Dietary Inorganic Nitrate Supplementation Research Articles

Can the dietary inorganic nitrate supplementation mitigate the vascular dysfunction in elderly with Alzheimer’s disease?

Aging and Alzheimer disease (AD) are both characterized by progressive reduction in nitric oxide bioavailability and endothelial function impairment. Promising studies on young healthy individuals underly the positive effect of dietary nitrate supplementation on endothelial function. However, the pharmacokinetics of the plasma nitrate and nitrite (PN) and the accompanying endothelial responsiveness following the oral nitrate ingestion in healthy elderly (HE) and patients with AD is not clear. Our hypothesis was that due to the reduction of nitric oxide bioavailability during aging and AD, an equal dose of oral nitrate (ON) would ameliorate the endothelial responsiveness more in the HE and even more in patients with AD in comparison to healthy young subjects (HY). Therefore, with the aim of investigating the pharmacokinetics of PN and the time-course endothelial responsiveness in response to a single dose ON, 10 HY (25±4 YRS), 10 HE (72±8 YRS) and 13 AD (73±7 YRS) were recruited. PN levels and endothelial responsiveness (single-passive leg movement (ΔPLM)) were measured in the recruited individuals prior to (T0) and hourly for 4 hours (T1, T2, T3, and T4) after: a) a single dose of ON; and b) a single dose of placebo. As expected at T0 both PN and ΔPLM were significantly reduced in the HE and even more reduced in the AD in comparison to the HY (all p<0.001). No changes in PN nor ΔPLM were detected in any group following placebo intake. PN increased significantly in all three groups at T1 (p<0.001) and constantly increased up to T4, but no differences were detected between time points T1 to T4 in any group. ΔPLM increased significantly in all three groups at T2, reaching highest values at T4 (p<0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to HY (p<0.0001) and HE (p<0.001). Significant correlation between PN and ΔPLM was found (p<0.001, R2=0.1654). Contrary to our hypothesis, the results of this study suggest that the PN pharmacokinetics following a single dose of ON is similar in HY, HE and AD. Moreover, the expected time-course amelioration of the endothelial responsiveness was reduced in the HE and even more reduced in the AD, suggesting that other factors, rather than the nitric oxide bioavailability, are playing a role in the age- and AD-related vascular dysfunction. Ricerca di Base 2017 - RBVR17XRSA - Effectiveness of exercise and nitrate supplementation on progression of dementia in patients with Alzheimer’s disease. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

NITRATE-RICH BEETROOT JUICE ALONE OR IN COMBINATION WITH FOLIC ACID REDUCES BLOOD PRESSURE IN HYPERTENSIVE TANZANIAN ADULTS: A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL

Objective: In Sub-Saharan Africa, current management strategies are struggling to control the burgeoning hypertension epidemic. Dietary interventions such as inorganic nitrate and folate could represent alternative strategies for reducing blood pressure in this setting. This study aims to explore the effects of dietary inorganic nitrate supplementation alone or in combination with folic acid supplementation on blood pressure in a group of adult individuals with elevated blood pressure in Tanzania. Design and method: A placebo-controlled, double blind, randomized controlled trial (RCT) was conducted. Forty seven participants were randomly assigned to three conditions for a period of 60 days: 1) high-nitrate beetroot juice (∼400 mg nitrate) and folic acid (∼5 mg folate), 2) high-nitrate beetroot juice and placebo, 3) nitrate-depleted beetroot juice and placebo. Clinic and 24-hour ambulatory blood pressure, markers of nitric oxide production, and measurements of intervention compliance were obtained prior to and following the intervention period. Results: Resting clinic-based systolic blood pressure was significantly lower after 60 days of nitrate supplementation alone (p = 0.01). Both alone and combined nitrate + folate interventions had a significant effect on 24-Hour systolic blood pressure. After 60 days systolic blood pressure dropped by −10.8 ± 9.8 mmHg (p < 0.001) and −6.1 ± 13.2 mmHg (p = 0.03) in the nitrate alone and nitrate + folate groups, respectively. There was a significant decrease in 24-hour diastolic blood pressure in the nitrate alone group (−5.4 ± 5.0 mmHg, p = 0.04). Conclusions: Dietary inorganic nitrate, alone or in combination with folic acid, represents a potential nutritional strategy to lessen the hypertension epidemic in Sub-Saharan Africa. These findings support the rationale for future long-term investigations exploring the efficacy of dietary nitrate for lowering blood pressure and attenuating CVD risk in this setting.

Nitrate-Rich Beetroot Juice Reduces Blood Pressure in Tanzanian Adults with Elevated Blood Pressure: A Double-Blind Randomized Controlled Feasibility Trial

ABSTRACTBackgroundIn Sub-Saharan Africa, current strategies are struggling to control the burgeoning hypertension epidemic. Dietary interventions such as inorganic nitrate or folic acid supplementation could represent promising strategies for reducing blood pressure (BP) in this setting.ObjectivesThis feasibility study explores the effects of dietary inorganic nitrate supplementation, alone or in combination with folic acid, on BP in Tanzanian adults with elevated BP in Tanzania.MethodsA placebo-controlled, double-blind, randomized controlled feasibility trial was conducted. Forty-seven middle-aged and older participants (age: 50–70 y, BMI: 26.3–29.1 kg/m2) were randomly assigned to 3 conditions for a period of 60 d: 1) high-nitrate beetroot juice (∼400 mg nitrate) and folic acid (∼5 mg folic acid) (N + F), 2) high-nitrate beetroot juice and placebo (N + P), or 3) nitrate-depleted beetroot juice and placebo (P + P). Clinic and 24-h ambulatory BP and measurements of compliance in plasma (nitrate and folate concentrations) and saliva (nitrate and nitrite) were obtained at baseline, 30 d, and 60 d.ResultsBaseline resting systolic and diastolic BP (mean ± SD) was 151.0 ± 19.4 mm Hg and 91.8 ± 11.7 mm Hg, respectively. Compliance to the interventions was high (>90%) in all groups which was confirmed by the significant increase in nitrate and folic acid concentrations in plasma and saliva samples in the treatment arms. After 60 d, 24-h systolic BP dropped by −10.8 ± 9.8 mm Hg (P < 0.001), −6.1 ± 13.2 mm Hg (P = 0.03), and −0.3 ± 9.7 mm Hg (P = 0.83) in the N + P, N + F, and P + P groups, respectively. There was a significant decrease in 24-h diastolic BP in the N + P group (−5.4 ± 5.0 mm Hg, P = 0.004), whereas changes were not significant in the N + F (−1.8 ± 8.1 mm Hg, P = 0.32) and P + P (1.6 ± 8.3 mm Hg, P = 0.43) groups.ConclusionsDietary inorganic nitrate represents a potential nutritional strategy to lessen the hypertension epidemic in Sub-Saharan Africa. These findings support the rationale for future long-term investigations exploring the efficacy of dietary nitrate for lowering BP and attenuating cardiovascular disease risk in this setting.This trial was registered at isrctn.com as ISRCTN67978523.

The Effect of Dietary Inorganic Nitrate Supplementation on Cardiac Function during Submaximal Exercise in Men with Heart Failure with Reduced Ejection Fraction (HFrEF): A Pilot Study.

Heart failure with reduced ejection fraction (HFrEF) is a common end point for patients with coronary artery disease and it is characterized by exercise intolerance due, in part, to a reduction in cardiac output. Nitric oxide (NO) plays a vital role in cardiac function and patients with HFrEF have been identified as having reduced vascular NO. This pilot study aimed to investigate if nitrate supplementation could improve cardiac measures during acute, submaximal exercise. Five male participants (61 ± 3 years) with HFrEF (EF 32 ± 2.2%) completed this pilot study. All participants supplemented with inorganic nitrate (beetroot juice) or a nitrate-depleted placebo for ~13 days prior to testing. Participants completed a three-stage submaximal exercise protocol on a recumbent cycle ergometer with simultaneous echocardiography for calculation of cardiac output (Q), stroke volume (SV), and total peripheral resistance (TPR). Heart rate and blood pressure were measured at rest and during each stage. Both plasma nitrate (mean = ~1028%, p = 0.004) and nitrite (mean = ~109%, p = 0.01) increased following supplementation. There were no differences between interventions at rest, but the percent change in SV and Q from rest to stage two and stage three of exercise was higher following nitrate supplementation (all p > 0.05, ES > 0.8). Both interventions showed decreases in TPR during exercise, but the percent reduction TPR in stages two and three was greater following nitrate supplementation (p = 0.09, ES = 0.98 and p = 0.14, ES = 0.82, respectively). There were clinically relevant increases in cardiac function during exercise following supplementation with nitrate. The findings from this pilot study warrant further investigation in larger clinical trials.

Dietary Inorganic Nitrate Supplementation And Ventilatory Threshold In Patients With Reduced Ejection Fraction Heart Failure

Patients with chronic heart failure (HF) are characterized by exercise intolerance. Maximal oxygen consumption (VO2peak) is predictive of health outcomes, but is often influenced by early onset fatigue or external factors. Oxygen consumption at the ventilatory threshold (VO2AT) is a submaximal marker of sustainable oxygen uptake and has been shown to predict 6 month mortality in HF. An intervention that increases VO2AT in HF would likely produce beneficial clinical and quality of life outcomes. Nitric oxide (NO) bioavailability is a mediator of skeletal muscle perfusion, mitochondrial function and contractile efficiency during exercise. Heart Failure with reduced ejection fraction (HFrEF) is characterized by a reduction in endothelial function and bioavailable NO. Dietary inorganic nitrate supplementation has been shown to increase NO bioavailability and exercise tolerance in patients with other cardiovascular diseases and HFpEF. PURPOSE: To determine the effect of dietary inorganic nitrate supplementation on VO2AT in patients with HFrEF. METHODS: Sixteen patients with HFrEF (15 men, 63 ± 4 y, BMI: 31.8 ± 2.1 kg·m-2) participated in a randomized, double-blind, crossover design study. Participants consumed either beetroot juice (BRJ - 16mmol nitrate/day), or a nitrate-depleted placebo (PL) for five days prior to completing a cardiopulmonary exercise test (CPX). RESULTS: Following BRJ supplementation plasma nitrite increased significantly compared to placebo (511.5 ± 461.0nM vs. 195.0 ± 176.8nM; p<0.05). No differences were observed for the onset of VT (BRJ: 611.0 ± 119.7s; PL: 611.0 ± 142.3s; p=0.9) or VO2AT (BRJ: 1159.7 ± 207.8ml·min-1; PL: 1132.4 ± 221.0ml·min-1; p=0.53). CONCLUSIONS: Dietary nitrate supplementation, despite significant increase in circulating nitrite, produced no changes time to anaerobic threshold or sustainable sub-maximal oxygen uptake. Supported by Australian Heart Foundation Vanguard Award 101389 to Jason D. Allen

Dietary Inorganic Nitrate Supplementation And Exercise Tolerance In Patients With Reduced Ejection Fraction Heart Failure

Exercise intolerance is the primary cause of morbidity and decreased quality of life in patients with chronic heart failure (HF). The strong prognostic value of exercise capacity in patients with HF warrants identification of interventions which maximize exercise capacity in this population. Although the etiology of HF is complex, reduced nitric oxide (NO) bioavailability is an underlying characteristic that has been shown to moderate physiological processes related to exercise including vascular function, tissue perfusion, mitochondrial function and contractile efficiency. Dietary inorganic nitrate supplementation has been shown to increase NO bioavailability and increase exercise tolerance in several clinical populations, including peripheral arterial disease, pulmonary disease, and HF with preserved ejection fraction. PURPOSE: To determine the effect of dietary inorganic nitrate supplementation on exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: Sixteen patients with HFrEF (15 men, 63 ± 4 y, BMI: 31.8 ± 2.1 kg·m-2) participated in a randomized, double-blind, crossover design study. Participants consumed either a nitrate rich beetroot juice (16mmol nitrate/day), or a nitrate-depleted placebo for five days prior to the first testing visit, with continued dosing until completion of a cardiopulmonary exercise test (CPX). Between treatment differences were analysed via paired- t-test analysis. Statistical significance was set a-priori at p< 0.05. RESULTS: Both plasma nitrate and nitrite increased following nitrate supplementation (933%, p<0.001 and 94%, p< 0.05, respectively). No differences were observed for VO2peak (nitrate 18.5 ± 5.7ml·kg-1·min-1, placebo: 19.3 ± 1.4ml·kg-1·min-1; p=0.13) or time to exhaustion (nitrate: 1165 ± 92sec, placebo: 1207 ± 96sec, p=0.16) following supplementation. Similarly, there were no differences between the two treatments in blood pressures or deoxygenated or oxygenated haemoglobin at rest or at any stage of the exercise testing. CONCLUSION: Inorganic nitrate supplementation did not improve exercise tolerance, blood pressures or tissue perfusion in patients with HFrEF. Supported by Australian Heart Foundation Vanguard Award 101389 to Jason D. Allen

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

IntroductionArterial 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...

Effects of Dietary Inorganic Nitrate Supplementation on Exercise Performance in Patients With Heart Failure: Protocol for a Randomized, Placebo-Controlled, Cross-Over Trial.

BackgroundChronic heart failure is characterized by an inability of the heart to pump enough blood to meet the demands of the body, resulting in the hallmark symptom of exercise intolerance. Chronic underperfusion of the peripheral tissues and impaired nitric oxide bioavailability have been implicated as contributors to the decrease in exercise capacity in these patients. nitric oxide bioavailability has been identified as an important mediator of exercise tolerance in healthy individuals, but there are limited studies examining the effects in patients with chronic heart failure.ObjectiveThe proposed trial is designed to determine the effects of chronic inorganic nitrate supplementation on exercise tolerance in both patients with heart failure preserved ejection fraction (HFpEF) and heart failure reduced ejection fraction (HFrEF) and to determine whether there are any differential responses between the 2 cohorts. A secondary objective is to provide mechanistic insights into the 2 heart failure groups’ exercise responses to the nitrate supplementation.MethodsPatients with chronic heart failure (15=HFpEF and 15=HFrEF) aged 40 to 85 years will be recruited. Following an initial screen cardiopulmonary exercise test, participants will be randomly allocated in a double-blind fashion to consume either a nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo (for 5 days). Participants will continue daily dosing until the completion of the 4 testing visits (maximal cardiopulmonary exercise test, submaximal exercise test with echocardiography, vascular function assessment, and vastus lateralis muscle biopsy). There will then be a 2-week washout period after which the participants will cross over to the other treatment and complete the same 4 testing visits.ResultsThis study is funded by National Heart Foundation of Australia and Victoria University. Enrolment has commenced and the data collection is expected to be completed in mid 2018. The initial results are expected to be submitted for publication by the end of 2018.ConclusionsIf inorganic nitrate supplementation can improve exercise tolerance in patients with chronic heart failure, it has the potential to aid in further refining the treatment of patients in this population.Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12615000906550; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368912 (Archived by WebCite at http://www.webcitation.org/6xymLMiFK)

Dietary nitrate reduces skeletal muscle oxygenation response to physical exercise: a quantitative muscle functional MRI study.

Dietary inorganic nitrate supplementation (probably via conversion to nitrite) increases skeletal muscle metabolic efficiency. In addition, it may also cause hypoxia‐dependent vasodilation and this has the potential to augment oxygen delivery to exercising skeletal muscle. However, direct evidence for the latter with spatial localization to exercising muscle groups does not exist. We employed quantitative functional MRI (fMRI) to characterize skeletal muscle oxygen utilization and replenishment by assessment of tissue oxygenation maximal change and recovery change, respectively. Eleven healthy subjects were enrolled, of whom 9 (age 33.3 ± 4.4 years, five males) completed the study. Each subject took part in three MRI visits, with dietary nitrate (7cl concentrated beetroot juice) consumed before the third visit. During each visit fMRIs were conducted concurrently with plantar flexion exercise at workloads of 15% and 25% maximum voluntary contraction (MVC). No significant changes were found between visits 1 and 2 in the fMRI measures. A decrease in maximal change was found at 15% MVC in soleus between visits 2 and 3 (5.12 ± 2.36 to 2.55 ± 1.42, P = 0.004) and between visits 1 and 3 (4.43 ± 2.12 to 2.55 ± 1.42, P = 0.043), but not at 25% MVC or within gastrocnemius. There was no difference in recovery change between visits. We found that dietary nitrate supplementation reduces tissue oxygenation alterations during physical exercise in skeletal muscle. This effect is more prominent in muscles with predominantly type 1 fibers and at lower workloads. This indicates that in healthy subjects dietary nitrate predominantly affects skeletal muscle energy efficiency with no change in oxygen delivery.

Influence of dietary nitrate supplementation on physiological and cognitive responses to incremental cycle exercise

Dietary inorganic nitrate supplementation causes physiological effects which may enhance exercise tolerance. However it is not known whether nitrate might alter cognitive function during exercise. In a double-blind, cross-over study, sixteen subjects ingested either nitrate-rich beetroot juice or a placebo and completed a continuous cycle exercise test involving 20min stages at 50% and 70% V˙O2peak and a final stage at 90% V˙O2peak until volitional exhaustion. Cognitive tasks were completed before, during and after exercise. In the dietary nitrate condition: plasma [nitrite] increased (p<0.01), systolic blood pressure decreased (p<0.05) and there was a trend for a reduced oxygen uptake at 50% V˙O2peak. Tissue oxygenation improved across exercise intensities and exercise tolerance was greater at 90% V˙O2peak (p<0.05). Rating of perceived exertion, energy levels and cognitive performance were similar between conditions with mental fatigue being evident from 70% V˙O2peak onwards (p<0.05). Dietary nitrate supplementation enhanced short-term endurance exercise performance with concomitant mental fatigue but did not improve cognitive performance post-fatigue.

Letter by Ahluwalia and Hobbs Regarding Article, “Nitrate-Nitrite-Nitric Oxide Pathway in Pulmonary Arterial Hypertension Therapeutics”

We read with interest the editorial by Sparacino-Watkins et al1 that accompanied our recent article2 demonstrating the beneficial effects of dietary inorganic nitrate supplementation in experimental models of pulmonary hypertension (PH). The editorial provides a timely overview of the scientific rationale for exploiting the recently characterized nitrate-nitrite-nitric oxide pathway in PH and other cardiovascular disorders. We agree with the authors that a therapeutic approach based on this pathway represents an exciting new avenue for a debilitating disease with very poor outcome. However, we wish to clarify an apparent misunderstanding regarding the dose required for efficacy in humans. Sparacino-Watkins et al suggest that the concentrations …

Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension

Reduced bioavailability of endogenous nitric oxide (NO) is a central pathophysiological event in hypertension and other cardiovascular diseases. Recently, it was demonstrated that inorganic nitrate from dietary sources is converted in vivo to form nitrite, NO, and other bioactive nitrogen oxides. We tested the hypothesis that dietary inorganic nitrate supplementation may have therapeutic effects in a model of renal and cardiovascular disease. Sprague-Dawley rats subjected to unilateral nephrectomy and chronic high-salt diet from 3 weeks of age developed hypertension, cardiac hypertrophy and fibrosis, proteinuria, and histological as well as biochemical signs of renal damage and oxidative stress. Simultaneous nitrate treatment (0.1 or 1 mmol nitrate kg⁻¹ day⁻¹), with the lower dose resembling the nitrate content of a diet rich in vegetables, attenuated hypertension dose-dependently with no signs of tolerance. Nitrate treatment almost completely prevented proteinuria and histological signs of renal injury, and the cardiac hypertrophy and fibrosis were attenuated. Mechanistically, dietary nitrate restored the tissue levels of bioactive nitrogen oxides and reduced the levels of oxidative stress markers in plasma (malondialdehyde) and urine (Class VI F2-isoprostanes and 8-hydroxy-2-deoxyguanosine). In addition, the increased circulating and urinary levels of dimethylarginines (ADMA and SDMA) in the hypertensive rats were normalized by nitrate supplementation. Dietary inorganic nitrate is strongly protective in this model of renal and cardiovascular disease. Future studies will reveal if nitrate contributes to the well-known cardioprotective effects of a diet rich in vegetables.