Unveiling NO2

Demystify these supplements, understand the advantages, and unravel the myths surrounding these products.

The article is divided into two parts. In this first edition, you'll learn about the definitions of the supplement and its action. In the next edition, we'll learn how to build a supplementation strategy with this supplement.

NO, NO2, and Nitrous Oxide: This subtitle might seem strange, but there is a lot of confusion regarding the “NO”s out there. Clarifying these acronyms:

The result of the union of one oxygen atom and one nitrogen atom, NO at room temperature is a colorless and odorless gas. A highly reactive compound, it oxidizes easily in the air and rapidly converts into nitrogen dioxide, and eventually into ozone. It is naturally produced in the atmosphere and also occurs in car engines. However, our interest is not in its free form in the air, but rather in the form produced within the organisms of animals and plants at all levels of the evolutionary scale.

Being a very small and highly reactive molecule, it rapidly diffuses throughout all body tissues, a property that makes it an important signaling molecule and a biologically active and ancient molecule, given that from the first living beings, NO activated some important cellular functions. Due to the fact that it is produced in one cell and stimulates a response in another, it can be considered a chemical mediator with an action similar to hormones. However, NO acts directly on the basic structure of proteins, enzymes, and cellular DNA and RNA, which alters the entire metabolism of the stimulated tissue. By acting at the deepest level of metabolism, NO has been one of the most studied compounds in the last 20 years, and the supplement industry, having recently discovered the compound, has extensively used its name and biological importance.

Thus, the first thing to know about “NO supplements” is that they do not contain NITRIC OXIDE. But then what is in these containers with “NO” stamped on the label? They contain NO precursors! Practically every cell in the body can produce NO and is influenced by it. The main NO-producing cells are in the endothelium of blood vessels, in macrophages, and in a specific group of neurons in the brain.

NO production occurs through the union of the amino acid arginine with oxygen, mediated by the enzyme nitric oxide synthase (NOS). When there is a higher concentration of arginine in the blood plasma, NO synthesis increases in all tissues, thus generating an indirect increase in the concentration of nitric oxide present in the body. It is this characteristic that NO supplements utilize to have an effect on individual performance. Thus, these “NO Supplements” are, in reality, arginine-based, generally associated with other compounds that assist in NO synthesis, arginine transport, or other functions that enhance the supplement's action. Therefore, we will focus on arginine and its “luxury metabolite,” which is NO itself.

The endothelial cells of blood vessels are large producers of NO and highly sensitive to nitric oxide. Upon reaching the smooth muscle in the walls of blood vessels, these relax, increasing blood flow and resulting in better tissue oxygenation, greater nutrient supply, more muscle pump, and more prominent veins in individuals with little subcutaneous fat. In addition, NO has various other functions. It increases the sensitivity of muscle cells to hypertrophy factors like NFACT-2 (a growth factor derived from arginine) and even to steroid hormones.

It also plays an important role in nerve formation and regeneration, in addition to increasing neurotransmitter activity. Although it is a multifunctional molecule, the main activity of NO as a supplement is to increase blood flow. Many athletes use NO with the aim of vascularization. This works, not only by making veins fuller due to arterial relaxation, but also due to its neovascularization function. Aicher et al (2003) in their article published in Nature described the influence of the NOS enzyme in the process of neovascularization, and established the necessity of NOS expression for new veins and arteries to form. Since then, various studies have demonstrated in vitro and in vivo that the expression of Vascular Endothelial Growth Factor (VEGF) is not only stimulated, but DEPENDENT on the presence of NO.

Supplementation with NO precursors, such as arginine, increases the rate of VEGF expression and accelerates angiogenesis (generation of blood vessels) in all animal species studied. This sensitivity to NO is one of the factors that makes an individual easily display visible veins, while other individuals have difficulty in expressing thick and turgid vessels. Angiogenesis is dependent on NO, but it is not activated by it. There are various factors that trigger new blood vessel formation, the main one being Prostaglandin E (PGE) – a neglected and little-known hormone among bodybuilding scholars. But, it is an immediate and direct response hormone to weight training. That is, with sufficient NO in circulation, the individual trains, releases PGE, and new blood vessels form to supply the muscles that need more nutrients.

An important issue concerns the selective activity of NO. Being highly fat-soluble, it possesses a very interesting property, the “slimming” effect. When arginine is ingested, NO is produced, which stimulates blood vessels to dilate. Thus, it will stimulate blood flow in adipose tissue, and then fat metabolism accelerates, facilitating its mobilization. One of the reasons it is so difficult to lose fat is that adipose tissue has deficient vascularization and low metabolism.

With NO, this metabolism can be increased, an excellent reason to include it in supplementation for definition and pre-contest. Traversing the blood-brain barrier, it moves rapidly through the central nervous system (CNS), which is a rich environment of lipids, especially in the myelin sheath of neurons. Studies such as those by Rettori et al (1994) and Garthwaite & Bolton (1995) demonstrated a clear relationship between NO expression in the CNS and the production of GH, GnRH, LH, FSH. The most compelling fact is the direct relationship between NO production and GH expression, described in various studies from the 90s and still generating important publications. The fact is that the greater the activity of NOS and the more NO exists in the brain, the more GH is produced, increasing the amplitude and frequency of production peaks.

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