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Nitric Oxide

What is Nitric Oxide?

Nitric oxide is an air pollutant, lung irritant, and overall toxic gas that is a byproduct of many industrial processes such as combustion of fossil fuels and is one of the hazardous components of smog and acid rain. This noxious gas has also been implicated as an offending substance related to chemical burns. So what is this gas doing in the human body? And further, why is it produced by the human body?

In 1977 it was discovered that nitric oxide was involved with signaling the smooth muscle of the artery wall to relax, thereby lowering blood pressure in the system. It took ten more years before it was discovered to be the molecule responsible for regulating blood pressure, preventing clumping of red blood cells, and thereby preventing atherosclerosis (plaque) in the artery wall. Because cardiovascular disease was then, and is now, the leading cause of death in the industrialized world, this discovery is considered today to be the most important discovery in history pertaining to the cause and prevention of heart attack and stroke. Indeed, in 1992 nitric oxide was hailed as "molecule of the year", and in 1998 the Nobel Prize for Medicine and Chemistry was awarded to the three scientists responsible for it's discovery.

Over half million people will die in the US this year due to heart attack or stroke, and although aging is inevitable and is a basic risk factor in cardiovascular disease risk, the primary risk factor for those as young as forty years of age is the inability to produce adequate nitric oxide levels.

Since the discovery of nitric oxide there has been a veritable avalanche of research published in the medical literature - over 130,000 studies espousing nitric oxide health benefits to date. 90% of those have been published since the 1998 Nobel Prize was awarded. Despite this deluge if positive information, the general public is still woefully unaware of the critical role nitric oxide plays in the prevention of disease. Although the Nobel Prize was awarded specifically for the impact nitric oxide has on heart attack and stroke risk, it has since been discovered to be responsible for the healthy functioning of the brain, kidneys, liver, intestines, peripheral nerves, and the immune system. Nitric oxide is involved in the proper function of virtually every organ in the human body and consequently many researchers often refer to degenerative diseases of aging as "diseases of nitric oxide decline".

How is Nitric Oxide Produced?

There are three enzymes used in the body to produce nitric oxide. The precursors to it's production come from organic nitrates and nitrites in leafy green plants such as kale, spinach, swiss chard, etc. Beets also have an extraordinary amount of nitrate that can be used by the body to promote nitric oxide production. Pomegranate, cocoa, hawthorn berries, blueberries, black tea, green tea, red wine and other functional foods contain polyphenols that magnify the production of nitric oxide, especially in the artery walls. Kale is absolutely the best source of nitric oxide precursor, with beets following close behind.

The first and most abundant source of nitric oxide comes from the enzyme known as eNOS (endothelial nitric oxide synthase). This enzyme is used by the endothelium to produce large quantities of nitric oxide, which thereby relaxes the artery wall and lowers blood pressure in the cardiovascular system. The endothelium (pronounced en-doetheel-ee-um) is a single-cell thick lining that coats the internal artery wall. The adult human body has roughly 60,000 miles of blood vessels coursing through it, and aside from veins and capillaries the arteries comprise almost a third of that distance. So if you were to remove the single-cell-thick endothelium and spread it out it would cover a standard soccer field, making the endothelium the largest organ in the human body. This huge organ (the endothelium), produces massive quantities of nitric oxide to regulate blood pressure within the arteries, which is an effect that is impossible to exaggerate with regard to importance for two reasons:

High blood pressure is the primary cause of damage to the internal artery wall, and it is this damage that leads to a cascade of events which culminates in the formation of plaque (atherosclerosis) along the artery wall. This further raises pressure within the arterial system, creates more damage to the artery, and leads to further plaque. This inevitably leads to a heart attack or stroke -- the leading cause of death.

Relaxation of the artery allows for maximum blood perfusion into all regions of the body. Since no cells can live without a blood supply, adequate blood perfusion is essential to the life and health of all cells, tissues, and organs.

The second most abundant source of nitric oxide comes from the nervous system, which is comprised of our brain, spinal cord, and peripheral nerves. The enzyme involved is called nNOS (neuronal nitric oxide synthase). This is crucial due to the fact that the nervous system uses nitric oxide to ensure proper function of neurotransmitters such as serotonin, dopamine, glutamate, and acetylcholine to co-ordinate and control every function within the human body. The brain acts as the master controller of every aspect of life and healthy function, right down to the cellular level. The accuracy of this control is dependent upon proper signaling between nerve cells (neurons), which results in proper balance of neurotransmitters. This becomes doubly important to those individuals taking prescription drugs that alter the delicate balance of these neurotransmitters such as Prozac, Xanax, Elavil, Pristiq, Wellbutrin, Zoloft, etc, etc simply because neurons can not respond appropriately to increases in neurotransmitters if nitric oxide production is compromised. This may lead to increased dosages of these drugs and this in turn may lead to serious side effects that are often life threatening. Simply put, the drugs work better when the neurons are healthier and more sensitive to signaling from surrounding neurons, and this requires adequate production of nitric oxide by the neurons.

The third enzyme used in the process of nitric oxide production is iNOS (inducible nitric oxide synthase) and it is used by the immune system, or more specifically immune cells called macrophages, neutrophils, and monocytes to destroy invading pathogens such as bacteria, viruses, and fungi. iNOS used by the immune system leads to the only proinflammatory effect of nitric oxide, as it is used to destroy cells. This is important in the prevention of cancer since the immune system must recognize and destroy mutated cells before they become cancerous. Trouble arises when the immune system accidentally mistakes our own normal cells for foreign invaders and attacks them as such. This is known as “autoimmunity”: when the immune system attacks and destroys normal healthy tissue. Rheumatoid arthritis, Hashimoto’s thyroiditis, Type I diabetes, Ulcerative Colitis, Psoriasis, Stiff Person Syndrome, and many other common ailments are all considered autoimmune. Although Nitroxyl is formulated to favor the eNOS and nNOS production of nitric oxide (as opposed to L-arginine based formulas), many individuals with autoimmune conditions will not benefit from its use due to an overactive production of iNOS which can be enhanced by any substance which drives the production of nitric oxide in general (see dosage instructions tab above). However, there have been hundreds of patients with autoimmune disorder who have benefitted greatly from the supplementation with Nitroxyl in a clinical setting.

To summarize: the production of nitric oxide by the lining of the arteries and by the nervous system results in anti-inflammatory protection of the heart, arteries, brain, peripheral nerves, and skin, and functions to keep these tissues healthy and slow the effects of aging. Since circulation and blood perfusion is required for the survival of all living cells within the body, the ability to produce nitric oxide in the artery wall is essential to the survival of the cells and therefore the whole body. It is the reduced ability of the endothelium to produce nitric oxide that leads to aging in general and many of the degenerative diseases associated with aging such as arthritis, wrinkling of the skin, graying of the hair, loss of flexibility, erectile dysfunction, reflux, constipation, inflammatory bowel, heart attack and stroke, peripheral neuropathy, etc. The production of nitric oxide by the brain / nervous system is crucial to properly balance neurotransmitters and to ensure proper signaling from the brain to the rest of the body. When there is not enough nNOS-produced nitric oxide in the brain, there is often an increase in iNOS by immune cells in the brain, which creates inflammation and overexcitation in neurons (brain cells) and this leads to neurodegenerative disease such as Alzheimer's and Parkinson's disease, and senile dementia.

Sustaining Nitric Oxide Production

Our ability to produce and sustain nitric oxide peaks at approximately 25 years of age, and afterward our levels begin to decline slowly. The speed of decline accelerates dramatically at 40 years of age, which is why so many people feel that after 40 “everything falls apart”. Indeed, many nitric oxide researchers now refer to degenerative diseases of aging as "diseases of nitric oxide decline". This has been born out in the medical literature as well. Individuals with higher nitric oxide production by the endothelium and the nervous system live longer and have drastically reduced incidence of disease, and maybe more importantly report much higher quality of life as compared with those individuals who do not have high production through eNOS and nNOS.

It may come as no surprise that our ability to sustain nitric oxide production comes from dietary and lifestyle factors primarily (although genetics play a role as well). A diet that is plant-based and is comprised of plenty of leafy green vegetables, berries, apples, black and green tea, cocoa, beets, and pomegranate will yield the best precursors for nitric oxide production in the arteries and brain. Diets heavy in saturated fats from animals, and too much animal protein will result in compromised production of nitric oxide. Extra virgin olive oil consumption has also been shown to improve nitric oxide production, which is a primary reason for the health benefits of the mediterranean diet.

Exercise also plays a key role in healthy nitric oxide balance. Taking a brisk walk for at least 30 minutes per day, five days per week, is essential to brain and artery nitric oxide production and has been shown to be as effective as Zoloft for the treatment of mild depression. Also short-term, high intensity training has been shown to improve nitric oxide balance (increase endothelial and neuronal production while regulating proinflammatory iNOS production) and this type of exercise may only take 5-10 minutes depending on individual fitness level.

Relaxation techniques and therapies such as meditation, massage, yoga, tai chi, sauna, acupuncture, and even lots of laughter have all been proven to improve nitric oxide levels.

How Do We Boost Nitric Oxide Production

All of the strategies mentioned above must be incorporated to some degree, especially after the age of forty, to improve nitric oxide production and balance. In addition, for individuals over forty years of age there is a huge advantage to using some key nutrients to boost the production of nitric oxide in the body. Nitroxyl is comprised of all of the key nutrients that have been overwhelmingly proven in the medical literature to improve nitric oxide benefits and production. But it's not just what is in Nitroxyl that makes it the best formula available on the market today: it's what’s missing.

The Problem with L-Arginine

Although the benefits of nitric oxide supplements may be profound it is wise to be aware of the presence of L-arginine. Since arginine (an amino acid) was discovered to be involved in the biochemical pathway that leads to nitric oxide production, many supplement manufacturers were quick to produce supplements that delivered massive doses of it for the purpose of facilitating the production of nitric oxide. While there is no question it works, there are some problems. Since only about 3% of the arginine supplemented contributes to increased production of nitric oxide, very high doses are required to achieve any significant increase of this precious gas. And the production occurs indiscriminately, meaning there is typically an increase in all three enzymatic pathways: the two anti-inflammatory pathways through eNOS and nNOS, and also the pro-inflammatory / catabolic pathway through iNOS. Historically and currently, it is most often body builders who use nitric oxide supplements, and the L-arginine based supplements can drive inflammation which can lead to injuries from training such as tendonitis, bursitis, torn rotator cuffs, torn meniscus, etc. Also, many individuals are unaware of non-symptomatic (sub-clinical) autoimmune processes and the increase in iNOS production of nitric oxide by the immune system can send these people into fullblown autoimmune disease states, and this is often life threatening but at the very least will shorten life span and destroy quality of life. Arginine will travel through eight different metabolic pathways when supplemented in high doses, and the resulting uncertainty in how it will affect each individual is another cause for concern and further research.

Nitroxyl is formulated instead with L-citrulline, another amino acid which is involved further “upstream” in the biochemical pathway involved in nitric oxide production. This is like the difference between using a shotgun vs. a rifle with a laser scope. Instead of eight separate biochemical pathways used as in the case of L-arginine, L-citrulline goes straight to the final steps in the production of nitric oxide, and has been proven safe to use even in high quantities. One study conducted in The Netherlands sought to determine whether L-citrulline was any different from L-arginine in terms of whether or not either could increase the anti-inflammatory eNOS derived nitric oxide and decrease the pro-inflammatory iNOS derived nitric oxide during severe infection and/or systemic inflammation, because this is considered an extremely important therapeutic intervention.

Quoted from the study: "In conclusion, L-Citrulline supplementation during endotoxemia and not L-Arginine reduced intestinal microcirculatory dysfunction and increased intracellular nitric oxide production." (Note: endotoxemia is a massive inflammatory response secondary to infection).

Polyphenols: Protecting Plants and People

Many plants contain high levels of compounds called polyphenols, which serve to protect them from ultraviolet radiation, bacteria, insects, fungi, and even plant-eating animals (due to the bitter taste). They also provide bright color to attract pollinating insects and seed-dispersing animals. Polyphenols are powerful antioxidants from plants that provide humans with powerful protection against free-radical damage, which is what drives the aging process and degenerative disease. Hawthorn berries contain several polyphenols that impart cardiovascular protection to humans, and consequently hawthorn has been recognized and used for centuries to treat cardiovascular disease, including high blood pressure. Hawthorn polyphenols nourish and protect the endothelium, which in turn improves nitric oxide production and thereby regulates blood pressure and halts or reverses atherosclerotic plaque formation that leads to heart attack or stroke. Polyphenols found in cocoa and pomegranate are also extremely powerful and are therefore used in combination with hawthorn to maximize the impact from the L-citrulline provided in Nitroxyl.