title: Gastric acid is the key modulator in the pathogenesis of non-steroidal anti-inflammatory drug-induced ulceration in rats.
abstract: 1. In the present study, we investigated the role of gastric acid (GA) secretion on non-steroidal anti-inflammatory drug (NSAID)-induced ulcerogenesis in vivo. Rats were administered single oral doses of selective cyclo-oxygenase (COX)-1 (SC-560; 2.5 mg/kg), COX-2 (DFU; 25 mg/kg) or non-selective COX (indomethacin; 25 mg/kg) inhibitors. Three groups (basal, histamine-stimulated and histamine with lansoprazole) were pylorus ligated 2 h after inhibitor administration and killed 2 h later. Another group without pylorus ligation received only inhibitors and was killed after 18 h. 2. At 4 h, indomethacin increased the ulcer index (UI) and myeloperoxidase (MPO) activity in basal and histamine-stimulated states, whereas SC-560 only increased MPO activity. Histamine-stimulated, but not basal, GA was further enhanced by indomethacin and SC-560 via increased proton pump expression. Lansoprazole (10 mg/kg) reduced the UI, MPO activity and GA to basal levels with SC-560 and DFU and to near basal with indomethacin. Indomethacin and SC-560 significantly inhibited prostaglandin (PG) E(2), without significantly affecting COX-1 and COX-2 expression. Although DFU inhibited PGE(2) by one-third, it did not affect COX expression. 3. At 18 h, indomethacin significantly increased the UI and MPO activity, whereas PGE(2) synthesis was less inhibited, indicating a return to control levels. In contrast, PGE(2) synthesis was higher than control with SC-560. Furthermore, COX-2 expression was significantly elevated with indomethacin and SC-560, explaining the source of augmented PGE(2) synthesis. Proton pump expression remained elevated, comparable with 4 h levels, with indomethacin and SC-560. However, DFU had no significant effect on the aforementioned parameters. 4. The data suggest that NSAID-induced ulcerogenesis is dependent on the amount of GA secretion derived from increased proton pump expression and requires inhibition of both COX-1 and COX-2.
authors.affiliation: Division of Gastroenterology, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Zinkievich
authors.forename: Sunil
authors.initials: S
authors.lastname: George
authors.forename: Shalinee
authors.initials: S
authors.lastname: Jha
authors.forename: Jyotirmoy
authors.initials: J
authors.lastname: Nandi
authors.forename: Robert A
authors.initials: RA
authors.lastname: Levine
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D015232:Dinoprostone / Q000032:analysis; D005663:Furans / Q000008:administration & dosage / Q000009:adverse effects; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D009195:Peroxidase / Q000032:analysis; D017494:Proton Pumps / Q000032:analysis; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000201:enzymology
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D017494:Proton Pumps; D011720:Pyrazoles; C115461:SC 560; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007213:Indomethacin