N sup G -methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: Implications for the involvement of nitric oxide

Journal Article · Tue May 01 00:00:00 EDT 1990 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.87.9.3629· OSTI ID:5317618

Kilbourn, R G; Adams, J ^[1]; Gross, S S; Griffith, O W; Levi, R ^[2]; Jubran, A; Lodato, R F ^[3]

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1. Univ. of Texas M. D. Anderson Cancer Center, Houston (USA)
2. Cornell Univ. Medical College, New York, NY (USA)
3. Univ. of Texas Health Science Center, Houston (USA)

Clinical assessment of the activity of tumor necrosis factor (TNF) against human cancer has been limited by a dose-dependent cardiovascular toxicity, most frequently hypotension. TNF is also thought to mediate the vascular collapse resulting from bacterial endotoxin. The present studies address the mechanism by which TNF causes hypotension and provide evidence for elevated production of nitric oxide, a potent vasodilator initially characterized as endothelium-derived relaxing factor. Nitric oxide is synthesized by several cell types, including endothelial cells and macrophages, from the guanidino nitrogen of L-arginine; the enzymatic pathway is competitively inhibited by N{sup G}-methyl-L-arginine. The authors found that hypotension induced in pentobarbital-anesthetized dogs by TNF was completely reversed within 2 min following administration of N{sup G}-methyl-L-arginine. In contrast, N{sup G}-methyl-L-arginine failed to reverse the hypotensive response to an equivalent depressor dose of nitroglycerin, a compound that acts by forming nitric oxide by a monenzymatic, arginine-independent mechanism. The effect of N{sup G}-methyl-L-arginine on TNF-induced hypotension was antagonized, and the hypotension restored, by administration of excess L-arginine findings suggest that excessive nitric oxide production mediates the hypotensive effect of TNF.

• OSTI ID: 5317618
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Vol. 87:9; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ARGININE
BIOCHEMISTRY
NITRIC OXIDE
BIOLOGICAL EFFECTS
PROTEINS
BIOCHEMICAL REACTION KINETICS
BLOOD PRESSURE
CARDIOVASCULAR SYSTEM
DOGS
DOSE-RESPONSE RELATIONSHIPS
ENDOTHELIUM
HYPOTENSION
NECROSIS
NEOPLASMS
TOXICITY
VASODILATORS
AMINO ACIDS
ANIMAL TISSUES
ANIMALS
BODY
CARBOXYLIC ACIDS
CARDIOVASCULAR AGENTS
CHALCOGENIDES
CHEMISTRY
DISEASES
DRUGS
KINETICS
MAMMALS
NITROGEN COMPOUNDS
NITROGEN OXIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
OXIDES
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
REACTION KINETICS
TISSUES
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology