Better NO boosters contain a combination of L-arginine and L-citrulline

Sports supplements with amino acids designed to boost the concentration of nitrogen monoxide [NO] work better if they contain not just L-arginine or L-citrulline but a combination of the two. Researchers at the Japanese manufacturers Kyowa Hakko Bio discovered this when they did an experiment on rabbits.


L-Arginine is a non-essential amino acid that is one of the building blocks for NO in the body. NO widens the blood vessels so that more oxygen, glucose and amino acids can be transported to the muscle cells. It also seems that muscle cells grow faster the higher the concentration of NO.

Despite this, L-arginine supplementation doesn’t have spectacular effects in athletes, probably because the liver breaks L-arginine down fast. Some supplements manufacturers get round this problem by using L-arginine’s metabolite, L-citrulline, in their products instead. The liver cannot break down L-citrulline, but enzymes in the body can convert L-citrulline into L-arginine.


In 2005 the Japanese published an animal study in which they showed that a combination of L-arginine and L-citrulline offered the animals’ blood vessels better protection against atherosclerosis than L-arginine alone or L-citrulline alone. [Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13681-6.] In the animal study that this posting is about the researchers took things a step further.

They gave rabbits water containing a hefty dose of L-arginine. The human equivalent would be about 12 grams.

A second group of rabbits was given an identical dose of L-citrulline, and a third group was given a mixture containing equal amounts of L-arginine and L-citrulline. The human equivalent of the doses that the third group of rabbits got would be about 6 grams L-arginine and 6 grams L-citrulline. Obscenely high, indeed, but the Japanese were after proof of principle.


Forty-five minutes after receiving the supplements the animals’ circulation improved. The effect of the mixture was greater than that of the amino acids when given separately.


The mixture of L-citrulline and L-arginine resulted in a bigger rise in the concentration of NO in the blood of the animals than the rise of the amino acids separately. The artery widening effect of NO is due to the activation of the enzyme cGMP. The concentration of this enzyme also rose by a greater amount when the rats were given the combined amino acids than when they were given them separately.

Circles = L-arginine; squares = L-citrulline; triangles = mixture.



“Our data suggest the clinical benefit on vascular function of L-citrulline plus L-arginine supplementation”, the researchers write. “However, we believe further study in humans is needed to be able to present a therapeutic option with clinical utility.”

Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability.



Chronic supplementation with L-citrulline plus L-arginine has been shown to exhibit anti-atherosclerotic effects. However, the short-term action of this combination on the nitric oxide (NO)-cGMP pathway remains to be elucidated. The objective of the present study was to investigate the acute effects of a combination of oral L-citrulline and L-arginine on plasma L-arginine and NO levels, as well as on blood circulation.


Rats or New Zealand white rabbits were treated orally with L-citrulline, or L-arginine, or a combination of each at half dosage. Following supplementation, plasma levels of L-arginine, NOx, cGMP and changes in blood circulation were determined sequentially.


L-Citrulline plus L-arginine supplementation caused a more rapid increase in plasma L-arginine levels and marked enhancement of NO bioavailability, including plasma cGMP concentrations, than with dosage with the single amino acids. Blood flow in the central ear artery in rabbits was also significantly increased by L-citrulline plus L-arginine administration as compared with the control.

Our data show for the first time that a combination of oral L-citrulline and L-arginine effectively and rapidly augments NO-dependent responses at the acute stage. This approach may have clinical utility for the regulation of cardiovascular function in humans.

PMID: 25445598 [PubMed – in process]

Source: http://www.ncbi.nlm.nih.gov/pubmed/25445598

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