Abstract
Competition for the amino acid arginine by endothelial nitric-oxide synthase (NOS3) and (pro-)inflammatory NO-synthase (NOS2) during endotoxemia appears essential in the derangement of the microcirculatory flow. This study investigated the role of NOS2 and NOS3 combined with/without citrulline supplementation on the NO-production and microcirculation during endotoxemia. Wildtype (C57BL6/N background; control; n = 36), Nos2-deficient, (n = 40), Nos3-deficient (n = 39) and Nos2/Nos3-deficient mice (n = 42) received a continuous intravenous LPS infusion alone (200 mu g total, 18 h) or combined with L-citrulline (37.5 mg, last 6 h). The intestinal microcirculatory flow was measured by side-stream dark field (SDF)-imaging. The jejunal intracellular NO production was quantified by in vivo NO-spin trapping combined with electron spin-resonance (ESR) spectrometry. Amino-acid concentrations were measured by high-performance liquid chromatography (HPLC). LPS infusion decreased plasma arginine concentration in control and Nos3(-/-) compared to Nos2(-/-) mice. Jejunal NO production and the microcirculation were significantly decreased in control and Nos2(-/-) mice after LPS infusion. No beneficial effects of L-citrulline supplementation on microcirculatory flow were found in Nos3(-/-) or Nos2(-/-)/Nos3(-/-) mice. This study confirms that L-citrulline supplementation enhances de novo arginine synthesis and NO production in mice during endotoxemia with a functional NOS3-enzyme (control and Nos2(-/-) mice), as this beneficial effect was absent in Nos3(-/-) or Nos2(-/-)/Nos3(-/-) mice.
Original language | English |
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Article number | 11940 |
Number of pages | 10 |
Journal | International Journal of Molecular Sciences |
Volume | 22 |
Issue number | 21 |
DOIs | |
Publication status | Published - 1 Nov 2021 |
Keywords
- nitric oxide synthase
- arginine
- microcirculation
- endotoxemia
- citrulline
- NOS3
- NOS2
- NITRIC-OXIDE PRODUCTION
- MICE LACKING
- SEPTIC SHOCK
- SYNTHASE
- SEPSIS
- METABOLISM
- EXPRESSION
- ENOS
- GUT
- MORTALITY