Ϫ ] increased in a dose-dependent manner, with the peak changes occurring at approximately 2-3 h. Compared with PL, 70 ml BR did not alter the physiological responses to exercise. However, 140 and 280 ml BR reduced the steady-state oxygen (O2) uptake during moderateintensity exercise by 1.7% (P ϭ 0.06) and 3.0% (P Ͻ 0.05), whereas time-to-task failure was extended by 14% and 12% (both P Ͻ 0.05), respectively, compared with PL. The results indicate that whereas plasma [NO 2 Ϫ ] and the O2 cost of moderate-intensity exercise are altered dose dependently with NO 3 Ϫ -rich BR, there is no additional improvement in exercise tolerance after ingesting BR containing 16.8 compared with 8.4 mmol NO 3 Ϫ . These findings have important implications for the use of BR to enhance cardiovascular health and exercise performance in young adults.nitrate; nitrite; nitric oxide; blood pressure; exercise economy; O2 uptake; exercise tolerance NITRIC OXIDE (NO) IS A GASEOUS signaling molecule that modulates human physiological function via its role in, for example, the regulation of blood flow, neurotransmission, immune function, glucose and calcium homeostasis, muscle contractility, and mitochondrial respiration (9, 36). 1 NO is generated through the oxidation of the amino acid L-arginine Ϫ ] peaked 3 h postingestion, remained close to peak values until 5 h postingestion, and returned to baseline after 24 h (39). The systolic and diastolic BP and the mean arterial pressure (MAP) were reduced significantly, by ϳ10, ϳ8, and ϳ8 mmHg, respectively, at 2.5-3 h after BR intake. The same research group later reported a dose-dependent increase in plasma [ ] was accompanied by significant reductions in both systolic BP (of ϳ2, ϳ6, and ϳ9 mmHg, respectively) and diastolic BP (of ϳ4, ϳ4, and ϳ6 mmHg, respectively). However, since BR contains polyphenols and antioxidants, which can facilitate the synthesis of NO from NO 2 Ϫ in the stomach (30), it is unclear whether BP is similarly impacted when different doses of BR are ingested compared with equivalent doses of NO 3 Ϫ salts. Given the growing interest in dietary NO 3 Ϫ supplementation in the form of BR amongst athletes and the general population, it is important to determine the pharmacokinetic-pharmacodynamic relationship between different volumes of BR consumption and changes in plasma [NO 2 Ϫ ] and BP to establish an optimal dose for beneficial effects.Recent investigations suggest that dietary NO 3 Ϫ supplementation has the potential to influence human physiology beyond 1 This article is the topic of an Invited Editorial by L. Burke (5a).

AM. Effects of shortterm dietary nitrate supplementation on blood pressure, O 2 uptake kinetics, and muscle and cognitive function in older adults. Am J Physiol Regul Integr Comp Physiol 304: R73-R83, 2013. First published November 21, 2012 doi:10.1152/ajpregu.00406.2012 Ϫ ) supplementation has been shown to reduce resting blood pressure and alter the physiological response to exercise in young adults. We investigated whether these effects might also be evident in older adults. In a double-blind, randomized, crossover study, 12 healthy, older (60 -70 yr) adults supplemented their diet for 3 days with either nitrate-rich concentrated beetroot juice (BR; 2 ϫ 70 ml/day, ϳ9.6 mmol/day NO 3 Ϫ ) or a nitrate-depleted beetroot juice placebo (PL; 2 ϫ 70 ml/day, ϳ0.01 mmol/day NO 3 Ϫ ). Before and after the intervention periods, resting blood pressure and plasma [nitrite] were measured, and subjects completed a battery of physiological and cognitive tests. Nitrate supplementation significantly increased plasma [nitrite] and reduced resting systolic (BR: 115 Ϯ 9 vs. PL: 120 Ϯ 6 mmHg; P Ͻ 0.05) and diastolic (BR: 70 Ϯ 5 vs. PL: 73 Ϯ 5 mmHg; P Ͻ 0.05) blood pressure. Nitrate supplementation resulted in a speeding of the V O2 mean response time (BR: 25 Ϯ 7 vs. PL: 28 Ϯ 7 s; P Ͻ 0.05) in the transition from standing rest to treadmill walking, although in contrast to our hypothesis, the O 2 cost of exercise remained unchanged. Functional capacity (6-min walk test), the muscle metabolic response to low-intensity exercise, brain metabolite concentrations, and cognitive function were also not altered. Dietary nitrate supplementation reduced resting blood pressure and improved V O2 kinetics during treadmill walking in healthy older adults but did not improve walking or cognitive performance. These results may have implications for the enhancement of cardiovascular health in older age.nitrate; nitrite; nitric oxide; blood pressure; exercise performance; cognitive performance; O2 uptake kinetics THE BENEFICIAL EFFECTS OF a vegetable-rich diet upon cardiovascular health (27) and longevity (79) have been well described. These positive effects have been attributed, in part, to inorganic nitrate (NO 3 Ϫ ), which is particularly rich in leafy greens and beetroot. The NO 3 Ϫ anion itself is inert, and any biological effects are likely to be the result of its conversion to the nitrite anion (NO 2 Ϫ ) in the mouth via facultative anaerobic bacteria on the surface of the tongue (25). When swallowed, NO 2 Ϫ can be further converted into nitric oxide (NO) (9), but it is clear that some NO 2 Ϫ enters the circulation. The subsequent reduction of NO 2 Ϫ to NO and other reactive nitrogen intermediates is facilitated in hypoxia (11). The production of NO via nitric oxide synthase (NOS) is impaired in hypoxia and, thus, it has been proposed that the NO 3 Ϫ -NO 2 Ϫ -NO pathway represents a complementary system for NO generation across a wide range of redox states (53). NO is an essential physiological signaling molecule with numerous functions in...

The gas exchange threshold and the critical power demarcate discrete exercise intensity domains. For the first time, we show that the limit of tolerance during whole body exercise within these domains is characterized by distinct metabolic and neuromuscular responses. Fatigue development during exercise greater than critical power is associated with the attainment of consistent “limiting” values of muscle metabolites, whereas substrate availability and limitations to muscle activation may constrain performance at lower intensities.

Recent studies have suggested that dietary inorganic nitrate (NO₃(-)) supplementation may improve muscle efficiency and endurance exercise tolerance but possible effects during team sport-specific intense intermittent exercise have not been examined. We hypothesized that NO₃(-) supplementation would enhance high-intensity intermittent exercise performance. Fourteen male recreational team-sport players were assigned in a double-blind, randomized, crossover design to consume 490 mL of concentrated, nitrate-rich beetroot juice (BR) and nitrate-depleted placebo juice (PL) over ~30 h preceding the completion of a Yo-Yo intermittent recovery level 1 test (Yo-Yo IR1). Resting plasma nitrite concentration ([NO₂(-)]) was ~400% greater in BR compared to PL. Plasma [NO₂(-)] declined by 20% in PL (P < 0.05) and by 54 % in BR (P < 0.05) from pre-exercise to end-exercise. Performance in the Yo-Yo IR1 was 4.2% greater (P < 0.05) with BR (1,704 ± 304 m) compared to PL (1,636 ± 288 m). Blood [lactate] was not different between BR and PL, but the mean blood [glucose] was lower (3.8 ± 0.8 vs. 4.2 ± 1.1 mM, P < 0.05) and the rise in plasma [K(+)] tended to be reduced in BR compared to PL (P = 0.08). These findings suggest that NO₃(-) supplementation may promote NO production via the nitrate-nitrite-NO pathway and enhance Yo-Yo IR1 test performance, perhaps by facilitating greater muscle glucose uptake or by better maintaining muscle excitability. Dietary NO₃(-) supplementation improves performance during intense intermittent exercise and may be a useful ergogenic aid for team sports players.

Ϫ ]), oxygen uptake (V O2) kinetics, and exercise tolerance in normoxia (N) and hypoxia (H). In a doubleblind, crossover study, 12 healthy subjects completed cycle exercise tests, twice in N (20.9% O2) and twice in H (13.1% O2). Subjects ingested either 140 ml/day of NO 3 Ϫ -rich beetroot juice (8.4 mmol NO3; BR) or NO 3 Ϫ -depleted beetroot juice (PL) for 3 days prior to moderate-intensity and severe-intensity exercise tests in H and N. Preexercise plasma [NO 2 Ϫ ] was significantly elevated in H-BR and N-BR compared with H-PL (P Ͻ 0.01) and N-PL (P Ͻ 0.01). The rate of decline in plasma [NO 2 Ϫ ] was greater during severe-intensity exercise in H-BR [Ϫ30 Ϯ 22 nM/min, 95% confidence interval (CI); Ϫ44, Ϫ16] compared with H-PL (Ϫ7 Ϯ 10 nM/min, 95% CI; Ϫ13, Ϫ1; P Ͻ 0.01) and in N-BR (Ϫ26 Ϯ 19 nM/min, 95% CI; Ϫ38, Ϫ14) compared with N-PL (Ϫ1 Ϯ 6 nM/min, 95% CI; Ϫ5, 2; P Ͻ 0.01). During moderate-intensity exercise, steady-state pulmonary V O2 was lower in H-BR (1.91 Ϯ 0.28 l/min, 95% CI; 1.77, 2.13) compared with H-PL (2.05 Ϯ 0.25 l/min, 95% CI; 1.93, 2.26; P ϭ 0.02), and V O2 kinetics was faster in H-BR (: 24 Ϯ 13 s, 95% CI; 15, 32) compared with H-PL (31 Ϯ 11 s, 95% CI; 23, 38; P ϭ 0.04). NO 3 Ϫ supplementation had no significant effect on V O2 kinetics during severe-intensity exercise in hypoxia, or during moderate-intensity or severe-intensity exercise in normoxia. Tolerance to severe-intensity exercise was improved by NO 3 Ϫ in hypoxia (H-PL: 197 Ϯ 28; 95% CI; 173, 220 vs. H-BR: 214 Ϯ 43 s, 95% CI; 177, 249; P ϭ 0.04) but not normoxia. The metabolism of NO 2 Ϫ during exercise is altered by NO 3 Ϫ supplementation, exercise, and to a lesser extent, hypoxia. In hypoxia, NO 3 Ϫ supplementation enhances V O 2 kinetics during moderate-intensity exercise and improves severe-intensity exercise tolerance. These findings may have important implications for individuals exercising at altitude. hypoxia; beetroot juice; nitric oxide; efficiency; performance NITRIC OXIDE (NO) IS A UBIQUITOUS, water-soluble, free radical gas that plays a crucial role in many biological processes. Effective NO production is important in normal physiological functioning, from the regulation of blood flow, muscle contractility, and mitochondrial respiration to host defense, neurotransmission, and glucose and calcium homeostasis (11,17,60). NO production via the oxidation of L-arginine, in a process catalyzed by nitric oxide synthase (NOS), may be blunted in conditions of reduced O 2 availability (52). It is now widely accepted that NO can also be generated via an alternative pathway, whereby inorganic nitrate (NO 3 Ϫ ) is reduced to nitrite (NO 2 Ϫ ) and further to NO. This NOS-and O 2 -independent NO 3 Ϫ -NO 2 Ϫ -NO pathway represents a complementary system for NO synthesis spanning a broad range of redox states (49). In addition to being produced endogenously, the body's NO 3 Ϫ stores can be increased via the diet, with green leafy vegetables and beetroot being particularly rich in NO 3 Ϫ . Upon ingestion, inorganic NO 3 Ϫ is absorbed from the ...

These findings suggest that dietary NO3 (-) enhances repeated sprint performance and may attenuate the decline in cognitive function (and specifically reaction time) that may occur during prolonged intermittent exercise.

Summary Purpose:  In this prospective study the early cognitive development of children born to women with epilepsy (n = 198) was assessed and compared to a group of children representative of the general population (n = 230). Methods:  The children were assessed when younger than the age of 2 years using the Griffiths Mental Development Scales, either in their local participating hospital or in their home. The assessments were completed by an assessor who was blinded to whether the child’s mother had epilepsy and to antiepileptic drug type. Results:  Children exposed to sodium valproate had a statistically significant increased risk of delayed early development in comparison to the control children. Linear regression analysis showed a statistically significant effect of sodium valproate exposure on the child’s overall developmental level that was not accounted for by confounding variables. Delayed early development is also noted for children within an ad hoc group of less commonly utilized antiepileptic drugs, although conclusions cannot be drawn due to the size of this group (n = 13). Children exposed to either carbamazepine or lamotrigine in utero did not differ significantly in their overall developmental ability. Differences noted in specific developmental areas for these two groups were not statistically significant after the control for confounders such as socioeconomic status and maternal IQ. Discussion:  Women with epilepsy should be informed of the risks posed to their potential offspring prior to pregnancy to allow for informed decisions regarding treatment. Children exposed in utero to antiepileptic drugs should be monitored throughout childhood to allow for early intervention when necessary.

Imbalances in the oral microbial community have been associated with reduced cardiovascular and metabolic health. A possible mechanism linking the oral microbiota to health is the nitrate (NO3-)-nitrite (NO2-)-nitric oxide (NO) pathway, which relies on oral bacteria to reduce NO3- to NO2-. NO (generated from both NO2- and L-arginine) regulates vascular endothelial function and therefore blood pressure (BP). By sequencing bacterial 16S rRNA genes we examined the relationships between the oral microbiome and physiological indices of NO bioavailability and possible changes in these variables following 10 days of NO3- (12 mmol/d) and placebo supplementation in young (18–22 yrs) and old (70–79 yrs) normotensive humans (n = 18). NO3- supplementation altered the salivary microbiome compared to placebo by increasing the relative abundance of Proteobacteria (+225%) and decreasing the relative abundance of Bacteroidetes (−46%; P < 0.05). After NO3-supplementation the relative abundances of Rothia (+127%) and Neisseria (+351%) were greater, and Prevotella (−60%) and Veillonella (−65%) were lower than in the placebo condition (all P < 0.05). NO3- supplementation increased plasma concentration of NO2- and reduced systemic blood pressure in old (70–79 yrs), but not young (18–22 yrs), participants. High abundances of Rothia and Neisseria and low abundances of Prevotella and Veillonella were correlated with greater increases in plasma [NO2-] in response to NO3- supplementation. The current findings indicate that the oral microbiome is malleable to change with increased dietary intake of inorganic NO3-, and that diet-induced changes in the oral microbial community are related to indices of NO homeostasis and vascular health in vivo.