The Nitric Oxide Paradox

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The Nitric Oxide Paradox

That Notorious Muscle Pump – The Good, the Bad and the Ugly Facts

By Ian Roothman. Photo of Mdu Green by Slade Mansfield (

You are a bodybuilder and your main quest is to build muscle. You want to experience that notorious muscle pump every time you train. You want to pack on muscle fast, shred fat like a steel melting furnace and get into your best shape ever. Outside of the gym you browse around supplement shops, surf the net, grab a few hardcore bodybuilding magazines and do your utmost to get into the mental zone for project bodybuilder! In this quest one supplement stands out above the rest and permeates the shelves of the bodybuilding supplement section – Nitric Oxide (NO) Boosters. Manufacturers claim this to be the ultimate supplement to aid in building muscle fast. Pro bodybuilders pose on posters claiming it is the ultimate muscle building agent. All good and well, but what is the real deal (scientifically speaking) about this much talked about molecule? How is it produced, what role does it play in muscle biochemistry, what does it do besides giving you a massive muscle pump and last, but not least, what happens when it is ultimately destroyed? The latest researched findings produced a paradox of scientific findings – we can literally call it the Good, the Bad and the Ugly facts about Nitric Oxide.

[A paradox is a statement or group of statements that leads to a contradiction or a situation which defies intuition. Also used for an apparent contradiction that actually expresses a non-dual truth. The word paradox is often used interchangeably with contradiction. It is also used to describe situations that are ironic – citation from wikipedia – the free encyclopedia]

The Nitric Oxide Paradox – aka the Nitrogen Paradox

Many paradoxes do not yet have universally accepted resolutions. Sometimes the term paradox is used for situations that are merely surprising. Some paradoxes, for instance, are unexpected but perfectly logical. Others are seeming absurdities that are nevertheless true. In the case of the NO paradox, it can be seen as being contradictory and surprising, which will finally resolve itself upon later inspection (in this case with continued scientific research).

What is Nitric Oxide?

Nitric oxide (common name) or nitrogen monoxide (systematic name) is a chemical compound with chemical formula NO. This gas is an important signaling molecule in the body of mammals, including humans, and is an extremely important intermediate in the biochemical industry.

NO is an important messenger molecule involved in many physiological and pathological processes within the mammalian body, both beneficial and detrimental. Appropriate levels of NO production are important in protecting an organ such as the liver from ischemic damage. However sustained levels of NO production may result in direct tissue toxicity – these findings still have to be resolved with further scientific research.

In biochemical terms, NO should not be confused with nitrous oxide (N2O), an anesthetic and greenhouse gas, or with nitrogen dioxide (NO2), a brown toxic gas and a major air pollutant. The NO molecule is a free radical, which is relevant to understanding its high reactivity. Despite being a simple molecule, NO is a fundamental player in the fields of neuroscience, physiology, biochemistry and immunology, and was proclaimed “Molecule of the Year” by the scientific community in 1992.

How NO is formed and reacts in the body (in vivo)

Nitric oxide syntheses (NOSs) are a family of eukaryotic enzymes that catalyze the production of NO from L-arginine (an amino acid found abundantly in all meats, nuts and dairy). The average person consumes between 3000 – 5000mg of L-arginine, so the body is accustomed to intake levels of several thousand milligrams every day. NO is an important cellular signaling molecule, having a vital role in many biological processes. A deficiency of L-arginine, however, does not generally disrupt NO synthesis because L-arginine availability is not the rate-limiting step in this process. In fact, research over the past five years has identified an endogenous (occurs in the body naturally) inhibitor called “asymmetric dimethylarginine” or ADMA, an amino acid that blocks the production of NO. By acting as an L-arginine mimic, this damaging look-alike effectively elbows out L-arginine and pushes it off to the side in the biochemical pathway leading to the synthesis of NO. ADMA is relatively elevated in patients with hypertension, high levels of cholesterol, triglycerides, homocysteine and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL), as well as with ageing itself. This inhibitor of NO synthesis may very well be the common factor shared by all of these abnormal conditions. Increased levels of this detrimental inhibitor (ADMA) block NO production, leading to endothelial dysfunction.

As a free radical NO reacts with a free radical superoxide to form the highly reactive and oxidising agent called Peroxynitrite. Peroxynitrate is in itself not a free radical, but is an oxidant and nitrating agent. Because of its oxidising properties, peroxynitrite can damage a wide array of molecules in cells, including DNA and proteins. Here is the reaction:
·O2 + ·NO → ONO2 (peroxynitrate or ONOO−)

NO activates Guanylate cyclase, which induces smooth muscle relaxation by:

  • Increased intracellular cGMP, which inhibits calcium entry into the cell, and decreases intracellular calcium concentrations
  • Activation of K+ channels, which leads to hyper-polarisation and relaxation
  • Stimulates a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to smooth muscle relaxation – and consequently vasodilation leading to the muscle pump.

So what does this mean and how does it effect your body?

The clinical biochemical significance of this is that peroxynitrate can cause oxidative damage to lipids (especially LDL), DNA, and proteins in the body. It has been widely published that lipid peroxidation (or oxidised LDL) is the major cause of atherosclerosis – leading to heart disease and strokes. The paradox of aerobic (oxygen dependent) life is that oxygen is toxic to biological molecules and cells. Oxygen, including the oxygen used in cellular respiration, tends to form free radicals in the body. These free radicals oxidise biological molecules, just as iron oxidises when it rusts. The oxygen that cellular respiration transforms into energy must therefore be considered a hazardous substance in the body. Biochemists call this the “oxygen paradox”.

An antioxidant defense system resolution

Nature’s resolution of this paradox is the antioxidant defense system. An antioxidant is a molecule that neutralises free radicals in the same way that baking soda (sodium bicarbonate) neutralises excess stomach acids. Every organism is endowed with a coordinated system of antioxidants, but this system is imperfect. Consequently, free radicals actively damage the three main classes of biological macromolecules-lipids (fats), nucleic acids (DNA, RNA) and proteins.

Nature’s second line of defense is a removal and repair system for damaged macromolecules, but this too is imperfect. Consequently, oxidative damage accumulates through life and increases in old age.

Oxidative stress is a relative term for an imbalance between the capacity of the body’s antioxidant defense system and the level of free radicals – in short, an imbalance between antioxidants and pro-oxidants. Oxidative stress increases when antioxidant defenses weaken or free radical levels rise. It is now widely accepted that oxidative stress figures prominently in cell transformation and other degenerative diseases.

Oxidative stress tends to escalate over time. When a cell or molecule is damaged by oxidative stress, it tends to malfunction, causing additional oxidative stress. Biochemists refer to such a downward spiral as a “catastrophic vicious cycle”. Oxidative stress and bioenergetic deficiency are also locked together in a vicious cycle. The downward spiral of increasing oxidative damage and dwindling cellular energy production is a hallmark of ageing and many degenerative diseases. The cumulative effect over time of this buildup of oxidative damage is ageing, degeneration and death. The greatest biohazard the body’s antioxidant defense system must face is the oxidation of lipids (fats). This occurs in cell membranes, the brain (over 50% fatty acid) and blood lipoproteins (which carry cholesterol). The oxidation of lipids, known as lipid peroxidation, is a chain reaction that damages the biological molecules in its path and generates toxic byproducts.

Breaking the vicious cycle

The vicious cycle of bioenergetic deficiency and oxidative stress depletes cellular vitality. Cells caught in this cycle produce little energy but a great deal of oxidative stress, and may eventually die. When a large enough proportion of the cells in a tissue or organ are lost or degraded in this way, it can no longer function adequately. The fat-soluble antioxidants – primarily vitamin E and CoQ10, protect against lipid peroxidation. This preserves the integrity of cell membranes and protects DNA, proteins and blood lipids from oxidative damage. Cellular respiration takes place in a lipid-rich membrane inside the mitochondria, and is itself a source of oxidative stress. The cellular respiratory chain is thus highly vulnerable to lipid peroxidation. CoQ10 helps protect the integrity of this membrane while shielding the respiratory chain from free radicals. This, coupled with CoQ10’s essential role in energy production, helps prevent the vicious cycle of bioenergetic decline and oxidative stress.

A Defensive Conclusion

The discovery that mammalian cells have the ability to synthesise the free radical NO has stimulated an extraordinary impetus for scientific research in all the fields of biology, medicine and sports nutrition. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, which includes vasodilation – leading to the notorious muscle pump. But it also acts as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. There are currently numerous studies being conducted worldwide, exploring the effect of NO in vivo (in the body). Novel pharmacological and biochemical strategies are aimed at presenting a solution to this otherwise complex scenario. The current ultimate solution is to take a very strong stance with a rigorous antioxidant supplement and dietary programme.


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