The DOI matches its Crossref record; 34 of the 35 references it cites were found in a registry or an index.
Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide
Open accessAbstract
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[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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Cites
Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor
Palmer, R. M. J., Ferrige, A. G., & Moncada, S. (1987) · Nature · doi:10.1038/327524a0 · Cited by 10,704
Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
Ignarro, L. J., Buga, G. M., Wood, K. S., Byrns, R. E., & Chaudhuri, G. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.24.9265 · Cited by 5,074
Vascular endothelial cells synthesize nitric oxide from L-arginine
Palmer, R. M. J., Ashton, D., & Moncada, S. (1988) · Nature · doi:10.1038/333664a0 · Cited by 4,786
Ding, A. H., Nathan, C., & Stuehr, D. J. (1988) · The Journal of Immunology · doi:10.4049/jimmunol.141.7.2407 · Cited by 2,840
Self-citationMacrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite
Hibbs, J. B., Taintor, R. R., & Vavrin, Z. (1987) · Science · doi:10.1126/science.2432665 · Cited by 1,527
Palmer, R. M. J., Rees, D. D., Ashton, D. S., & Moncada, S. (1988) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(88)81362-7 · Cited by 1,348
Martin, W., Villani, G. M., Jothianandan, D., & Furchgott, R. F. (1985) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)20898-9 · Cited by 1,259
Stuehr, D. J., & Marletta, M. A. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.22.7738 · Cited by 1,126
Self-citationHibbs, J. B., Vavrin, Z., & Taintor, R. R. (1987) · The Journal of Immunology · doi:10.4049/jimmunol.138.2.550 · Cited by 938
The Role of Endothelium in the Responses of Vascular Smooth Muscle to Drugs
Furchgott, R. F. (1984) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pa.24.040184.001135 · Cited by 937
Cited by
Sorted by citations
Nitric oxide as a secretory product of mammalian cells
Nathan, C. (1992) · The FASEB Journal · doi:10.1096/fasebj.6.12.1381691 · Cited by 4,350
Self-citationStuehr, D. J., & Nathan, C. F. (1989) · The Journal of Experimental Medicine · doi:10.1084/jem.169.5.1543 · Cited by 1,744
Self-citationRole of nitric oxide synthesis in macrophage antimicrobial activity
Nathan, C. F., & Hibbs, J. B. (1991) · Current Opinion in Immunology · doi:10.1016/0952-7915(91)90079-g · Cited by 1,523
Self-citationCleeter, M. W. J., Cooper, J. M., Darley-Usmar, V. M., Moncada, S., & Schapira, A. H. V. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00424-2 · Cited by 1,241
Boehning, D. F., & Snyder, S. H. (2003) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.26.041002.131047 · Cited by 1,235
Metadata
- Authors
- Stuehr, D. J., Gross, S. S., Sakuma, I., Levi, R., & Nathan, C. F.
- Affiliations
- Cornell University (US)
- 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
- 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 (medical) › 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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