1Nathan S. Bryan, Ph.D., 2Ernst Schwarz, M.D., Ph.D.
1Baylor College of Medicine, Houston, TX 2Cedars Sinai Medical Center, Los Angeles, CA
Nitric oxide or NO has become one of the hottest topics in modern medicine. After a 1998 Nobel Prize in Physiology or Medicine to three US scientists credited with the discovery, NO being recognized as Molecule of the Year by Science Magazine in 1992 and over 130,000 published papers on the subject, it is now clear that it is one of the most important molecules produced within the human body. NO is responsible for maintaining normal blood pressure, inhibiting platelet aggregation and preventing leukocytes and monocytes from adhering to the endothelial lining of the blood vessels and regulating blood flow to working muscles and sex organs. These are just a few of the numerous actions of NO within the cardiovascular system. Fundamentally though, NO is a cell signaling molecule that allows the cells in our body to communicate with one another. Loss of NO production is recognized as being one of the earliest events in the onset and progression of cardiovascular disease. As such there are many products and therapies on the market that are designed to restore and replete NO production. However, most available NO products on the market today that are available to health care practitioners do not and cannot work effectively. It is only after we understand the enzymology and biochemistry of how NO is normally produced in the body and what goes wrong with these production pathways that we can then begin to develop safe and effective NO therapies and supplements.
Fueling a Broken System
The first pathway discovered for the production of NO is the enzymatic conversion of L-arginine to NO by a group of enzymes called nitric oxide synthase (NOS). The endothelial NOS (eNOS) catalyzes a very complex, multi-step five-electron oxidation of the guanidino nitrogen of L-arginine into NO with L-citrulline as a bi-product (Figure 1, pathway 1). This reaction requires the presence of at least 8 different co-factors and substrates that when not available or become oxidized shut down the production of NO from L-arginine. Once the eNOS enzyme becomes uncoupled and dysfunctional it cannot generate NO from L-arginine. In fact it will generate superoxide instead. This is apparent in patients with endothelial dysfunction. Many NO based products contain L-arginine or L-citrulline as their active ingredients. Simply giving more L-arginine to a patient with a dysfunctional NOS will not provide any benefit since the enzyme that converts L-arginine to NO is the underlying problem. You cannot fuel a system that is broken. We have to restore endothelial function so that conversion of L-arginine can be accomplished. Products must also contain the components and co-factors that can recouple the NOS enzyme.
Inherent Inefficiencies in Metabolism Can Limit Product Efficacy
A second pathway for endogenous NO production exist that comes from diet via consuming nitrate rich foods such as beet root or green leafy vegetables. Humans do not have a nitrate reductase enzyme. Therefore the metabolism of inorganic nitrate requires the presence of nitrate reducing bacteria in the oral cavity that reduce nitrate to nitrite. Nitrite can then be transported throughout the body where it can be used as a substrate for NO production by a few mammalian enzymes. Without the presence of nitrate reducing bacteria in the oral cavity, nitrate based strategies or supplements will not work. Furthermore, the conversion of nitrate to nitrite to NO is very inefficient so there is a nitrate threshold that is needed for any meaningful NO production. Only about 5-6% of consumed nitrate is converted to nitrite. There are many NO products that now have added beet root juice powders as an ingredient. We have analyzed over 400 different ingredients found in most NO product and have found that some beetroot powders contain no nitrate and other natural products such as hawthorne berry have lost all their biological activity. There is as much as a 500 fold difference in ingredient activity from one supplier to the next. Many of these ingredients undergo stringent heating conditions during the dessication process that produces powder from high concentrate liquids. This destroys much of the biological activity and many of the necessary nutrients needed for activity. There are very few ingredients that maintain quality and nutrient density.
Strong Basic Science and Clinical Evidence Are a Must
It is very important for physicians and other healthcare practitioners, especially in the supplement industry, to be able to recognize and differentiate between creative marketing and real science when it comes to recommending or administering NO therapies or supplements to their patients. Just because a product contains beetroot juice powder does not mean that it contains enough nitrate if any at all to lead to any appreciable NO formation when consumed. Unless the ingredients are tested for specific nutrients, nitrate for example, as well as the ability to generate authentic NO gas, then those products cannot and will not work in patients who are NO deficient. Using gas phase chemiluminescence to detect and quantify authentic NO along with high performance liquid chromatography to determine absolute amounts of nitrate and/or formed nitrite is the only way to ensure product efficacy when it comes to NO. When products or technologies that meet this standard of quality are put to the test, it can provide a real improvement in patient care.
One such product has been put to the test and shown impressive effects in published clinical trials. Neo40 backed by 14 years of basic science research, four issued patents and 5 published clinical trials shows that it can safely and effective restore and replete NO production and normalize blood pressure in pre-hypertension , improve blood pressure, endothelial function, arterial compliance and dilate blood vessels in patients with elevated blood pressure , improve blood pressure in a pediatric patient with an inborn error in metabolism , lower triglycerides  and improve athletic performance in moderately trained athletes . Data from the pre-hypertension trial reveal that 30 days of Neo40 can normalize blood pressure in patients with pre-hypertension . This is critically important since it is known that 95% of pre-hypertensive patients become hypertensive eventually. NO is such potent molecule, any product that is marketed towards NO should have clinical trials to validate and demonstrate its safety and efficacy. The truth is very few actually do since very few actually work. Neogenis Labs, Inc. is a company that has invested in the research and clinical trials to put its patented technology to the test. For more information please visit www.neogenismedical.com
Figure 1: The two pathways for NO production in the human body.
 Biswas, O.S., V.R. Gonzalez, and E.R. Schwarz, Effects of an Oral Nitric Oxide Supplement on Functional Capacity and Blood Pressure in Adults With Prehypertension. J Cardiovasc Pharmacol Ther, 2014.
 Houston, M. and L. Hays, Acute effects of an oral nitric oxide supplement on blood pressure, endothelial function, and vascular compliance in hypertensive patients. J Clin Hypertens (Greenwich), 2014. 16(7): p. 524-9.
 Nagamani, S.C., et al., Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet, 2012. 90(5): p. 836-46.
 Zand, J., et al., All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans. Nutr Res, 2011. 31(4): p. 262-9.
 Lee, J., et al., Caffeinated Nitric Oxide-releasing Lozenge Improves Cycling Time Trial Performance. Int J Sports Med. 2014 Oct 6.