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.

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.

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.

NITRATE-CIN Study: Protocol of a Randomized (1:1) Single-Center, UK, Double-Blind Placebo-Controlled Trial Testing the Effect of Inorganic Nitrate on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography for Acute Coronary Syndromes.

BACKGROUND: Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is a significant cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for novel effective treatments. Evidence suggests that delivery of nitric oxide (NO) through chemical reduction of inorganic nitrate to NO may offer a novel therapeutic strategy to reduce CIN and thus preserve long term renal function. DESIGN: The NITRATE-CIN trial is a single-center, randomized, double-blind placebo-controlled trial, which plans to recruit 640 patients presenting with acute coronary syndromes (ACS) who are at risk of CIN. Patients will be randomized to either inorganic nitrate therapy (capsules containing 12 mmol KNO3) or placebo capsules containing potassium chloride (KCl) daily for 5 days. The primary endpoint is development of CIN using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. A key secondary endpoint is renal function over a 3-month follow-up period. Additional secondary endpoints include serum renal biomarkers (e.g. neutrophil gelatinase-associated lipocalin) at 6 h, 48 h and 3 months following administration of contrast. Cost-effectiveness of inorganic nitrate therapy will also be evaluated. SUMMARY: This study is designed to investigate the hypothesis that inorganic nitrate treatment decreases the rate of CIN as part of semi-emergent coronary angiography for ACS. Inorganic nitrate is a simple and easy to administer intervention that may prove useful in prevention of CIN in at-risk patients undergoing coronary angiographic procedures.

Dietary Nitrate Intake Is Positively Associated with Muscle Function in Men and Women Independent of Physical Activity Levels.

BACKGROUND: Nitrate supplements can improve vascular and muscle function. Whether higher habitual dietary nitrate is associated with better muscle function remains underexplored. OBJECTIVE: The aim was to examine whether habitual dietary nitrate intake is associated with better muscle function in a prospective cohort of men and women, and whether the relation was dependent on levels of physical activity. METHODS: The sample (n = 3759) was drawn from the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab) (56% female; mean ± SD baseline age: 48.6 ± 11.1 y). Habitual dietary intake was assessed over 12 y by obtaining an average [of at least 2 time points, e.g., baseline (2000/2001) and 2004/2005 and/or 2011/2012] from a food-frequency questionnaire. Nitrate intake was calculated from a validated nitrate database and other published literature. Muscle function was quantified by knee extension strength (KES) and the 8-ft-timed-up-and-go (8ft-TUG) test performed in 2011/2012. Physical activity was assessed by questionnaire. Generalized linear models and logistic regression were used to analyze the data. RESULTS: Median (IQR) total nitrate intake was 65 (52-83) mg/d, with ∼81% derived from vegetables. Individuals in the highest tertile of nitrate intake (median intake: 91 mg/d) had 2.6 kg stronger KES (11%) and 0.24 s faster 8ft-TUG (4%) compared with individuals in the lowest tertile of nitrate intake (median intake: 47 mg/d; both P < 0.05). Similarly, individuals in the highest tertile of nitrate intake had lower odds for weak KES (adjusted OR: 0.69; 95% CI: 0.47, 0.73) and slow 8ft-TUG (adjusted OR: 0.63; 95% CI: 0.50, 0.78) compared with those in the lowest tertile. Physical activity did not influence the relationship between nitrate intake and muscle function (KES; P-interaction = 0.86; 8ft-TUG; P-interaction = 0.99). CONCLUSIONS: Higher habitual dietary nitrate intake, predominantly from vegetables, could be an effective way to promote lower-limb muscle strength and physical function in men and women.

Effects of acute dietary nitrate supplementation on cold-induced vasodilation in healthy males.

PURPOSE: Cold-induced vasodilation (CIVD) is a paradoxical rise in blood flow to the digits that occur during prolonged cold exposure. CIVD is thought to occur through active vasodilation and/or sympathetic withdrawal, where nitric oxide (NO) may play a key role in mediating these mechanisms. Beetroot juice (BRJ) is high in dietary nitrate (NO3-) which undergoes sequential reduction to nitrite (NO2-) and subsequently NO. Using a double-blind, randomized, crossover design, we examined the effect of acute BRJ supplementation on the CIVD response in 10 healthy males. METHODS: Participants had a resting blood pressure measurement taken prior to ingesting 140 mL of nitrate-rich BRJ (13 mmol NO3-) or a NO3--free placebo (PLA). After 2 h, participants immersed their hand in neutral water (~ 35 °C) for 10 min of baseline before cold water immersion (~ 8 °C) for 30 min. Laser-Doppler fluxmetry and skin temperature were measured continuously on the digits. RESULTS: Compared to PLA (100 ± 3 mmHg), acute BRJ supplementation significantly reduced mean arterial pressure at -30 min (96 ± 2 mmHg; p = 0.007) and 0 min (94 ± 2 mmHg; p = 0.008). Acute BRJ supplementation had no effect on Laser-Doppler fluxmetry during CIVD (expressed as cutaneous vascular conductance) measured as area under the curve (BRJ: 843 ± 148 PU mmHg-1 s; PLA: 1086 ± 333 PU mmHg-1 s), amplitude (BRJ: 0.60 ± 0.12 PU mmHg-1; PLA: 0.69 ± 0.14 PU mmHg-1), and duration (BRJ: 895 ± 60 s; PLA: 894 ± 46 s). CONCLUSION: Acute BRJ supplementation does not augment the CIVD response in healthy males.

Trabodenoson on trabecular meshwork rejuvenation: a comprehensive review of clinical data.

INTRODUCTION: Trabodenoson is an adenosine mimetic acting selectively at the A1 receptor (A1R) subtype, involved in multiple signaling pathways including matrix metalloproteinase (MMP-2) associated with glaucoma pathological processes. It has been developed as a Phase 3 candidate for the treatment of patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH). AREA COVERED: This review summarizes the molecular traits of Trabodenoson in intraocular pressure (IOP) regulations and provides a scientific interpretation of the Phase 2 clinical study results. This article sheds light on the root causes of the two pivotal Phase 3 clinical trial failures in patients with POAG or OH; it further highlights the discovery of MMP-2 in trabecular meshwork (TM) rejuvenation, which has strategic importance in long-term glaucoma patient care. EXPERT OPINION: Trabodenoson is a BID glaucoma eye drop with a possible QD dose as maintenance. Its Phase 3 pivotal clinical trials failed at the wrong dose and dosing regimen because of the misinterpretation of the complex IOP results from the Phase 2 monotherapy and combination studies. The future development should focus on the TM benefits whilst unleashing its potential of neural protection through nanoparticle eye drops, medical coating, and sustained release drug delivery.

No thermoregulatory or ergogenic effect of dietary nitrate among physically inactive males, exercising above gas exchange threshold in hot and dry conditions.

The aim of this study was to determine the effect of five days dietary nitrate (NO3-) consumption on exercise tolerance and thermoregulation during cycling in hot, dry conditions. In a double-blind, randomised crossover design, 11 healthy males participated in an exercise tolerance test (Tlim) in the heat (35°C, 28% relative humidity), cycling above the thermoneutral gas exchange threshold, after five days of dietary supplementation, with either NO3-rich beetroot juice (BR; ∼ 9.2 mmol NO3-) or placebo (PLA). Changes in plasma [NO3-] and nitrite [NO2-], core and mean skin temperatures, mean local and whole-body sweat rates, heart rate, perceptual ratings and pulmonary gas exchange were measured during exercise, alongside calorimetric estimations of thermal balance. Mean arterial pressures (MAP) were recorded pre-Tlim. There were no differences in Tlim between conditions (BR = 22.8 ± 8.1 min; Placebo = 20.7 ± 7.9 min) (P = 0.184), despite increases in plasma [NO3-] and [NO2-] (P < 0.001) and a 3.8% reduction in resting MAP (P = 0.004) in the BR condition. There were no other differences in thermoregulatory, cardio-metabolic, perceptual or calorimetric responses to the Tlim between conditions (P > 0.05). Dietary NO3- supplementation had no effect on exercise tolerance or thermoregulation in hot, dry conditions, despite reductions in resting MAP and increases in plasma [NO3-] and [NO2-]. Healthy, yet physically inactive individuals with no known impairments in vasodilatory and sudomotor function do not appear to require BR for ergogenic or thermolytic effects during exercise in the heat.

The effect of dietary nitrate and vitamin C on endothelial function, oxidative stress and blood lipids in untreated hypercholesterolemic subjects: A randomized double-blind crossover study.

BACKGROUND: Vitamin C may enhance nitric oxide (NO) production through stepwise reduction of dietary nitrate (NO3) to nitrite (NO2) to NO. The combined effect of vitamin C and NO3 supplementation is relatively unexplored in untreated hypercholesterolemia. AIMS: We aimed to examine whether co-administration of vitamin C and nitrate for 4-weeks would improve endothelial function (primary outcome), plasma NO metabolites, oxidative stress, and blood lipids (secondary outcomes). METHODS: Subjects 50-70 years of age with low density lipoprotein (LDL) > 130 mg/dL and RHI ≤2 were enrolled in this randomized double-blind crossover study. Subjects were assigned to two 4-week supplementation treatments starting with 70 ml of concentrated beetroot juice (CBJ) with 1000 mg of vitamin C (NC) or CBJ with matched placebo (N), then switched to alternate treatment following 2-week washout. The change in reactive hyperemia index (RHI), sum of plasma NO metabolites (NO2 + NO3 (NOx)), oxidized LDL (oxLDL), and serum lipids were assessed at baseline and at 4-weeks of each treatment period. RESULTS: Eighteen subjects (11M:7F) completed all study visits. No significant treatment differences were observed in RHI change (N: 0.21 ± 0.12; NC: 0.20 ± 0.17; p = 0.99). Secondary analysis revealed that a subgroup of NC subjects who started with a baseline RHI of <1.67 (threshold value for ED) had greater improvements in RHI compared to subjects with RHI >1.67 (1.23 ± 0.15 to 1.96 ± 0.19; n = 8 vs. 1.75 ± 0.11 to 1.43 ± 0.10; n = 8; p = 0.02). Compared to N, NC experienced a significant increase in plasma NOx (N: 94.2 ± 15.5 µmol/L; NC: 128.7 ± 29.1 µmol/L; p = 0.01). Although there was no significant difference in oxLDL change between treatments (N: -1.08 ± 9.8 U/L; NC: -6.07 ± 9.14 U/L; p = 0.19), NC elicited significant reductions in LDL (N: 2.2 ± 2; NC: -10.7 ± 23; p = 0.049), triglycerides (N: 14.6 ± 43; NC: -43.7 ± 45; p = 0.03), and no change in serum high density lipoprotein. Within treatment group comparisons showed that only NC reduced oxLDL significantly from baseline to 4 weeks (p = 0.01). CONCLUSIONS: No between intervention differences were observed in RHI. RHI only improved in NC subjects with ED at intervention baseline. Four weeks of NC enriched the NO pool and promoted reduction of blood lipids and oxidative stress in subjects with hypercholesterolemia. These preliminary findings highlight a supplementation strategy that may reduce the progression of atherosclerotic disease and deserves further attention in studies using flow mediated dilation methods. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT04283630).

Influence of Dietary Nitrate Supplementation on High-Intensity Intermittent Running Performance at Different Doses of Normobaric Hypoxia in Endurance-Trained Males.

This study investigated whether supplementation with nitrate-rich beetroot juice (BR) can improve high-intensity intermittent running performance in trained males in normoxia and different doses of normobaric hypoxia. Eight endurance-trained males (V˙O2peak, 62 ± 6 ml·kg-1·min-1) completed repeated 90 s intervals at 110% of peak treadmill velocity, from an initial step incremental test, interspersed by 60 s of passive recovery until exhaustion (Tlim). Participants completed the first three experimental trials during days 3, 5, and 7 of BR or nitrate-depleted beetroot juice (PLA) supplementation and completed the remaining experimental visits on the alternative supplement following at least 7 days of washout. The fraction of inspired oxygen during visits 1-3 was either 0.209, 0.182, or 0.157, equivalent to an altitude of 0, 1,200, and 2,400 m, respectively, and this order was replicated on visits 4-6. Arterial oxygen saturation declined dose dependently as fraction of inspired oxygen was lowered (p < .05). Plasma nitrite concentration was higher pre- and postexercise after BR compared with PLA supplementation (p < .05). There was no difference in Tlim between PLA and BR at 0 m (445 [324, 508] and 410 [368, 548] s); 1,200 m (341 [270, 390] and 332 [314, 356] s); or 2,400 m (233 [177, 373] and 251 [221, 323] s) (median and [interquartile range]; p > .05). The findings from this study suggest that short-term BR supplementation does not improve high-intensity intermittent running performance in endurance-trained males in normoxia or at doses of normobaric hypoxia that correspond to altitudes at which athletes typically train while on altitude training camps.

Nitrate-nitrite exposure through drinking water and diet and risk of colorectal cancer: A systematic review and meta-analysis of observational studies.

BACKGROUND: Considerable controversy exists regarding the association between nitrate intake and risk of colorectal cancer. Therefore, we performed a dose-response meta-analysis of observational studies. METHODS: We identified relevant studies by searching PubMed, Scopus and ISI Web of Knowledge until April 2020 and references of retrieved relevant articles. The random-effects model was used to calculate pooled effect size (ESs) and 95% confidence intervals (CIs). RESULTS: Fifteen prospective cohort and case-control papers were included in this systematic review and meta-analysis. In total, 2,573,524 participants with an age range between 20 and 85 years were included. The total number of colorectal cancer cases was 38,848. Intake of nitrate from diet was associated with a risk of colorectal cancer (Pooled HR: 1.13; 95% CI: 1.04-1.23, I2 = 38%; P = 0.08). Nitrite in diet was not significantly associated with risk of colorectal cancer (pooled HR: 1.07; 95% CI: 0.95-1.21, I2 = 61.6%; P = 0.005). Nitrate in water did not show an association with risk of colorectal cancer (pooled HR: 1.04; 95% CI: 0.92-1.19, I2 = 64.7%; P = 0.002). Non-linear dose-response analysis revealed no significant association of dietary nitrite and also nitrate of drinking water with risk of colorectal cancer. However, dietary nitrate was marginally associated with a greater risk of colorectal cancer. Linear dose-response analysis of nitrate from diet was not associated with colorectal cancer risk by an additional 50 mg per day. Such a non-significant association was also seen for colorectal cancer risk by an additional 1 mg per day and 1 mg/l from dietary nitrite and water nitrate respectively. CONCLUSIONS: Dietary nitrate was related to a higher risk of colorectal cancer risk. However, intake of nitrite from diet and nitrate from the drinking water was not associated with colorectal cancer risk.

Net reductions in greenhouse gas emissions from feed additive use in California dairy cattle.

The livestock industry is one of the main contributors to greenhouse gas emissions and there is an increasing demand for the industry to reduce its carbon footprint. Several studies have shown that feed additives 3-nitroxypropanol and nitrate to be effective in reducing enteric methane emissions. The objective of this study was to estimate the net mitigating effect of using 3-nitroxypropanol and nitrate on total greenhouse gas emissions in California dairy industry. A life cycle assessment approach was used to conduct a cradle-to-farm gate environmental impact analysis based on dairy production system in California. Emissions associated with crop production, feed additive production, enteric methane, farm management, and manure storage were calculated and expressed as kg CO2 equivalents (CO2e) per kg of energy corrected milk. The total greenhouse gas emissions from baseline, 3-nitroxypropanol and nitrate offered during lactation were 1.12, 0.993, and 1.08 kg CO2e/kg energy corrected milk, respectively. The average net reduction rates for 3-nitroxypropanol and nitrate were 11.7% and 3.95%, respectively. In both cases, using the feed additives on the whole herd slightly improved overall carbon footprint reduction compared to limiting its use during lactation phase. Although both 3-nitroxypropanol and nitrate had effects on decreasing the total greenhouse gas emission, the former was much more effective with no known safety issues in reducing the carbon footprint of dairy production in California.

Dietary nitrate supplementation does not influence thermoregulatory or cardiovascular strain in older individuals during severe ambient heat stress.

NEW FINDINGS: What is the central question of this study? Does dietary nitrate supplementation with beetroot juice attenuate thermoregulatory and cardiovascular strain in older adults during severe heat stress? What is the main finding and its importance? A 7-day nitrate supplementation regimen lowered resting mean arterial pressure in thermoneutral conditions. During heat stress, core and mean skin temperatures, vasodilatory responses, sweat loss, heart rate and left ventricular function were unchanged, and mean arterial pressure was only transiently reduced, post-supplementation. These data suggest nitrate supplementation with beetroot juice does not mitigate thermoregulatory or cardiovascular strain in heat-stressed older individuals. ABSTRACT: This study tested the hypothesis that dietary nitrate supplementation with concentrated beetroot juice attenuates thermoregulatory and cardiovascular strain in older individuals during environmental heat stress. Nine healthy older individuals (six females, three males; aged 67 ± 5 years) were exposed to 42.5 ± 0.1°C and 34.0 ± 0.5% relative humidity conditions for 120 min before (CON) and after 7 days of dietary nitrate supplementation with concentrated beetroot juice (BRJ; 280 ml, ∼16.8 mmol of nitrate daily). Core and skin temperatures, body mass changes (indicative of whole-body sweat loss), skin blood flow and cutaneous vascular conductance, forearm blood flow and vascular conductance, heart rate, arterial blood pressures and indices of cardiac function were measured. The 7-day beetroot juice regimen increased plasma nitrate/nitrite levels from 27.4 ± 15.2 to 477.0 ± 102.5 µmol l-1 (P < 0.01) and lowered resting mean arterial pressure from 90 ± 7 to 83 ± 10 mmHg at baseline under thermoneutral conditions (P = 0.02). However, during subsequent heat stress, no differences in core and skin temperatures, skin blood flow and vascular conductance, forearm blood flow and vascular conductance, whole-body sweat loss, heart rate, and echocardiographic indices of systolic function and diastolic filling were evident following nitrate supplementation (all P > 0.05). Mean arterial pressure was lower in BRJ vs. CON during heat stress (treatment-by-time interaction: P = 0.02). Overall, these findings suggest that dietary nitrate supplementation with concentrated beetroot juice does not attenuate thermoregulatory or cardiovascular strain in older individuals exposed to severe ambient heat stress.

Pediatrics patients head-up tilt test with pharmacological challenge, it is safe?

Syncope in pediatrics represents an important cause of visits to the emergency units. For this reason, excluding a cardiac or malignant origin is essential at the time of the initial approach in order to determine what is the next step in management, or if they need to be referred to a pediatric cardiologist and/or electrophysiologist. Vasovagal syncope is the most frequent cause of syncope in pediatrics, in which a detailed clinical history is enough to make the diagnosis. If no diagnosis is concluded by the history, or if it is necessary to define the hemodynamic response of the patients, the head-up tilt test is indicated; this will trigger syncope due to an orthostatic stress caused by the angulated table (passive phase). If a negative response remains, it can be followed by a pharmacologic challenge in order to trigger the hemodynamic response, which is still controversial in pediatrics. The pharmacologic challenge increases the sensitivity with a slight reduction in test specificity. Although there is not a specific drug for the challenge in pediatric patients yet, the most commonly drugs used are nitrates and isoproterenol, the latter related to a great number of adverse effects. Sublingual administration of nitrates in the challenge has been proven to be ideal, effective and safe in this specific age group. The aim of this article is to make a literature search in order to demonstrate the effectiveness and safety of the pharmacologic challenge during the head-up tilt test in pediatrics, emphasizing a study conducted at the National Institute of Cardiology with isosorbide dinitrate.

El síncope en edades pediátricas representa una causa importante en las visitas a unidades de urgencias, por lo que excluir un origen cardíaco o maligno es fundamental al momento del abordaje inicial para determinar la conducta a seguir o la necesidad de derivar al cardiólogo pediatra o electrofisiólogo. El síncope vasovagal (SVV) es la causa más frecuente de síncope en pediatría, para cuyo diagnóstico basta una historia clínica detallada. Cuando ésta no es suficiente para determinar el diagnóstico de síncope reflejo o es necesario definir el tipo de respuesta que lo origina, está indicada una prueba de mesa inclinada que produce un estrés ortostático por la angulación y ello desencadena un síncope (fase pasiva). En pruebas no concluyentes está indicado un reto farmacológico para precipitar la respuesta hemodinámica, pero aún es un tema de controversia en edades pediátricas. El reto farmacológico incrementa la sensibilidad de la prueba, con una ligera reducción de la especificidad. Si bien no existe todavía un medicamento específico para la población pediátrica, los más empleados son los nitratos y el isoproterenol, este último relacionado con un mayor número de efectos adversos. La administración sublingual de los nitratos utilizados ha demostrado ser ideal, efectiva y segura en los pacientes pediátricos. El objetivo del artículo es realizar una revisión de las publicaciones médicas que demuestran la efectividad y seguridad del reto farmacológico durante la prueba de mesa inclinada en pacientes pediátricos, con énfasis en un estudio conducido en el Instituto Nacional de Cardiología con dinitrato de isosorbida (DNIS).

Influence of muscle oxygenation and nitrate-rich beetroot juice supplementation on O2 uptake kinetics and exercise tolerance.

We tested the hypothesis that acute supplementation with nitrate (NO3-)-rich beetroot juice (BR) would improve quadriceps muscle oxygenation, pulmonary oxygen uptake (V˙O2) kinetics and exercise tolerance (Tlim) in normoxia and that these improvements would be augmented in hypoxia and attenuated in hyperoxia. In a randomised, double-blind, cross-over study, ten healthy males completed two-step cycle tests to Tlim following acute consumption of 210 mL BR (18.6 mmol NO3-) or NO3--depleted beetroot juice placebo (PL; 0.12 mmol NO3-). These tests were completed in normobaric normoxia [fraction of inspired oxygen (FIO2): 21%], hypoxia (FIO2: 15%) and hyperoxia (FIO2: 40%). Pulmonary V˙O2 and quadriceps tissue oxygenation index (TOI), derived from multi-channel near-infrared spectroscopy, were measured during all trials. Plasma [nitrite] was higher in all BR compared to all PL trials (P < 0.05). Quadriceps TOI was higher in normoxia compared to hypoxia (P < 0.05) and higher in hyperoxia compared to hypoxia and normoxia (P < 0.05). Tlim was improved after BR compared to PL ingestion in the hypoxic trials (250 ± 44 vs. 231 ± 41 s; P = 0.006; d = 1.13), with the magnitude of improvement being negatively correlated with quadriceps TOI at Tlim (r = -0.78; P < 0.05). Tlim was not improved following BR ingestion in normoxia (BR: 364 ± 98 vs. PL: 344 ± 78 s; P = 0.087, d = 0.61) or hyperoxia (BR: 492 ± 212 vs. PL: 472 ± 196 s; P = 0.273, d = 0.37). BR ingestion increased peak V˙O2 in hypoxia (P < 0.05), but not normoxia or hyperoxia (P > 0.05). These findings indicate that BR supplementation is more likely to improve Tlim and peak V˙O2 in situations when skeletal muscle is more hypoxic.

The effect of prolonged dietary sodium nitrate treatment on the hypothalamus-pituitary-gonadal axis and testicular structure and function in streptozotocin-induced diabetic male rats.

The aim of this study was to evaluate the effect of prolonged dietary nitrate supplementation on the gonadotropin level, testicular histology and morphometry, expression of miR-34b and p53 mRNA, and spermatogenesis in streptozotocin-induced diabetic male rats. METHODS: Fifty male Wistar rats were divided into 5 groups: Control (C), control + nitrate (CN), diabetes (D), diabetes + insulin (DI), and diabetes + nitrate (DN). Diabetes was induced using 45 mg kg-1 of streptozotocin intraperitoneally. Rats in the CN and DN groups were administered sodium nitrate in drinking water (100 mg L-1). NPH insulin (2-4 U d-1) was injected subcutaneously in the DI group for 2 months. Nitrate and insulin supplementation was started one month after confirmation of diabetes. RESULTS: Nitrate supplementation in the DN group significantly increased the body weight (p < 0.05), sperm parameters (p < 0.001), indices of spermatogenesis (p < 0.001), and testis histopathology as well as decreased the blood glucose level (p < 0.001) compared to the untreated diabetic group, although it had no significant effect on testicular parameters, LH and FSH levels. Nitrate administration in the DN group also decreased miR-34b (p < 0.001) and p53 mRNA (p < 0.001) expression, and increased serum insulin and NOx levels compared to the untreated diabetic rats. CONCLUSIONS: Chronic nitrate supplementation in streptozotocin-induced diabetic rats improved fertility parameters, which may be associated with increased miR-34b and decreased p53 mRNA.

The relationship between consumption of nitrite or nitrate and risk of non-Hodgkin lymphoma.

Epidemiologic studies of the relationship between nitrite or nitrate consumption and risk of non-Hodgkin lymphoma (NHL) remain controversial. The current meta-analysis aimed to reexamine the evidence and quantitatively evaluate that relationship. Manuscripts were retrieved from the Web of Science, Chinese National Knowledge Infrastructure and PubMed databases up to May 2019. From the studies included in the review, results were combined and presented as odds ratios (OR). To conduct a dose-response (DR) analysis, studies presenting risk estimates over a series of categories of exposure were selected. Our data indicate that the consumption of nitrite was linked to a significantly increased hazard of NHL (OR: 1.37; 95% CI: 1.14-1.65), rather than nitrate (OR: 1.02; 95% CI: 0.94-1.10). According to Egger's and Begg's tests (P > 0.05), there was no evidence of significant publication bias. Moreover, our DR analysis indicated that the risk of NHL grew by 26% for each additional microgram of nitrite consumed in the diet per day (OR: 1.26; 95% CI: 1.09-1.42). Through subset analysis of the nitrite studies, data from the high-quality studies indicated that consumption was positively associated with carcinogenicity, leading to NHL (OR: 1.44; 95% CI: 1.17-1.77) and positively correlated with the development of diffuse large B-cell lymphoma (OR: 1.55; 95% CI: 1.07-2.26), but not other NHL subtypes. In addition, the data suggested that females (OR: 1.50; 95% CI: 1.15-1.95) and high levels of nitrite intake (OR: 1.64; 95% CI: 1.28-2.09) had a higher risk of NHL. Our meta-analysis supports the hypothesis that nitrite intake, but not that of nitrate, raises the risk of developing NHL. In the future, better designed prospective research studies should be conducted to confirm our findings, clarify potential biological mechanisms and instruct clinicians about NHL prophylaxis.

Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans.

BACKGROUND: Inorganic nitrate, abundant in leafy green vegetables and beetroot, is thought to have protective health benefits. Adherence to a Mediterranean diet reduces the incidence and severity of coronary artery disease, whereas supplementation with nitrate can improve submaximal exercise performance. Once ingested, oral commensal bacteria may reduce nitrate to nitrite, which may subsequently be reduced to nitric oxide during conditions of hypoxia and in the presence of "nitrite reductases" such as heme- and molybdenum-containing enzymes. OBJECTIVE: We aimed to explore the putative effects of inorganic nitrate and nitrite on mitochondrial function in skeletal muscle. METHODS: Mice were subjected to a nitrate/nitrite-depleted diet for 2 wk, then supplemented with sodium nitrate, sodium nitrite, or sodium chloride (1 g/L) in drinking water ad libitum for 7 d before killing. Skeletal muscle mitochondrial function and expression of uncoupling protein (UCP) 3, ADP/ATP carrier protein (AAC) 1 and AAC2, and pyruvate dehydrogenase (PDH) were assessed by respirometry and Western blotting. Studies were also undertaken in human skeletal muscle biopsies from a cohort of coronary artery bypass graft patients treated with either sodium nitrite (30-min infusion of 10 µmol/min) or vehicle [0.9% (wt:vol) saline] 24 h before surgery. RESULTS: Neither sodium nitrate nor sodium nitrite supplementation altered mitochondrial coupling efficiency in murine skeletal muscle, and expression of UCP3, AAC1, or AAC2, and PDH phosphorylation status did not differ between the nitrite and saline groups. Similar results were observed in human samples. CONCLUSIONS: Sodium nitrite failed to improve mitochondrial metabolic efficiency, rendering this mechanism implausible for the purported exercise benefits of dietary nitrate supplementation. This trial was registered at clinicaltrials.gov as NCT04001283.