15
Journal of Exercise Physiologyonline
August 2014
Volume 17 Number 4
Editor-in-Chief
Official Research Journal of
Tommy
the American
Boone, PhD,
Society
MBA
of
Review
Board
Exercise
Physiologists
Todd Astorino, PhD
Julien Baker,
ISSN 1097-9751
PhD
Steve Brock, PhD
Lance Dalleck, PhD
Eric Goulet, PhD
Robert Gotshall, PhD
Alexander Hutchison, PhD
M. Knight-Maloney, PhD
Len Kravitz, PhD
James Laskin, PhD
Yit Aun Lim, PhD
Lonnie Lowery, PhD
Derek Marks, PhD
Cristine Mermier, PhD
Robert Robergs, PhD
Chantal Vella, PhD
Dale Wagner, PhD
Frank Wyatt, PhD
Ben Zhou, PhD
Official Research Journal
of the American Society of
Exercise Physiologists
ISSN 1097-9751
JEPonline
Acute Dietary Nitrate Supplementation Decreases
Systolic Blood Pressure and Increases Dry Static
Apnea Performance in Females
Brandon Collofello, Brian Moskalik, Eric Essick
Department of Natural Sciences, University of St. Francis, Joliet, IL,
USA, 60435
ABSTRACT
Collofello BS, Moskalik B, Essick EE. Acute Dietary Nitrate
Supplementation Decreases Systolic Blood Pressure and Increases
Dry Static Apnea Performance in Females. JEPonline 2014;17(4):1526. Recently, dietary inorganic nitrate has been explored as a sports
nutrition supplement, and has been shown to enhance exercise
performance by reducing metabolic oxygen cost and lowering blood
pressure. The aim of this research was to study the effects of nitrate
supplementation on cardiovascular function and duration of dry static
apnea in 12 healthy females. The subjects were assigned to receive
70 ml of organic beetroot juice (BR; containing ~5.0 mmol of nitrate)
and a nitrate-depleted beetroot juice placebo (PLC; ~0.003 mmol of
nitrate) in a randomized, double blind, crossover design. After 2.5 hrs
post-ingestion of the supplement, the subjects performed three 20-sec
submaximal static apneas separated by 90 sec of rest, followed by a
maximal effort apnea. The duration of maximum dry static apnea,
resting systolic pressure (SP), resting heart rate (HR) were statistically
analyzed. The BR supplementation significantly decreased resting SP
compared to the nitrate PLC conditions (x̄ = -4.82%, SD ± 4.06,
Binomial test0.50 P=0.039). Although a trend was noted for an increase
in the BR maximal apnea duration (52.6 sec) versus the PLC (48.7
sec), the difference was not statistically significant (Binomial test0.50
P=0.098). These results indicate that acute dietary nitrate decreases
resting SP, but does not increase maximum static apnea in young
healthy females. These findings may be advantageous for hypoxia
associated athletic activities such as swimming and exercising at high
altitude.
Key Words: Apnea, Blood Pressure, Nitrate, Exercise Performance
16
INTRODUCTION
Ingested inorganic nitrate (NO3–) is thought to be metabolized to bioactive nitrite and eventually into
nitric oxide (NO), contributing to vasodilation and enhanced blood flow and oxygen delivery to
metabolically active tissues (3,15,33). Furthermore, dietary nitrate is thought to increase nitric oxide
bioactivity/bioavailability by increasing endogenous vascular nitric oxide generation and decreasing
reactive oxygen species and inflammation, both of which appear to have cardiovascular preserving
effects (33). Nitric oxide has also been reported to promote smooth muscle cell production and
growth, stimulate leukocyte migration, platelet motion and accumulation, and increase expression of
particular adhesion molecules (33). Furthermore, nitrate supplementation may also help improve
symptoms against peripheral arterial disease (PAD) and other cardiovascular diseases (5,17,24,25,
34,38).
Dietary inorganic nitrate sources commonly come from plant foods, particularly vegetables such as
beets, spinach, rucola, lettuce, green beans, and a few fruits. It has been well documented that nitrate
rich beet root juice (BR) is a safe and significant source of nitrate that increases plasma nitrite (NO2–)
levels (1,6,11,13,25,27,33,47,48). The acceptable daily intake (ADI) for nitrate is 3.7 mg·kg-1 of body
weight per day, approximately 222 mg·day-1 of nitrate for a 60 kg adult (10). On average an individual
eating 400 g of mixed vegetables would receive 157 mg·day-1 of dietary nitrate, an amount that is
notably lower than the suggest ADI (10). In the past few years, numerous studies have examined the
cardiovascular and pulmonary effects of nitrate supplementation through nitrate-rich BR (1,2,6,11,25,
27,47,48). This has been shown to reduce systolic blood pressure (SP) and to reduce maximal
oxygen consumption (VO2 max) while increasing exercise tolerance as compared to the nitratedepleted beet root juice control (PLC) (4,6,8,27,31,36,45,48,49). Past studies have indicated that
nitric oxide donors can improve aerobic and anaerobic tolerance during exercise in untrained or
moderately trained healthy subjects but not in highly trained subjects (3,7,37). This appears to
indicate that non-elite healthy subjects may benefit the most from nitric oxide donors. Furthermore,
research has shown that the beneficial ergonomic effects dietary nitrate donors may be limited to
submaximal aerobic activities (35).
Dry static apnea is the act of holding one’s breath in a waterless environment while remaining
stationary. Because static apnea reduces oxygen availability to muscles and other tissues, it is often
used as an important measure of athletic performance, particularly for open water free dive and other
athletic activities where oxygen availability is limited (40,42). Because nitrate supplementation
reduces oxygen requirements (i.e., consumption), the general thought may be that the longer one is
able to hold his or her breath, the better that individual may perform when oxygen demand begins to
exceed oxygen supply or availability (hypoxia). Interestingly, recent studies have shown that acute
ingestion of dietary nitrate supplements increases dry static apnea performance in highly trained
competitive breath holders (10,43). However, the exact mechanism that allows for dietary nitrate to
have these effects remains unknown, but may involve a decrease in metabolic cost and oxygen
consumption (20). Additionally, most studies have focused on male subjects (33). Therefore, the
purpose of the present study was to examine the effects of BR on dry static apnea and blood
pressure in healthy young female subjects. This is the first of its kind to specifically examine the
effects of nitrate supplementation on young female subjects. It is hypothesized that the nitrate rich BR
supplement will increase the duration of maximum dry static apnea and reduce the SP in the young
female test subjects, similar to the findings observed in male dominated studies (10,27,48,49).
17
METHODS
Subjects and Group Assignments
Twelve healthy women (BMI range: 18.5 to 24.9; x̄ = 21.9, SD ±1.9; age 18 to 30) participated in this
study. The subjects were asked to: (a) maintain their normal lifestyle throughout the duration of the
study; and (b) undergo a familiarization trial to reduce test anxiety prior to data collection. The
familiarization protocol was performed in the same environment using the same apnea testing as the
experimental protocol except that no measurements were made and the subjects did not consume
any supplement.
On the days of the experiment, the subjects were instructed to arrive in a fully hydrated and rested
state at was ≥3 hours post-prandial to prevent any interference with the supplement digestion and
uptake. The subjects were told to: (a) avoid strenuous exercise for the 24 hrs preceding the testing;
(b) avoid any uncontrolled substances affecting experimental testing; (c) refrain from forms of caffeine
and nicotine for 6 hrs and alcohol for 24 hrs before each test period as previously described (27); and
(c) abstain from use of mouth wash and chewing gum 24 hrs before and throughout the experiment,
given that the entero-salivary system has been found to interfere with NO metabolism (15).
Experimental protocol
Using a double-blind, randomized, crossover design, the subjects were assigned to receive a dietary
supplementation with 70 ml concentrated BR (~5.0 mmol of NO3– ) or a nitrate-depleted beetroot juice
placebo (PLC; ~0.003 mmol of NO3–) on separate days. The design was randomized and coded
using a computer program (Random.org) to randomly assign supplements.
The subjects consumed the assigned supplement 2.5 hrs prior to each test and at least 3 hrs postprandial, allowing for peaked plasma NO2– concentrations during testing (24,33). Each subject
participated in two experimental test days separated by a 2-day period where no NO3– supplements
were ingested, allowing for any remaining NO3–/NO2– to be metabolized. The two experimental days
took place at the same time of day (± 30 min). On experimental days, forced vital capacity (VC) was
initially measured in the standing position using a hand-held spirometer (Microlab Spirometer, Micro
Medical Ltd, Kent, UK). VC was measured three times, and the largest value was recorded. The
subjects were instructed to lie down in the supine position for a 5-min rest period before completing
the dry static apnea test as previously described (11). The test consisted of three 20-sec
(submaximum effort) apneas. Each effort was separated by a 1.5-min rest period, followed by a 3min rest before a final maximum effort apnea (Figure 1). All apnea testing and resting periods were
performed in the supine position on a floor mattress as an additional safety precaution.
Subjects were notified at the countdown time points of 2 min, 1 min, and
10 sec prior to the max apnea bout.
Without a prior hyperventilation, each
subject was instructed to exhale
completely, which was followed by a
deep, but not maximal, inspiration to
begin the apnea. Schagatay has
shown this to fill 85% of vital capacity
volume, which is ideal for dry apneas
and reduces the chance of over filling
and potential syncope due to hindered
Figure 1. Experimental Protocol.
18
venous return (39). During sub-maximal apneas, the subjects were given time cues and the apneas
were ended by verbal command. For the maximal effort apneas, the subjects were notified when they
passed 20 sec of dry apnea duration.
Experimental Measurements
Time of apnea duration was timed using a stopwatch. Heart rate and blood oxygen saturation (SaO2)
were recorded using LabScribe and i-Worx physiologic data acquisition systems (i-Worx Systems
Inc., Dover, NH). Non-invasive resting blood pressure was measured automatically. At ~10 min
before maximum apnea, an average of three readings 1 min apart was recorded using an automatic
arm cuff system (Omron BP786) attached to the left arm.
Statistical Analyses
A binomial t-test with probability (0.50) was used to compare apnea duration and percent change of
SP, DP, and MAP of the BR and PLC conditions. For all data, statistical significance was accepted at
P≤0.05. Trends were noted at P<0.10. The data were presented as mean ± standard deviation (SD)
for N = 12 subjects. All data were tested for normality and heterogeneity of variance and normal
distribution using a Shapiro-Wilk W test (P<0.10), which indicated a randomly sampled population.
RESULTS
All subjects had a calculated BMI between 18.5 and 24.9 (x̄ = 21.9, SD ±1.9). None of the subjects
experienced an increase in SP with BR as compared to the PLC (Table 1). There was a significant
percent decrease in SP for individuals given BR as compared to subjects given PLC (x̄ = -4.82%, SD
± 4.06, Binomial test0.50 P=0.039; Figure 2). In addition, the mean SP of the subjects during BR
condition (x̄ = 101.25 mmHg) was less than the mean SP during PLC conditions (x̄ = 106.58 mmHg).
Relative to the PLC, BR reduced SP by 5% with a -5.3 mmHg average change in SP from PLC to BR
supplement. Although not significant, mean DP and mean MAP decreased by 3.18 percent (± 7.05%)
and 3.94 (± 5.04%), respectively.
Table 1. Systolic Blood Pressures (mmHg) for BR and PLC Supplement Conditions for All
Subjects with Averages and Difference between Conditions.
SP (mmHg)
SP (mmHg)
Change (mmHg)
Subject
BR Conditions
PLC
PLC-BR
1
2
3
4
5
6
7
8
9
10
11
12
AVG
94
94
104
84
101
111
107
109
94
96
109
112
101.25
96
95
120
94
101
116
112
114
94
101
115
121
106.60
-2
-1
-16
-10
0
-5
-5
-5
0
-5
-6
-9
-5.3
19
Relative to PLC, BR showed a trend to
increase maximal apnea duration by
7.4% (PLC: 48.7 sec vs. BR: 52.6 sec;
Binomial test0.50 P=0.098; Figures 3
and 4). The mean maximal apnea
duration after BR supplementation (x̄ =
52.58 sec) was not significantly
greater under PLC conditions (x̄ =
48.75 sec; P≥0.10). In addition, the BR
supplementation showed an average
increase in apnea time of 10.29% ±
15.19% compared to PLC that was not
significant, P≥0.10). Finally, there was
no significant difference between the
average percentage change in resting
HR between individuals after the BR
supplementation compared to the PLC
conditions.
Figure 2. Mean ± SD Percent Pressure Change in Response
to BR (Compared to PLC; N=12).
Using repeated measures AVOVA, we showed that there were intrinsic differences between
individuals (Between Subjects Effects ANOVA F1,12=123.69, P<0.0001), but there was no significant
change within individuals by treatment (within subjects ANOVA F 1,12=3.28, P=0.098). There was no
significant impact on effect of order (i.e., when the subject took the supplement) on the data (Table 2;
two tailed t-test).
BR
PLC
Figure 3. Mean ± SD Apnea Time from
the Maximal Apnea during the BR and
PLC Condition Trials. (N=12, *P=0.098)
PLC
BR
Figure 4. Individual Apneic Time from
Maximal Apnea during PLC and BR
Supplementation Trials. (N=12)
20
Table 2. t-Ratio, DF, and P Values from Two-Tailed t-Test Evaluating Effect of Order on
Maximum Apnea Duration and Festing SP, DP, HR, and MAP.
Parameter
t Ratio
Degrees of
P value
Freedom
Max Apnea Duration
0.28
22
0.78
Systolic Pressure (SP)
-0.12
21
0.91
Diastolic Pressure (DP)
-0.03
21
0.98
Heart Rate (HR)
0.87
22
0.39
Mean Arterial Pressure (MAP)
-0.07
20
0.95
DISCUSSION
Our results show that beetroot juice supplementation increases maximum apnea and decreases SP
compared to a placebo, thus supporting the stated hypothesis. Although the exact mechanism
remains unclear, it is likely that it involves improving the efficiency of nutrient and oxygen delivery to
vital organs and reducing metabolic cost. Exogenous nitrate sources are metabolized into bioactive
nitric oxide, which targets vascular smooth muscle causing vasodilation that contributes to a reduction
in SP (33). This has previously been demonstrated in males, where nitrate reduces SP after ingestion
compared to the control (8,27,48,49). Additionally, nitric oxide may enhance nutrient and oxygen
transfer to active muscle allowing for prolonged apnea and exercise. This may explain the trend for
increased maximum apnea duration observed after BR supplementation (3,11,33). It is important to
note that forced vital capacity was not significantly different between trials in the present study. This
finding suggests there is likely a physiological mechanism behind the change in apnea, and that it is
not due to a change in pre-apnea gas storage capacity.
Both animal and human studies have concluded that dietary nitrate supplementation can reduce
blood pressure in both normotensive as well as hypertensive test subjects (9,46). In a study that
examined the effects of nitrate supplementation in exercising rats, Ferguson and colleagues (12)
showed that MAP was significantly reduced in fast twitch type II muscles compared to the control. We
noted a significant reduction in SP, and a non-significant trend was noted for a decrease in MAP and
DP after BR supplementation. It could be that the nitrate dose in our supplement was not high enough
to cause a significant difference. In the present study, nitrate may not affect DP since the vasodilation
effects of bioactive nitric oxide may only be pronounced during systole. Similar to our results, Bond Jr.
and colleagues (4) showed that beetroot juice treatment decreased SP but not DP in young adult
healthy females. According to a systematic review and meta-analysis of randomized clinical trials (44)
over a 6 yr period, inorganic nitrate and beetroot juice consumption were associated with greater
changes in SP than in DP. Gilchrist et al. (14) showed that dietary nitrate supplementation did not
lower MAP or improve endothelial function in their subjects. However, the lack of response may have
been due to the fact that they studied type 2 diabetic subjects.
21
Conversely, some studies (16,28) have found that nitrate supplements significantly lowered both DP
and MAP. For instance, Hobbs et al. (16) reported that acute ingestion of bread containing beetroot
lowered DP, but not SP in healthy male subjects. Their findings also showed an increase in
vasodilation that was independent of the endothelium, thus suggesting an alternative mechanism. It
is known that during conditions of arterial hypoxia (low oxygen), nitrites can be converted into nitric
oxide, which is known to have several beneficial effects on the vascular system that includes
vasodilation and angiogenesis of which can reduce MAP (20,21). There continues to be a growing
amount of data that demonstrates nitrate supplementation leads to vascular smooth muscle
relaxation via reduction to nitric oxide and activation of the classical NO→sGC→cGMP pathway
(19,32). Therefore it can be deduced that vasodilation is playing a mechanistic role in the lowering of
blood pressure after nitrate supplementation. However, further investigation is needed to investigate
the specific contribution of nitrate-induced angiogenesis in blood pressure reduction.
Dietary nitrate supplementation is associated with a reduction in oxygen consumption (VO2), which
can lead to an improvement in exercise efficiency (20,30). Larsen and colleagues (30) showed that
nitrate supplementation lowered VO2 by 5% compared to control in healthy trained subjects.
Furthermore, both animal and human studies (22,26) have concluded that nitric oxide is involved in
regulation of VO2, as inhibition of nitric oxide synthase (NOS) reduces nitric oxide and, subsequently,
results in an increase in VO2. This indicates that reduction of nitrates and nitrites to nitric oxide is
necessary for these effects to occur. A recent study (11) suggested that the physiological cost of
maintaining metabolic rate is a key limiting factor for static apnea performance, and that acute dietary
nitrate supplementation may increase the duration of apnea by reducing metabolic cost and VO2.
Although the exact mechanism is unknown, the nitrate/nitrite/nitric oxide reduction pathway appears
to be enhanced during conditions of hypoxia, thus leading to a reduced ATP cost during muscular
contraction, improved mitochondrial efficiency, and enhanced mitochondrial synthesis (18,20,27,29).
There has been some controversy on whether the ergonomic benefits of nitrate supplementation are
observed more in lower intensity exercise compared to high intensity exercise. For example, Martin
and colleagues (35) showed that dietary nitrate had no beneficial effects on performance in a
repeated sprint test in team-sport athletes. Because VO2 is near a maximal rate during high intensity
exercise, it might be inferred that nitrate’s ergonomic benefits are only effective when oxygen
availability is low. This is supported by the fact that nitrate and nitrite reduction to nitric oxide is
enhanced during hypoxia (20).
Despite the significant research on nitrate supplementation, female and elderly populations have
continually been underrepresented or absent in the majority of the studies. With most of the
experimental designs focusing on young, athletic, male populations, or involving only a few female
subjects, often there is no distinction between sexes provided in the results or explanation in the
discussion. As a result, numerous conclusions have been stated based on averaging the results over
subject groups, leading one to make potentially biased and faulty generalizations about parallel
effects of nitrate on females despite data from male dominated experiment designs.
Faulty generalizations, in the sense that if the effects between sex groups are not identically
correlated, BR effects may not have the same beneficial effects, or have an attenuated effect, on
women as compared to men. Coles and Clifton (8) showed that females given a dietary nitrate
supplement had an average 2.5 mmHg decrease in their SP compared to an average of 4.7 mmHg in
male subjects (P<0.05) at 6 hrs post-supplement ingestion. The authors stated the differences are
unclear, but maybe due to older ages in the female group, medication interference, and/or differences
between sexes. Nonetheless, the attenuated decrease in SP observed in females provides
22
preliminary evidence for a difference in nitrate supplementation effects on blood pressure between
sexes.
CONCLUSIONS
Based on this present study, nitrate supplementation might offer a way to improve exercise
performance by decreasing SP and increasing apnea duration in untrained healthy and young
females. Although additional research is necessary, nitrate supplementation may enhance
performance ability for females in sports where VO2 may be restricted, such as during swimming and
anaerobic exercises. It should also be noted that the experiments by Engan et al. (11) were done on
subjects who were trained for breath-hold diving, and the results showed a significant increase in their
maximal apnea durations during BR compared to PLC. Future studies should consider doing a
comparative study with an increased the sample size and an equal number of males and females.
Additionally, research that examines the effects of nitrate supplements is of considerable interest
since currently little research has been done in that area (33). Lastly, finding an optimal safe and
efficacious dose may provide more significant data that may identify effects of nitrate supplementation
on apnea performance and blood pressure in females.
Address for correspondence: Eric Essick, PhD, Department of Natural Sciences, University of St.
Francis, Joliet, IL, USA, 60435, Email: eessick@stfrancis.edu
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