title: Citrulline Supplementation Improves Organ Perfusion and Arginine Availability under Conditions with Enhanced Arginase Activity.
abstract: 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.
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. n.wijnands@maastrichtuniversity.nl.
authors.forename: Karolina A P
authors.initials: KA
authors.lastname: Wijnands
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. d.meesters@maastrichtuniversity.nl.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Meesters
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. k.vanbarneveld@maastrichtuniversity.nl.
authors.forename: Kevin W Y
authors.initials: KW
authors.lastname: van Barneveld
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. r.visschers@maastrichtuniversity.nl.
authors.forename: Ruben G J
authors.initials: RG
authors.lastname: Visschers
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht 6200, The Netherlands. j.briede@maastrichtuniversity.nl.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Briedé
authors.affiliation: Department of Molecular Biomedical Research, VIB, Ghent B-9000, Belgium. benjamin.vandendriessche@dmbr.ugent.be.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9000, Belgium. benjamin.vandendriessche@dmbr.ugent.be.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vandendriessche
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. hmh.vaneijk@maastrichtuniversity.nl.
authors.forename: Hans M H
authors.initials: HM
authors.lastname: van Eijk
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. imnoteviliam@hotmail.com.
authors.forename: Babs A F M
authors.initials: BA
authors.lastname: Bessems
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. n.vandenhoven@student.maastrichtuniversity.nl.
authors.forename: Nadine
authors.initials: N
authors.lastname: van den Hoven
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. c.von.wintersdorff@mumc.nl.
authors.forename: Christian J H
authors.initials: CJ
authors.lastname: von Wintersdorff
authors.affiliation: Department of Molecular Biomedical Research, VIB, Ghent B-9000, Belgium. Peter.Brouckaert@dmbr.vib-ugent.be.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9000, Belgium. Peter.Brouckaert@dmbr.vib-ugent.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. n.bouvy@mumc.nl.
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Bouvy
authors.affiliation: Department of Anatomy & Embryology, Maastricht University Medical Center, Maastricht 6200, The Netherlands. wh.lamers@maastrichtuniversity.nl.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
authors.affiliation: Department of Molecular Biomedical Research, VIB, Ghent B-9000, Belgium. anje.cauwels@vib-ugent.be.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9000, Belgium. anje.cauwels@vib-ugent.be.
authors.forename: Anje
authors.initials: A
authors.lastname: Cauwels
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. m.poeze@maastrichtuniversity.nl.
authors.forename: Martijn
authors.initials: M
authors.lastname: Poeze
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism* / Q000494:pharmacology; D001120:Arginine / Q000172:deficiency / Q000378:metabolism*; D002956:Citrulline / Q000494:pharmacology*; D007583:Jejunum / Q000098:blood supply; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis*
chemical_list: D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D001119:Arginase
keywords: arginase; arginine; citrulline; microcirculation; nitric oxide