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April 04, 2013

What's Wrong With Nitric Oxide - Part 1


Recently, a group of surgeons performing a bowel resection operation on a young man were alarmed to notice the patient bleeding profusely during the surgery. In a frantic attempt to save the patient’s life, as one standard procedure after another failed to normalize the bleeding, the surgeons were eventually forced to perform a full blood transfusion. Though the operation was eventually a success, the physicians were perplexed, as, according to the patient’s records, he wasn’t consuming any medications which could account for such massive and life–threatening bleeding.

But, with a little biological sleuthing, it was soon found that the patient had been taking a very popular nitric oxide–boosting nutritional supplement sold as an “energy and performance igniter” for bodybuilding training. It turned out that the product contained not only various nitric oxide precursors, but several herbal nitric oxide–boosting ingredients which also happen to be potent blood thinners.

The above situation, relayed to us by one of the surgeons performing the operation, is an extreme but telling example of the dangers of accepting the nutritional supplement industry’s hype at face value. In recent years some supplement companies – especially companies specializing in bodybuilding supplements – have been able to convince their customers that there are benefits to be gained by increasing the body’s levels of the vasoactive chemical, nitric oxide. Yet, in an industry never known to let safety concerns stand in the way of profit, any mention of the potential short and long–term side effects of increasing ones nitric oxide levels has been conspicuously absent.

As a vasodilator, or, substance which dilates blood vessels, nitric oxide is known to influence blood flow as well as nutrient and oxygen delivery to cells; and some companies have speculated that increasing nitric oxide to supraphysiological levels, may result in greater increases in nutrient delivery to working muscles, and a subsequent increase in muscle growth.

Nitric oxide–boosting supplements have also been widely promoted for increasing the muscular “pump” – the localized inflammatory swelling of muscle – which is especially evident during weight training.

But the physiology of the blood vessels and blood flow (what scientists call hemodynamics) is infinitely more complicated than many within the supplement industry would have you believe. Despite the impression you may get from reading bodybuilding and fitness magazines, the study of nitric oxide as a biological chemical is still in its infancy, and looking at the existing scientific literature will give any rational, intelligent person reason to think twice about attempting to increase nitric oxide levels. Although nitric oxide is an important signaling molecule essential for life, there’s also reason to believe that purposefully stimulating its production is wrought with both short–term and long–term risks.

In this edition of the Integrated Supplements Newsletter, we’ll set the record straight on what is really known about the biological role of nitric oxide – in particular, we’ll look at its effects on vasodilation, blood flow, blood vessel integrity, bleeding, hemorrhage, septic shock, energy metabolism, exercise performance, and oxidative stress. And in part two of this series, we’ll look at the long–term effects of nitric oxide over a lifetime, and we’ll examine the integral role of nitric oxide plays as an accelerator of aging and degenerative disease.

Nitric Oxide – From Humble Beginnings

In 1867, Alfred Nobel (for whom the Nobel Prize is named), received a patent for an invention which stabilized the highly explosive chemical, nitroglycerin, by combining it with silica. The resulting malleable paste allowed the explosive power of nitroglycerine to be harnessed and controlled, and proved useful in such endeavors as mining and drilling. His invention was, of course, called dynamite.

And, in an odd coincidence, during the latter part of his life, Nobel’s physician prescribed nitroglycerin as treatment for the noted industrialist’s heart disease. Nobel, however, refused to take it, knowing from experience that the chemical caused him headaches. It would take nearly 100 years for science to discover that the factor responsible for both nitroglycerins’ role in reducing symptoms of heart disease, and Nobel’s headaches, was a vasodilating chemical called nitric oxide.

During the mid 1980’s it was discovered that nitric oxide (NO) was the mysterious biological substance which caused the dilation of blood vessels – a particularly shocking revelation considering that this gaseous chemical had previously been known as a mere industrial pollutant.

And in 1998, the Nobel Prize for medicine was awarded to a group of scientists who discovered that nitric oxide played major roles as an endogenous signaling molecule in the vascular, nervous, and immune systems of the human body. Since that time, research into the complex biological role of nitric has exploded, but still a relative newcomer to the biological scene, many questions remain as to the varied functions of this enigmatic molecule.

At first glance, much of the existing research on nitric oxide makes the chemical seem beneficial – it can indeed lower blood pressure by causing a dilation of the blood vessels, which is precisely what has made NO–boosting drugs like nitroglycerin beneficial for cardiovascular patients suffering from angina.

But as nitric oxide research has progressed, the two–faced nature of nitric oxide has begun to come to light. Some studies have surfaced indicating that certain nitric oxide–increasing therapies may have serious and potentially deadly drawbacks. In 2006, a particularly notable study using the common nitric oxide–boosting nutrient, l–arginine, in heart disease patients had to be stopped due to a dramatic increase in death in the treatment group.

Study Link – L–Arginine Therapy in Acute Myocardial Infarction – The Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial.

Quote from the above study:

Because of the safety concerns, the data and safety monitoring committee closed enrollment. . . L–Arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L–Arginine should not be recommended following acute myocardial infarction.

And subsequent research has served to dampen the initial enthusiasm for nitric oxide–boosting therapies even further. As with most chemicals which signal cellular stress, nitric oxide can be beneficial or harmful depending upon the amount released, and the energetic state of the cells with which it comes in contact. While, in some contexts, nitric oxide may be a chemical signal for vasodilation, cell growth and adaptation, an excess of nitric oxide has been shown to cause cellular fatigue, cellular damage, and even cellular death.

So, clearly in biology, nothing is as simple as it at first seems, and this appears to be especially true of nitric oxide. As a highly reactive and potentially damaging chemical, the effects of nitric oxide have proven incredibly difficult to predict. As more studies have emerged indicating that nitric oxide–boosting nutrients may be harmful in some treatment groups, many researchers now believe that, in certain circumstances, we should actually take steps to decrease our production of nitric oxide, not increase it.

Study Link – L–Arginine Supplementation in Peripheral Arterial Disease – No Benefit and Possible Harm.

Quote form the above study:

Although absolute claudication distance improved in both L–arginine– and placebo–treated patients, the improvement in the L–arginine–treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024). . . As opposed to its short–term administration, long–term administration of L–arginine is not useful in patients with intermittent claudication and PAD.

Study Link – Effects of chronic treatment with L–arginine on atherosclerosis in apoE knockout and apoE/inducible NO synthase double–knockout mice.

Quote from the above study:

This raises the possibility that L–arginine supplementation may paradoxically contribute to, rather than reduce, lesion formation by mechanisms that involve lipid oxidation, peroxynitrite formation, and NOS uncoupling.

But, even though the work of world–renowned biologists and chemists clearly shows that nitric oxide is a double edged–sword whose benefits have yet to be harnessed without risk, we need only to open the pages of any bodybuilding or fitness magazine to witness the reckless hucksters of the supplement industry touting products specifically designed to dramatically increase our nitric oxide levels. If their past track record is any indication, we can expect these companies to largely ignore the growing body of research which paints nitric oxide, and nitric oxide–boosting nutrients in a negative light, simply because such research doesn’t help them sell products.

The Products and Their Claims

The advertising for nitric oxide–boosting products in the bodybuilding realm usually centers around claims of increased blood flow to muscles, better nutrient delivery, enhanced “pumps” while training, and overall, an increase in muscular size and strength.

NO–boosting products are also sold as aids to erectile function, and (despite the above–listed studies) to support cardiovascular health. Whatever the claim or target demographic, the underlying mechanism for these products revolves around the same basic biological function – the ability of nitric oxide to dilate blood vessels.

Most nitric oxide–boosting products are formulated with various types of arginine – the amino acid from which nitric oxide is produced in the body. And although simple l–arginine supplements have been available for decades, as studies on the biological role of nitric oxide began to fill medical journals, certain enterprising individuals within the supplement industry decided to blow the dust off of this amino acid, and re–introduce it to the bodybuilding world in the form of novel arginine–containing salts like arginine alpha–ketoglutarate (AAKG) – possibly the most common ingredient in the current group of nitric oxide boosting supplements.

Because both arginine, and ketoglutarate are known to increase arginine levels in the body, it’s reasonable to believe that AAKG may increase arginine levels (and subsequently, nitric oxide) to a greater extent than l–arginine alone. But given the scientific–sounding jargon of many supplement advertisements, many people are surprised to learn that little to no research has been performed on AAKG in relation to nitric oxide levels. And as we have seen, even some studies which look at the effects of orally administered l–arginine (a relatively modest NO–booster at best), still give us reason for concern.

Dozens of other ingredients are often added to nitric oxide–boosting products including other salts of arginine as well as citrulline, an amino acid which is converted to arginine in vivo (in the body). And complicating matters even further is the common presence of compounds (especially blood thinning nutrients and herbs) which can potentially amplify the vascular effects of arginine and its metabolites. Because of this, the risk of excessive and pathological bleeding and hemorrhage is a very real concern even with the short–term usage of some nitric oxide–boosting products. But before we get too far ahead of ourselves, a little perspective on the true biological roll of nitric oxide is probably in order.

A Little Perspective on NO

Because the literature on nitric oxide is often conflicting, it’s important to sketch a bird’s eye view of its function within the body. Those attempting to sell you nitric oxide–boosting formulas often have a tendency to cherry pick the literature, showing you only studies (if they reference valid studies at all), which support their claims in limited contexts. For example, nitric oxide, as the supplement industry has so widely advertised, does indeed cause dilation of blood vessels. And this vasodilation may increase blood flow and allow the cells to temporarily produce energy more efficiently (with less oxygen consumption) under periods of stress.

But it’s important to always remember that the production of nitric oxide, and the dilation of blood vessels, is a defensive response of the body to stressful stimuli. As with all defensive responses, if the body lacks the ability to “shut off” the response, the response self–perpetuates, and the overall effects will be damaging and sometimes deadly. It’s crucial to recognize this fact, because there is often the mistaken belief that biological functions which can be harmful are under “tight control,” and that it’s nearly impossible to harm oneself with mere nutrients or nutritional supplements. But in the presence of certain stressors, we find that a great amount of damage can be done before the body is able to restore balance. As an example, we can see the quintessential illustration of the self–perpetuating nature of the nitric oxide stress response in the phenomena of sepsis and septic shock.

In the previous issue of the Integrated Supplements Newsletter, we saw how the presence of a “leaky gut” can allow bacteria and bacterial components called endotoxin to enter the bloodstream from the intestines, causing chronic systemic inflammation.

When such translocation of bacteria from the intestines into the bloodstream is significant, the condition is called sepsis, or what is often known in layman’s terms as blood poisoning. One of the bodies’ primary responses to sepsis is an increase in the production of nitric oxide. In the very short term, NO can dilate blood vessels and increase nutrient delivery to cells possibly allowing them to counter the stress by increasing their energy production. Very quickly, however, the hypotension (low blood pressure) caused by NO can lead to the exact opposite phenomenon –a dangerous decrease in blood flow to vital organs like the brain and kidneys, and an overall reduction in protective energy production throughout the body.

The vasodilating effects of NO are so strong in septic shock, that the blood vessels remain dilated despite the body’s best efforts to normalize them with vasoconstricting agents like adrenaline. The heart frantically attempts to compensate for the lowered blood pressure by pumping blood at an accelerated rate, but often, to no avail. As the heart soon weakens, blood pressure drops even further, causing blood vessels to leak, leading to bleeding (especially in the lungs, causing difficulty breathing), hemorrhage, cardiac failure, and often, death.

In relation to the surgery patient we mentioned in the introduction, and noting nitric oxide’s fundamental role in this chain of events, we see why none of the surgeons’ interventions worked to stop the young man’s bleeding and hypotension, until they supplied his body with more blood via a transfusion – sufficiently increasing blood volume (and therefore, pressure) and oxygen delivery to stop the bleeding and save his life.

Nitric oxide is so fundamental to the vicious chain of events in sepsis, that strategies for combating sepsis now often involve therapies aimed at dramatically reducing the production of nitric oxide.

Study Link – Nitric oxide in the pathogenesis of sepsis.

Quote from the above study:

In sepsis and septic shock, inflammatory mediators result in the production of increased concentrations of nitric oxide (NO) from the enzymatic breakdown of the amino acid L–arginine. The increased amounts of NO are responsible for changes in vasomotor tone, decreased vasopressor responsiveness, and decreased myocardial function, characteristic of septic insult. Therapeutic strategies designed to reduce the concentration of NO by inhibiting the action of the nitric oxide synthase enzyme, or by scavenging the excess NO, offer the potential to treat directly the vasomotor abnormalities and myocardial depression seen in sepsis and other inflammatory states.

Study Link – Circulatory failure in septic shock. Nitric oxide: too much of a good thing?

Quote from the above study:

One of the characteristic features of septic shock is profound hypotension caused by a decrease in peripheral vascular resistance. This hypotension is unusually resistant to both volume replacement and vasoconstrictor agents.

And it’s important to remember as well, that nitric oxide doesn’t just affect the blood vessels. Cells of the immune system and the nervous system also synthesize nitric oxide, and cumulatively, the nitric oxide produced by various cells can cause massive tissue damage via NO’s free radical–generating capacity.

A quote from the same study:

. . . production of large quantities of nitric oxide leads not only to haemodynamic instability but also to widespread production of nitric oxide–based free radicals which have the potential to cause considerable damage to tissues. Evidence from clinical studies supports this.

So, let’s get it straight right from the beginning: nitric oxide is an inflammatory chemical, which is produced in response to stress, injury, and trauma. Like other inflammatory chemicals, nitric oxide has a role in normal human physiology, but an excess of it, or prolonged stimulation of it is decidedly harmful. Nitric oxide synergizes with and stimulates other inflammatory chemicals, including prostaglandins, and cytokines. NO reduces blood pressure and oxygen utilization, increases lactic acid production, impairs mitochondrial energy production, promotes excitotoxicity, and causes (either directly or indirectly) various types of cell death.

And knowing that nitric oxide is able to overwhelm the body’s hemodynamic regulatory systems should make us think twice about consuming large amounts of arginine, or other nitric oxide precursors or boosters. An abundance of nitric oxide precursors in the body could make even everyday stresses (like workouts) harmful and, in rare cases, even catastrophic.

For example, it’s known that exercise weakens intestinal barrier function, and causes bacteria and endotoxin to be absorbed. Sepsis and exercise share so many inflammatory factors in common, that intense exercise has even been proposed as a model for studying sepsis.

Study Link – Sepsis and mechanisms of inflammatory response: is exercise a good model?

Study Link – Are similar inflammatory factors involved in strenuous exercise and sepsis?

Study Link – Strenuous exercise causes systemic endotoxemia.

Quote from the above study:

Eighteen triathletes were studied before and immediately after competing in an ultradistance triathlon. Their mean plasma lipopolysaccharide (LPS) concentrations increased from 0.081 to 0.294 ng/ml (P less than 0.001), and their mean plasma anti–LPS immunoglobulin G (IgG) concentrations decreased from 67.63 to 38.99 micrograms/ml (P less than 0.001).

So, we should be aware that in exercise, and in sepsis, the same principles of nitric oxide metabolism apply – the difference is merely one of degree. This, of course, is a fact which is conspicuously absent from the advertising of nitric oxide–boosting supplements, but it’s an important fact to recognize if we are to accurately assess the risks associated with these products.

Nitric Oxide and Peroxynitrite – General Toxic Effects

But it’s not simply the vasodilating effects of NO which may prove harmful in excess. As alluded to above, nitric oxide and its metabolites are also able to produce massive amounts of free radical damage – damage which has been shown to be toxic to the well–known “power plants” of the cells, the mitochondria.

As the science of biology advances, mitochondrial function is turning out to be the key to the mysteries of aging and degenerative disease. If you take nothing else from this article, let it be this:

Maintaining healthy mitochondria – mitochondria which are undamaged physically, and which produce energy efficiently – is the key to a long, energetic, happy, and disease–free life.

The energy produced by our mitochondria creates a “force field” of protection around the cell, allowing it to grow, adapt, and survive various stressors. Think of your cells as being constantly protected by an invisible electric fence, the power for which is supplied by the mitochondria – cut the power (damage or poison the mitochondria), and the cell becomes susceptible and increasingly vulnerable to all sorts of cellular stressors. The cells lose the ability to “fight back” and can no longer grow stronger and more resilient in response to stress – eventually they simply wave the white flag of defeat in response to any threat which comes along. Poison enough of these power plants and you accelerate your descent into aging, depression, atrophy, and degenerative disease.

One of the keys to the generally toxic effects of nitric oxide on the mitochondria is the NO derivative, called peroxynitrite (ONOO –). Being a gas, and a free radical, nitric oxide doesn’t stick around long once it’s produced. It rapidly reacts with surrounding molecules, especially the free radical superoxide, producing the particularly harmful oxidizing and nitrating agent, peroxynitrite.

On a cellular level, both NO and peroxynitrite have been shown to decimate mitochondrial function.

In fact, the following study and quote show clearly that NO and peroxynitrite impair mitochondrial function in almost every conceivable way – inhibiting multiple mitochondrial enzymes, chewing up antioxidants, damaging proteins, spilling redox–active iron, as well as causing lipid peroxidation, cell swelling, calcium release, and membrane permeability (all direct precursors to cell death).

Study Link – Nitric oxide and mitochondrial respiration.

Quote from the above study:

Nitric oxide (NO) and its derivative peroxynitrite (ONOO−) inhibit mitochondrial respiration by distinct mechanisms. Low (nanomolar) concentrations of NO specifically inhibit cytochrome oxidase in competition with oxygen, and this inhibition is fully reversible when NO is removed. Higher concentrations of NO can inhibit the other respiratory chain complexes, probably by nitrosylating or oxidising protein thiols and removing iron from the iron–sulphur centres. Peroxynitrite causes irreversible inhibition of mitochondrial respiration and damage to a variety of mitochondrial components via oxidising reactions. Thus peroxynitrite inhibits or damages mitochondrial complexes I, II, IV and V, aconitase, creatine kinase, the mitochondrial membrane, mitochondrial DNA, superoxide dismutase, and induces mitochondrial swelling, depolarisation, calcium release and permeability transition. . . The NO inhibition of cytochrome oxidase may also be involved in the cytotoxicity of NO, and may cause increased oxygen radical production by mitochondria, which may in turn lead to the generation of peroxynitrite. Mitochondrial damage by peroxynitrite may mediate the cytotoxicity of NO, and may be involved in a variety of pathologies.

So, in layman’s terms, nitric oxide and peroxynitrite can act as agents of wholesale cellular destruction, choking the life out of our cells at the most fundamental level. And once the cell is weakened in this way, even “normal” stresses and stimulation can become deadly to the cell.

And such damaging effects on a cellular level are easy to extrapolate to a macroscopic level as in the role of NO and peroxynitrite in degenerative disease:

Study Link – Nitric oxide and peroxynitrite in health and disease.

Quote from the above study:

Since its early description as an endothelial–derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. . . In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorder.

Nitric Oxide, NMDA, and Chronic Fatigue

Given what we now know about nitric oxide’s effects on cellular energy production, it seems especially strange that various nitric oxide–boosting products are being touted as energy boosters and performance enhancers. Many of these products are spiked with caffeine or creatine, both of which may impart energizing effects, but one thing’s for certain – nitric oxide itself certainly does not lead to an increase in energy production. In fact, quite the opposite is true. Some researchers have actually implicated an excess of nitric oxide production as the central metabolic defect underlying the chronic fatigue syndrome.

Without the damage caused by nitric oxide, and the subsequent drain on cellular defenses, stimulation of the excitatory NMDA receptor may simply be a normal physiological event involved in such phenomenon as memory and learning. In the presence of nitric oxide, however, uncontrolled nervous excitation, and cell death may result from the very same stimulation. Nitric oxide has been shown to be a necessary co–factor in the toxic effects of NMDA stimulation by excitatory amino acids. We’ve seen in previous Integrated Supplements Newsletters that the stimulation of the NMDA receptor is often a self–perpetuating sequence which drains cellular energy to the point of cell death.

Study Link – Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.

Quote from the above study:

We show that the nitric oxide synthase inhibitors, N omega–nitro–L–arginine (EC50 = 20 microM) and N omega–monomethyl–L–arginine (EC50 = 170 microM), prevent neurotoxicity elicited by N–methyl–D–aspartate and related excitatory amino acids. This effect is competitively reversed by L–arginine. Depletion of the culture medium of arginine by arginase or arginine–free growth medium completely attenuates N–methyl–D–aspartate toxicity. . . These data establish that NO mediates the neurotoxicity of glutamate.

Individuals with excess production of nitric oxide may suffer from NMDA over–stimulation, and may be predisposed to chronic pain, fatigue, chemical sensitivity, and they may even be especially susceptible to the negative effects of excitotoxic food additives like MSG and the artificial sweetener, aspartame.

The following study found that the amino acid citrulline (a “byproduct” of arginine’s production of nitric oxide), is consistently elevated in chronic fatigue patients.

Study Link – Levels of Nitric Oxide Synthase Product Citrulline Are Elevated in Sera of Chronic Fatigue Syndrome Patients.

Quote from the above study:

Serum citrulline levels were found to be significantly elevated in CFS patients and, in addition, there was a trend towards higher levels in CFS patients with stronger symptoms. These results provide support for the view that nitric oxide synthase activity tends to be elevated in CFS patients, thus supporting a prediction of the elevated nitric oxide/peroxynitrite theory of CFS etiology.

And it has also been proposed that the link between chronic fatigue syndrome and other related disorders stems from an elevation in nitric oxide synthesis.

Study Link – Elevated Nitric Oxide/Peroxynitrite Mechanism for the Common Etiology of Multiple Chemical Sensitivity, Chronic Fatigue Syndrome, and Posttraumatic Stress Disorder.

In relation to chronic fatigue, it’s interesting to note that chronic fatigue patients often manifest low blood pressure. It’s usually assumed that this low blood pressure has much to do with adrenal exhaustion. The thinking is that the adrenal glands of chronic fatigue patients aren’t sufficiently producing the adrenaline needed for energy and proper blood vessel tone. But if chronic fatigue patients do indeed overproduce nitric oxide, the vasodilating effect of nitric oxide could be another cause of the low blood pressure often noted in these patients.

This possibility opens up multiple avenues for treatment, and not coincidentally, the researchers who implicate nitric oxide in these disorders recommend nutrients and drugs aimed specifically at scavenging nitric oxide, lowering NMDA activity, and restoring mitochondrial function.

For example, the energizing effect of vitamin B–12 is well known, but few people realize that this effect may be due to B–12’s ability to scavenge and deactivate nitric oxide.

Study Link – Cobalamin Used in Chronic Fatigue Syndrome Therapy Is a Nitric Oxide Scavenger.

Other nutrients which may improve energy production by minimizing NO/peroxynitrite–induced damage include Co–Q10, niacinamide, magnesium and vitamin C.

What About Antioxidants?

Noting that the stimulation of nitric oxide is well–known to induce cellular and tissue damage via the free radical activity of peroxynitrite, some sellers of nitric oxide–boosting supplements have taken to formulating their products with a sprinkling of various antioxidants, supposedly acting as some sort of “damage control.”

But while the inclusion of antioxidants in these products may be somewhat beneficial, it’s unclear to what extent these antioxidants actually help counter an “artificially elevated” nitric oxide level. As for now, the inclusion of antioxidants with nitric oxide boosters (like so much else in the nutritional supplement industry) amounts to little more than simply wishful speculation.

But, it’s worth noting that some antioxidants do have unique and potentially positive effects on nitric oxide metabolism, and they may be beneficial in keeping nitric oxide levels within a normal, healthy range – assuming we don’t overwhelm the system with nitric oxide precursors or boosters.

The potent thiol (sulfur–containing) antioxidant, lipoic acid, has been shown to increase nitric oxide–mediated vasodilation in disease states, but not in healthy subjects. This effect is likely a clue that the way to ensure proper, healthy, nitric oxide production lifelong is via reducing our levels of oxidative stress – not by increasing our intake of arginine and similar nitric oxide precursors.

Study Link – Beneficial effects of α – lipoic acid and ascorbic acid on endothelium–dependent, nitric oxide–mediated vasodilation in diabetic patients: relation to parameters of oxidative stress.

Quote from the above study:

The impairment of nitric oxide (NO)–mediated vasodilation in diabetes has been attributed to increased vascular oxidative stress. Lipoic acid has been shown to have substantial antioxidative properties. . . Lipoic acid improved NO–mediated vasodilation in diabetic patients, but not in controls.

It’s known that the nitric oxide response of the blood vessels decreases in aging and disease (meaning that diseased blood vessels don’t respond to nitric oxide by dilating as effectively as healthy blood vessels do), but if, as the above study indicates, oxidative stress (and not lack of arginine) is the cause of the faulty nitric oxide response, then reducing oxidative stress is the most logical and physiologically sound solution – this is why taking arginine supplements won’t necessarily help, and is likely to do more harm, as has been shown in various studies.

Excess Nitric Oxide – Concerns in Exercise

Even people with little biological knowledge seem to understand the simplistic notion that the stress of weight training causes “damage” to the muscle, which, under ideal conditions, the body responds to by growing larger, stronger, or more efficient. Nitric oxide release is a normal response to the stress of training, and the damage which is caused by nitric oxide may be a part of the “damage” of training which the body adapts to by growing larger or stronger.

It’s conceivable that, in otherwise healthy people, and in the short–term, one of the responses to the cellular assault inflicted by nitric oxide and its metabolites may be an increase in muscle growth as a protective measure – assuming other factors like nutrition and rest are accounted for properly. But people taking nitric oxide–boosting products should know full–well, and without any ambiguity, that they are doing further damage to the body, and adding to the stress of training with these products, and not simply “supplying more nutrients to the muscle” as is commonly implied in product advertising.

Similarly, as relates to the “pump” experienced during training, this effect may indeed be partly due to increased blood flow to the muscle, but tissue swelling is a well–known to be a response to tissue damage and fatigue – and is probably not due to the simple dilation of blood vessels. In this sense, because nitric oxide does cause tissue damage and mitochondrial damage (leading to the more rapid onset of muscular fatigue), it’s fair to say that NO may stimulate a “pump” during training. But the fact that muscular swelling during exercise is largely due to a localized (and potentially harmful) inflammatory response, and not simply to increased blood flow as is sometimes implied, means that the marketers of NO–boosting products are simply spinning the science to make their advertising copy seem pleasing to an uneducated clientele.

And noting that nitric oxide decreases energy production on a cellular level, it’s interesting to look at studies which have shown significant decreases in exercise performance when the NO–precursor, arginine, was ingested – especially in endurance sports.

The following study, which looked at the effects of arginine on several metabolic markers during and after a marathon, found that arginine supplementation led to an average finish time 23 minutes longer than predicted.

Study Link – The effect of arginine or glycine supplementation on gastrointestinal function, muscle injury, serum amino acid concentrations and performance during a marathon run.

Arginine supplementation tends to fare a bit better in strength sports, but we can’t necessarily attribute this effect solely to nitric oxide. There are simply far too many metabolic fates for arginine besides NO to make such an assumption valid. Arginine, for example is a precursor to the well–known performance enhancer creatine, increased production of which could easily account for any marginal increases in strength or performance noted with arginine supplementation.

But, even in the highly “cosmetic” sport of bodybuilding, where a good pump is often just as important as improved performance, it’s hard to justify the use of nitric oxide supplements in light of the relevant research.

Unlike some unhealthy lifestyle habits, for which the repercussions manifest over decades, the negative effects of stimulating nitric oxide production can potentially be short–term and catastrophic. As we’ve seen, the threat of excessive bleeding and hemorrhage when nitric oxide is increased is very real.

Along these lines, a particularly strong warning should be made against the use of nitric oxide–boosting products for contact athletes such as football players, hockey players, and martial artists. The last thing these athletes want is high levels of nitric oxide and nitric oxide precursors running through their bloodstream during competition. If stimulated by contact, the over–production of nitric oxide could lead to excessive and uncontrollable bleeding.

The effect of nitric oxide–boosting drugs, such as nitroglycerine, on bleeding has been known for decades, and studies have shown that inhibiting the enzyme from which NO is produced, significantly shortens bleeding time.

Study Link – Effect of nitric oxide synthase inhibition on bleeding time in humans.

Quote from the above study:

These data show that systemic inhibition of NO production shortens [bleeding time] in humans.

And various other studies and reports have linked nitric oxide with excessive bleeding, cerebral hemorrhage, and hemorrhagic shock.

Study Link – Novel roles of nitric oxide in hemorrhagic shock.

Quote from the above study:

Thus, induced nitric oxide, in addition to being a "final common mediator" of hemorrhagic shock, is essential for the up–regulation of the inflammatory response in resuscitated hemorrhagic shock. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of peroxynitrite, with its associated toxicities, and indirectly through the amplification of the inflammatory response.

Study Link – Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis

Quote from the above study:

We reported the case of a 29–year–old woman with a hypertensive crisis treated with [the nitric oxide–increasing drug] sodium nitroprusside for blood pressure control who sustained an intracerebral hemorrhage after being normotensive on therapy for 24 hours.

And, lest you think that nitric oxide–boosting nutritional supplements must somehow be safer than nitric oxide–boosting drugs, realize that the “witches’ brew” formulations of many nitric oxide–boosting supplements often contain dozens of vasoactive substances haphazardly thrown together – including shockingly potent blood–thinning agents in addition to arginine substrates.

One such blood–thinning ingredient is rutaecarperine from the herb called evodia rutaecarpa. On a molar basis, retaecarperine has been shown to prolong bleeding time twice as long as aspirin.

Study Link – Antithrombotic effect of rutaecarpine, an alkaloid isolated from Evodia rutaecarpa, on platelet plug formation in in vivo experiments.

Quote from the above study:

On a molar basis, rutaecarpine was approximately twofold more potent than aspirin at prolonging the occlusion [bleeding] time.

So, although the “blood–thinning” effect of nitric oxide and related substances is often simply assumed to be beneficial, such simply isn’t the case. Certainly, blood with an excessive tendency to clot is a risk factor for cardiovascular disease in the long–term, but, on the other side of the coin, blood which doesn’t clot sufficiently can be even more acutely dangerous in situations where bleeding is a possibility.

Very similarly, high blood pressure is a known risk factor for cardiovascular disease, but as we’ve seen, low blood pressure, as a result of excessive nitric oxide production, can often be deadly in certain stressful situations. Clearly, balance is the key, and nitric oxide stimulation can play a major role in upsetting this balance greatly – even in the short–term.

In part two of our series on nitric oxide, we’ll look at the long–term role nitric oxide plays in various degenerative diseases. But hopefully, the research we’ve presented here on the general and shorter–acting effects of NO is already sufficient enough to allow any rational person to look at nitric oxide–boosting products in a whole new light.

With their typical reckless abandon, and biological shortsightedness, the sellers of nitric oxide–boosting supplements are asking you to accept far more risk than you may realize, while offering you far fewer benefits than they promise. But, in many ways, with nitric oxide–boosting products, it’s the same formula we see far too often in this industry – wild baseless speculation, is backed by cherry picked research, and stunningly ignorant oversimplifications of complex biological processes are proffered as the latest in “cutting edge science.”

If you value your health, your longevity, your performance, your intellect, or even simply the money you’ve worked so hard for, you’ll let the current nitric oxide fad run its course – without becoming one of its casualties.

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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