Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide

Stuehr, D J; Gross, S S; Sakuma, I; Levi, R; Nathan, C F

doi:10.1084/jem.169.3.1011

Cited by 457Nitric Oxide and Endothelin EffectsImmune cells in cancerNeutrophil, Myeloperoxidase and Oxidative Mechanisms

Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide

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Stuehr, D J, Gross, S S, Sakuma, I, Levi, R, Nathan, C F·1989·The Journal of experimental medicine

DOI 10.1084/jem.169.3.1011PMC PMC2189276

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Abstract

L-arginine-dependent synthesis of nitrite (NO2-) and nitrate (NO3-) by macrophages correlates with and is required for their execution of nonspecific cytotoxicity toward some tumor cells and microbes. However, the bioactive L-arginine metabolites responsible for cytotoxicity are unknown. Mammalian endothelial cells have recently been shown to release nitric oxide (NO.); we therefore determined if this reactive metabolite was synthesized by activated murine macrophages. Macrophage-derived NO. was detected by two independent methods: a bioassay for NO.-mediated relaxation of preconstricted rings of rabbit aorta; and a spectroscopic measurement of the reaction of NO. with clostridial ferredoxin, an Fe-S protein. After activation with IFN-gamma and LPS, macrophages continuously secreted a substance that relaxed rabbit aortic rings denuded of endothelium. Production of the vasorelaxant was enhanced by 0.5 mM L-arginine and inhibited reversibly by NG-methylated L-arginine analogs that block macrophage NO2-/NO3- synthesis. The vasorelaxant was scavenged by ferrous myoglobin, was labile, and was neither NO2- nor a cyclooxygenase metabolite. Activated M phi also secreted a substance that bleached Fd, a reaction carried out by NO. and NO2, but not NO2-. Macrophage bleaching of Fd correlated directly with time, cell number, and concomitant NO2-/NO3- production, required L-arginine, and was independent of reactive oxygen intermediates. Thus, activated murine M phi release NO. and/or a closely related, highly reactive nitrogen oxide such as NO2, during their conversion of L-arginine to NO2-/NO3-. NO. and NO2 may mediate L-arginine-dependent pathologic effects of M phi, as well as physiologic effects not previously considered for this widely distributed cell type.

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Consequently, microbial diversity is reduced while local and systemic inflammation and decreased NO bioavailability persist, propagating vascular injury and the risk of developing PH.
“Consequently, microbial diversity is reduced[325,326] while local and systemic inflammation and decreased NO bioavailability persist, propagating vascular injury and the risk of developing PH.”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [326]

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Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endotheliumderived relaxing factor and the chemical reactivity of nitric oxide.J. Exp. Med
Stuehr, J., Gross, S. S., Sakuma, I. I., Levi, R., I, & Nathan, C. F. (1989)
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Authors: Stuehr, D. J., Gross, S. S., Sakuma, I., Levi, R., & Nathan, C. F.
Affiliations: Cornell University (US)
ORCID: Stuehr, D J
Gross, S S
Sakuma, I
Levi, R
Nathan, C F
Venue: The Journal of experimental medicine
Publisher: Rockefeller University Press
Published: 1989-03-01
Volume: 169
Issue: 3
Pages: 1011-1020
ISSN: 0022-1007 (ISSN-L)
1540-9538
DOI: 10.1084/jem.169.3.1011
PMC: PMC2189276
OpenAlex: W1975644913
Cited by: 457
References: 35
Citations by year: 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 6 · 2015: 8 · 2014: 9 · 2013: 10 · 2012: 4
FWCI: 30.53
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Journal of Experimental Medicine (publishedVersion)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (HL37407, HL-34215)
National Cancer Institute (CA-43610)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords: macrophages, nitric oxide, arginine metabolism, endothelium-derived relaxing factor, nitrite, nitrate, vasorelaxation, myoglobin, interferon-gamma, LPS, macrophage activation, reactive nitrogen species, macrophage cytotoxicity
MeSH terms: Animals, Aorta, Arginine, Biological Assay, Biological Factors, Chemistry, Endothelium, Vascular, Ferredoxins, Macrophage Activation, Macrophages, Mice, Inbred C3H, Muscle Relaxation, Muscle, Smooth, Vascular, Nitrates, Nitric Oxide, Nitrites, Nitrogen Dioxide, Rabbits, Spectrophotometry, Mice, Chemical Phenomena

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Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide

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