Tetrahydrobiopterin and GTP cyclohydrolase I in a rat model of endotoxic shock: relation to nitric oxide synthesis.
Induction of the inducible isoform of nitric oxide synthase (iNOS) in various types of cells is implicated as the cause of septic shock. We evaluated the concentration of tetrahydrobiopterin (BH4), a cofactor of NOS, in plasma and various other tissues of rats treated with lipopolysaccharide (LPS; 10 mg/kg I.V.). The activity of GTP cyclohydrolase I (GTPCH), the first and rate-limiting enzyme in the de novo synthesis of BH4, in rat tissues was also determined. Three hours after administration of LPS, rats showed plasma levels of BH4 and NOx (NO3- and NO2-) that were elevated by 137 and 206%, respectively. GTPCH was expressed in liver and, to a lesser extent, in the lung, heart and kidney of control rats. In control rats, although a high concentration of BH4 was detected in the liver, its level was lower in lung, heart, kidney and aorta. Three hours after LPS administration, a significant increase in BH4 concentration and/or GTPCH activity was observed in all tissues examined except the liver. Our results demonstrate that the de novo synthesis of BH4 is upregulated by LPS in the rat in vivo, which may, at least in part, account for the increases in plasma level and tissue concentration of BH4 after the administration of LPS.
Hattori
Y
Y
Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan.
Nakanishi
N
N
Kasai
K
K
Murakami
Y
Y
Shimoda
S
S
D000768:Anesthesia, General; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity; D004790:Enzyme Induction / Q000187:drug effects; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000201:enzymology / Q000378:metabolism*; D014018:Tissue Distribution; D015854:Up-Regulation
D004731:Endotoxins; D008070:Lipopolysaccharides; D001708:Biopterins; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli; D019001:Nitric Oxide Synthase; D006136:GTP Cyclohydrolase; C003402:sapropterin