The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat.
1. The effect of endotoxin (E. coli lipopolysaccharide) on the induction of nitric oxide synthase (NOS) and the changes in vascular permeability in the colon and jejunum over a 5 h period have been investigated in the rat. 2. Under resting conditions, a calcium-dependent constitutive NOS, determined by the conversion of radiolabelled L-arginine to citrulline, was detected in homogenates of both colonic and jejunal tissue. 3. Administration of endotoxin (3 mg kg-1, i.v.) led, after a 2 h lag period, to the appearance of calcium-independent NOS activity in the colon and jejunum ex vivo, characteristic of the inducible NOS enzyme. 4. Administration of endotoxin led to an increase in colonic and jejunal vascular permeability after a lag period of 3 h, determined by the leakage of radiolabelled albumin. 5. Pretreatment with dexamethasone (1 mg kg-1 s.c., 2 h prior to challenge) inhibited both the induction of NOS and the vascular leakage induced by endotoxin. 6. Administration of the NO synthase inhibitor NG-monomethyl-L-arginine (12.5-50 mg kg-1, s.c.) 3 h after endotoxin injection, dose-dependently reduced the subsequent increase in vascular permeability in jejunum and colon, an effect reversed by L-arginine (300 mg kg-1, s.c.). 7. These findings suggest that induction of NOS is associated with the vascular injury induced by endotoxin in the rat colon and jejunum.
Boughton-Smith
N K
NK
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
Evans
S M
SM
Laszlo
F
F
Whittle
B J
BJ
Moncada
S
S
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D003106:Colon / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology*; D003907:Dexamethasone / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004926:Escherichia coli; D007583:Jejunum / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D019001:Nitric Oxide Synthase; D051381:Rats; D017208:Rats, Wistar; D019323:omega-N-Methylarginine
D004731:Endotoxins; D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D003907:Dexamethasone; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases