1. ADVANCES
VOLUME 3 • ISSUE 10
IN ORTHOMOLECULAR RESEARCH
321
NOx Technology
The Power of Nitric Oxide
The Power of NOx: Say Yes to No!
Nitric Oxide and Cardiovascular Health
Nitric Oxide, Exercise and Endurance
Nitric Oxide and Gastrointestinal Health
Antimicrobial and Healing Effects of NO
The Safety of Nitrates
research-driven botanical integrative orthomolecular innovative

2. ADVANCES
VOLUME 3 • ISSUE 10
IN ORTHOMOLECULAR RESEARCH
1. The Power of NOx: Say Yes to No!
8. Nitric Oxide and Cardiovascular Health
16. Nitric Oxide, Exercise and Endurance
18. Nitric Oxide and Gastrointestinal Health
21. Antimicrobial and Healing Effects of NO
24. The Safety of Nitrates
1 16 21
8 18 24
ADVANCES
Advances in Orthomolecular Research
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ADVANCES in orthomolecular research Volume 3 Issue 8

3. NO is now known to be a signaling molecule;
The Power of meaning that is acts as a messenger to facilitate
communication between cells, the relaying of
messages and other cellular chatter. The body relies
on a wide variety of signaling molecules including
Nitric Oxide: hormones, nerve impulses and chemicals like
cytokines, hydrogen and carbon dioxide. These
signaling molecules help the body perform vital
functions including the mobilization of the body’s
Say Yes to NO! immune defense systems against invading foreigners
like viruses, bacteria, toxins and carcinogens, as well
as the modulation of other body functions like
temperature and blood pressure.
Besides being a simple molecule consisting of two of
What is Nitric Oxide? the most abundant and well know elements, NO is
also a radical. This means that NO has an unpaired
Nitric Oxide (NO) is a simple molecule consisting of electron, making it a very reactive molecule! NO’s
one atom of nitrogen and one of oxygen, making it unpaired electron means that it has extensive reactivity
even simpler than water itself! Research into the effects with virtually anything and everything from body cells
of this small but important molecule began in the and tissues to other chemicals and molecules
1970’s when scientists started to examine why blood circulating in the system. This reactivity is essential in
vessels relaxed when certain compounds were added. enabling NO to carry out its many biological functions.
This led to the discovery of NO and it’s amazing
How is NO generated?
effects in the body, with NO being named the
The conventional method of NO synthesis is from the
molecule of the year in 1992! In 1998, twenty-some
amino acid L-Arginine (see Figure 1). L-Arginine is
years after this research first began, a Nobel Prize was
awarded to these researchers for their breakthrough oxidized via a series of steps involving a family of
discoveries regarding NO. Unfortunately, one of the enzymes called nitric oxide synthases (NOSs). There
pioneering researchers in the field of NO-research, are essentially three common NOSs termed isozymes;
Salvador Moncada, was overlooked by the Nobel Prize these are iNOS, eNOS and nNOS. Each of these
committee, showing that there is indeed a political side enzymes plays a different role in the generation of NO
to science! Over the last two decades NO research has in different tissues like the nerves, endothelium or
continued to grow, and there has been an exponential blood vessels or on demand. In each case however,
increase in the number of publications on this normal oxygen conditions (also called “normoxia”) as
fascinating molecule. well as a neutral to high (alkaline) pH level are
Figure 1: The production of Nitric Oxide ( NO) from
L-Arginine by enzymes called NO synthases (NOSs)
Nitric Oxide Synthases (NOS’s)
L-Arginine Nitric Oxide
Volume 3 Issue 10 ADVANCES in orthomolecular research 1

4. KEY TERMS AND DEFINITIONS
Mediterranean Diet
Consumption of fruits and vegetables has been known for some time to protect against Cardiovascular Disease (CVD) and Cancer. In the mid 1960’s
an ambitious study called the Seven Countries Epidemiological Study was conducted. The study included the following countries: United States,
Italy, Greece, Japan, Holland, the former Yugoslavia and Finland. A five year follow up of their diet, including intake of fruits, vegetables, saturated
fats and meat was recorded as well as the incidence of cardiovascular disease and cancer. The study was unique in that it standardized for a number of
factors, including risk factors of heart disease, accurate measurement of diet and blinding (meaning that no one would know who was on which diet).
A careful and extensive analysis of the data revealed that the incidence of CVD was significantly lower in Italy, Japan and Greece than in the other
four countries included in the study. Dr. Ancel Keys, the lead author, coined the term “The Mediterranean Diet” to describe the diet followed by the
Japanese, Italians and the Greeks. In each of these countries the intake of fruits and vegetables was significantly greater and corresponded
to a reduced rate of cardiovascular disease. The Mediterranean diet is now universally recognized as a healthy diet.
DASH Diet
(Dietary Attempts to Stop Hypertension) is Oxidation
modeled after the Mediterranean diet.
In the DASH diet an intake of fruits and vegetables Oxidation is a term that means an increased number of oxygen atoms
of upwards of 8-10 servings per day is recommended. (strictly speaking it refers to the loss of electrons) for example when NO undergoes
oxidation the number of oxygen atoms increases: NO NO2 NO3.
Hypoxia
Reduction Hypoxia is a condition when oxygen availability is greatly reduced.
For example, such a condition is likely to occur during ischemia,
Reduction is a term that is the which is when there is an interruption of blood flow to the tissues
opposite of oxidation and refers
to the loss of oxygen atoms
NOS (e.g. the heart during a heart attack).
(again strictly speaking it is the gain of electrons) NOSs are Nitric Oxide Synthases,
for example when NO undergoes which are a diverse range of enzymes
reduction the number of oxygen that facilitate the formation of NO
atoms decreases: NO3 NO2 NO. from various starting molecules (substrates)
like L-Arginine.
Free Radicals
Free Radicals are molecules that are very reactive due
to an unpaired electron. Free radicals are generally
Genetic Knock-Out considered to have negative health implications but
that isn’t the universal case. For example,
Genetic knock-out mice/rats are widely used to test NO itself is a free radical!
what happens when a certain gene is deleted. When a
gene is deleted the mouse can no longer produce a certain protein
or enzyme. For example, using rodents lacking a specific gene that
codes for NOS enzymes, one can test the effect of a lack of NO and
its health implications. Bioavailability
Bioavailability is a term that refers to the amount of an active molecule
that reaches the target site of action. Poor bioavailability is a huge
problem for large number of natural and pharmaceutical compounds.
There is active research into various ways of delivering more of the molecule
at lower doses.
Mole
Mole is a measurement widely used in chemistry that equates how
much of the active molecule is present. The mole and/or milli-mole
Reactive Oxygen Species (ROS)
(mM - a thousandth of a mole) is widely used to express the concentration Reactive oxygen species (ROS) is another term
of an active compound in the blood. for free radicals; species that are very reactive.
Half Life
Half-life is the time taken for the concentration of a compound to be reduced by half. Various metabolic processes in the body
act to ensure that molecules do not “linger” about for longer than is necessary by degrading them via enzymatic function,
binding with various proteins, elimination via increased excretion by the kidneys, and other mechanisms.
2 ADVANCES in orthomolecular research Volume 3 Issue 10

5. required. When these conditions are met the NOS- reduced (see key terms pg 2) in the mouth by bacteria
dependent conversion of L-Arginine occurs efficiently. that are normally present on the back of the tongue.
Production of NO is the primary reason for the dietary These specialized bacteria use the nitrate to help them
intake of L-Arginine. However, under low oxygen make energy in the form of ATP In return, the bacteria
.
conditions (also called “hypoxia”) the conversion of L- utilize their own nitrate reducing enzyme called Nitrate
Arginine to NO is severely limited. Low oxygen Reductase to generate nitrite, which as we shall see is
conditions can occur for a variety of reasons. For very useful to us! This special relationship is an
interesting example of human-bacteria symbiosis: a
example, partial or complete blockage of a blood
mutually beneficial relationship.
vessel (ischemia), conditions of extreme physical
exercise or high altitude situations like mountaineering The nitrite is a much more active molecule than nitrate
can all result in reduced blood flow and thus reduced and is present in high concentrations in the saliva
which is swallowed into the stomach where conditions
oxygen delivery to the body’s tissues and cells.
of low oxygen (relative to the mouth) and high acid are
Moreover, such low oxygen conditions are also
present. These conditions are ideal for further
accompanied by an increased production of lactic acid
reduction of nitrite into NO. The entire reduction
which reduces pH making the tissue condition both process of nitrate into nitrite and then into NO occurs
hypoxic and acidic. As such, a body builder pumping without the intervention of NOS enzymes. These
iron or an energetic aerobic class or a middle to long enzymes wouldn’t be active in these low oxygen and
distance runner derive little if any benefit from L- low pH conditions anyway. It should be noted that low
Arginine in terms of NO generation. oxygen and low pH conditions don’t just occur in the
stomach, they can also occur throughout the body in
certain situations including extreme physical exercise,
A New Discovery! A Second Pathway to NO heart disease and psychological and physical stress!
Generation: The NOx 3,2,1 pathway Both pathways of NO generation are depicted in
However, there is good news for these athletes! Figure 3, below.
Recently a novel pathway to NO generation from
dietary nitrates has been discovered by researchers at L-Arginine Nitric Oxide
the Karolinska Institute in Stockholm, Sweden and by (NO)
Normal Low
Oxygen Conditions Oxygen Conditions
researchers from the University of London, England. (Normoxia) (Hypoxia)
The Swedish researchers, led by Jon Lundberg and NOS- NOS-
Eddie Weitzberg, along with Nigel Benjamin from Dependant
Pathway
Independent
Pathway
London, were trying to discover why certain diets, like Oxidation Reduction
the Mediterranean diet, vegetarian diets, Japanese
diets and the famed DASH diet (Dietary Advice for
Stopping Hypertension) were particularly protective of Nitric Oxide Nitrate & Nitrite
- -
(NO) (NO 3 /NO 2 )
the heart. Both groups independently reported that the
key to the success of these diets was the consumption
of leafy green vegetables, and that a key component Figure 3. There are two ways that the body generates NO depicted as Ying
Yang. Each pathway has special requirements. NO can be produced from
of all these diets was the high nitrate content. The L-Arginine and oxygen by a family of enzymes, the NO synthases (NOSs).
In a more recently discovered pathway, inorganic nitrate and nitrite are
researchers proposed that the nitrate was converted reduced to form NO in blood and tissues when oxygen levels are low.
into NO via a reductive process as follows: Although NO generation by the L-Arginine pathway is ineffective as oxygen
levels fall, the nitrate–nitrite–NO pathway is enhanced! (From Lundberg et
Essentially, the highly nitrate-rich vegetables are al., 2008)
Figure 2: The conversion of dietary nitrates
to nitrite and finally to nitric oxide.
Conversion of nitrate to Reduction of nitrite to
nitrite by bacterial enzymes NO in the stomach
in the mouth or blood
Nitrate (NO3- ) Nitrite (NO2-) Nitric Oxide (NO)
Volume 3 Issue 10 ADVANCES in orthomolecular research 3

6. Oxidation is a step-wise increase in the number of See Table 1 for a detailed comparison between nitrate,
oxygen and reduction is the opposite with oxygen nitrite and NO.
being reduced from 3 to 2 to 1; hence the term All of this begs the question: “How is it that a molecule
NOx3,2,1 pathway. Besides specific conditions like with such a short half-life can exert biological effects at
oxygen status and pH, other factors like the presence
of certain reducing compounds will also help to Table 1: Comparing Nitrate, Nitrite and NO (from Hord et al.,
enhance the conversion of nitrates into NO. These 2009). See Box 1 for an explanation of terms used in this table.
helpful reducing compounds include vitamin C, alpha
Concentration in
lipoic acid and many polyphenols like green tea NOx Species Half Life NOx Species
Blood (nmol/L)
catechins (EGCG) and resveratrol.
20,000 - From diet or from
Once NO is generated in the stomach it is rapidly Nitrate 5-8 Hours the oxidation of
50,000 nitrite in the body
absorbed across the cell membrane into the blood
vessels and from there it is carried all over the body. 1-5
From diet, nitrate,
Nitrite 100 - 500 or from the
However, as mentioned before, NO is a free radical Minutes oxidation of NO
and is therefore a highly reactive species that lasts only
a few milliseconds (a few thousandths of a second) Nitric Oxide Less than 1 1-2 From nitrite in the
Miliseconds body
before it is oxidized back into both nitrite and nitrates.
Figure 4:
Nitrate in the blood can also be
The Entero-Salivary
picked up by the salivary glands
and start the cycle of NO Circulation cycle showing
production all over again the complex interconversion
of nitrate, nitrite and NO in
the body and the
concentration and
Nitrate and some
nitrite from food
recirculation of nitrates in
the salivary glands. (From
Lundberg et al., 2008)
Some nitrate and nitrite reach the
blood and can be converted
into NO when oxygen levels are low
Bacteria in the
oral cavity convert
nitrate to nitrite
The acidic environment of the stomach
results in the conversion of nitrite to
NO. This NO can go on to have effects
throughout the body Any left over nitrate and nitrite are Excess nitrate is excreted
absorbed in the intestine by the kidneys
4 ADVANCES in orthomolecular research Volume 3 Issue 10

7. distant sites in the body?” The answer, it seems, lies in salivary glands is 100-fold greater than in the blood
the fact that NO is converted back into nitrite and and that of nitrite it is 1000-fold greater! The rest of
nitrate. Although NO lasts only a short time and may the nitrate is eventually excreted in the urine. So both
only act directly and locally before it is oxidized into urine and saliva are particularly rich in nitrate and
nitrite and then nitrate, this rapid oxidation to both nitrite. It is interesting then why animals lick their
nitrite and especially nitrate, allows these much more wounds or that urinating on an injury is considered
stable molecules to then travel to distant sites for re- beneficial – the potential benefits of these behaviours
conversion back into NO as and when the specific will be discussed in detail in later articles in this
tissue requires. In effect, both the nitrite and nitrate act magazine.
as pro-drug forms of NO; in other words, nitrate and In summary the opposite biochemical processes of
nitrite act as a stable reservoir and a depot for future oxidation and reduction of L-arginine and nitrate
NO requirements by all cellular tissues throughout the bioconversion into NO respectively may be viewed as
body. In this manner NO can act both locally and at “ying-yang” with the more conventional L-Arginine
distant sites in a similar manner to various hormones pathway occurring in conditions when there is plentiful
secreted by the thyroid or adrenal glands. of oxygen and the nitrate pathway as a “back-up”
An interesting feature of nitrate in the blood is that system occurring in conditions when there is lack of
approximately 25% of the nitrate is concentrated back oxygen. The key point is that without this vital back-up
in the salivary glands via the entero-salivary circulation system our bodies would not be able to carry out a
cycle (See Figure 4). The concentration of nitrate in the number of biological functions.
REJUVE
NOX
REDUCES STRESS
AND BOOSTS ENERGY
TECHNOLOGY
Volume 3 Issue 10 ADVANCES in orthomolecular research 5

8. DIET
Nitrates/Nitrites
Higher or Low
Oxygen
VASODILATOR
NO
Anti inflammatory
Antioxidant
Lowers BP
Helps arthritis,
joint pain &
inflammation
Diuretic
Improves oxygen
delivery to the body Gastric Mucosal
Protection
Benefits conditions
like sickle cell disease
Prevents
Ulcers &
Infections
6 ADVANCES in orthomolecular research Volume 3 Issue 10

9. THE ROLE OF NITRATES IN THE BODY
Cholesterol
Platelets
L-Arginine
High Oxygen
Only
Anti-platelet Prevents Clots
Prevents Prevents
LDL Oxidation Arterial Plaque
Prevents
Heart
Atttacks
Anti-bacterial
Prevents Prevents
Ulcers & Strokes
Infections
Volume 3 Issue 10 ADVANCES in orthomolecular research 7

10. found to be as effective as a single prescription
NITRIC OXIDE therapy for blood pressure!
Researchers from Johns Hopkins University reported
AND THE an 18% reduction in the 10 year risk of heart disease
with the DASH diet. The researchers stated that, “In
addition to reducing blood pressure, the DASH diet
CARDIOVASCULAR should substantially reduce the risk of coronary heart
disease”.
SYSTEM
Cardiovascular Disease (CVD) which includes high
blood pressure (hypertension), angina (ischaemia),
arterial damage (atherosclerosis), stroke and heart
attack is still the number one cause of morbidity and
mortality world-wide. One in three Americans is Similarly, the lower incidence of CVD in patients
affected by CVD, and over a billion people worldwide consuming Mediterranean, vegetarian and Japanese
are affected by high blood pressure alone. In Canada, diets has been attributed to the high fruit and
someone dies from heart attack or stroke every 7 vegetable intake associated with these diets. In fact
minutes, with CVD accounting for 30% of all deaths in some researchers have reported that the greatest
Canada annually. The costs associated with CVD are protection against CVD is offered by diets with the
quite staggering with 2006 cost estimated in the EEC highest content of leafy green vegetables (See Table 2).
to be over 200 billion Euros. In Canada, the costs This has led scientists to ask some important questions;
associated with CVD in 2009 were estimated at $22.2 “What is the common denominator in such diets?” and
billion in physician services, hospital costs, lost wages therefore “What are potential CVD protective
and decreased productivity. compounds associated with these diets?”
In recognition of these alarming statistics there is a It appears that the riddle has been finally solved. A
serious initiative on the part of the government to group of researchers principally from Sweden, the UK
increase the daily intake of fruits, vegetables and fiber and the US have independently and collaboratively
as well as to encourage people to exercise more. In shown that the nitrate and nitrites in our fruits and
North America, the previous recommendation of five vegetables may be the answer and have forwarded
servings of fruits and vegetables has been upgraded to convincing evidence to support their hypothesis.
a recommended nine servings per day.
Are Inorganic Nitrates the Answer?
Various epidemiological and cohort studies have Nitrates can be classified into two categories: organic
repeatedly and unequivocally reported a lower and inorganic. Organic nitrates are what most of us
incidence of CVD with higher intake of fruits and are familiar with; for example glyceryl trinitrate (GTN)
vegetables. These findings have culminated in the is what is in the tiny tablets usually dispensed by
famed Dietary Approaches to Stop Hypertension pharmacists in glass vials and recommended to be
(DASH) study. The DASH diet was specifically designed placed under the tongue for anginal pains. Another
to lower blood pressure and recommends eight to ten common organic nitrate compound it isosorbide
servings of fruits and vegetables a day, along with dinitrate, which is a more advanced and stable form of
consumption of low-fat dairy products. The results of GTN. These organic nitrates have been in use since the
the DASH diet in reducing blood pressure have been mid 1800’s. Then there are the inorganic nitrates,
8 ADVANCES in orthomolecular research Volume 3 Issue 10

11. which include potassium nitrate and sodium nitrate. nitrate/nitrite content. As can been seen from Table 2
These inorganic nitrates are commonly found as salt the vegetables with the highest nitrate/nitrite content
forms in soils, rocks and plants and have been used are spinach, cabbage and Bok Choy. Other
for thousands of years in gun powder, food vegetables such as beet root, collard greens and leeks
preservation and for heart ailments by early Chinese also have very high nitrate content. Not only are these
physicians. vegetables loaded with nitrate but many of them also
A recently discovered 1000 year old Chinese have a high content of the enzyme nitrate reductace
manuscript translated by scholars at Cambridge which assists the conversion of nitrate into nitrite,
University shows the use of inorganic nitrates by thereby facilitating the conversion of nitrite into NO.
Buddhist monks for heart ailments! (See Figure 5) It is This is particularly true for the Eastern herb
quite remarkable that the Chinese physicians knew not Cinnamomum. This herb is rarely used by itself for
only about the inorganic nitrates but more importantly CVD because it has a fairly low nitrate/nitrite content.
they understood their proper use as evidenced by their However, when it is combined with herbs like Dan
advice to their patients to “Administer under tongue Shen, which do have high nitrate content, the effect is
and have patient swallow the saliva” It is as if the pronounced! In this combination, Dan Shen provides
physicians knew back then about the entero-salivary the high nitrate content and Cinnamomum provides
circulation of nitrate! the necessary enzyme to reduce nitrate into nitrite and
eventually to NO for therapeutic efficacy.
Putting under the tongue to cause
heart ”qi” to flow freely. Table 2: The nitrate/nitrite content of various widley consumed
For treating symptoms such as struck by evil,
acute heart pains and cold in the hands and feet
western vegetables
which can kill a patient in an instant.
Look at the patients fingers and those with
greenish-black nails are such cases. NITRITE NITRATE
Take potassium nitrite (5 measures of a bi spoon)
and arsenic sulphide (1 measure of a bi spoon) VEGETABLE CONTENT CONTENT
and combine the two into a fine powder.
Lift the patients tongue and sprinkle 1 measure
(mg/100g) (mg/100g)
of a bi spoon under the tongue.
If saliva is produced have the patient swallow it. Root Vegetables
This is a sure cure.
Carrot 0.002 - 0.023 92 - 195
Figure 5. A medical recipe from Buddhist monks at Dunhuang
Mustard Leaf 0.012 - 0.064 90 - 95
from medieval times showing that the benefits of nitrates were
recognized as early as 900 years ago. (From Lundberg et al.,
2008)
Green Vegetables
Dr. Nathan Bryan and his colleagues have investigated Lettuce 0.008 - 0.215 12.3 - 267.8
the nitrate/nitrite content of various herbs and Spinach 0 - 0.073 23.9 - 387.2
vegetables consumed in the West and by the Eastern
cultures. Interestingly, they have found that herbs and Cabbage
plants that have been associated with a reduction in
CVD are also those with the highest nitrate/nitrite Chinese Cabbage 0 - 0.065 42.9 - 161
content. For example the herb Radix miltiorrhizae, also Bok Choy 0.009 - 0.242 102.3 - 309.8
known as Dan Shen, has a very high nitrate content
and is a widely used Traditional Chinese Medicine Cabbage 0 - 0.041 25.9 - 125.0
(TCM) for conditions like angina, myocardial infarction
or stroke. Its therapeutic efficacy has been associated Cole 0.364 - 0.535 76.6 - 136.5
with its ability to dramatically raise NO levels. Clinical Melon
studies have shown that Dan Shen’s therapeutic
benefit is nearly comparable to GTN. Furthermore, Wax Gourd 0.001 - 0.006 35.8 - 68.0
Dan Shen does not produce the tolerance that
Cucumber 0 - 0.011 1.2 - 14.3
normally develops with most organic nitrates;
inorganic nitrates seem to be free of this restriction. Nightshade
Similarly, Bryan’s research group has looked at various Eggplant 0.007 - 0.049 25 - 42.4
commonly consumed western vegetables and their
Volume 3 Issue 10 ADVANCES in orthomolecular research 9

12. NO and Reduction of Blood Pressure
Nitrite
blood pressure (mmHg) concentration (μM)
Hypertension or high blood pressure is defined as a
concentration (μM)
400 Nitrate 0.8
Blood nitrate
Systolic Blood Pressure (SBP) of 140 mmHg or higher Systolic blood
Blood nitrite
pressure
or a Diastolic Blood Pressure (DBP) of 90 mmHg or 200 0.4
higher, with normal blood pressure being defined as
120/80 mmHg or lower. However, the risk of negative
0 0
health effects and death is increased in individuals 3 6 12 24
0
whose blood pressure is consistently 115/75 mmHg or TIME (H)
Change in systolic
higher, with the risk of cardiovascular disease doubling
with each increment of 20/10 mmHg above 115/75 -5
mmHg. Figure 6. Association of changes in
plasma nitrate and nitrite concentration
High blood pressure is associated with an increased -10
with blood pressure. (from Kapil et al.,
risk of stroke, myocardial infarction (heart attack), 2010)
heart failure, kidney failure and cognitive impairment.
SBP above 115 is the most important determinant of plasma nitrate levels resulting from consumption of
the risk of death world-wide and is responsible for 7- sodium nitrate was accompanied by a reduction in
8 million deaths annually and over 20,000 deaths blood pressure. This suggests that the blood pressure
each year in the United States. In Canada more than lowering effect was due to the nitrate being converted
one in five people (22.7%) of Canadian adults aged into nitrite and then into NO. Although such changes
20 years and older were living with diagnosed in blood pressure appear relatively small, it must be
hypertension. Since approximately 17% of individuals remembered that the dose of nitrate used was not
with hypertension are not aware of their condition, the large; equivalent to a single serving of salad
true prevalence of hypertension is likely higher. The (approximately a plate or 250 g). Even so, these small
statistics in the US are similar, with approximately 22% results could still have meaningful health effects when
of adults living with diagnosed hypertension. It has considered over the lifetime of the individuals. For
been suggested that in moderately hypertensive instance, over the long term, even a small reduction in
patients a 5 mmHg reduction in blood pressure might blood pressure will help reduce the stress put on blood
reduce the incidence of stroke by 22 % and coronary vessel walls due to high blood pressure. Additionally, it
heart disease by 16 %! is important to consider that the study was conducted
The beneficial effects of fruits and vegetables on blood in healthy patients with normal blood pressure levels.
pressure are well known. For example, a comparison It is expected that a significantly greater fall in blood
of the effect of a traditional Japanese diet (with a high pressure would be observed in hypertensive patients.
nitrate content) to that of a diet with low nitrate content Following up on the important findings of the Swedish
(as much as 20-times less nitrate) in the same 25 researchers, Dr. Amrita Ahluwalia and her group in
subjects (a cross-over study), demonstrated a London conducted an elegant study to prove the point
significantly lower DBP by 5 mmHg. that the nitrate rich vegetables can reduce blood
Because vegetables are naturally rich in nitrates it pressure via conversion into NO. Again in a double-
seems reasonable to investigate whether the blind randomized placebo controlled study, healthy
consumption of inorganic nitrate alone, corresponding adult volunteers were given 500 mL of beetroot juice
to the amount present in a plate of salad for example, to drink. The amount of nitrate present in the juice was
could affect blood pressure in healthy subjects. Dr. Jon three times the amount administered in the Lundberg
Lundberg and Dr. Eddie Weitzberg’s group in Sweden study. Three hours after consuming the beetroot juice
tested exactly this hypothesis in a small double-blind there were significant reductions in both SBP and DBP
placebo controlled, cross-over designed study. Sodium of 10 mmHg and 8 mmHg respectively. The beauty of
nitrate in a dose of 7 millimoles of nitrate (see page 2: this study was the clear demonstration of a cause and
What is a mole?) per 70 kg adult male was effect relationship between the nitrate/nitrite and the
administered for three days after which blood pressure reduction in blood pressure. By monitoring plasma
was measured. It was found that DBP was indeed nitrate and nitrite levels as well as blood pressure
reduced by a significant 4 mmHg compared to the levels, the researchers were able to show that
placebo (sodium chloride with equivalent amount of increased plasma nitrate and nitrite levels
sodium). The researchers found that the rise in corresponded directly to a decrease in blood pressure.
10 ADVANCES in orthomolecular research Volume 3 Issue 10

13. There are three noteworthy points that are raised by blocked the NOS enzyme (responsible for NO
this study. First, the half to one hour delay that occurs production via the L-Arginine pathway) with specific
between the intake of juice and the reduction in blood enzyme inhibitors of the enzyme. As a result of
pressure represents the time taken for nitrite to be blocking this enzyme the animals developed
converted to nitrate by the bacteria in the mouth and hypertension. This effect was reduced by administering
then to be converted into NO in the stomach. Second, nitrites in the drinking water. In a more recent 2011
the study demonstrates a dose response relationship, study, this research group has shown that
meaning that the higher the dose the greater the administering nitrates to hypertensive animals (caused
effect. Finally, an exquisite relationship was established by removing the kidney) not only reduced blood
between raised plasma levels of nitrate/nitrite and pressure but also reduced scarring and other damage
blood pressure reduction. For scientists there is no to the tissues in these animals. Furthermore, a much
better evidence than a physiological cause-and-effect lower dose of nitrite that did not reduce blood pressure
relationship, and this study accomplishes this! still protected against kidney damage, suggesting the
A second study by Dr. Ahluwalia’s group provided use of much lower doses of nitrates as a preventive
further evidence, and also demonstrated that the measure. More studies are needed in this exciting
blood pressure effect they observed could be achieved field.
with a lower 250mL intake of beetroot juice. More
importantly, they showed that the effects of dietary Other CVD Protective Effects of Nitrates,
nitrate from beetroot juice can be sustained over a
Nitrites and NO
longer period, with the reduced blood pressure effects
In addition to their blood pressure lowing effects,
lasting for over 24 hours!
inorganic nitrates have been shown to have numerous
Lundberg and Weitzberg’s group have also used other cardiovascular protective effects including
animal hypertensive models to provide further improved endothelial function, improved platelet
evidence of the benefits of inorganic nitrates for function, a reduction in the symptoms of metabolic
reducing blood pressure. In one of these models they syndrome and improved oxygen delivery to the tissues.
A Note on Sunlight: Is it good for your Heart?
In a recent publication of the European Heart Journal Dr. Martin Feelisch takes a deeper look at this question. Although there
is a definite relationship between UV light as a predisposing factor for non-melanoma and melanoma skin cancers especially
in light skinned people, there is fair amount of data suggesting that exposure to sunlight can reduce blood pressure as well
as offering other health benefits. Previous researchers have attributed these benefits to the formation of vitamin D and
melatonin by the skin, however, Dr. Feelisch presents a novel hypothesis to explain this phenomenon. He suggests that there
is also a benefit due to the skin acting as a significant storage site for NO in the form of nitrate and nitrate from the diet. In
fact the skin has a significantly higher nitrite concentration than the blood.
A recent human study has demonstrated that UVA radiation can increase plasma nitrite levels by over 40%. A similar
increase in animals has been shown to offer significant cardiac and circulatory protection. In addition, all-cause mortality risk
is tightly related to latitude, and seasonal variations in light intensity are correlated with seasonal variations in the incidence
of CVD-related events and deaths. Rates of strokes, angina and heart disease are all higher in the winter months than
summer. Of course other factors like diet and exercise need also to be taken into account. Dr. Feelisch argues that since nitrate
and nitrite levels are under dietary control it could be possible to greatly enhance plasma levels and thereby allow the body
to produce NO on demand, where and when the body desires to achieve optimal health benefits.
Volume 3 Issue 10 ADVANCES in orthomolecular research 11

14. Diseased
Healthy Vessel
Vessel Endothelial Dysfunction
Build up of Arterial Plaque
Reduced Vessel Elasticity
Decreased Blood Flow
Decreased Oxygen Delivery
Decreased Limb Function
Nitrite &
NO
Improved Endothelial Funtion
Increased Vessel Elasticity
Increased Vessel Growth
Increased Blood Flow
Increased Oxygen Delivery
Increased Limb Function
Figure 7. A comparison of a normal healthy blood vessel and a diseased showing damaged endothelial cells and a
build-up of atherosclerotic plaque. The figure shows the beneficial effect of nitrite therapy on diseased blood vessels.
(from Patillo et al., 2011).
The human circulatory system is the largest organ in cause damage to the fragile endothelial layer. For
the body. The health of this enormously important example, high blood pressure results in an excess of
system depends on the proper functioning of a specific mechanical sheer forces to be exerted on the layer,
type of cell that lines the inside of the blood vessels. which can damage the endothelial cells. On the other
These cells are called endothelial cells, and they form hand, tobacco smoke may damage the cells by
the lining of every blood vessel in your body, from the causing an excessive generation of free radicals or
large aorta to the tiniest capillaries. The endothelial reactive oxygen species. As the name implies these are
layer is only one cell thick and plays a vital role in the highly reactive molecules, and they can attack the
health of the blood vessel. Any abnormality or endothelial cells, damaging them. Similarly, poor diet
damage leads to these cells leads to a condition called in the form of excessive consumption of sugar or
endothelial dysfunction, which is thought to be a key cholesterol can initiate endothelial damage. In each
initiating factor in the pathology of CVD. case, the net result is the formation of plaques in the
High blood pressure, inhaled or ingested toxins (e.g. blood vessels. These plaques are highly dangerous as
tobacco smoke), excessive alcohol intake, poor diet they can cause the rupture and release of blood clots,
(e.g. excessive cholesterol or sugar) and stress can all resulting in further damage to distant sites and can
12 ADVANCES in orthomolecular research Volume 3 Issue 10

15. also lead to blood vessel blockage - causing heart innate tendency towards “togetherness’, in other
attacks or strokes. Once the damage to endothelial words they tend to aggregate or clump together. In
cells begins; it is like a chain reaction, with the normal circumstances this is a good thing, since the
damage spreading from endothelial cell to endothelial clotting caused by platelets is required to prevent
cell. Essentially, one plaque breeds more plaques, excessive blood loss when an injury occurs. However,
causing inflammation to spread like wildfire and platelet adhesion, activation and aggregation are also
contributing to atherosclerosis of the blood vessel. known to be key factors in the progression of
Atherosclerosis is a build-up of plaque inside the atherosclerosis and thus, modulation of platelet
arteries, which can thicken and harden over time (see function is an important therapeutic strategy for the
Figure 7, next pg). This results in a loss of blood vessel prevention of atherosclerosis. Both beetroot juice and
elasticity and flexibility which is critical to how the potassium nitrate have been shown to reduce platelet
blood vessel responds to pressure changes. Any blood aggregation. Reduced platelet aggregation or
vessel that has reduced elasticity will have increased “stickiness” not only helps to prevent the inappropriate
pressure inside it. clumping of cells that can lead to colt formation and
Endothelial cells are also important because they are artery blockage, but also allows blood flow to take
one of the key sites in the body where NO is place more easily thereby reducing the burden on the
synthesized. NO acts as a local signaling molecule heart.
and hormone to the neighboring cells, allowing for
monitoring of the environment in the vessel and A B C
VESSEL DIAMETER
ensuring that proper blood pressure and other factors
( nmol/L)
10
10
0.8
0.8
300
300
% CHANGE IN
( mm )
are maintained. NO also has direct actions on the 0.7
0.7
250
250
blood vessel itself. It can travel to the smooth muscle 8 8
0.6
0.6
cells located directly beneath the endothelial cell lining 200
200
0.5
0.5
where it caused vasodilatation or widening of the 6 6
0.4 150
blood vessels. In a situation where excessive free
0.4 150
4
radicals are present, NO is unable to do its job
4
0.3
0.3
100
100
properly since the free radicals will act to “mop” up the 0.2
0.2
2 2
NO, reducing the amount of NO that is able to act to 0.1
0.1
50
50
cause vasodilatation, which is not a good thing! 0 0 00.0 00
Studies using genetic knockout mice (see page 2) that Flow mediated dilation
(vessel elasticity)
Blood vessel thickness Nitrite levels
in the blood
lack the endothelial NOS enzyme have shown that
Healthy Individuals with
these animals are highly prone to cardiovascular Individuals endothelial dysfunction
complications. However, nitrite supplementation was
able to reduce such endothelial disturbances and help Figure 8. The association between blood nitrite levels and
to prevent resulting damage. The Ahluwalia study endothelial dysfunction. Healthy individuals show high nitrite levels
discussed above showed a similar beneficial effect in which are associated with high levels of artery elasticity. Individuals
humans. They found that beetroot juice effectively with endothelial dysfunction show low nitrite levels, reduced artery
reduced endothelial damage as assessed by various elasticity and thicker artery walls.
inflammatory markers like C-Reactive Proteins (CRP).
Recently, a direct relationship between reduced Metabolic Syndrome
endothelial damage and plasma nitrite levels has In 1985, Reaven coined the term Metabolic Syndrome
been established in humans (see Figure 8). Overall, to describe a cluster of symptoms that often appear
the data points towards a very important role for together and may have a common initiating or
nitrate/nitrite in the preservation and support of causative event. This cluster of symptoms include:
healthy endothelial function. obesity, hypertension, high lipid/cholesterol levels and
diabetes. These deadly conditions are the four
Platelet function horsemen of the apocalypse that have targeted one
Platelets are cells present in the blood that are distinct quarter of the world’s adult population.
from the other two major blood cell types, red and Collectively, these four conditions act to increase the
white blood cells. The primary function of the platelets risk of CVD in a synergistic fashion, meaning that the
is to aggregate at sites of damage causing clotting. risk increases exponentially rather than additively as
Platelets are able to cause this clotting due to their more and more factors become involved.
Volume 3 Issue 10 ADVANCES in orthomolecular research 13

16. Animal studies using knockout mice lacking the NOS
enzyme gene (thus preventing NO formation) result in
full-blown metabolic syndrome. Various researchers Metabolic Syndrome:
have suggested that metabolic syndrome may be due
to a deficiency of NO. Addition of nitrate and/or nitrite
Are you at risk?
Metabolic Syndrome is characterized by the following
to the drinking water of these knock-out mice has been collection of symptoms:
shown to protect the animals, significantly reduces
their lipid and triglyceride levels and also reduces the For Men:
• Waist circumference > 40 inches • Triglycerides > 150 mg/dL
incidence of diabetes and weight gain. These results • HDL Cholesterol < 40 mg/dL • Blood Pressure > 130/85 mmHg
present an intriguing possibility for the prevention and • Fasting Glucose > 100 mg/dL
control of metabolic syndrome in humans, although
human studies are required to verify these results. For Women:
• Waist circumference > 35 inches • Triglycerides > 150 mg/dL
Ischemia • HDL Cholesterol < 50 mg/dL • Blood Pressure > 130/85 mmHg
• Fasting Glucose > 100 mg/dL
Ischemia occurs when there is a lack of oxygen
delivery to tissues, often due to partial or complete
obstruction of blood flow. For example, endothelial
dysfunction leading to atherosclerosis can result in reduced to NO. This production of NO during
ischemia. Angina (chest pains), heart attacks and ischemic events is the body’s way of protecting the
strokes are examples of ischemic events. When cells and tissues during periods of reduced oxygen
ischemia occurs, the tissues that are deprived of blood supply. Studies in mice and rats have shown that an
and oxygen suffer irreversible damage which can infusion of nitrite during an ischemic event can
result in death. Tissues like the heart, the kidneys and significantly improve recovery and reduce tissue
the brain are particularly sensitive to an interruption in damage and death in the heart, lungs, kidney and
blood supply. Besides helping to reduce the incidence liver. Other animal studies have also found that
of ischemic events in the first place through its ability pretreatment with inorganic nitrate helps to enhance
to widen the blood vessels (thereby improving oxygen blood flow to damaged areas following an ischemic
delivery to the tissues) and through its improvement of event, which can help to minimize damage. Overall,
endothelial function, NO can also have direct effects the evidence points to a preventative and protective
in the prevention of ischemic injury. Animal studies effect of nitrates and NO for ischemia. Further studies
have shown that during ischemic events, low oxygen in humans will provide further support for the role of
acidic conditions result, which causes nitrite to be nitrates in these conditions.
CARDIO NOX CardioNOx combines
nitric oxide enhancing
nitrates with co-enzyme
Q10 for superior
cardiovascular support
TECHNOLOGY
14 ADVANCES in orthomolecular research Volume 3 Issue 10

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18. For example, Lundberg and Weitzberg’s group in
NITRIC OXIDE , Sweden conducted a small human randomized
double-blind-placebo-controlled study, where healthy
male athletes were given a dose of 7 millimoles of
inorganic nitrate for three days prior to an episode of
EXERCISE AND
low-intensity exercise on a cycle. This dose of the
nitrate corresponded to the amount of nitrate that
would be found in a plate of salad.
ENDURANCE
It is widely recognized that exercise improves a
plethora of cardiovascular symptoms including
cholesterol, blood pressure, risk of stroke, vascular
inflammation, and many others. Furthermore,
researchers in the field of Applied Physiology and
Sports Medicine have found that exercise also
improves the function of the heart, accelerates cardiac
rehabilitation, controls congestive heart failure (a
condition where the heart is unable to pump the blood The researchers showed that supplementing with even
efficiently) and prevents intermittent leg pains caused this low dose of nitrate significantly improved the
by poor blood flow due to blockage and hardening of performance of the athletes as measured by amount
the arteries. of oxygen being consumed (Vox). In other words,
consumption of nitrates reduced the body’s demand
Recent research seems to suggest strongly that the for oxygen during exercise. Furthermore, in addition to
benefits of exercise on cardiovascular health are in reducing the body’s oxygen requirement, or “oxygen
large part due to raised NO levels. Exercise increases cost”, the researchers also noticed that the time taken
the production of NO by the endothelial cells. Since to reach exhaustion was also increased. This suggests
NO is a potent vasodilator and increased production that consuming nitrates prior to exercise can actually
of this molecule causes blood vessels to become reduce and/or prevent exercise fatigue! In a follow-up
relaxed and widened, thereby allowing more blood study by the same research group showed that nitrates
flow and increased oxygen delivery to the body’s acted in the same positive way when athletes
tissues. Lack of exercise, improper diet and lifestyle performed high intensity exercise as well!
and ageing will all eventually lead to reduced NO
generation at the tissue level, and particularly in the These findings were further supported by the British
blood vessels, resulting in a consequent worsening of researchers at Exeter University. Led by Dr. Nigel
cardiovascular symptoms. Benjamin, one of the pioneers of the nitrate/nitrite/NO
research, this group used beetroot juice instead of
Although it is acknowledged that exercise positively sodium nitrate. The effect of beetroot juice was evident
influences NO levels one wonders if the reverse is also as quickly as 1 hour after consumption, and reached
true. Namely can higher NO levels improve exercise maximum effect after three hours. The studies using
capacity? beetroot juice confirmed the findings that nitrates
Again researchers at University of Exeter in the UK and reduce oxygen consumption and fatigue during
the Karolinska Institute in Sweden have looked into this exercise. A second study by the same British group
phenomenon in great detail and have independently showed a similar effect when beetroot juice was taken
come up with some surprising findings! Essentially for a longer time period of 15 days. In other words,
these researchers have found that raising NO levels the positive effects were still evident when nitrates were
can indeed have a positive impact on exercise capacity being consumed on a longer term basis. This was not
and endurance! solely an acute phenomenon!
16 ADVANCES in orthomolecular research Volume 3 Issue 10

19. Interestingly, both the British and Swedish studies explain its cell protective effects. At the cellular level,
noted that there was no increase in production of lactic NO acts to reduce the generation of reactive oxygen
acid in the athletes consuming nitrates! Lactic acid species, which prevents cellular and DNA damage and
production normally occurs following exercise and is also helps to prevent apoptosis or cell death.
one reason why athletes become fatigued. As oxygen In terms of athletic performance, the potential benefits
becomes rate limiting, and tissues start becoming of inorganic nitrates are enormous. For athletes, this
starved of oxygen, the body resorts to an alternative, small, but important molecule may open the door for
less efficient mechanism of energy production that improved performance without the negative health
produces lactic acid as a by-product. However, these and legal implications associated with other sport
studies demonstrated that in the presence of NO, enhancing drugs!
energy production in the muscles remains efficient,
which in turn improves the body’s ability to tolerate
high intensity exercise for longer time periods. It has
been shown that nitrate supplementation prevents the
EXERCISE
depletion of a key muscle protein called Increased blood flow and vascular shear
phosphocreatine; phosphocreatine measurements are stress due to increased blood pressure
an indicator of energy usage in the form of ATP .
Research results have suggested that nitrates cause
muscle contractions to use less energy. Blood Vessel
Skeletal Heart
Increased production of
Maximal
Muscle NO from L-Arginine
Mitochondrial Mitochondrial Energy
Efficiency Production NO
2.0 150
120
NO2 -
1.5
ATP ( % of placebo )
Increased nitrite storage
90
1.0
60 Heart NO2 -
0.5
30 Oxygen levels decrease as
exercise intensity and duration increase
0.0 0
placebo nitrate placebo nitrate In response to
Low oxygen levels can ischaemia the
cause cardiac ischaemia body mobilizes NO
from its stored nitrite
Figure 9. Graph showing improvements to mitochondrial function
associated with an increased intake of dietary nitrate. Higher NO availability
enhanced
nitrate levels were shown to improve two key measures of
NO
mitochondrial function: the efficiency of energy (ATP) production
(as measured by oxidative phosphorylation ratio) and also the
maximal energy (ATP) production. This means that increasing THE HEART IS
dietary nitrates enables mitochondria to produce more energy
more efficiently!
PROTECTED
Nitrite has also been shown to interact directly with the
Figure 10. Diagram showing the stress imposed by exercise on
mitochondria; the cellular powerhouses or energy tissues like the heart and how nitrate/nitrite can increase NO
generating factories of the cells. Mitochondria produce availability and protect the heart tissue when oxygen is limited
energy in the form of ATP which is the energy currency
,
that all cell processes require to function. Dr. Sruti However, the significance of all of these findings
Shiva at the University of Pittsburg School of Medicine extends far beyond the field of exercise physiology. For
has studied the complex actions and interactions of instance nitrates could be of great benefit to
NO at the mitochondrial level and proposes that the individuals suffering from reduced motility or exercise
unique exercise enhancing effects of inorganic nitrates capacity. The ability of NO to reduce muscle energy
and vegetables rich in nitrates may well be due to their use and extend the time to fatigue could be highly
specific interactions with various enzymes involved in beneficial to ambulatory convalescing patients, seniors
energy production in the mitochondria. These and heart patients who have a reduced exercise
interactions not only explain the exercise enhancing capacity and require assistance in recovery times from
and oxygen sparing effects of NO but also help to their illness.
Volume 3 Issue 8
10 ADVANCES in orthomolecular research 17

20. Maintaining healthy colonies of bacterial flora
Nitric Oxide and throughout the GIT is essential for good health.
Unfortunately, this delicate balance is easily disturbed
by poor diet, an unhealthy lifestyle, the use of certain
prescription medications like antibiotics and many
Gastrointestinal other factors.
INTESTINAL MICROFLORA
Health 1000 Billion Microorganisms comprising over 500 Different Species
Lactobacilli
Stomach 1 to 10 thousand
The explosion of NO research in recent years has been
accompanied by some provocative, brilliant and trend Streptococci
Lactobacilli
setting findings about this simple molecule. NO plays 100 thousand to 1 million
Small
a critical role in the health of the gut by protecting Enterobacteria Intestine
against various bacterial invaders and by maintaining Enterococcus
Faecalis
the integrity of the stomach lining, called the gastric Bacteroides 10 thousand to 100 million
Bifidobacteria
mucosa. The gastric mucosa is a layer of mucous that Peptococcus
lines the inside of the stomach, and it essential for Peptostreptococcus Large
Ruminococcus Intestine
protecting the cells of the stomach, and the rest of the Clostridia (colon) 10 billion to 10 trillion
body, from the acidic environment within. Lactobacilli
The human gastrointestinal tract (GIT) is a long
Figure 11. The bacteria or “microflora” of your gastrointestinal
winding tube consisting of various types of cells from
tract. A healthy balance of these microorganisms is essential for
the mucosal cells in the mouth to the epithelial cells of maintaining good health.
the intestines and everything in between. Proper
functioning of the GIT is crucial for the maintenance of In the mouth, saliva plays a critical role in not only
optimal health. However, the GIT and its cells must lubricating the food to facilitate swallowing but also in
constantly cope with a complex assortment of friendly the production of key enzymes that begin the digestive
and pathogenic bacteria, yeasts, toxins, chemicals, process. Humans produce approximately 1 liter of
enzymes and nutrients like fats, carbohydrates, saliva per day. This salvia is produced in the mouth
proteins and fiber. Further adding to the enormous and eventually makes its way into the stomach.
complexity of this task is the fact that all of this must Nitrates obtained from the diet (for example from the
take place across a wide range of pH levels, from consumption of lettuce, beetroot, spinach, leeks etc.)
acidic, to neutral to alkaline. are rapidly converted into nitrite by a specific type of
bacteria housed on the surface of the tongue. Spitting
or not swallowing the saliva following consumption of
Gut Microflora and NO the above nitrate rich foods results in a lower nitrite
In terms of cell number, bacterial cells in the GIT concentrations in the blood; hence the age-old but
outnumber human cells by a staggering 9 times! These sensible advice, “eat your greens but don’t spit”.
bacterial cells encompass many different species and Similarly, the use of mouthwash also results in lower
have a wide range of functions – some of them friendly blood nitrite levels due to the destruction of the
and some of them detrimental. For example, some bacteria on the tongue. It is therefore advisable not to
bacteria in the gut are responsible for the synthesis of use mouthwash immediately after eating vegetables,
certain essential nutrients like B vitamins, vitamin K so as not to negate the benefits of these nitrate rich
and folic acid, others are important for facilitating the foods. A better strategy would be to drink a cup of
absorption of nutrients like calcium, and still others green tea after consuming a plate of salad or spinach;
produce harmful toxins. Real estate in the GIT is highly this is a healthy alternative that will not destroy these
sought after, resulting in intense competition between important nitrate reducing bacteria. It is also important
all the different bacteria for nutrients and space. The to note that the conversion of nitrates into nitrite is
two key sites with the highest density of the bacterial enhanced by the presence of certain natural
cells are the mouth and the large intestines. compounds like vitamin C, and antioxidants like the
18 ADVANCES in orthomolecular research Volume 3 Issue 10