Glucocorticoid regulation of nitric oxide and tetrahydrobiopterin in a rat model of endotoxic shock.
Wistar rats injected intravenously with bacterial lipopolysaccharide (LPS) developed endotoxic shock with severe hypotension, significantly elevated concentrations of NOx (nitrate and nitrite) and biopterin in the plasma, and lung expression of high levels of the mRNAs for inducible NO synthase (iNOS) and GTP cyclohydrolase I (GTPCH). Pretreatment of the rats with dexamethasone (DEX) prevented the hypotension, attenuated the increase in plasma NOx and biopterin concentrations, and significantly inhibited the increase in lung biopterin content caused by LPS treatment. DEX also inhibited the induction of iNOS mRNA but not GTPCH mRNA. Adrenalectomized (ADX) rats developed a more severe form of circulatory shock in response to low-dose LPS accompanied by a substantial increase in circulating NOx as well as biopterin, which was prevented by pretreatment with DEX. Thus, glucocorticoids may protect against endotoxic shock by inhibiting the induction of NO synthesis, not only by attenuating iNOS protein induction but also by limiting biopterin availability. Although endogenous glucocorticoids may inhibit the production of NO as well as biopterin after LPS in rats, the mechanisms for these effects appear to be different.
Hattori
Y
Y
Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan. yhattori@dokkyomed.ac.jp
Akimoto
K
K
Nakanishi
N
N
Kasai
K
K
D000315:Adrenalectomy; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D004926:Escherichia coli; D006136:GTP Cyclohydrolase / Q000096:biosynthesis; D005938:Glucocorticoids / Q000494:pharmacology; D007022:Hypotension / Q000378:metabolism / Q000517:prevention & control; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D009573:Nitrites / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000378:metabolism / Q000503:physiopathology*; D014158:Transcription, Genetic / Q000187:drug effects*
D005938:Glucocorticoids; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D001708:Biopterins; D009569:Nitric Oxide; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D006136:GTP Cyclohydrolase; C003402:sapropterin