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OtherNEUROPHARMACOLOGY

Nitric Oxide- and Superoxide-Mediated Toxicity in Cerebral Endothelial Cells

Glenn T. Gobbel, Thelma Y.-Y. Chan and Pak H. Chan
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1600-1607;
Glenn T. Gobbel
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Thelma Y.-Y. Chan
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Pak H. Chan
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Abstract

Nitric oxide and superoxide are free radicals that appear to contribute to the pathogenesis of a number of brain disorders, and cerebral endothelial cells are a potential target of these agents. Because of the capacity for these two agents to combine, it has been suggested that nitric oxide might either enhance or inhibit the toxic effects of superoxide. To establish the effect of the generation of superoxide and nitric oxide alone and in combination, cerebral endothelial cells were exposed to sodium nitroprusside, a source of nitric oxide, and/or paraquat, a source of superoxide. Paraquat enhanced the toxicity of sodium nitroprusside, as did diethyldithiocarbamate, an inhibitor of superoxide dismutase, which supports the hypothesis that enhanced levels of superoxide can combine with nitric oxide to form a more toxic product. Also, the toxicity of paraquat could be partially inhibited by blocking endogenous nitric oxide synthesis using NG-monomethyl-l-arginine. When ascorbate was administered along with sodium nitroprusside to increase nitric oxide generation, as little as 5 μM sodium nitroprusside was toxic when superoxide dismutase was inhibited. Whereas concentrations of 50 to 500 μM sodium nitroprusside and 0.4 mM ascorbate caused ∼100% toxicity, there was no measurable toxicity when these doses were accompanied by 2 mM glutathione or 50 U/ml of catalase; this suggests that peroxides may also contribute to nitric oxide toxicity. These results suggest that the simultaneous generation of nitric oxide and superoxide is synergistic, resulting in enhanced toxicity.

Footnotes

  • Send reprint requests to: Glenn T. Gobbel, D.V.M., Ph.D., Brain Tumor Research Center, Dept. of Neurological Surgery, Box 0520, 505 Parnassus Ave., University of California, San Francisco, CA 94143.

  • ↵1 This work was supported by the American Brain Tumor Association and by grants CA 13525, NS 14543, NS 25372 and AG 08938 from the National Institutes of Health.

  • Abbreviations:
    ANOVA
    analysis of variance
    BCA
    bathocuproinedisulfonic acid
    DDC
    diethyldithiocarbamate
    GSHpx
    glutathione peroxidase
    GSH
    reduced glutathione
    GSSG
    oxidized glutathione
    LDH
    lactate dehydrogenase
    NMDA
    N-methyl-d-aspartate
    NMMA
    NG-monomethyl-l-arginine
    PBS
    phosphate-buffered saline
    SIN-1
    3-morpholinosydnonimine
    SNP
    sodium nitroprusside
    SOD
    Cu,Zn-superoxide dismutase
    SNAP
    S-nitroso-N-acetyl-dl-penicillamine
    • Received November 18, 1996.
    • Accepted May 27, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherNEUROPHARMACOLOGY

Nitric Oxide- and Superoxide-Mediated Toxicity in Cerebral Endothelial Cells

Glenn T. Gobbel, Thelma Y.-Y. Chan and Pak H. Chan
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1600-1607;

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OtherNEUROPHARMACOLOGY

Nitric Oxide- and Superoxide-Mediated Toxicity in Cerebral Endothelial Cells

Glenn T. Gobbel, Thelma Y.-Y. Chan and Pak H. Chan
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1600-1607;
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