Citrulline Supplementation Improves Organ Perfusion and Arginine Availability under Conditions with Enhanced Arginase Activity

Nina Wijnands*, Dennis M. Meesters, Kevin W. Y. van Barneveld, Ruben G. J. Visschers, Jacob J. Briede, Benjamin Vandendriessche, Hans M. H. van Eijk, Babs A. F. M. Bessems, Nadine van den Hoven, Christian J. H. von Wintersdorff, Peter Brouckaert, Nicole D. Bouvy, Wouter H. Lamers, Anje Cauwels, Martijn Poeze

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Web of Science)


Enhanced arginase-induced arginine consumption is believed to play a key role in the pathogenesis of sickle cell disease-induced end organ failure. Enhancement of arginine availability with L-arginine supplementation exhibited less consistent results; however, L-citrulline, the precursor of L-arginine, may be a promising alternative. In this study, we determined the effects of L-citrulline compared to L-arginine supplementation on arginine-nitric oxide (NO) metabolism, arginine availability and microcirculation in a murine model with acutely-enhanced arginase activity. The effects were measured in six groups of mice (n = 8 each) injected intraperitoneally with sterile saline or arginase (1000 IE/mouse) with or without being separately injected with L-citrulline or L-arginine 1 h prior to assessment of the microcirculation with side stream dark-field (SDF)-imaging or in vivo NO-production with electron spin resonance (ESR) spectroscopy. Arginase injection caused a decrease in plasma and tissue arginine concentrations. L-arginine and L-citrulline supplementation both enhanced plasma and tissue arginine concentrations in arginase-injected mice. However, only the citrulline supplementation increased NO production and improved microcirculatory flow in arginase-injected mice. In conclusion, the present study provides for the first time in vivo experimental evidence that L-citrulline, and not L-arginine supplementation, improves the end organ microcirculation during conditions with acute arginase-induced arginine deficiency by increasing the NO concentration in tissues.
Original languageEnglish
Pages (from-to)5217-5238
Issue number7
Publication statusPublished - Jul 2015


  • arginase
  • arginine
  • citrulline
  • microcirculation
  • nitric oxide

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