery: a randomised controlled trial.

BACKGROUND: Nitric oxide (NO) is an important signalling molecule in the cardiovascular system with protective properties in ischaemia-reperfusion injury. Inorganic nitrate, an oxidation product of endogenous NO production and a constituent in our diet, can be recycled back to bioactive NO. We investigated if preoperative administration of inorganic nitrate could reduce troponin T release and other plasma markers of injury to the heart, liver, kidney, and brain in patients undergoing cardiac surgery. METHODS: This single-centre, randomised, double-blind, placebo-controlled trial included 82 patients undergoing coronary artery bypass surgery with cardiopulmonary bypass. Oral sodium nitrate (700 mg×2) or placebo (NaCl) were administered before surgery. Biomarkers of ischaemia-reperfusion injury and plasma nitrate and nitrite were collected before and up to 72 h after surgery. Troponin T release was our predefined primary endpoint and biomarkers of renal, liver, and brain injury were secondary endpoints. RESULTS: Plasma concentrations of nitrate and nitrite were elevated in nitrate-treated patients compared with placebo. The 72-h release of troponin T did not differ between groups. Other plasma biomarkers of organ injury were also similar between groups. Blood loss was not a predefined outcome parameter, but perioperative bleeding was 18% less in nitrate-treated patients compared with controls. CONCLUSION: Preoperative administration of inorganic nitrate did not influence troponin T release or other plasma biomarkers of organ injury in cardiac surgery. CLINICAL TRIAL REGISTRATION: NCT01348971.

The effects of dietary nitrate supplementation on endurance exercise performance and cardiorespiratory measures in healthy adults: a systematic review and meta-analysis.

BACKGROUND: Nitrate supplementation is thought to improve performance in endurance sports. OBJECTIVE: To meta-analyze studies evaluating the effect of nitrate supplementation on endurance sports performance among adults. DATA SOURCES: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science and CINAHL without language restrictions. METHODS: We included studies that: 1) compared nitrate supplementation with placebo; 2) enrolled adults engaging in an endurance-based activity; and 3) reported a performance measure or surrogate physiologic outcome. We evaluated risk of bias using the Cochrane Collaboration tool and pooled data with a random-effects model. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate confidence in estimates. RESULTS: We included 73 studies (n = 1061). Nitrate supplementation improved power output (MD 4.6 watts, P < 0.0001), time to exhaustion (MD 25.3 s, P < 0.00001), and distance travelled (MD 163.7 m, P = 0.03). We found no significant difference on perceived exertion, time trial performance and work done. Nitrate supplementation decreased VO2 (MD - 0.04 L/min, P < 0.00001) but had no significant effect on VO2max or blood lactate levels. CONCLUSION: The available evidence suggests that dietary nitrate supplementation benefits performance-related outcomes for endurance sports.

Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 µM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.

Effect of hypoxia and nitrate supplementation on different high-intensity interval-training sessions.

PURPOSE: To test the hypothesis that interval-training (IHT) would be impaired by hypoxia to a larger extent than repeated-sprint training (RSH) and that dietary nitrate (NO3-) would mitigate the detrimental effect of hypoxia to a larger extent during IHT than RSH. METHODS: Thirty endurance-trained male participants performed IHT (6 × 1 min at 90%∆ with 1 min active recovery) and RSH (2 sets of 6 × 10 s "all-out" efforts with 20 s active recovery) on a cycle ergometer, allocated in one of three groups: normobaric hypoxia (~ 13% FiO2) + NO3- - HNO, n = 10; normobaric hypoxia + placebo - HPL, n = 10; normoxia (20.9% FiO2) + placebo - CON, n = 10. Submaximal oxygen uptake ([Formula: see text]O2), time spent above 90% of maximal [Formula: see text]O2 (≥ 90 [Formula: see text]O2max) and heart rate (≥ 90 HRmax) were compared between IHT and RSH sessions and groups. Additionally, mean power output (MPO), decrement score and % of power associated with [Formula: see text]O2max (%p[Formula: see text]O2max) in RSH sessions were analyzed. RESULTS: [Formula: see text]O2 at sub-maximal intensities did not differ between training protocols and groups (~ 27 ml kg-1 min-1). ≥ 90 HRmax was significantly higher in IHT compared to RSH session (39 ± 8 vs. 30 ± 8%, p = 0.03) but only in HNO group. MPO (range 360-490 W) and decrement score (10-13%) were similar between groups although %p[Formula: see text]O2max was significantly higher (p = 0.04) in CON (166 ± 16 W) compared with both HPL (147 ± 15 W) and HNO (144 ± 10 W) groups. CONCLUSION: IHT responses were neither more impaired by hypoxia than RSH ones. Moreover, dietary NO3- supplementation impacted equally IHT and RSH training responses' differences between hypoxia and normoxia.

The effect of beetroot inorganic nitrate supplementation on cardiovascular risk factors: A systematic review and meta-regression of randomized controlled trials.

OBJECTIVES: Inorganic nitrate is one of the most effective compounds in beetroot for improving cardiovascular function due to its conversion to nitric oxide in the body. This review and meta-analysis aimed to investigate the role of beetroot inorganic nitrate supplementation on adults' cardiovascular risk factors. METHODS: We conducted a systematic literature review of articles published without time limitation until November 2020 in PubMed, Embase, ISI Web of Science, Scopus, Cochrane Library, and gray literature databases. We included the original randomized clinical trials (RCTs) in which the effect of beetroot inorganic nitrate supplementation on endothelial function, arterial stiffness, and blood pressure was studied. RESULTS: 43 studies were included for qualitative synthesis, out of which 27 were eligible for meta-analysis. Beetroot inorganic nitrate supplementation significantly decreased Arterial Stiffness (Pulse Wave Velocity (-0.27 m/s, p = 0.04)) and increased Endothelial function (Flow Mediated Dilation: 0.62%, p = 0.002) but did not change other parameters (p > 0.05). CONCLUSION: Beetroot inorganic nitrate supplementation might have a beneficial effect on cardiovascular risk factors. Further high-quality investigations will be needed to provide sufficient evidence.

Direct comparison of inorganic nitrite and nitrate on vascular dysfunction and oxidative damage in experimental arterial hypertension.

Arterial hypertension is one of the major health risk factors leading to coronary artery disease, stroke or peripheral artery disease. Dietary uptake of inorganic nitrite (NO2-) and nitrate (NO3-) via vegetables leads to enhanced vascular NO bioavailability and provides antihypertensive effects. The present study aims to understand the underlying vasoprotective effects of nutritional NO2- and NO3- co-therapy in mice with angiotensin-II (AT-II)-induced arterial hypertension. High-dose AT-II (1 mg/kg/d, 1w, s. c.) was used to induce arterial hypertension in male C57BL/6 mice. Additional inorganic nitrite (7.5 mg/kg/d, p. o.) or nitrate (150 mg/kg/d, p. o.) were administered via the drinking water. Blood pressure (tail-cuff method) and endothelial function (isometric tension) were determined. Oxidative stress and inflammation markers were quantified in aorta, heart, kidney and blood. Co-treatment with inorganic nitrite, but not with nitrate, normalized vascular function, oxidative stress markers and inflammatory pathways in AT-II treated mice. Of note, the highly beneficial effects of nitrite on all parameters and the less pronounced protection by nitrate, as seen by improvement of some parameters, were observed despite no significant increase in plasma nitrite levels by both therapies. Methemoglobin levels tended to be higher upon nitrite/nitrate treatment. Nutritional nitric oxide precursors represent a non-pharmacological treatment option for hypertension that could be applied to the general population (e.g. by eating certain vegetables). The more beneficial effects of inorganic nitrite may rely on superior NO bioactivation and stronger blood pressure lowering effects. Future large-scale clinical studies should investigate whether hypertension and cardiovascular outcome in general can be influenced by dietary inorganic nitrite therapy.

Lost-in-Translation of Metabolic Effects of Inorganic Nitrate in Type 2 Diabetes: Is Ascorbic Acid the Answer?

Beneficial metabolic effects of inorganic nitrate (NO3-) and nitrite (NO2-) in type 2 diabetes mellitus (T2DM) have been documented in animal experiments; however, this is not the case for humans. Although it has remained an open question, the redox environment affecting the conversion of NO3- to NO2- and then to NO is suggested as a potential reason for this lost-in-translation. Ascorbic acid (AA) has a critical role in the gastric conversion of NO2- to NO following ingestion of NO3-. In contrast to AA-synthesizing species like rats, the lack of ability to synthesize AA and a lower AA body pool and plasma concentrations may partly explain why humans with T2DM do not benefit from NO3-/NO2- supplementation. Rats also have higher AA concentrations in their stomach tissue and gastric juice that can significantly potentiate gastric NO2--to-NO conversion. Here, we hypothesized that the lack of beneficial metabolic effects of inorganic NO3- in patients with T2DM may be at least in part attributed to species differences in AA metabolism and also abnormal metabolism of AA in patients with T2DM. If this hypothesis is proved to be correct, then patients with T2DM may need supplementation of AA to attain the beneficial metabolic effects of inorganic NO3- therapy.

Marching to the Beet: The effect of dietary nitrate supplementation on high altitude exercise performance and adaptation during a military trekking expedition.

PURPOSE: The aim was to investigate the effect of dietary nitrate supplementation (in the form of beetroot juice, BRJ) for 20 days on salivary nitrite (a potential precursor of bioactive nitric oxide), exercise performance and high altitude (HA) acclimatisation in field conditions (hypobaric hypoxia). METHODS: This was a single-blinded randomised control study of 22 healthy adult participants (12 men, 10 women, mean age 28 ± 12 years) across a HA military expedition. Participants were randomised pre-ascent to receive two 70 ml dose per day of either BRJ (~12.5 mmol nitrate per day; n = 11) or non-nitrate calorie matched control (n = 11). Participants ingested supplement doses daily, beginning 3 days prior to departure and continued until the highest sleeping altitude (4800 m) reached on day 17 of the expedition. Data were collected at baseline (44 m altitude), at 2350 m (day 9), 3400 m (day 12) and 4800 m (day 17). RESULTS: BRJ enhanced the salivary levels of nitrite (p = 0.007). There was a significant decrease in peripheral oxygen saturation and there were increases in heart rate, diastolic blood pressure, and rating of perceived exertion with increasing altitude (p=<0.001). Harvard Step Test fitness scores significantly declined at 4800 m in the control group (p = 0.003) compared with baseline. In contrast, there was no decline in fitness scores at 4800 m compared with baseline (p = 0.26) in the BRJ group. Heart rate recovery speed following exercise at 4800 m was significantly prolonged in the control group (p=<0.01) but was unchanged in the BRJ group (p = 0.61). BRJ did not affect the burden of HA illness (p = 1.00). CONCLUSIONS: BRJ increases salivary nitrite levels and ameliorates the decline in fitness at altitude but does not affect the occurrence of HA illness.

Effect of inorganic nitrate supplementation on blood pressure in older adults: A systematic review and meta-analysis.

BACKGROUND: Previous clinical studies have shown controversial results regarding the effect of inorganic nitrate supplementation on blood pressure (BP) in older individuals. We performed this systematic review and meta-analysis to assess the effect of inorganic nitrate on BP in older adults. METHODS: Eligible studies were searched in Cochrane Library, PubMed, Scopus, Web of Science, and Embase. Randomized controlled trials which evaluated the effect of inorganic nitrate consumption on BP in older adults were recruited. The random-effect model was used to calculate the pooled effect sizes. RESULTS: 22 studies were included in this meta-analysis. Overall, inorganic nitrate consumption significantly reduced systolic blood pressure (SBP) by -3.90 mmHg (95% confidence interval: -5.23 to -2.57; P < 0.001) and diastolic blood pressure (DBP) by -2.62 mmHg (95% confidence interval: -3.86 to -1.37; P < 0.005) comparing with the control group. Subgroup analysis showed that the BP was significantly reduced when participants' age≥65, BMI>30, or baseline BP in prehypertension stage. And both SBP and DBP decreased significantly after acute nitrate supplementation of a single dose (<1 day) or more than 1-week. However, participants with hypertension at baseline were not associated with significant changes in both SBP and DBP. Subgroup analysis of measurement methods showed that only the resting BP group showed a significant reduction in SBP and DBP, compared with the 24-h ambulatory BP monitoring (ABPM) group and daily home BP measurement group. CONCLUSION: These results demonstrate that consuming inorganic nitrate can significantly reduce SBP and DBP in older adults, especially in whose age ≥ 65, BMI＞30, or baseline BP in prehypertension stage.

Multiple-day high-dose beetroot juice supplementation does not improve pulmonary or muscle deoxygenation kinetics of well-trained cyclists in normoxia and hypoxia.

Dietary nitrate (NO3-) supplementation via beetroot juice (BR) has been reported to lower oxygen cost (i.e., increased exercise efficiency) and speed up oxygen uptake (VO2) kinetics in untrained and moderately trained individuals, particularly during conditions of low oxygen availability (i.e., hypoxia). However, the effects of multiple-day, high dose (12.4 mmol NO3- per day) BR supplementation on exercise efficiency and VO2 kinetics during normoxia and hypoxia in well-trained individuals are not resolved. In a double-blinded, randomized crossover study, 12 well-trained cyclists (66.4 ± 5.3 ml min-1∙kg-1) completed three transitions from rest to moderate-intensity (~70% of gas exchange threshold) cycling in hypoxia and normoxia with supplementation of BR or nitrate-depleted BR as placebo. Continuous measures of VO2 and muscle (vastus lateralis) deoxygenation (ΔHHb, using near-infrared spectroscopy) were acquired during all transitions. Kinetics of VO2 and deoxygenation (ΔHHb) were modeled using mono-exponential functions. Our results showed that BR supplementation did not alter the primary time constant for VO2 or ΔHHb during the transition from rest to moderate-intensity cycling. While BR supplementation lowered the amplitude of the VO2 response (2.1%, p = 0.038), BR did not alter steady state VO2 derived from the fit (p = 0.258), raw VO2 data (p = 0.231), moderate intensity exercise efficiency (p = 0.333) nor steady state ΔHHb (p = 0.224). Altogether, these results demonstrate that multiple-day, high-dose BR supplementation does not alter exercise efficiency or oxygen uptake kinetics during normoxia and hypoxia in well-trained athletes.