Acute L-arginine supplementation does not increase nitric oxide production in healthy subjects

Journal Title (Medline/Pubmed accepted abbreviation):Nutr. Metab.
Year: 2012
Volume: 9
First page: 54
doi: 10.1186/1743-7075-9-54

Summary of Background and Research Design

Background: Nitric oxide (NO) is a compound present in the blood stream that promotes blood flow. It is thought that increased blood flow can increase the rate at which nutrients are delivered to exercising tissues, as well as promote removal of waste products, thereby enhancing muscle performance during exercise. NO can be produced from the amino acid arginine in the body.

Hypothesis: Supplementation with arginine will increase blood concentrations of NO.

Subjects: 17 healthy males, age 25.5 ± 30.5 y

Experimental design: randomized, double-blind, placebo-controlled trial

Treatments : Consumed with 400 mL water
Arginine: 6 g encapsulated l-arginine hydrochloride
Placebo: corn starch, prepared the same way as the arginine

Protocol : The day before the study, the participants consumed a diet low in nitrite and nitrate (which can also be made into NO). On the day of the study, the participants arrived at the laboratory and consumed the supplement. After 10 min, blood was drawn and treated for analysis of nitrite + nitrate (NOx), which reflects NO concentrations. Blood was also assessed for concentrations of arginine as well as citrulline and ornithine, two amino acids that are metabolites of arginine.

Summary of Research Findings
  • Although those that consumed arginine exhibited slightly greater concentrations of NOx in the plasma at every time point, results were not statistically significant.
  • The area under the curve for NOx concentration vs. time was 15% greater for those that consumed the arginine supplement compared to those that had the placebo. However, the difference did not reach statistical significance.
  • Plasma arginine concentrations were significantly greater in the arginine group compared to the placebo group at 30, 60, 90, and 120 min post-ingestion.
  • There were no differences between groups in plasma citrulline or ornithine levels at any time point. Citrulline, specifically, is a byproduct of NO production. In accord with the NOx data (point 1), these observations also suggest that NO production was similar between the two groups.
  • There was no change in the plasma concentration of ADMA, a nitric oxide synthase (NOS) inhibitor, or SDMA, a molecule that interferes with arginine transport within the cell.

Key practice applications

The biochemical pathways that control the production of NO from arginine appear to be highly internally regulated.  Supplemental arginine in a single dose of 6 g was not effective at increasing the concentration of NO in the body.


After taking the supplement, the participants remained at rest during the blood draws.  Physiology is obviously much different during exercise (ex. much more metabolism is occurring, blood is being pumped faster) and these results may not apply to the exercise state.

Also, nitric oxide is very difficult to measure directly.  In this study, plasma nitrate and nitrite were measured as surrogate biomarkers of NO, since they are formed from NO.  Because these species are in a predictable equilibrium with one another, the sum of the species was assumed to reflect NO concentrations.  However, there is a chance that this assumption is not valid. 
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