Why L-Arginine is Ineffective at NO Restoration

by Nathan S. Bryan, PhD

Consider the facts:

• Nitric Oxide is one of the most important molecules produced in your body to support a number of areas of human health, most notably cardiovascular function.
• Companies have been attempting to develop therapies around Nitric Oxide for years.
• Literally thousands of studies have been published on the importance of Nitric Oxide, in the most credible medical journals in the world.
• L-arginine is still the therapy of choice for enhancing NO, yet grossly ineffective.

However, Nitric Oxide is often associated with products to support workouts or in products offered for improving male sexual performance. If you Google Nitric Oxide, the first several pages are all links related to someone trying to sell a workout product or a product that enhances male sexual desire. This is due primarily to the fact that a number of companies have exploited Nitric Oxide as a vasodilator that can enhance exercise performance, muscle gain, endurance and sexual performance by supplementing with L-arginine. The vast majority of these products have no scientific basis for the claims they make. In order to understand the limitations of L-arginine-based products, we must first understand the metabolism of L-arginine in the cell and how it relates to NO production.

L-Arginine is Not the Answer

L-arginine is classified as a semi-essential or conditionally essential amino acid because the ability of the body to synthesize sufficient quantities to meet its needs varies according to developmental age and health status.¹ The biosynthetic pathway, however, does not produce sufficient L-arginine, and some must still be consumed through diet. Individuals who have poor nutrition or certain physical conditions may be advised to increase their intake of foods containing L-arginine. L-arginine is found in a wide variety of foods, including:

Animal sources such as dairy products (e.g., cottage cheese, ricotta, milk, yogurt, whey protein drinks), beef, pork (e.g. bacon, ham), gelatin, poultry (chicken and turkey light meat), wild game (pheasant, quail), seafood (halibut, lobster, salmon, shrimp, snails, tuna), plant sources such as wheat germ and flour, buckwheat, granola, oatmeal, peanuts, nuts (coconut, pecans, cashews, walnuts, almonds, Brazil nuts, hazelnuts, pinenuts), seeds (pumpkin, sesame, sunflower), chick peas, and cooked soybeans.

L-arginine is one of the more metabolically versatile amino acids, giving rise to nitric oxide (NO), urea, ornithine, citrulline, creatine, agmatine, glutamate, proline and polyamines (Fig. 1).² It is therefore no surprise that its metabolism is complex and highly regulated.³ This complexity arises not only from the diversity of enzymes involved in metabolism of L-arginine and its metabolites but also from their cell-specific patterns of expression. Tissue arginase activity and tissue L-arginine content are inversely related; liver, with the highest arginase activity, has the lowest L-arginine content, while kidney, muscle and spleen have only 1 percent the arginase activity of liver, yet have a 5- to 10-fold higher L-arginine content.⁴ On an organ level, the vast majority of endogenous L-arginine synthesis in adult mammals (60 percent) occurs in the kidney.⁵ In the liver, L-arginine is a urea cycle intermediary that plays a significant role in the clearance of ammonia nitrogen but does not contribute to the net synthesis of L-arginine.

L-arginine is the natural substrate of nitric oxide synthases (NOS) for generating nitric oxide (NO). The first pathway to be discovered for the endogenous production of NO was that involving L-arginine. The availability of intracellular L-arginine is potentially a rate-limiting factor in cellular NO production; however, extracellular and exogenous sources should theoretically be able to replace L-arginine deficiencies within the cell. For NO synthesis, it can occur at the level of NOS expression and activity as well as the presence of endogenous inhibitors, e.g., NG-hydroxy-arginine⁶ and asymmetric dimethyl-arginine (ADMA),⁷ and reduced cofactor availability, e.g., tetrahydrobiopterin (BH4). It is estimated that only about 3-5 percent of the intracellular L-arginine is directed through the NO pathway.

As a byproduct of the NOS reaction, L-citrulline is also formed from L-arginine. Citrulline can be recycled back to L-arginine by argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL), forming the citrulline-NO cycle (Figure 1). It has been hypothesized that such intracellular metabolite channeling forms the basis for compartmentalization that distinguishes extracellular and intracellular pools of L-arginine, though this has not yet been proven in vivo. What is clear is that L-arginine availability does not necessarily mean more NO production due to many competing catabolic processes.

However, for years scientists and physicians have investigated L-arginine supplementation as a means to enhance NO production. This strategy has been shown to work effectively in young healthy individuals with functional endothelium or in older patients with high levels of asymmetric dimethyl L-arginine (ADMA) where the supplemental L-arginine can out compete this natural inhibitor of NO production. Patients with endothelial dysfunction, however, by definition, are unable to convert L-arginine to NO and, therefore, this strategy has failed in clinical trials. In fact, the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial published in the JAMA in 2006, concluded that L-arginine, when added to standard postinfarction therapies, did not improve vascular stiffness measurements or ejection fraction and was associated with higher postinfarction mortality.⁸ L-arginine should not be recommended following acute myocardial infarction (MI). Further, supplementing L-arginine to promote Nitric Oxide production in people with risk factors for poor heart health such as smoking, being overweight, imbalanced blood pressure, subpar insulin sensitivity, imbalanced cholesterol, sedentary lifestyle and history of heart concerns does not work. By definition these people have endothelial dysfunction, which means that their endothelium (the cells that line every blood vessel in the body) cannot convert L-arginine into Nitric Oxide.

Once we understand the complexity of systems that metabolize L-arginine combined with the complexity of the reaction to convert L-arginine to NO, we can begin to understand why L-arginine supplementation is not effective, especially in the aging population or in individuals with known cardiovascular health risk factors and endothelial dysfunction. The production of NO from L-arginine is one of the most complicated reactions in the human body. This reaction is a five-electron oxidation requiring 8 different co-factors and substrates and is an energy consuming process. There are many steps that may be altered and affect ultimate NO production along the reaction pathway. Providing the enzyme NOS with supplemental L-arginine because of lowered availability of L-arginine does not appear to be rate limiting since the intracellular levels of the amino acid are in the millimolar range,⁹ and the enzyme’s Michaelis constant (KM) for substrate is in the micromolar range (2.9 µmol/L).¹⁰ Circulating L-arginine measured in plasma of healthy humans as well as in plasma of patients with inefficient vascular function is in the range of 45–100 µmol/L.¹¹ This is up to 15 to 30-fold higher than the concentration required to saturate the NOS enzyme. This biochemical discrepancy is termed as the “arginine paradox.”

Hopefully you begin to see the problem with L-arginine-based supplements designed to enhance Nitric Oxide. The people that need Nitric Oxide the most cannot convert it, regardless of how much L-arginine they receive. This is due to only 3-5 percent going through the NOS pathway and the fact that the NOS pathway is dysfunctional and unable to convert this portion of the L-arginine pool into NO. It is clear that L-arginine supplementation is not the right therapeutic strategy for a number of patients with vascular health concerns.

A More Effective Solution

The scientists behind the new Neo40® products have discovered a better solution to NO restoration. Neo40 Daily’s proprietary blend of natural ingredients with robust Nitric Oxide activity can overcome the body’s inability to convert L-arginine, and in fact utilizes a completely different production pathway. Neo40 Daily has been shown in clinical trials to restore NO homeostasis and support heart health in patients over the age of 40, a population that cannot utilize L-arginine for NO production.¹² Understanding safe and effective strategies to restore NO homeostasis in your patients will certainly have a positive outcome for promoting optimal health and wellness.

Based upon the above information, hopefully you will be convinced that L-arginine products CANNOT work. All Nitric Oxide supplements are NOT created equal.

References

1. Barbul, A., Arginine: biochemistry, physiology, and therapeutic implications. JPEN J Parenter Enteral Nutr, 1986. 10(2): p. 227-38.

2. Morris, S.M., Jr., Enzymes of arginine metabolism. J Nutr, 2004. 134(10 Suppl): p. 2743S-2747S; discussion 2765S-2767S.

3. Morris, S.M., Jr., Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr, 2002. 22: p. 87-105.

4. Gopalakrishna, R. and B. Nagarajan, Effect of growth & differentiation on distribution of arginase & arginine in rat tissues. Indian J Biochem Biophys, 1979. 16(2): p. 66-8.

5. Windmueller, H.G. and A.E. Spaeth, Source and fate of circulating citrulline. Am J Physiol, 1981. 241(6): p. E473-80.

6. Boucher, J.L., et al., N omega-hydroxyl-L-arginine, an intermediate in the L-arginine to nitric oxide pathway, is a strong inhibitor of liver and macrophage arginase. Biochem Biophys Res Commun, 1994. 203(3): p. 1614-21.

7. Kielstein, J.T., D. Tsikas, and D. Fliser, Effects of asymmetric dimethylarginine (ADMA) infusion in humans. Eur J Clin Pharmacol, 2006. 62 Suppl 13: p. 39-44.

8. Schulman, S.P., et al., L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. Jama, 2006. 295(1): p. 58-64.

9. Gold, M.E., P.A. Bush, and L.J. Ignarro, Depletion of arterial L-arginine causes reversible tolerance to endothelium-dependent relaxation. Biochem Biophys Res Commun, 1989. 164(2): p. 714-21.

10. Bredt, D.S. and S.H. Snyder, Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A, 1990. 87(2): p. 682-5.

11. Boger, R.H. and S.M. Bode-Boger, The clinical pharmacology of L-arginine. Annu Rev Pharmacol Toxicol, 2001. 41: p. 79-99.

12. 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.