The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat

• Published in: British journal of pharmacology Vol. 110; no. 3; pp. 1189 - 1195
• Main Authors: Boughton‐Smith, Nigel K., Evans, Steven M., Laszlo, Ferenc, Whittle, Brendan J.R., Moncada, Salvador
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.1993; Nature Publishing; Nature Publishing Group
• Subjects: Amino Acid Oxidoreductases - biosynthesis; Amino Acid Oxidoreductases - metabolism; Animals; Arginine - analogs & derivatives; Arginine - pharmacology; Bacteriology; Biological and medical sciences; Capillary Permeability - drug effects; Colon - blood supply; Colon - drug effects; Colon - enzymology; corticosteriods; Dexamethasone - pharmacology; endotoxin; Endotoxins - pharmacology; Enzyme Induction - drug effects; Escherichia coli; Fundamental and applied biological sciences. Psychology; inducible nitric oxide synthase; intestinal inflammation; Jejunum - blood supply; Jejunum - drug effects; Jejunum - enzymology; Lipopolysaccharides - toxicity; Male; Microbiology; NG‐monomethyl‐l‐arginine; Nitric oxide; Nitric Oxide Synthase; NO synthase inhibitor; omega-N-Methylarginine; Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains; Rats; Rats, Wistar; vascular permeability; Pathophysiology; Rat; Enzyme; Rodentia; Gut; Permeability; Endotoxin; Nitric-oxide synthase; Vertebrata; Mammalia; Blood vessel; Nitrogen monoxide; Oxidoreductases; Mechanism of action
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1993.tb13940.x

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 radiolabeled 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.