WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• L-Arginine is a semiessential amino acid that is converted to nitric oxide (NO) by NO synthase (NOS).• NO improves endothelial function by elevating cyclic guanosine monophosphate.• However, oral L-arginine treatment in humans is hampered by extensive metabolism. WHAT THIS STUDY ADDS• Oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.• L-Citrulline may thus be an alternative to L-arginine in patients with impaired NOS activity. AIMSOral L-arginine supplementation has been used in several studies to improve endothelium-dependent, nitric oxide (NO)-mediated vasodilation. L-Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L-citrulline is readily absorbed and at least in part converted to L-arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects. METHODSIn a double-blind, randomized, placebo-controlled cross-over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (Cmax, Tmax, Cmin, AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L-arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow-mediated vasodilation (FMD) was measured to assess pharmacodynamic effects. RESULTSL-Citrulline dose-dependently increased AUC and Cmax of plasma L-arginine concentration more effectively than L-arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the Cmin of plasma L-arginine and improved the L-arginine/ADMA ratio from 186 Ϯ 8 (baseline) to 278 Ϯ 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 Ϯ 10 to 125 Ϯ 15 mmol mmol -1 creatinine (P = 0.01, 95% CI 8, 58) and from 38 Ϯ 3.3 to 50 Ϯ 6.7 nmol mmol -1 creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD. CONCLUSIONOur data show for the first time that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.

The study was able to define a reference value for ADMA plasma levels with 0.36-1.17 micromol L(-1) and found sex dependent correlations between ADMA and age. Women showed a significant increase in ADMA plasma levels with onset of menopause.