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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.
- Source :
-
The Journal of experimental medicine [J Exp Med] 1989 Mar 01; Vol. 169 (3), pp. 1011-20. - Publication Year :
- 1989
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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.
- Subjects :
- Animals
Aorta
Arginine pharmacology
Biological Assay
Chemical Phenomena
Chemistry
Endothelium, Vascular
Ferredoxins metabolism
Mice
Mice, Inbred C3H
Muscle Relaxation drug effects
Muscle, Smooth, Vascular physiology
Nitrates metabolism
Nitric Oxide analysis
Nitric Oxide pharmacology
Nitrites metabolism
Nitrogen Dioxide analysis
Nitrogen Dioxide metabolism
Rabbits
Spectrophotometry
Arginine metabolism
Biological Factors pharmacology
Macrophage Activation
Macrophages metabolism
Nitric Oxide metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1007
- Volume :
- 169
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 2784476
- Full Text :
- https://doi.org/10.1084/jem.169.3.1011