Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men

Int J Cardiol. 2012 Mar 8;155(2):257-61. doi: 10.1016/j.ijcard.2010.10.004. Epub 2010 Nov 9.


Background: Nitric oxide (NO) plays a key role in the maintenance of vascular tone, contributing to the functional regulation of arterial stiffness. Although oral L-citrulline could become the effective precursor of L-arginine (substrate for endothelial NO synthase) via the L-citrulline/ L-arginine pathway, little is known about the efficacy of L-citrulline application on arterial stiffness.

Objective: We examined the short-term effects of L-citrulline supplementation on arterial stiffness in humans.

Methods: In a double-blind, randomized, placebo-controlled parallel-group trial, 15 healthy male subjects (age: 58.3 ± 4.4 years) with brachial-ankle pulse wave velocity (baPWV; index of arterial stiffness >1400 cm/sec) were given 5.6g/day of L-citrulline (n=8) or placebo (n=7) for 7 days. baPWV and various clinical parameters were measured before (baseline) and after oral supplementation of L-citrulline or placebo.

Results: Compared with the placebo group, baPWV was significantly reduced in the L-citrulline group (p<0.01). No significant differences in blood pressure (BP) were found between the two groups, and no correlation was observed between BP and baPWV. The serum nitrogen oxide (NOx, the sum of nitrite plus nitrate) and NO metabolic products were significantly increased only in the L-citrulline group (p<0.05). Plasma citrulline, arginine and the ratio of arginine/asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (arginine/ADMA ratio) were significantly increased in the L-citrulline group compared with the placebo group (p<0.05, p<0.01, p<0.05, respectively). Moreover, there was a correlation between the increase of plasma arginine and the reduction of baPWV (r=-0.553, p<0.05).

Conclusion: These findings suggest that short-term L-citrulline supplementation may functionally improve arterial stiffness, independent of blood pressure, in humans.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Ankle Brachial Index
  • Arginine / analogs & derivatives
  • Arginine / blood
  • Blood Pressure / physiology
  • Citrulline / administration & dosage*
  • Citrulline / blood
  • Humans
  • Male
  • Middle Aged
  • Nitric Oxide / blood
  • Nitric Oxide Synthase Type III / metabolism
  • Placebos
  • Pulsatile Flow / drug effects*
  • Vascular Stiffness / drug effects*
  • Vascular Stiffness / physiology*


  • Placebos
  • Citrulline
  • Nitric Oxide
  • N,N-dimethylarginine
  • Arginine
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III