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

Biochem Biophys Res Commun. 2014 Nov 7;454(1):53-7. doi: 10.1016/j.bbrc.2014.10.029. Epub 2014 Oct 14.


Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Blood circulation; Cyclic GMP; Nitric oxide; l-Arginine; l-Citrulline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Arginine / administration & dosage*
  • Arginine / blood*
  • Atherosclerosis / prevention & control
  • Biological Availability
  • Citrulline / administration & dosage*
  • Cyclic GMP / blood
  • Dietary Supplements*
  • Drug Synergism
  • Humans
  • Male
  • Nitric Oxide / blood*
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects


  • Citrulline
  • Nitric Oxide
  • Arginine
  • Cyclic GMP