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April 04, 2013

What's Wrong With Nitric Oxide - Part 3


Ask a cardiologist about the effects of nitric oxide, and there’s a good chance you’ll hear about the chemical’s role in dilating blood vessels, lowering blood pressure, and supporting cardiovascular health.

Ask a neurologist about nitric oxide, and you’ll likely to hear about the widespread cellular damage this chemical can cause, and how an excess of nitric oxide in the brain is now thought to be a major contributing factor to degenerative neurological diseases like Alzheimer’s disease, Parkinson’s disease, and ALS.

And, ask an oncologist for yet a third opinion, and you may hear about nitric oxide’s role in either suppressing tumor growth – as a potent tumor–killing agent of the immune system; or, conversely, its role in stimulating tumor growth by triggering angiogenesis, the formation of the new blood vessels tumors need to survive.

So, clearly, nitric oxide has many varied effects within our bodies – some beneficial, and some very harmful. This is the fundamental reason why so many attempts to manipulate nitric oxide levels, either pharmacologically or nutritionally, have met with failure.

As relates to the cardiovascular system, for example, it was initially thought that increasing nitric oxide levels would be the key to correcting what was simplistically assumed to be a “deficiency” of nitric oxide in cardiovascular disease. But this approach is quickly being abandoned, as a myriad of unforeseen (and sometimes fatal) side effects have accompanied nitric oxide–boosting therapies.

Of course, some nutritional supplement companies, and some health practitioners (whose products and recommendations lag decades behind the actual research) continue to recommend that we indiscriminately increase our nitric oxide levels with various nitric oxide–boosting concoctions. But the flaws inherent in such an approach are now well–documented, even if not yet well–publicized.

In light of what we now know about the often harmful effects of nitric oxide, it seems that we’ll want to do everything we can, not merely to increase nitric oxide levels, but to keep nitric oxide production under tight control throughout the body.

A Brief Review

When produced, nitric oxide rapidly reacts with a chemical called superoxide, to form a particularly damaging chemical called peroxynitrite. It’s now believed that this process is largely to blame for many of the harmful effects of nitric oxide.

When nitric oxide–boosting therapies are employed – like the use of the amino acid precursor to nitric oxide, arginine – or the nitric oxide pro–drug, nitroglycerin, the production of peroxynitrite increases right along with nitric oxide itself. And the result has often been a short–term benefit, marred by longer–term harm.

Recent research has found, however, that we may be able to give our nitric oxide metabolism a nutritional “tune–up,” without increasing our burden of harmful nitric oxide byproducts. The answer lies not in “boosting” nitric oxide, but in supplying our body with the nutrients needed to metabolize nitric oxide safely and efficiently.

In the last Integrated Supplements Newletter, we looked at nutritional factors like folic acid, Vitamin B6, and Vitamin B12 which may reduce homocysteine and simultaneously protect the fragile nitric oxide cofactor, called tetrahydrobiopterin.

We saw how antioxidant nutrients like Vitamin E, Vitamin C, selenium, and whey protein isolate may help to reduce the oxidative stress which constantly threatens nitric oxide metabolism.

We even saw how cocoa flavonols and creatine monohydrate may exert especially beneficial effects on nitric oxide metabolism.

Building on these strategies, we’ll now look at other nutritional factors which will help support proper nitric oxide metabolism in the cardiovascular system and beyond.

This Is Your Brain on Nitric Oxide

In the late 1980’s, an iconic public service announcement on television depicted a frying egg, while an actor sternly warned an entire generation of impressionable Americans, “This is your brain on drugs.” And while this PSA offered a powerful visual metaphor of the effects certain drugs can have on brain function, it may serve us well to look a little deeper into the molecular biology of the matter.

It turns out that much of the toxicity associated with neuro–active drugs is ultimately due to the actions of nitric oxide. In fact, the chemical inhibition of the enzymes which produce nitric oxide has been shown to abolish the toxicity associated with both methamphetamine and cocaine.

Study Link – Nitric oxide (NO) synthase inhibitors abolish cocaine–induced toxicity in mice.

Quote from the above study:

Repeated administration of cocaine (45 mg/kg/day) for 7 days to Swiss–Webster mice resulted in a progressive increase in the convulsive response to cocaine and augmentation in lethality rate. Pretreatment with the nitric oxide (NO) synthase inhibitors, L–NAME (100 mg/kg/day) or NO–Arg (25 mg/kg/day), prior to cocaine administration completely abolished the sensitization to the convulsive and lethal responses to cocaine. These findings suggest a role for NO in cocaine–induced toxicity.

Study Link – Role of nitric oxide in methamphetamine neurotoxicity : Protection by 7–nitroindazole, an inhibitor of neuronal nitric oxide synthase.

Quote from the above study:

These findings indicate a role for nitric oxide in methamphetamine–induced neurotoxicity and also suggest that blockade of NOS may be beneficial for the management of Parkinson's disease.

And you don’t have to be a drug–user to be susceptible to the neurotoxic effects of nitric oxide. The damage caused by nitric oxide and its metabolites has been very strongly linked with age–related brain degeneration, and disorders such as Parkinson’s disease, ALS, and Alzheimer’s disease.

Study Link – Nitric oxide neurotoxicity.

Quote from the above study:

NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO−), the reaction product from NO and superoxide anion.

Study Link – Widespread Peroxynitrite–Mediated Damage in Alzheimer's Disease.

Quote from the above study:

These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer's disease.

Studies have found, as well, that mice bred to be deficient in one of the nitric oxide–producing enzymes had decreased mortality, and were significantly protected from many of the manifestations of Alzheimer’s disease:

Study Link – Protection from Alzheimer's–like disease in the mouse by genetic ablation of inducible nitric oxide synthase.

Quote from the above study:

Deficiency of iNOS substantially protected the AD–like mice from premature mortality, cerebral plaque formation, increased ß–amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of ß–amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

And, in addition to degenerative brain diseases, nitric oxide has also been implicated in other neurological disorders such as migraine headaches:

Study Link – Nitric oxide is a key molecule in migraine and other vascular headaches.

Study Link – Nitric oxide–induced headache in patients with chronic tension–type headache.

Study Link – Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain.

The following study even found that those with migraine headaches may be at increased risk of developing Alzheimer’s disease later in life. The common role of nitric oxide in each disorder helps to explain why.

Study Link – Risk factors for Alzheimer's disease: a population–based, longitudinal study in Manitoba, Canada.

Quote from the above study:

The association of AD with a history of migraines and occupational exposure to defoliants/fumigants is of particular interest because these are biologically plausible risk factors.

Nitric oxide is even suspected to play a major role in the development of the chronic ringing in the ears known as tinnitus:

Study Link – The NO/ONOO– cycle as the etiological mechanism of tinnitus.

Study Link – Pharmacological models for inner ear therapy with emphasis on nitric oxide.

At first glance, it may seem ironic that nitric oxide, a compound deemed so beneficial for cardiovascular health, could be so universally maligned for its harmful role in neurological health.

But of course, we now know that there is much more to nitric oxide metabolism than was once assumed. Though a certain amount of nitric oxide is necessary for cardiovascular function, any excess can be decidedly harmful. As we’ll see, the same general principles (ensuring the proper metabolism of nitric oxide) apply when addressing nitric oxide metabolism in the brain and in the neurological system.

Nitric Oxide – Inflammatory Chemical

One of the ways in which nitric oxide can be produced in the body is via an enzyme known as inducible nitric oxide synthase (iNOS). Immune cells, called macrophages, contain iNOS, and can produce nitric oxide to destroy invading viruses or bacteria, or under other conditions of stress and trauma. This means that nitric oxide is an integral part of our bodies’ immune system and inflammatory response, but it also means that the production of nitric oxide by macrophages can very easily spiral out of control.

Unlike endothelial nitric oxide synthase (eNOS, the form of nitric oxide synthase which produces NO in the blood vessels), iNOS can churn out massive amounts of nitric oxide virtually non–stop. This excess nitric oxide (and the metabolites produced from it) can be particularly harmful to the delicate, lipid–rich structures of the brain. And, as we now know, inflammation and tissue damages often proceeds in a vicious downward spiral, perpetuating even more tissue damage and inflammation. This is a major reason why nitric oxide production needs to be kept under control in conditions of stress, aging, and disease.

As we mentioned in previous issues of the Integrated Supplements Newsletter, we ideally want any inflammatory response of our immune system to be “short and sweet” – sufficient enough to deal with the stress at hand, but not excessive enough to cause a self–perpetuating spiral of tissue destruction.

Reducing Inflammation Safely

It’s now widely accepted that all degenerative diseases share the common thread of excessive and uncontrolled inflammation – including the over–production of nitric oxide. But, for as many anti–inflammatory foods, drugs, and supplements as we have at our disposal, reducing systemic inflammation safely still takes a bit of biochemical know–how.

For instance, it’s well–documented that some “anti–inflammatory” strategies may ultimately be destined to do more harm than good. The dangerous side effects associated with the wildly popular COX–2 inhibitor medication, Vioxx® are a chilling reminder of this; and, in the May 2008 edition of the Integrated Supplements Newsletter, we saw how even many of the “anti–inflammatory” fats often recommended by the health–food and nutritional supplement crowd (omega–3s, for example) may predispose us to tissue fragility and destruction when consumed in excess.

On the other hand, when we attempt to reduce inflammation in a physiologically sound manner, we’ll find that the pieces of the puzzle fit together in such a way as to actually give us far–reaching health benefits.

As relates to nitric oxide, we’ll find that some nutritional substances can serve to reduce the excess production of inflammatory nitric oxide produced by the immune system, while at the same time improving the bioavailability of the nitric oxide produced within the cardiovascular system. The most important nutrient offering such a two–pronged benefit is likely to be the often overlooked mineral, magnesium.

Magnesium and Nitric Oxide

According to data from the United States Department of Agriculture, a full 68% of Americans fail to consume the minimum recommended amount of magnesium each day; and a stunning body of scientific evidence indicates that very few nutritional deficiencies are as widespread, or as deadly, as magnesium deficiency.

Many people know that the electrolyte mineral, magnesium, is involved in “electrical” functions of the body like the heartbeat, and nerve impulses, but very few people realize that the presence of a magnesium deficiency leads to an absolutely massive increase in various markers of systemic inflammation.

The list of biological substances increased in the body when magnesium is deficient reads like a “who’s–who” of inflammatory chemicals. C–reactive protein, substance P, cytokines, prostaglandins, histamine, and of course, nitric oxide all become elevated when magnesium levels are sub–optimal.

Study Link – The nerve–heart connection in the pro–oxidant response to Mg–deficiency.

Quote from the above study:

In rodent models of dietary MgD [magnesim deficiency], a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene–related peptide among others, was observed within days (1–7) of initiating the Mg–restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early "neurogenic inflammation" phase may be mediated in part, by the Mg–gated N–methyl–D–aspartate (NMDA) receptor/channel complex. Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory–motor C–fibers to promote the subsequent pro–inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE(2) levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants. Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1–3 weeks MgD) inflammatory/pro–oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co–existing with other pathologies, may enhance the risk of developing chronic heart failure.

And, as relates specifically to nitric oxide, it’s interesting to note that magnesium deficiency has the effect of increasing the “inflammatory” nitric oxide (produced by iNOS), rather than the cardioprotective type produced by eNOS (called constitutive NOS in the following study):

Study Link – Magnesium deficiency in rats induces a rise in plasma nitric oxide.

Quote from the above study:

Magnesium deficiency in rats leads to an oxidative stress involving an increased production of radical oxygen species. The present study was designed to examine the effect of experimental magnesium deficiency on plasma nitric oxide (NO) level and nitric oxide synthases (NOS) activities in rats. The data show that the concentration of NO is markedly increased in plasma of magnesium–deficient rats. This rise in plasma NO results from activation of inducible nitric oxide synthase (iNOS) rather than of the constitutive form (cNOS) of the enzyme. These data are in agreement with previous observations indicating that inflammation occurs during magnesium–deficiency and provide an additional cause of oxidative lesions through formation of peroxynitrite from nitric oxide and superoxide anion.

Study Link – Magnesium–deficient medium enhances NO production in alveolar macrophages isolated from rats.

Quote from the above study:

These results suggest that Mg(2+) deficiency enhances NO production via iNOS by alveolar macrophages.

And knowing that nitric oxide is largely responsible for much of the brain deterioration of Alzheimer’s, it’s interesting to find that there may be a direct correlation between magnesium status and the progression of the disease. The following study found that as magnesium status worsened so too did the progression of Alzheimer’s disease as evidenced by falling scores on cognitive tests:

Study Link – Serum magnesium level and clinical deterioration in Alzheimer's disease.

Quote from the above study:

Our data suggest that there is a relationship between serum Mg levels and the degree of Alzheimer's disease and that the determination of the Mg level at various stages may provide valuable information in further understanding the progression and treatment of Alzheimer's disease.

Because of the multiple roles magnesium plays in reducing systemic inflammation and excessive nitric oxide production, a lack of magnesium can exert effects at every level of biological functioning. As evidence, the widespread magnesium deficiency caused by our modern diet is known to be a major factor in the increasing prevalence of all degenerative diseases of aging, including not only brain diseases, but heart disease, diabetes and cancer as well.

And considering the fact that so few individual foods contain high amounts of magnesium (and the fact that multivitamins never contain sufficient amounts) it’s safe to say that a stand–alone magnesium product is often the single most important nutritional supplement a health–conscious person can take. But, even magnesium alone may not be enough to fully rectify a magnesium deficiency. Other nutritional factors, such as selenium, potassium, vitamin B6, and vitamin D, are also needed for proper magnesium absorption and metabolism.

Study Link – The multifaceted and widespread pathology of magnesium deficiency.

Quote from the above study:

Unfortunately, Mg absorption and elimination depend on a very large number of variables, at least one of which often goes awry, leading to a Mg deficiency that can present with many signs and symptoms. Mg absorption requires plenty of Mg in the diet, [selenium], parathyroid hormone (PTH) and vitamins B6 and D.

Curcumin and Nitric Oxide

In addition to correcting outright nutritional deficiencies, there are many other steps we can take to reduce the inflammatory over–production of nitric oxide.

It seems that nature, in her infinite wisdom, has supplied us with many plant–based anti–inflammatory substances which may impart particularly powerful effects when it comes to scavenging nitric oxide. One of the most notable of such substances is the yellow/orange pigment from turmeric, called curcumin.

Turmeric, a member of the ginger family, is a spice which has been long–used in Indian and Chinese cuisine, and respective systems of medicine. Recent research has uncovered that many of the health–promoting benefits traditionally associated with turmeric may be attributable specifically to curcumin; and interestingly, we find that curcumin may act as a powerful scavenger of nitric oxide.

Study Link – Nitric oxide scavenging by curcuminoids.

Quote from the above study:

The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free–radical scavenging properties, including those toward nitric oxide.

And, although some research indicates that curcumin may be poorly absorbed, there’s reason to believe that curcumin and turmeric may exert their health–benefits despite this fact. Even though turmeric contains only about 3% curcumin at the most, and curcumin is likely to be poorly absorbed, preliminary studies conducted in India (where turmeric is very widely used in cooking) have shown some of the lowest levels of Alzheimer’s disease ever recorded – results which held true for both rural and urban communities:

Study Link – Incidence of Alzheimer's disease in a rural community in India: the Indo–US study.

Quote from the above study:

These are the first AD incidence rates to be reported from the Indian subcontinent, and they appear to be among the lowest ever reported. However, the relatively short duration of follow–up, cultural factors, and other potential confounders suggest caution in interpreting this finding.

Study Link – Prevalence of dementia in an urban Indian population.

Quote from the above study:

In the population surveyed, the prevalence of AD and other dementias is less than that reported from developed countries but similar to results of other studies in India.

If these results have anything to do with turmeric consumption, the chances are good that most of us can benefit from simply adding more turmeric–rich meals to our diet. Curcumin extracts do exist as nutritional supplements, but they are very costly relative to the very inexpensive spice, turmeric.

And research indicates that we can find many other inexpensive ways to reduce the inflammatory effects of nitric oxide as close as the local grocery store. Antioxidant compounds in (green and black) tea, coffee, red wine, cocoa, and pomegranate have all been shown to protect against the inflammatory over–production of nitric oxide.

Study Link – Protection against nitric oxide toxicity by tea.

Study Link – The coffee diterpene kahweol suppress the inducible nitric oxide synthase expression in macrophages.

Study Link – Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway

Study Link – Effects of an aqueous extract of cocoa on nitric oxide production of macrophages activated by lipopolysaccharide and interferon–gamma.

Study Link – Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide.

As we’ve seen in this series of articles, nitric oxide metabolism can be more than a bit complicated. And despite a frenzy of conflicting nitric oxide research, we’ve seen the unfortunate tendency of both the medical community and the nutritional supplement industry to “jump the gun”, and rush to market products based upon dangerous misinterpretations of the scientific evidence.

But, yet again, only as we look deeper into the research, does the big picture become clear. Only then can we address fundamental biological imbalances, and not merely symptoms or biological markers.

And again, we see that carefully–chosen, time–tested natural foods and nutrients offer us the greatest long–term benefit – with little to no risk. The nutrients and foods mentioned in this series of articles are the substances the human body has always needed to support health, but they are often the substances most conspicuously lacking from our modern food supply.

In the final analysis, nitric oxide is just another example of a biological chemical whose actions can seem baffling and paradoxical when we forget to look first to nature for the answers. Only when we remember our role as a part of nature, will the pieces of the puzzle fall neatly into place.

About Us: At Integrated Supplements, our goal is to bring you the wellness information and products you need to live your life to the fullest. We are dedicated to producing the highest–quality, all–natural nutritional supplements; and to educating the world on the health promoting power of proper nutrition. You can find out more by visiting: www.IntegratedSupplements.com


These statements have not been evaluated by the FDA. No Integrated Supplements product is intended to diagnose, treat, cure or prevent any disease.



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