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Molecular Pharmacology

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Research ArticleArticle

Inhibition of Glucocorticoid Receptor Binding by Nitric Oxide

Mario D. Galigniana, Graciela Piwien-Pilipuk and Jamil Assreuy
Molecular Pharmacology February 1999, 55 (2) 317-323; DOI: https://doi.org/10.1124/mol.55.2.317
Mario D. Galigniana
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Graciela Piwien-Pilipuk
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Jamil Assreuy
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Abstract

Septic shock is a dangerous condition with high mortality rates. In sepsis, the inducible form of nitric oxide (NO) synthase is induced, releasing high amounts of NO. Glucocorticoids have potent anti-inflammatory properties and are very effective in inhibiting the induction of this enzyme if administered before the shock onset. It is known that glucocorticoid receptor (GR) has critical cysteine residues for steroid binding in its hormone-binding and DNA-binding domains. It has also been reported that NO reacts with —SH groups, formingS-nitrosothiols. Therefore, we examined the potential effect of NO on the ligand-binding ability of GR. NO donors (S-nitroso-acetyl-dl-penicillamine,S-nitroso-dl-penicillamine, orS-nitroso-glutathione) decreased, in a time- and dose-dependent manner, the binding of [3H]triamcinolone to immunoprecipitated GR from mouse L929 fibroblasts. The nonnitrosylated parent molecules,N-acetyl-dl-penicillamine, and reduced gluthatione were without effect. Scatchard plots revealed that the number of ligand binding sites and K d were reduced (50%) by NO donors. Western blot analysis ruled out the possibility that dissociation of GR/heat shock protein 90 heterocomplex or decrease in GR protein would account for the inhibitory effect of NO. Decreased ligand binding to GR was found when NO donors were incubated with intact fibroblasts. Incubation with NO donors also decreased the steroid-induced reduction in [3H]uridine incorporation into RNA. All of these NO effects were inhibited by the thiol-protecting agent dithiothreitol. Therefore,S-nitrosylation of critical —SH groups in GR by NO with consequent decreases in binding and affinity may be the mechanisms which explain the failure of glucocorticoids to exert their anti-inflammatory effects in septic shock.

Footnotes

    • Received June 2, 1998.
    • Accepted November 13, 1998.
  • Send reprint requests to: Dr. Jamil Assreuy, Department of Pharmacology, Universidade Federal de Santa Catarina, Rua Ferreira Lima 82, Florianopolis, SC, 88015-420, Brazil. E-mail:assreuy{at}farmaco.ufsc.br

  • J.A. is recipient of Research Fellowship and Research Grant from CNPq (Brazil).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (2)
Molecular Pharmacology
Vol. 55, Issue 2
1 Feb 1999
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Research ArticleArticle

Inhibition of Glucocorticoid Receptor Binding by Nitric Oxide

Mario D. Galigniana, Graciela Piwien-Pilipuk and Jamil Assreuy
Molecular Pharmacology February 1, 1999, 55 (2) 317-323; DOI: https://doi.org/10.1124/mol.55.2.317

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Research ArticleArticle

Inhibition of Glucocorticoid Receptor Binding by Nitric Oxide

Mario D. Galigniana, Graciela Piwien-Pilipuk and Jamil Assreuy
Molecular Pharmacology February 1, 1999, 55 (2) 317-323; DOI: https://doi.org/10.1124/mol.55.2.317
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