Dexamethasone suppresses iNOS yet induces GTPCH and CAT-2 mRNA expression in rat lungs.
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.
Skimming
Jeffrey W
JW
Department of Child Health, University of Missouri, Columbia, MO 65212, USA. skimmingj@missouri.edu
Nasiroglu
Omer
O
Huang
Chun-Jen
CJ
Wood
Charles E
CE
Stevens
Bruce R
BR
Haque
Ikram U L
IU
Scumpia
Philip O
PO
Sarcia
Paul J
PJ
D000280:Administration, Inhalation; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D027202:Cationic Amino Acid Transporter 2 / Q000235:genetics*; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D006136:GTP Cyclohydrolase / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D027202:Cationic Amino Acid Transporter 2; D017931:DNA Primers; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D009569:Nitric Oxide; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006136:GTP Cyclohydrolase