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NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric
R G Kilbourn1, S S Gross, A Jubran
1Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Abstract:
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 NG-methyl-L-arginine. We found that hypotension induced in pentobarbital-anesthetized dogs by TNF (10 micrograms/kg, i.v., resulting in a fall in mean systemic arterial pressure from 124.7 +/- 7 to 62.0 +/- 22.9 mmHg; 1 mmHg = 133 Pa) was completely reversed within 2 min following administration of NG-methyl-L-arginine (4.4 mg/kg, i.v.). In contrast, NG-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 nonenzymatic, arginine-independent mechanism. The effect of NG-methyl-L-arginine on TNF-induced hypotension was antagonized, and the hypotension restored, by administration of excess L-arginine (100 mg/kg, i.v.). Our findings suggest that excessive nitric oxide production mediates the hypotensive effect of TNF.
Insights
Tumor necrosis factor (TNF) causes hypotension by increasing nitric oxide (NO) production. Inhibiting NO synthesis with NG-methyl-L-arginine reversed this effect, suggesting NO mediates TNF-induced cardiovascular toxicity.
Area of Science:
- Cardiovascular Pharmacology
- Immunology
- Biochemistry
Background:
- Tumor necrosis factor (TNF) exhibits anti-cancer activity but is limited by dose-dependent cardiovascular toxicity, primarily hypotension.
- TNF is implicated in the vascular collapse associated with bacterial endotoxin.
Purpose of the Study:
- To investigate the mechanism underlying TNF-induced hypotension.
- To determine the role of nitric oxide (NO) in TNF-mediated cardiovascular effects.
Main Methods:
- Administered TNF to anesthetized dogs to induce hypotension.
- Utilized NG-methyl-L-arginine, an inhibitor of NO synthesis, to assess its effect on TNF-induced hypotension.
- Compared the effects of NG-methyl-L-arginine with nitroglycerin, a non-enzymatic NO donor.
- Investigated the impact of L-arginine administration on TNF-induced hypotension and NG-methyl-L-arginine's inhibitory effect.
Main Results:
- TNF administration induced significant hypotension in dogs.
- NG-methyl-L-arginine completely reversed TNF-induced hypotension, indicating NO involvement.
- NG-methyl-L-arginine did not affect hypotension induced by nitroglycerin, highlighting an enzymatic pathway difference.
- Excess L-arginine antagonized the effect of NG-methyl-L-arginine, restoring TNF-induced hypotension.
Conclusions:
- Excessive nitric oxide production mediates the hypotensive effects of TNF.
- Targeting NO synthesis may offer a therapeutic strategy to mitigate TNF-induced cardiovascular toxicity.