A Cauwels

B Vandendriessche

BAP Bessems

DM Meesters

HMH van Eijk

JJ Briedé

KAP Wijnands

M Poeze

P Brouckaert

WAP Buurman

Springer - Publisher Connector

POSTER PRESENTATION Open Access
0521. A functional citrulline-arginine-no pathway
and nos3 complex is essential to maintain
microcirculatory function during endotoxemia
KAP Wijnands1*, DM Meesters1, B Vandendriessche2, JJ Briedé3, BAP Bessems4, HMH van Eijk4, P Brouckaert2,
WAP Buurman4, A Cauwels2, M Poeze1
From ESICM LIVES 2014
Barcelona, Spain. 27 September - 1 October 2014
Introduction
Sepsis is associated with high mortality rates as a result of
the development of multiple organ failure (MOF). In MOF
the competition for the amino acid arginine between the
microcirculation and the inflammatory response is impor-
tant. The endothelial nitric-oxide synthase (eNOS) uses
arginine to produce nitric oxide (NO), which results in
microcirculatory vasodilatation, whereas arginase and the
inflammatory nitric-oxide synthase (iNOS) use arginine in
the inflammatory response to produce acute phase pro-
teins and to stimulate the host response. Enhanced argi-
nine consumption combined with decreased arginine de
novo synthesis from citrulline results in arginine deficiency
for eNOS, eNOS uncoupling, and a decreased organ
perfusion.
Objectives
To investigate the role of the NOS enzymes during
endotoxemia and the effect of citrulline supplementation
on the arginine-NO synthesis and microcirculation.
Methods
Wildtype (n= 39), deficient iNOS mice, (iNOS-/-; n= 39),
deficient eNOS mice (eNOS-/-; n= 39) and double
knock-out (KO) mice (mice deficient for iNOS and
eNOS; n=39) received a continuous LPS (200µg total)
infusion for 18 hrs alone or combined with citrulline
(37.5mg) for the last 6 hrs. SDF-imaging was used to
evaluate the microcirculation in jejunal villi and the NO
production in jejunal tissue was determined by in vivo
NO spin trapping and quantified by electron spin-
resonance spectrometry. After the microcirculatory mea-
surements or in vivo NO spin trapping, mice were sacri-
ficed, blood and tissues were sampled. Amino-acid
concentrations in blood and tissue were measured by
High Performance Liquid Chromotography.
Results
LPS infusion significantly decreased plasma arginine avail-
ability in all mouse strains. However, in the jejunal tissue
of iNOS-/- or eNOS-/- mice this was not accompanied by a
decreased intracellular arginine availability. Jejunal NO
production was significantly decreased in all mouse strains
during endotoxemia, except for eNOS-/- mice. LPS infu-
sion resulted in a significantly decrease in jejunal microcir-
culation in wildtype and iNOS-/- mice. However, mice
lacking a functional eNOS enzyme, as present in eNOS-/-
and double KO mice, perfusion in jejunal tissue did not
decrease during LPS infusion. Also the beneficial effects of
citrulline supplementation during LPS infusion on the
microcirculation were not present in eNOS-/- or double
KO mice, although citrulline significantly enhanced the
plasma arginine availability in all mouse strains. In addi-
tion, tissue arginine availability did not increase in citrul-
line supplemented NOS deficient mice.
Conclusions
Citrulline improves the arginine de novo synthesis during
sepsis, however to enhance the microcirculation during
sepsis, citrulline requires a functional eNOS enzyme.
Therefore, future research needs to focus both on
improvement of the arginine de novo synthesis and main-
tenance of a functional eNOS enzyme during sepsis.
1Maastricht University Medical Center, Department of Surgery, Maastricht,
Netherlands
Full list of author information is available at the end of the article
Wijnands et al. Intensive Care Medicine Experimental 2014, 2(Suppl 1):P30
http://www.icm-experimental.com/content/2/S1/P30
© 2014 Wijnands et al; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Authors’ details
1Maastricht University Medical Center, Department of Surgery, Maastricht,
Netherlands. 2Ghent University, Inflammation Research Center, VIB, Ghent,
Belgium. 3Maastricht University, Maastricht, Netherlands. 4Maastricht
University, Department of Surgery, Maastricht, Netherlands.
Published: 26 September 2014
doi:10.1186/2197-425X-2-S1-P30
Cite this article as: Wijnands et al.: 0521. A functional citrulline-arginine-
no pathway and nos3 complex is essential to maintain microcirculatory
function during endotoxemia. Intensive Care Medicine Experimental 2014 2
(Suppl 1):P30.
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Wijnands et al. Intensive Care Medicine Experimental 2014, 2(Suppl 1):P30
http://www.icm-experimental.com/content/2/S1/P30
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0521. A functional citrulline-arginine-no pathway and nos3 complex is essential to maintain microcirculatory function during endotoxemia

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0521. A functional citrulline-arginine-no pathway and nos3 complex is essential to maintain microcirculatory function during endotoxemia

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