Dexamethasone suppresses iNOS yet induces GTPCH and CAT-2 mRNA expression in rat lungs

Jeffrey W. Skimming, Omer Nasiroglu, Chun Jen Huang, Charles E. Wood, Bruce R. Stevens, Ikram U L Haque, Philip O. Scumpia, Paul J. Sarcia

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15 Citations (Scopus)

Abstract

The in vivo mechanism by which glucocorticoids inhibit nitric oxide expression await detailed investigation. In cell culture experiments, glucocorticoids have been shown to inhibit inducible nitric oxide synthase (iNOS) formation and activity. Glucocorticoids can inhibit iNOS activity in cultured cells by blocking arginine transport and inhibiting tetrahydrobiopterin biosynthesis. We recently reported that changes in intrapulmonary formation of nitric oxide in endotoxemic rats correspond with change in transcription of the predominant arginine transporter cationic amino acid transporter (CAT)-2. Realizing that hemorrhagic shock induces nitric oxide overproduction in intact animals, we sought to explore whether glucocorticoids atteruate hemorrhagic shock-induced increases in intrapulmonary nitric oxide formation and whether they might do so by inhibiting the formation of tetrahydrobiopterin, iNOS protein, and CAT-2. We randomly assigned 10 male Sprague-Dawley rats to receive dexamethasone or normal saline. Bleed ing the animals to a mean systemic blood pressure of between 40 and 45 mmHg created the hemorrhagic shock. Dexameth asone abrogated the increase in exhaled nitric oxide concentrations caused by hemorrhagic shock. At the end of th experiment, plasma nitrate/nitrite values were lower in the dexamethasone group than in the control group. The iNOS protein concentrations were also lower in the dexamethasone group than in the control group. Dexamethasone decreased the intrapulmonary iNOS mRNA concentrations yet in creased both guanosine triphosphate cyclohydrolase I mRNt and CAT-2 mRNA. Our results support the idea that dexamethasone inhibits nitric oxide formation in a manner that is independent of tetrahydrobiopterin and arginine transport yet dependent on downregulation of iNOS mRNA expression.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume285
Issue number2 29-2
Publication statusPublished - Aug 1 2003
Externally publishedYes

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Keywords

  • Arginine
  • Cationic amino acid transporter 2
  • Glucocorticoids
  • Guanosine triphosphate cyclohydrolase I
  • Hemorrhage
  • Hemorrhagic shock
  • Multiple organ failure
  • Nitric oxide
  • Shock

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Skimming, J. W., Nasiroglu, O., Huang, C. J., Wood, C. E., Stevens, B. R., Haque, I. U. L., Scumpia, P. O., & Sarcia, P. J. (2003). Dexamethasone suppresses iNOS yet induces GTPCH and CAT-2 mRNA expression in rat lungs. American Journal of Physiology - Lung Cellular and Molecular Physiology, 285(2 29-2).