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Updated: Aug 8, 2026
Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
Dexamethasone suppresses iNOS yet induces GTPCH and CAT-2 mRNA expression in rat lungs
Jeffrey W Skimming1, Omer Nasiroglu, Chun-Jen Huang
1Department of Child Health, University of Missouri, Columbia, MO 65212, USA. skimmingj@missouri.edu
Abstract:
The in vivo mechanisms 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 changes 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 attenuate 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. Bleeding the animals to a mean systemic blood pressure of between 40 and 45 mmHg created the hemorrhagic shock. Dexamethasone abrogated the increase in exhaled nitric oxide concentrations caused by hemorrhagic shock. At the end of the 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 increased both guanosine triphosphate cyclohydrolase I mRNA 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.
Insights
Glucocorticoids like dexamethasone reduce nitric oxide (NO) overproduction during hemorrhagic shock. This effect is achieved by decreasing inducible nitric oxide synthase (iNOS) mRNA, not by altering tetrahydrobiopterin or arginine transport.
Area of Science:
- Physiology
- Pharmacology
- Biochemistry
Background:
- Glucocorticoids are known to inhibit nitric oxide synthase (NOS) in vitro.
- Mechanisms of glucocorticoid inhibition of nitric oxide (NO) in vivo remain unclear.
- Hemorrhagic shock increases NO production, but glucocorticoid effects are not well-established.
Purpose of the Study:
- To investigate if glucocorticoids attenuate hemorrhagic shock-induced increases in intrapulmonary NO.
- To determine if dexamethasone affects tetrahydrobiopterin, inducible nitric oxide synthase (iNOS) protein, or cationic amino acid transporter (CAT)-2.
Main Methods:
- Male Sprague-Dawley rats were subjected to hemorrhagic shock.
- Animals received either dexamethasone or saline.
- Exhaled NO, plasma nitrate/nitrite, and iNOS, guanosine triphosphate cyclohydrolase I, and CAT-2 mRNA levels were measured.
Main Results:
- Dexamethasone administration abrogated the shock-induced increase in exhaled NO.
- Plasma nitrate/nitrite and iNOS protein levels were lower in the dexamethasone group.
- Dexamethasone decreased iNOS mRNA but increased guanosine triphosphate cyclohydrolase I and CAT-2 mRNA.
Conclusions:
- Dexamethasone inhibits NO formation during hemorrhagic shock.
- Inhibition appears independent of tetrahydrobiopterin and arginine transport.
- The primary mechanism involves downregulation of iNOS mRNA expression.
