Andrew M. Jones, PhD
KEY POINTS
- Nitric
oxide (NO) is vitally important in human physiology and it modulates
many of the processes that are essential to exercise performance.
- Recent
evidence indicates that NO availability can be enhanced by dietary supplementation with inorganic nitrate which is abundant in green leafy
vegetables and beetroot.
- Dietary nitrate supplementation with
5-7 mmol nitrate (~0.1 mmol/kg body mass) reduces resting blood
pressure, lowers the oxygen cost of sub-maximal exercise (i.e., enhances
muscle efficiency) and may enhance exercise performance.
- These
physiological effects can be observed as little as 3 h following
nitrate consumption and can be maintained for at least 15 days if
supplementation is continued.
- The optimal nitrate ‘loading’
regimen and the physical activities and populations in which nitrate
supplementation might be most effective remain to be determined.
- Due
to possible health risks associated with the consumption of nitrate
salts, it is recommended that athletes wishing to explore the ergogenic
potential of nitrate supplementation do so through increased consumption
of nitrate-rich vegetable products such as beetroot juice.
INTRODUCTION
Nitric
oxide (NO) is an important physiological signaling molecule that can
modulate skeletal muscle function through its role in the regulation of
blood flow, muscle contractility, glucose and calcium homeostasis, and
mitochondrial respiration and biogenesis. Until quite recently, it was
considered that NO was generated solely through the oxidation of the
amino acid L-arginine in a reaction catalysed by nitric oxide synthase
(NOS), and that nitrite (NO
2-) and nitrate (NO
3-) were inert by-products of this process. However, it is now clear that these metabolites can be recycled back into bioactive
Figure 1: Relationship between nitric oxide (NO), nitrite (NO
2-) and nitrate (NO
3-). (NOS, nitric oxide synthase)
NO under certain physiological conditions. The reduction of NO
3- to NO
2- and subsequently of NO
2-
to NO may be important as a means to increase NO production when NO
synthesis by the NOS enzymes is impaired and in conditions of low O
2 availability, such as may occur in skeletal muscle during exercise.
It
is now known that tissue concentrations of nitrate and nitrite can be
increased by dietary means. Green leafy vegetables such as lettuce,
spinach, rocket, celery and beetroot are particularly rich in nitrate.
Therefore, dietary nitrate supplementation represents a practical method
to increase circulating plasma [NO
2-] and thus NO
bioavailability. This has been demonstrated after ingestion of nitrate
salts such as sodium nitrate (Larsen et al., 2007, 2010), as well as
following nitrate-rich beetroot juice ingestion (Bailey et al., 2009,
2010; Vanhatalo et al., 2010; Webb et al., 2008). It is also possible to
increase plasma [NO
2-] through increased consumption of
whole nitrate-rich vegetables but nitrate content can vary according to
soil conditions, time of year and storage. Given the importance of NO in
vascular and metabolic control, there are sound theoretical reasons why
augmenting NO bioavailability might be important in optimizing skeletal
muscle function during exercise. Indeed, recent evidence indicates that
elevating plasma [NO
2-] through dietary nitrate supplementation is associated with enhanced muscle efficiency, fatigue resistance and performance.
RESEARCH REVIEW
Nitrate and exercise. Larsen et al. (2007) reported that three days of sodium nitrate supplementation increased plasma [NO
2-] and reduced the O
2 cost of sub-maximal cycle exercise. These findings were surprising because it is well established that the O
2
Figure 1: Relationship between nitric oxide (NO), cost of exercising at
a given sub-maximal power output is highly predictable. For example,
during cycle ergometry, it is expected that pulmonary O
2 uptake (VO
2)
will increase by approximately 10 mL per minute for every additional
Watt of external power output (i.e., the functional ‘gain’ is ~10
mL/min/W). The results of the Larsen et al. (2007) study were of
considerable interest because they suggested that a shortterm dietary
intervention might improve exercise efficiency (i.e., reduce the energy
required to exercise at the same intensity) and have the potential to
enhance performance.
The findings of Larsen et al. (2007) were
corroborated in the study of Bailey et al. (2009) in which nitrate was
administered in the form of beetroot juice. Following three days of
beetroot juice supplementation (0.5 L/day), the plasma [NO
2-] was doubled, the steady-state VO
2 during moderate-intensity exercise was reduced (Figure 2) and the VO
2
‘slow component’ during severeintensity exercise was attenuated. These
results suggested that a short-term, natural dietary intervention
improved the efficiency of muscular work.
Figure 2: Reduction in O
2 uptake during 6 min of
moderate-intensity cycle exercise following dietary nitrate
supplementation (closed symbols) compared to placebo (open symbols).
The reduction in steady-state VO
2
after nitrate supplementation was of the order of 5% in the studies of
Larsen et al. (2007) and Bailey et al. (2009) in which supplementation
was continued for 3-6 days. A similar reduction in steady-state VO
2
during moderate-intensity cycle ergometry has been reported following
acute nitrate supplementation. Vanhatalo et al. (2010) reported a
significant reduction in steady-state VO
2 just 2.5 h
following beetroot juice ingestion, an effect that was maintained when
supplementation was continued for 15 days (Figure 3). Importantly,
habitual dietary nitrate intake was not restricted in this study, and
yet resting blood pressure and steady-state VO
2 were still significantly reduced. The reduction in VO
2
following nitrate administration is not unique to cycling exercise,
having also been observed during two-legged knee-extensor exercise
(Bailey et al., 2010) and treadmill walking and running (Lansley et al.,
2011a). Importantly, no reduction in VO
2 was observed
compared to a control condition when the subjects were supplemented with
a placebo beetroot juice that had been depleted of nitrate using an
ion-exchange resin (Lansley et al., 2011a). This confirmed that nitrate
is the key ‘active’ ingredient responsible for the physiological changes
observed following beetroot juice supplementation. It does not rule
out, however, a synergistic role for other components of beetroot juice
such as antioxidants, which may facilitate the reduction of nitrate to
nitrite and NO. Collectively, these results indicate that the reduced VO
2
following nitrate supplementation is reproducible and can be observed
across a range of different supplementation regimens and exercise
modalities.
Figure 3: Reduction in the ‘gain’ of O
2 uptake following
nitrate supplementation (closed symbols) compared to placebo (open
symbols) and non-supplemented baseline (BL; gray symbol). Note that the
gain is reduced from ~10 to ~9 mL/min/W following nitrate
supplementation acutely (after 2.5 h) and that this effect persists if
supplementation is continued for 15 days.
EXERCISE PERFORMANCE
Plasma [NO
2-]
has recently been identified as an important correlate of exercise
tolerance in healthy humans (Dreissigacker et al., 2010; Rassaf et al.,
2007). Given that NO
3- supplementation increases plasma [NO
2-],
this intervention may therefore have the potential to improve exercise
tolerance. This hypothesis was tested in the study of Bailey et al.
(2009). Plasma [NO
2-] was doubled and highintensity exercise tolerance was enhanced by 16% following NO
3-
-rich beetroot juice supplementation. Subsequent experiments have
reported improvements in exercise tolerance of 25% during two-legged
knee-extensor exercise (Bailey et al., 2010), and 15% during treadmill
running (Lansley et al., 2011a) following 6 days of beetroot juice
supplementation. Improved incremental exercise performance has also been
noted following 6 days of beetroot juice supplementation during
single-legged knee extension exercise (Lansley et al., 2011a) and after
15 days of beetroot juice supplementation during cycle exercise
(Vanhatalo et al., 2010).
It is well documented that exercise performance is compromised in a hypoxic environment relative to normoxia (21% O
2:
sea level). In this regard, it is noteworthy that Vanhatalo et al.
(2011) reported that nitrate supplementation with beetroot juice
restored muscle performance in hypoxia (14% inspired O
2;
equivalent to ~4000 meters or ~13,000 feet altitude) to that observed in
the normoxic control condition. Specifically, in hypoxia, nitrate
supplementation resulted in a 20% extension of the time-to-exhaustion
during high-intensity knee-extensor exercise. Vanhatalo et al. (2011)
also reported that nitrate supplementation improved muscle oxidative
function in hypoxia, suggesting that muscle oxygenation may have been
enhanced. Consistent with this interpretation, Kenjale et al. (2011)
reported that beetroot juice supplementation resulted in a 17- 18%
longer time to claudication pain and peak walking time during
incremental exercise in patients with peripheral arterial disease. The
authors attributed these effects to NO
2- -related improvement
in peripheral tissue oxygenation. Collectively, these results have
potential performance implications for athletes competing at altitude
and for improving functional capacity in clinical conditions where
tissue O
2 supply may be compromised.
As summarized
above, during high-intensity constant-work-rate exercise, the improved
exercise tolerance at a given power output following nitrate
supplementation has been reported to be in the range of 16-25% (Bailey
et al., 2009, 2010; Lansley et al., 2011a). However, the magnitude of
improvement in ‘actual’ exercise performance would be expected to be far
smaller; indeed, using the predictions of Hopkins et al. (1999), a ~20%
improvement in time-to-exhaustion would be expected to correspond to an
improvement in exercise performance (time taken to cover a set
distance) of ~1-2%. This hypothesis was tested in the study of Lansley
et al. (2011b) where competitive but sub-elite cyclists completed 4.0
and 16.1 km time trials on separate days, following acute beetroot juice
ingestion. Consistent with the experimental hypothesis, nitrate
administration improved 4.0 km and 16.1 km time trial performance by
~2.7 % compared to the placebo conditions (Lansley et al., 2011b). These
improvements in exercise performance were consequent to the maintenance
of a higher mean power output and an increase in the power output/VO
2
ratio. Therefore, trained subjects were able to produce a higher power
output for the same oxidative energy turnover (i.e., the inverse of a
lower VO
2 for the same power output; Bailey et al. 2009;
Larsen et al., 2007), resulting in an improved exercise performance
following nitrate supplementation. Improved cycle time trial performance
following nitrate supplementation has also been reported by Cermak et
al. (2012). These authors reported that six days of beetroot juice
supplementation (8 mmol/ day) significantly reduced VO
2 at two sub-maximal work rates and improved mean power output and 10 km time trial performance (by 1.2%) in trained cyclists.
Despite
these positive results with ‘sub-élite’ athletes, it remains unclear
whether nitrate supplementation might enhance performance in athletes of
the highest caliber. One study has reported that acute sodium nitrate
administration did not significantly alter sub-maximal VO
2 or
incremental exercise performance in endurance athletes (Bescós et al.,
2011). There may be several explanations for this apparent discrepancy.
The resting plasma [NO
3-] and [NO
2-] is higher in
athletes (Jungersten et al., 1997; Schena et al., 2002), which may
reduce the scope for nitrate supplementation to improve exercise
efficiency and performance in this population. Alternately, very highly
trained individuals may require a larger nitrate dose to elicit similar
changes in plasma [NO
2-] and exercise efficiency to those
observed in recreationally active participants. Wilkerson et al. (2012)
reported that acute nitrate supplementation did not enhance 50 km time
trial performance in a group of well-trained cyclists, but also found a
significant correlation (r = -0.83) between the increase in plasma [NO
2-]
and the improvement in time trial performance. In this regard, the
nitrate dosing regimen (i.e., amount and timing of ingestion) may be
critical. It should also be considered that highly trained subjects are
likely to have: 1) higher NOS activity such that the nitrate-nitrite-NO
pathway may be relatively less important for the generation of NO; and
2) greater mitochondrial and capillary density which might limit the
development of hypoxia and acidosis in skeletal muscle during exercise,
preserving NOS function and reducing the requirement for nitrite
reduction to NO. It should also be considered that it may be more
difficult to discern possible performance improvements in elite athletes
for methodological reasons. The likely performance effect might be ≤ 1%
which, while still potentially highly meaningful during competition,
may be difficult to measure reproducibly due to experimental noise and
day-to-day variability. Further research is needed to elucidate the
influence of NO
3- supplementation on exercise efficiency in athletes.
MECHANISMS
The reduced O
2
cost of exercise following nitrate supplementation is not associated
with an elevated blood [lactate] (Bailey et al., 2009; Larsen et al.,
2007), suggesting that there is no compensatory increase in anaerobic
energy production as might be expected if oxidative metabolism were
somehow inhibited. This indicates that nitrate supplementation results
in a ‘real’ improvement in muscle efficiency. Theoretically, a lower O
2
cost of exercise for the same power output could result from: 1) a
lower ATP cost of muscle contraction for the same force production
(i.e., improved muscle contractile efficiency); and/or 2) a lower O
2 consumption for the same rate of oxidative ATP resynthesis (i.e., improved mitochondrial efficiency).
Bailey
et al. (2010) investigated the first of these possibilities using
calibrated 31P-magnetic resonance spectroscopy (31P-MRS). This procedure
permitted the in vivo assessment of absolute muscle concentration
changes in phosphocreatine ([PCr]), inorganic phosphate ([Pi]), and
adenosine diphosphate ([ADP]), as well as pH. The ATP supply contributed
by PCr hydrolysis, anaerobic glycolysis and oxidative phosphorylation
during knee-extensor exercise was also calculated. The estimated ATP
turnover rates from PCr hydrolysis and oxidative phosphorylation were
lower following six days of beetroot juice supplementation, with there
being no change in the estimated ATP turnover rate from anaerobic
glycolysis, such that there was a significant reduction in the estimated
total ATP turnover rate during both low- and high-intensity exercise
(Bailey et al., 2010). It is known that the ATP turnover rate in
contracting muscle cells is determined principally by the activity of
the actomyosin ATPases and Ca2+-ATPases. NO has been shown to slow
myosin cycling kinetics (Evangelista et al., 2010) and to reduce
Ca2+-ATPase activity (Ishii et al., 1998). As such, elevated NO
production following nitrate supplementation may have reduced skeletal
muscle ATP turnover by reducing the activity of actomyosin ATPase and/or
Ca2+-ATPase. The intramuscular accumulation of ADP and Pi, and the
extent of PCr depletion, were blunted following nitrate supplementation
(Bailey et al., 2010). The smaller changes in [ADP], [Pi] and [PCr]
following NO
3- supplementation would be predicted to reduce the stimuli for increasing oxidative phosphorylation (Mahler, 1985).
The
accumulation of metabolites such as [ADP] and [Pi], and the rate of
depletion of the finite intramuscular [PCr] reserves, are important
contributors to muscle fatigue development (Allen et al., 2008). While
the intramuscular [ADP], [Pi] and [PCr] were similar at exhaustion in
the nitrate-supplemented and placebo conditions in the study of Bailey
et al. (2010) and also Vanhatalo et al. (2011), the time taken to
achieve these critical concentrations was delayed following nitrate
supplementation and this, in part, may explain the improved exercise
tolerance. It should be noted that while the improved muscle efficiency
and reduced metabolic perturbation may be responsible for the enhanced
exercise tolerance observed following nitrate supplementation, it is
possible that the intervention results in a simultaneous improvement in
muscle O
2 availability (Kenjale et al., 2011; Vanhatalo et
al., 2011). This, too, might contribute to a blunting of muscle PCr
depletion and improved exercise performance.
The second
possibility, that nitrate supplementation enhances mitochondrial
efficiency, has been investigated by Larsen et al. (2011). These authors
isolated mitochondria from the vastus lateralis muscle of healthy
humans supplemented with sodium nitrate. It was reported that nitrate
supplementation reduced proton leakage and uncoupled respiration, which
increased the mitochondrial P/O ratio (the amount of ATP produced/oxygen
used). Importantly, the increased P/O ratio following nitrate
supplementation was correlated with the reduction in whole body VO
2
during exercise (Larsen et al., 2011). It appears therefore that
nitrate supplementation may improve exercise efficiency by improving the
efficiency of both muscle contraction (reduced ATP cost of force
production) and mitochondrial oxidative phosphorylation (increased P/O
ratio).
PRACTICAL APPLICATIONS
- Dietary supplementation with 5-7 mmol nitrate (~0.1 mmol/kg body mass) results in a significant increase in plasma [NO2-] and associated physiological effects including a lower resting blood pressure, reduced pulmonary O2
uptake during submaximal exercise and, perhaps, enhanced exercise
tolerance or performance. This ‘dose’ of nitrate can readily be achieved
through the consumption of 0.5 L of beetroot juice or an equivalent
high-nitrate foodstuff.
- Following a 5-6 mmol ‘bolus’ of nitrate, plasma [NO2-]
typically peaks within 2-3 h and remains elevated for a further 6-8 h
before returning to baseline after about 24 h (Webb et al., 2008). It is
recommended that nitrate is consumed ~3 h prior to competition or
training. A daily dose of a high-nitrate supplement is required if
plasma [NO2-] is to remain elevated.
- Most of the
published studies to date have involved recreational or
moderately-trained subjects and it is not known if nitrate
supplementation substantially elevates plasma [NO2-] or is ergogenic in elite athletes.
- While
the ingestion of 5-6 mmol of nitrate appears to be effective, studies
are ongoing to determine the ‘dose-response’ relationship between
nitrate supplementation and changes in exercise efficiency and
performance. This will provide new information on the ‘optimal’ loading
regimen for performance enhancement.
- While nitrate
supplementation appears to be ergogenic in continuous maximal activity
of 5-25 min duration, possible effects on shorter-term high-intensity
exercise, intermittent exercise, and longer-term endurance exercise
performance have not been established.
- It is presently unclear
if sustained dietary nitrate supplementation might impact upon
adaptations to training: on the one hand, increased NO bioavailability
might simulate mitochondrial and capillary biogenesis; on the other
hand, nitrate has antioxidant properties that might potentially blunt
cellular adaptations.
- Dietary or environmental exposure to
nitrate has historically been considered to be harmful to human health
due to a possible increased risk of gastric cancer. More recent evidence
challenges this view and indicates that dietary nitrate may instead
confer benefits to health (Gilchrist et al., 2010). Until more is known,
it is recommended that athletes wishing to explore possible ergogenic
effects of nitrate supplementation employ a natural (beetroot juice,
leafy vegetables), rather than pharmacological, approach.
SUMMARY
Dietary
nitrate appears to hold promise as a natural means to enhance NO
bioavailability. NO production through the oxidation of L-arginine, in a
reaction catalysed by the NOS enzymes, is impaired in older age and a
variety of disease states and also in hypoxic tissue. The O
2-independent
reduction of nitrite to NO may therefore represent an essential
‘back-up’ system for NO generation in situations where NOS may be
dysfunctional. Dietary nitrate supplementation reduces resting blood
pressure and may therefore be important in maintaining and promoting
cardiovascular health. It is now well established that acute and chronic
nitrate supplementation can reduce the O
2 cost of
sub-maximal exercise. This improvement in muscular efficiency may be
linked to a reduced energy cost of muscle contraction and/or to enhanced
efficiency of mitochondrial ATP production. Since muscle efficiency is
an important determinant of exercise performance, it is possible that
nitrate might be classified as an ergogenic aid. Indeed, several studies
indicate that, at least in recreational or moderately trained subjects,
nitrate supplementation can extend exercise tolerance and improve time
trial performance. However, additional work is required before the
effectiveness of nitrate supplementation on performance in different
types of physical activity and in different human populations is fully
understood.
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