title: Induction of nitric oxide synthase and microvascular injury in the rat jejunum provoked by indomethacin.
abstract: 1. The role of nitric oxide (NO) formed by the inducible isoform of NO synthase (NOS) in the generation of indomethacin-induced intestinal microvascular leakage was investigated in the rat. 2. Indomethacin (10 mg kg-1, s.c.) provoked an elevation of vascular leakage of radiolabelled human serum albumin in the jejunum over 48 h, commencing 18 h after its administration. This was associated with the induction of a calcium-independent NOS, as assessed by the conversion of radiolabelled L-arginine to citrulline. 3. Pretreatment with the glucocorticoid, dexamethasone (1 mg kg-1 day-1, s.c.) inhibited the induction of NOS and reduced jejunal microvascular leakage, determined 24 and 48 h after indomethacin. 4. Administration of the broad-spectrum antibiotic, ampicillin (800 mg kg-1 day-1, p.o.) likewise inhibited both the induction of NOS and the plasma leakage observed 24 and 48 h after indomethacin. 5. Ampicillin pretreatment did not, however, inhibit the induction of NOS, determined 5 h following endotoxin (3 mg kg-1 i.v.) challenge. Furthermore, incubation with ampicillin (1 mM, 10 min) did not inhibit the activity of the calcium-independent isoform in vitro. 6. Administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 2-10 mg kg-1, s.c.), at the time of the detectable expression of the inducible NOS (18 h after indomethacin), dose-dependently attenuated the plasma leakage, determined 6 later. This effect was reversed by pretreatment with L-arginine (300 mg kg-1, s.c.) 15 min before L-NAME. 7. These findings suggest that induction of a calcium-independent NOS following indomethacin administration involves gut bacteria and leads to microvascular injury in the rat jejunum.
authors.affiliation: Wellcome Foundation Ltd, Beckenham, Kent.
authors.forename: B J
authors.initials: BJ
authors.lastname: Whittle
authors.forename: F
authors.initials: F
authors.lastname: László
authors.forename: S M
authors.initials: SM
authors.lastname: Evans
authors.forename: S
authors.initials: S
authors.lastname: Moncada
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D018407:Bacterial Physiological Phenomena; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007579:Jejunal Diseases / Q000139:chemically induced / Q000473:pathology*; D007583:Jejunum / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010406:Penicillins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012711:Serum Albumin, Radio-Iodinated
chemical_list: D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D010406:Penicillins; D012711:Serum Albumin, Radio-Iodinated; D000667:Ampicillin; D003907:Dexamethasone; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin