Life Extension Magazine®
Poor blood flow is a serious health risk. It can lead to heart disease and potentially fatal cardiovascular events.1
That's where nitric oxide comes in. Produced by the body's cells, it signals blood vessels to relax and expand, promoting greater blood flow and arterial health.2
Nitric oxide is synthesized in the body primarily from the amino acid L-arginine.2
The problem is that most of the arginine people ingest is degraded before being synthesized to nitric oxide in the arterial wall.3,4
To counter this, scientists developed an improved form of L-arginine, known as inositol-stabilized arginine silicate.
This stabilized form is more bioavailable. This means more remains in the bloodstream longer, to encourage nitric oxide production, helping support systemic circulatory health.5-8
The Importance of Nitric Oxide
As we age, the risk of developing cardiovascular disease increases.
One reason is endothelial dysfunction.9-11
The inner lining of our arteries, called the endothelium, plays a critical role in regulating the flow of blood.9-11
It does so by producing nitric oxide, which signals blood vessels to dilate (widen/relax).10 This allows for greater blood flow to tissues, including the heart and brain.
However, as we age, our bodies tend to make less nitric oxide.12,13 Because of this, blood vessels may be unable to dilate as needed, reducing blood flow.13-16
The consequences of this endothelial dysfunction include diminished circulation, high blood pressure, abnormal clotting, and atherosclerosis (the buildup of plaque in arteries). These are major causes of cardiovascular disease, strokes, heart attacks, and sudden cardiac death.9,10,17,18
Endothelial dysfunction is surprisingly common. It can lead to a host of problems including increased risks of dementia and kidney failure.14,19,20
But if we can increase the nitric oxide in our blood vessels, it may stop and even reverse endothelial dysfunction.
L-Arginine’s Essential Role
Nitric oxide is synthesized in the body primarily from the amino acid L-arginine–a direct precursor that blood vessels use to make nitric oxide.21
To work properly, blood vessels make nitric oxide for themselves from the amino acid L-arginine.
Scientists evaluated whether taking oral L-arginine improved blood vessel dilation, with the goal of improving systemic circulation and lowering risk for vascular diseases.22-27
In a clinical trial, patients with high blood pressure were given a single dose of L-arginine or a placebo. Measurements were taken of flow-mediated dilation (FMD)–how much a blood vessel widens in response to an increase in blood flow.27
While the placebo group had no change in blood vessel dilation, flow-mediated dilation in those receiving L-arginine improved from an average of 1.7% to 5.9%.27
Considering that each 1% improvement in flow-mediated dilation has been correlated with a 12% lower risk of cardiovascular events such as heart attack and stroke, the maintenance of endothelial health is critical.28,29
Some longer-term clinical studies demonstrate that L-arginine supplementation can lower blood pressure and reduce symptoms associated with coronary artery disease.22,30
L-arginine, however, is quickly metabolized and eliminated from the bloodstream.3,4
What You Need to Know
Boost Nitric Oxide Levels
- The body produces nitric oxide, a gas that signals blood vessels to dilate, allowing blood to flow through.
- Aging tends to decrease nitric oxide production, contributing to endothelial dysfunction and an increased risk for cardiovascular disease, heart attacks, and strokes.
- L-arginine is an amino acid the body uses to make nitric oxide. Scientists have developed a more bioavailable form of L-arginine called inositol-stabilized arginine silicate.
- This superior form promotes higher L-arginine levels in the bloodstream for a longer period. That can significantly boost nitric oxide production, reducing risk for cardiovascular events.
- In a clinical trial, consumption of inositol-stabilized arginine silicate was found to be associated with a significant improvement in flow mediated dilation.
Longer-Acting Arginine
A key drawback to taking L-arginine has been that it needs about an hour to take effect and does not stay in the bloodstream for long.6
An enzyme called arginase degrades about 40% of ingested arginine within the intestinal tract before it can be absorbed into the bloodstream.31,32
L-arginine is further degraded by other enzymes in the bloodstream, leaving only a small amount available to be converted to nitric oxide.4
Seeking a way around this problem, scientists developed a more bioavailable form of L-arginine called inositol-stabilized arginine silicate that allows L-arginine to remain present in the plasma for a greater length of time.5,6,33
Clinical studies have demonstrated that in response to inositol-stabilized arginine silicate, arginine levels in the blood were increased within 30 minutes and plasma arginine levels were sustained for up to six hours.5,6,33
How It Works
L-arginine supports production of nitric oxide.
Inositol-stabilized arginine silicate raises plasma levels of arginine and encourages production of nitric oxide, which helps improve blood flow.5-7
Inositol-stabilized arginine silicate appears to keep L-arginine levels higher because it inhibits arginase, the primary enzyme that breaks down L-arginine.33
This allows more L-arginine to enter the blood and circulate longer compared to standard L-arginine.33
As a result, this stabilized form of L-arginine has demonstrated clinical benefits that standard L-arginine has not been shown to achieve.7,8
In a three-arm crossover design trial of physically active males with normal blood pressure, participants received a one-time dose of either8:
- 1,500 mg of inositol-stabilized arginine silicate,
- 8 grams of citrulline malate (indirect precursor to nitric oxide), or
- placebo.
Flow mediated dilation of the brachial artery was measured before ingestion of the supplement and one hour after. After the single dose there was a washout period of 7-28 days. It was found that the single dose of inositol-stabilized arginine silicate or citrulline resulted in improvements in flow mediated dilation of about 31%, a significant increase compared to placebo.
In another clinical trial, subjects taking 1,500 mg of this improved form of L-arginine daily had reduced markers of post-workout muscle damage and reported greater feelings of energy than those taking a placebo.7
Encouraging the synthesis of nitric oxide with inositol-stabilized arginine silicate is one way to support cardiovascular health.
Arginine's Formidable Task in Converting to Nitric Oxide
Ingested ARGININE
40% degraded by Intestinal ARGINASE
Additional ARGININE DEGRADATION by Enzymes in the blood
ARGINASE ARGININE DEIMINASE, ARGININE DECARBOXYYLASE, ARGININE GLYCINE AMIDINOTRANSFERASE
Remaining ARGININE Synthesized by NITRIC OXIDE SYNTHASE to
Endothelial NITRIC OXIDE
The typical American ingests about 4.5 grams of arginine each day.4
But only a tiny amount of ingested arginine is available to convert to endothelial nitric oxide.
When arginine is ingested, a substantial percentage of it (about 40%) is degraded in the small intestine by the enzyme arginase. This enzyme is naturally present to degrade the dietary arginine humans ingest each day.4
After the remaining intestinal arginine is absorbed into the blood, there are more enzymes that rapidly degrade it into a variety of metabolites including ornithine, creatine, proline, glutamine, and various polyamines.
The primary enzymes that degrade arginine are:
- Arginase,
- Arginine decarboxylase, and
- Arginine Glycine amidinotransferase.
Any arginine that is spared from enzymatic degradation in the body can be converted by the enzyme nitric oxide synthase into nitric oxide.4
Some studies show that supplemental arginine increases nitric oxide levels in the body, while other studies reveal no increase in nitric oxide levels in response to arginine supplementation.34,35
The reason that standard arginine does not consistently elevate nitric oxide may be that not enough arginine is able to be acted upon by nitric oxide synthase to synthesize endothelial nitric oxide.
Around four hours after standard arginine is ingested, blood levels of arginine return completely to baseline.36
A new stabilized arginine formula reduces enzymatic degradation by arginase to enable higher blood levels of arginine, sustained for about six hours, to support production of endothelial nitric oxide.33
Summary
Nitric oxide is produced by the body to support blood flow, improving circulatory and cardiovascular health.
Nitric oxide production tends to decline with age, and this decline has a negative impact on endothelial function. Endothelial dysfunction is a contributor to atherosclerosis and increases the risk of cardiovascular disease, heart attacks, and strokes.
L-arginine is the amino acid the body uses to make nitric oxide. Taken orally, it gets degraded by enzymes and only a small amount is available to support the endothelium.
Scientists have developed a better form of L-arginine called inositol-stabilized arginine silicate. More of it is absorbed into the bloodstream after ingestion and it remains in the body for a longer time.
This improved L-arginine may boost nitric oxide production, reducing the risk for cardiovascular events.
If you have any questions on the scientific content of this article, please call a Life Extension Wellness Specialist at 1-866-864-3027.
References
- Available at: https://www.nhs.uk/conditions/cardiovascular-disease/. Accessed May 29, 2024.
- Ahmad A, Dempsey SK, Daneva Z, et al. Role of Nitric Oxide in the Cardiovascular and Renal Systems. Int J Mol Sci. 2018;19(9).
- Szlas A, Kurek JM, Krejpcio Z. The Potential of L-Arginine in Prevention and Treatment of Disturbed Carbohydrate and Lipid Metabolism-A Review. Nutrients. 2022;14(5):961.
- Wu G, Bazer FW, Davis TA, et al. Arginine metabolism and nutrition in growth, health and disease. Amino Acids. 2009;37(1):153-68.
- Kalman DS, Feldman S, Samson A, Krieger DR. A clinical evaluation to determine the safety, pharmacokinetics, and pharmacodynamics of an inositol-stabilized arginine silicate dietary supplement in healthy adult males. Clin Pharmacol. 2015;7:103-9.
- Komorowski J, Perez Ojalvo S. A pharmacokinetic evaluation of the duration of the effect of inostiol-stabilized arginine silicate and arginine hydrochloride in healthy adult males. The Journal of the Federation of American Societies for Experimental Biology. 2016.
- James Komorowski DG. Inositol-Stabilized Arginine Silicate Reduces Exercise Induced Muscle Damage and Increases Perceived Energy. Journal of Exercise and Nutrition. 2023;6(1).
- Rogers JM, Gills J, Gray M. Acute effects of Nitrosigine(R) and citrulline malate on vasodilation in young adults. J Int Soc Sports Nutr. 2020;17(1):12.
- Sun HJ, Wu ZY, Nie XW, Bian JS. Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Front Pharmacol. 2019;10:1568.
- Little PJ, Askew CD, Xu S, Kamato D. Endothelial Dysfunction and Cardiovascular Disease: History and Analysis of the Clinical Utility of the Relationship. Biomedicines. 2021;9(6):699.
- Pacinella G, Ciaccio AM, Tuttolomondo A. Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases. Int J Mol Sci. 2022;23(24).
- Shannon OM, Clifford T, Seals DR, et al. Nitric oxide, aging and aerobic exercise: Sedentary individuals to Master's athletes. Nitric Oxide. 2022;125-126:31-9.
- Poeggeler B, Singh SK, Sambamurti K, Pappolla MA. Nitric Oxide as a Determinant of Human Longevity and Health Span. International Journal of Molecular Sciences. 2023;24(19):14533.
- Sverdlov AL, Ngo DT, Chan WP, et al. Aging of the nitric oxide system: are we as old as our NO? J Am Heart Assoc. 2014;3(4).
- Torregrossa AC, Aranke M, Bryan NS. Nitric oxide and geriatrics: Implications in diagnostics and treatment of the elderly. J Geriatr Cardiol. 2011;8(4):230-42.
- Rocha BS. The Nitrate-Nitrite-Nitric Oxide Pathway on Healthy Ageing: A Review of Pre-clinical and Clinical Data on the Impact of Dietary Nitrate in the Elderly. Front Aging. 2021;2:778467.
- Eelen G, de Zeeuw P, Simons M, Carmeliet P. Endothelial cell metabolism in normal and diseased vasculature. Circ Res. 2015;116(7):1231-44.
- Huveneers S, Daemen MJ, Hordijk PL. Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. Circ Res. 2015;116(5):895-908.
- Fang YC, Hsieh YC, Hu CJ, Tu YK. Endothelial Dysfunction in Neurodegenerative Diseases. Int J Mol Sci. 2023;24(3).
- Luca M, Luca A. Oxidative Stress-Related Endothelial Damage in Vascular Depression and Vascular Cognitive Impairment: Beneficial Effects of Aerobic Physical Exercise. Oxid Med Cell Longev. 2019;2019:8067045.
- Wu G, Meininger CJ, McNeal CJ, et al. Role of L-Arginine in Nitric Oxide Synthesis and Health in Humans. Adv Exp Med Biol. 2021;1332:167-87.
- Lerman A, Burnett JC, Jr., Higano ST, et al. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation. 1998;97(21):2123-8.
- Clarkson P, Adams MR, Powe AJ, et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest. 1996;97(8):1989-94.
- Bode-Boger SM, Boger RH, Galland A, et al. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol. 1998;46(5):489-97.
- Gambardella J, Khondkar W, Morelli MB, et al. Arginine and Endothelial Function. Biomedicines. 2020;8(8):277.
- Yaman H, Tiryaki-Sönmez G, Gürel K. Effects of oral L-arginine supplementation on vasodilation and VO2max in male soccer players. Biomedical Human Kinetics. 2010;2(2010):25-9.
- Lekakis JP, Papathanassiou S, Papaioannou TG, et al. Oral L-arginine improves endothelial dysfunction in patients with essential hypertension. Int J Cardiol. 2002;86(2-3):317-23.
- Shimbo D, Grahame-Clarke C, Miyake Y, et al. The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort. Atherosclerosis. 2007;192(1):197-203.
- Matsuzawa Y, Kwon TG, Lennon RJ, et al. Prognostic Value of Flow-Mediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2015;4(11).
- McRae MP. Therapeutic Benefits of L-Arginine: An Umbrella Review of Meta-analyses. J Chiropr Med. 2016;15(3):184-9.
- Ming X-F, Yang Z. Functions and Mechanisms of Arginase in Age-Associated Cardiovascular Diseases. Current Translational Geriatrics and Experimental Gerontology Reports. 2013;2(4):268-74.
- Kurhaluk N. The Effectiveness of L-arginine in Clinical Conditions Associated with Hypoxia. Int J Mol Sci. 2023;24(9).
- Komorowski J, Perez Ojalvo S, Sylla S, Veledar E. Poster Presentation presented at the American Society for Nutrition’s Annual Meeting 2018. Arginase inhibition by inositol-stabilized arginine silicate (ASI; Nitrosigine); a novel mechanism by which ASI enhances arginine bioavailability. Current Developments in Nutrition. 2018.
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