Role of bacteria and inducible nitric oxide synthase activity in the systemic inflammatory microvascular response provoked by indomethacin in the rat.
The role of bacteria and nitric oxide (NO), formed by the inducible isoform of NO synthase (iNOS), in a widespread systemic inflammatory microvascular response that follows indomethacin administration, has been investigated in the rat. Subcutaneous administration of indomethacin (10 mg kg(-1)) daily for 2 days produced an increase in microvascular leakage of radiolabelled albumin accompanied by expression of iNOS activity in the lung, liver, spleen and kidney, as well as in the jejunum, caecum, colon and ileum. Pretreatment with dexamethasone (1 mg kg(-1) day(-1), s.c.) reduced indomethacin-provoked microvascular leakage and the expression of iNOS activity in all the tissues studied. The widespread microvascular leakage and iNOS activity was also inhibited by pretreatment with ampicillin (200 mg kg(-1) day(-1), p.o.), metronidazole (200 mg kg(-1) day(-1), p.o.) or by polymyxin B (15 mg kg(-1) day(-1), s.c.). Administration of the highly selective iNOS inhibitor GW 273629 (3-[[2-(ethanimidoylamino)ethyl]sulphonyl]-L-alanine; five doses of 5 mg kg(-1), s.c. over 48 h) substantially inhibited the microvascular leakage in the affected organs. Such findings suggest the involvement of indigenous gut bacteria, lipopolysaccharide and iNOS expression following indomethacin-induced enteropathy in this widespread systemic inflammatory microvascular response.
Evans
Steven M
SM
GlaxoSmithKline Research and Development, 6S204 Asthma Disease Biology, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. steve.m.evans@gsk.com
Whittle
Brendan J R
BJ
D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001419:Bacteria / Q000472:pathogenicity*; D002199:Capillary Permeability; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D007213:Indomethacin; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000382:microbiology*; D007422:Intestines / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008297:Male; D008795:Metronidazole / Q000494:pharmacology; D008833:Microcirculation; D009102:Multiple Organ Failure / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009928:Organ Specificity; D011112:Polymyxin B / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012711:Serum Albumin, Radio-Iodinated; D013450:Sulfones / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; C409003:GW 273629; D012711:Serum Albumin, Radio-Iodinated; D013450:Sulfones; D008795:Metronidazole; D000667:Ampicillin; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011112:Polymyxin B; D007213:Indomethacin