Effects of dietary nitrate supplementation on peak power output: Influence of supplementation strategy and population.

Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability and its potential ergogenic effects across various population groups. This review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular peak power output in healthy adults, athletes, older adults and some clinical populations. Effect sizes were calculated for peak power output and absolute and/or relative nitrate doses were considered where applicable. There was no relationship between the effect sizes of peak power output change following nitrate supplementation and when nitrate dosage when considered in absolute or relative terms. Areas for further research are also recommended including a focus on nitrate dosing regimens that optimize nitric oxide bioavailability for enhancing peak power at times of increased muscular work in a variety of healthy and disease populations.

Effects of dietary nitrate supplementation on muscular power output: Influence of supplementation strategy and population.

Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability its potential ergogenic effects across various population groups. This narrative review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular power output in healthy adults, athletes, older adults and some clinical populations. Areas for further research are also recommended including a focus individualized nitrate dosing regimens to optimize nitric oxide bioavailability and to promote muscular power enhancements in different populations.

Skeletal muscle as a reservoir for nitrate and nitrite: The role of xanthine oxidase reductase (XOR).

Recent studies have identified skeletal muscle as a tissue compartment where nitrate and nitrite can be stored and utilized to potentially maintain nitric oxide (NO) homeostasis. Given its capacity to reduce nitrate and nitrite, the molybdopterin-containing enzyme, xanthine oxidoreductase (XOR) has been suggested as a key enzyme within skeletal muscle which catalytically reduces these N-oxides; however, there remains limited insight into the role of XOR in this process as well as how different conditions (e.g. health vs disease and rest vs exercise) may determine when and where, within skeletal muscle, XOR could serve as a significant source of NO. A key factor that determines the extent by which XOR may or may not contribute to NO generation in a biologically relevant manner is the biochemical landscape (e.g. oxygen tension, pH, isoform of XOR (XDH vs. XO) and substrate levels of the microenvironment in normal versus stressed skeletal muscle. As such, a critical focus of this review is the evaluation of the biochemical and physiologic data supporting the role of XOR within skeletal muscle for supplying nitrite and/or NO from endogenous and exogenous sources during pathophysiologic conditions and/or exercise stress.

Dietary nitrate supplementation in cardiovascular health: an ergogenic aid or exercise therapeutic?

Oral consumption of inorganic nitrate, which is abundant in green leafy vegetables and roots, has been shown to increase circulating plasma nitrite concentration, which can be converted to nitric oxide in low oxygen conditions. The associated beneficial physiological effects include a reduction in blood pressure, modification of platelet aggregation, and increases in limb blood flow. There have been numerous studies of nitrate supplementation in healthy recreational and competitive athletes; however, the ergogenic benefits are currently unclear due to a variety of factors including small sample sizes, different dosing regimens, variable nitrate conversion rates, the heterogeneity of participants' initial fitness levels, and the types of exercise tests used. In clinical populations, the study results seem more promising, particularly in patients with cardiovascular diseases who typically present with disruptions in the ability to transport oxygen from the atmosphere to working tissues and reduced exercise tolerance. Many of these disease-related, physiological maladaptations, including endothelial dysfunction, increased reactive oxygen species, reduced tissue perfusion, and muscle mitochondrial dysfunction, have been previously identified as potential targets for nitric oxide restorative effects. This review is the first of its kind to outline the current evidence for inorganic nitrate supplementation as a therapeutic intervention to restore exercise tolerance and improve quality of life in patients with cardiovascular diseases. We summarize the factors that appear to limit or maximize its effectiveness and present a case for why it may be more effective in patients with cardiovascular disease than as ergogenic aid in healthy populations.

Dose-dependent effects of dietary nitrate on the oxygen cost of moderate-intensity exercise: Acute vs. chronic supplementation.

PURPOSE: To investigate whether chronic supplementation with a low or moderate dose of dietary nitrate (NO3(-)) reduces submaximal exercise oxygen uptake (V˙O2) and to assess whether or not this is dependent on acute NO3(-) administration prior to exercise. METHODS: Following baseline tests, 34 healthy subjects were allocated to receive 3 mmol NO3(-), 6 mmol NO3(-) or placebo. Two hours following the first ingestion, and after 7, 28 and 30 days of supplementation, subjects completed two moderate-intensity step exercise tests. On days 28 and 30, subjects in the NO3(-) groups completed the test 2 h post consumption of a NO3(-) dose (CHR + ACU) and a placebo dose (CHR). RESULTS: Plasma nitrite concentration ([NO2(-)]) was elevated in a dose-dependent manner at 2 h, 7 days and 28-30 days on the CHR + ACU visit. Compared to pre-treatment baseline, 6 mmol NO3(-) reduced the steady-state V˙O2 during moderate-intensity exercise by 3% at 2 h (P = 0.06), 7 days and at 28-30 days (both P < 0.05) on the CHR + ACU visit, but was unaffected by 3 mmol NO3(-) at all measurement points. On the CHR visit in the 6 mmol group, plasma [NO2(-)] had returned to pre-treatment baseline, but the steady-state V˙O2 remained reduced. CONCLUSION: Up to ∼4 weeks supplementation with 6 but not 3 mmol NO3(-) can reduce submaximal exercise V˙O2. A comparable reduction in submaximal exercise V˙O2 following chronic supplementation with 6 mmol NO3(-) can be achieved both with and without the acute ingestion of NO3(-) and associated elevation of plasma [NO2(-)].

Limited Effects of Inorganic Nitrate Supplementation on Exercise Training Responses: A Systematic Review and Meta-analysis.

BACKGROUND: Inorganic nitrate (NO3-) supplementation is purported to benefit short-term exercise performance, but it is unclear whether NO3- improves longer-term exercise training responses (such as improvements in VO2peak or time to exhaustion (TTE)) versus exercise training alone. The purpose of this systematic review and meta-analysis was to determine the effects of NO3- supplementation combined with exercise training on VO2peak and TTE, and to identify potential factors that may impact outcomes. METHODS: Electronic databases (PubMed, Medscape, and Web of Science) were searched for articles published through June 2022 with article inclusion determined a priori as: (1) randomized placebo-controlled trials, (2) exercise training lasted at least three weeks, (3) treatment groups received identical exercise training, (4) treatment groups had matched VO2peak at baseline. Study quality was assessed using the Cochrane Risk-of-Bias 2 tool. Standardized mean difference (SMD) with 95% confidence intervals (CI) were calculated using restricted maximum likelihood estimation between pre- and post-training differences in outcomes. Moderator subgroup and meta-regression analyses were completed to determine whether the overall effect was influenced by age, sex, NO3- dosage, baseline VO2peak, health status, NO3- administration route, and training conditions. RESULTS: Nine studies consisting of eleven trials were included: n = 228 (72 females); age = 37.7 ± 21 years; VO2peak: 40 ± 18 ml/kg/min. NO3- supplementation did not enhance exercise training with respect to VO2peak (SMD: 0.18; 95% CI: -0.09, 0.44; p = 0.19) or TTE (SMD: 0.08; 95% CI: - 0.21, 0.37; p = 0.58). No significant moderators were revealed on either outcome. Subset analysis on healthy participants who consumed beetroot juice (BRJ) revealed stronger trends for NO3- improving VO2peak (p = 0.08) compared with TTE (p = 0.19), with no significant moderators. Sunset funnel plot revealed low statistical power in all trials. CONCLUSIONS: NO3- supplementation combined with exercise training may not enhance exercise outcomes such as VO2peak or TTE. A trend for greater improvement in VO2peak in healthy participants supplemented with BRJ may exist (p = 0.08). Overall, future studies in this area need increased sample sizes, more unified methodologies, longer training interventions, and examination of sex as a biological variable to strengthen conclusions.

The effects of inorganic nitrate supplementation on exercise economy and endurance capacity across the menstrual cycle.

Oral inorganic nitrate (NO3-) supplementation has been shown to increase bioavailable NO and provide potential ergogenic benefits in males; however, data in females is scarce. Estrogen is known to increase endogenous NO bioavailability and to fluctuate throughout the menstrual cycle (MC), being lowest in the early follicular (EF) phase and highest during the late follicular (LF) phase. This study examined the effects of oral NO3- supplementation on exercise economy, endurance capacity, and vascular health in young females across the MC. Ten normally menstruating females' MCs were tested in a double-blinded, randomized design during both the EF and LF phases of the MC. Participants consumed ∼13 mmol NO3-, in the form of 140 mL beetroot juice (BRJ) or an identical NO3--depleted placebo (PL) for ∼3 days before lab visits and 2 h before testing on lab visits. Plasma nitrate, nitrite, and estradiol were assessed, as was blood pressure and pulse wave velocity. Moderate-intensity exercise economy and severe intensity time to exhaustion (TTE) were tested on a cycle ergometer. As expected, plasma estradiol was elevated in the LF phase, and plasma nitrite and nitrate were elevated in the BRJ condition. Exercise economy was unaltered by BRJ or the MC, however TTE was significantly worsened by 48 s (∼10%) after BRJ supplementation (P = 0.04), but was not different across the MC with no interaction effects. In conclusion, NO3- supplementation did not affect exercise economy or vascular health and worsened aerobic endurance capacity (TTE), suggesting healthy females should proceed with caution when considering supplementation with BRJ.NEW & NOTEWORTHY Although inorganic nitrate (NO3-) supplementation has increased in popularity as a means of improving exercise performance, data in females at different phases of the menstrual cycle are lacking despite known interactions of estrogen with NO. This study revealed neither NO3- supplementation nor the menstrual cycle influenced exercise economy or vascular health in healthy young naturally menstruating females, while NO3- supplementation significantly worsened endurance capacity (10%) independent of the menstrual cycle phase.

Sex differences in the effects of inorganic nitrate supplementation on exercise economy and endurance capacity in healthy young adults.

Dietary nitrate (NO3-) is a widely used supplement purported to provide beneficial effects during exercise. Most studies to date include predominantly males. Therefore, the present study aimed to investigate if there is a sex-dependent effect of NO3- supplementation on exercise outcomes. We hypothesized that both sexes would exhibit improvements in exercise economy and exercise capacity following NO3- supplementation, but males would benefit to a greater extent. In a double-blind, randomized, crossover study, twelve females (24 ± 4 yr) and fourteen males (23 ± 4 yr) completed two 4-min moderate-intensity (MOD) exercise bouts followed by a time-to-exhaustion (TTE) task after following 3 days of NO3- supplementation (beetroot juice or BRJ) or NO3--depleted placebo (PL). Females were tested during the early follicular phase of the menstrual cycle. During MOD exercise, BRJ reduced the steady-state V̇o2 by ∼5% in males (M: Δ -87 ± 115 mL·min-1; P < 0.05) but not in females (F: Δ 6 ± 195 mL·min-1). Similarly, BRJ extended TTE by ∼15% in males (P < 0.05) but not in females. Dietary NO3- supplementation improved exercise economy during moderate-intensity exercise and exercise capacity during severe-intensity TTE in males but not in females. These differences could be related to estrogen levels, antioxidant capacity, nitrate-reducing bacteria, or a variety of known physiologic differences such as skeletal muscle calcium handling, and/or fiber type. Overall, our data suggests the ergogenic benefits of oral NO3- supplementation found in studies predominantly on male subjects may not be applicable to females.NEW & NOTEWORTHY While inorganic nitrate (NO3-) supplementation has increased in popularity as an ergogenic aid to improve exercise performance, the role of sex in NO3- supplementation on exercise outcomes is lacking despite known physiological differences during exercise between sex. This study revealed that males, but not females, improved exercise economy during submaximal exercise and exercise capacity during exercise within the severe-intensity domain following NO3- supplementation.

The acute effects of exercise intensity and inorganic nitrate supplementation on vascular health in females after menopause.

Menopause is associated with reduced nitric oxide bioavailability and vascular function. Although exercise is known to improve vascular function, this is blunted in estrogen-deficient females post-menopause (PM). Here, we examined the effects of acute exercise at differing intensities with and without inorganic nitrate (NO3-) supplementation on vascular function in females PM. Participants were tested in a double-blinded, block-randomized design, consuming ∼13 mmol NO3- in the form of beetroot juice (BRJ; n = 12) or placebo (PL; n = 12) for 2 days before experimental visits and 2 h before testing. Visits consisted of vascular health measures before (time point 0) and every 30 min after (time points 60, 90, 120, 150, and 180) calorically matched high-intensity exercise (HIE), moderate-intensity exercise (MIE), and a nonexercise control (CON). Blood was sampled at rest and 5-min postexercise for NO3-, NO2-, and ET-1. BRJ increased N-oxides and decreased ET-1 compared with PL, findings which were unchanged after experimental conditions (P < 0.05). BRJ improved peak Δflow-mediated dilation (FMD) compared with PL (P < 0.05), defined as the largest ΔFMD for each individual participant across all time points. FMD across time revealed an improvement (P = 0.05) in FMD between BRJ + HIE versus BRJ + CON, while BRJ + MIE had medium effects compared with BRJ + CON. In conclusion, NO3- supplementation combined with HIE improved FMD in postmenopausal females. NO3- supplementation combined with MIE may offer an alternative to those unwilling to perform HIE. Future studies should test whether long-term exercise training at high intensities with NO3- supplementation can enhance vascular health in females PM.NEW & NOTEWORTHY This study compared exercise-induced changes in flow-mediated dilation after acute moderate- and high-intensity exercise in females postmenopause supplementing either inorganic nitrate (beetroot juice) or placebo. BRJ improved peak ΔFMD postexercise, and BRJ + HIE increased FMD measured as FMD over time. Neither PL + MIE nor PL + HIE improved FMD. These findings suggest that inorganic nitrate supplementation combined with high-intensity exercise may benefit vascular health in females PM.

Effect of inorganic nitrate on exercise capacity, mitochondria respiration, and vascular function in heart failure with reduced ejection fraction.

Chronic underperfusion of the skeletal muscle tissues is a contributor to a decrease in exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF). This underperfusion is due, at least in part, to impaired nitric oxide (NO) bioavailability. Oral inorganic nitrate supplementation increases NO bioavailability and may be used to improve exercise capacity, vascular function, and mitochondrial respiration. Sixteen patients with HFrEF (fifteen men, 63 ± 4 yr, body mass index: 31.8 ± 2.1 kg/m2) participated in a randomized, double-blind, crossover design study. Following consumption of either nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo for 5 days, participants completed separate visits for assessment of exercise capacity, endothelial function, and muscle mitochondrial respiration. Participants then had a 2-wk washout before completion of the same protocol with the other intervention. Statistical significance was set a priori at P < 0.05, and between-treatment differences were analyzed via paired t test analysis. Following nitrate supplementation, both plasma nitrate and nitrite increased (933%, P < 0.001 and 94%, P < 0.05, respectively). No differences were observed for peak oxygen consumption (nitrate: 18.5 ± 1.4 mL·kg-1·min-1, placebo: 19.3 ± 1.4 mL·kg-1·min-1; P = 0.13) or time to exhaustion (nitrate: 1,165 ± 92 s, placebo: 1,207 ± 96 s; P = 0.16) following supplementation. There were no differences between interventions for measures of vascular function, mitochondrial respiratory function, or protein expression (all P > 0.05). Inorganic nitrate supplementation did not improve exercise capacity and skeletal muscle mitochondrial respiratory function in HFrEF. Future studies should explore alternative interventions to improve peripheral muscle tissue function in HFrEF.NEW & NOTEWORTHY This is the largest study to date to examine the effects of inorganic nitrate supplementation in patients with heart failure with reduced ejection fraction (HFrEF) and the first to include measures of vascular function and mitochondrial respiration. Although daily supplementation increased plasma nitrite, our data indicate that supplementation with inorganic nitrate as a standalone treatment is ineffective at improving exercise capacity, vascular function, or mitochondrial respiration in patients with HFrEF.