Cytoprotective effects of CI-959 in the rat gastric mucosa: modulation of leukocyte adhesion.
OBJECTIVE
CI-959 is an anti-inflammatory agent that inhibits neutrophil adhesion, respiratory burst, and mast cell histamine release in vitro. In view of the emerging role of neutrophils in gastric erosive damage, the goals of this study were to assess the gastric cytoprotective effects of CI-959 and identify the mechanism responsible for this action.


METHODS
Cytoprotective effects in the rat nonsteroidal anti-inflammatory drug and ethanol erosion models were assessed using image analysis. The in vivo effects of CI-959 on gastric acid secretion, arachidonic acid metabolism, and intracellular sulfhydryl and leukocyte adhesion were also examined.


RESULTS
CI-959 protected prophylactically against the erosive damage induced by aspirin, indomethacin, and ethanol with 50% effective doses (ED50s) of 0.05, 1.0, and 0.07 mg/kg administered orally, respectively. When administered after indomethacin or ethanol, CI-959 had no effect on the healing of erosive damage. CI-959 did not alter gastric acid secretion, arachidonic acid metabolism, or intracellular sulfhydryl levels. In vivo, CI-959 blocked leukocyte adhesion in intravital microscopy studies using indomethacin (ED50, < 5 mg/kg orally) or platelet-activating factor (50% inhibiting concentration, approximately 10 mumol/L) as the adhesion stimulus.


CONCLUSIONS
The most likely mechanism responsible for the cytoprotective effects of CI-595 is its inhibitory effects on leukocyte trafficking and/or adhesion.
Low
J
J
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, Michigan, USA.
Grabow
D
D
Sommers
C
C
Wallace
J
J
Lesch
M
M
Finkel
M
M
Schrier
D
D
Metz
A
A
Conroy
M C
MC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000009:adverse effects; D002448:Cell Adhesion / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D000431:Ethanol / Q000009:adverse effects; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects*; D006633:Histamine Antagonists / Q000494:pharmacology*; D007213:Indomethacin / Q000009:adverse effects; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D017997:Leukotriene C4 / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006633:Histamine Antagonists; D010972:Platelet Activating Factor; D013438:Sulfhydryl Compounds; D013777:Tetrazoles; D013876:Thiophenes; C061662:CI 959; D016718:Arachidonic Acid; D017997:Leukotriene C4; D000431:Ethanol; D015232:Dinoprostone; D001241:Aspirin; D007213:Indomethacin