title: Factors involved in upregulation of inducible nitric oxide synthase in rat small intestine following administration of nonsteroidal anti-inflammatory drugs.
abstract: We investigated the functional mechanisms underlying the expression of inducible nitric oxide (NO) synthase (iNOS) in the rat small intestine following the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and found a correlation with the intestinal ulcerogenic properties of NSAIDs. Conventional NSAIDs (indomethacin, diclofenac, naproxen, and flurbiprofen), a selective cyclooxygenase (COX)-1 inhibitor (SC-560) and a selective COX-2 inhibitor (rofecoxib) were administered p.o., and the intestinal mucosa was examined 24 hours later. Indomethacin decreased prostaglandin E2 (PGE2) production in the intestinal mucosa and caused intestinal hypermotility and bacterial invasion as well as the upregulation of iNOS expression and NO production, resulting in hemorrhagic lesions. Other NSAIDs similarly inhibited PGE2 production and caused hemorrhagic lesions with intestinal hypermotility as well as iNOS expression. Hypermotility in response to indomethacin was prevented by both PGE2 and atropine but not ampicillin, yet all these agents inhibited not only bacterial invasion but also expression of iNOS as well, resulting in prevention of intestinal lesions. SC-560, but not rofecoxib, caused a decrease in PGE2 production, intestinal hypermotility, bacterial invasion, and iNOS expression, yet this agent neither increased iNOS activity nor provoked intestinal damage because of the recovery of PGE2 production owing to COX-2 expression. Food deprivation totally attenuated both iNOS expression and lesion formation in response to indomethacin. In conclusion, the expression of iNOS in the small intestine following administration of NSAIDs results from COX-1 inhibition and is functionally associated with intestinal hypermotility and bacterial invasion. This process plays a major pathogenic role in the intestinal ulcerogenic response to NSAIDs.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, 607, Japan. takeuchi@ mb.kyoto-phu.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Aya
authors.initials: A
authors.lastname: Yokota
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takahira
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004755:Enterobacteriaceae / Q000187:drug effects; D005480:Flurbiprofen / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007410:Intestinal Diseases / Q000378:metabolism / Q000382:microbiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism / Q000382:microbiology; D007783:Lactones / Q000494:pharmacology; D008297:Male; D009288:Naproxen / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D011720:Pyrazoles; D012333:RNA, Messenger; C115461:SC 560; D013450:Sulfones; C116926:rofecoxib; D004008:Diclofenac; D009569:Nitric Oxide; D009288:Naproxen; D005480:Flurbiprofen; D052247:Nitric Oxide Synthase Type II; D015232:Dinoprostone; D007213:Indomethacin