Reduction of shock-induced gastric damage by a nitric oxide-releasing aspirin derivative: role of neutrophils.
The gastric damage associated with hemorrhagic shock appears to occur, at least in part, through neutrophil-dependent mechanisms. Nitric oxide (NO)-releasing derivatives of aspirin have been shown to spare the gastrointestinal tract of injury. As NO can inhibit neutrophil adherence, it is possible that such a derivative of aspirin (NCX-4016) would exert inhibitory effects on neutrophil adherence and therefore be capable of protecting the stomach against shock-induced gastric damage. This hypothesis was tested in this study. Oral administration of NCX-4016 or glyceryl trinitrate or depletion of circulating neutrophils with antineutrophil serum significantly reduced the extent of gastric damage induced by hemorrhagic shock, whereas aspirin had no effect. NCX-4016 and antineutrophil serum pretreatment resulted in significant preservation of gastric blood flow during the shock period. Moreover, NCX-4016, but not aspirin, was capable of inhibiting N-formyl-Met-Leu-Phe-induced leukocyte adherence to postcapillary mesenteric venules. These results suggest that an NO-releasing aspirin derivative reduces the susceptibility of the stomach to shock-induced damage through inhibitory effects on neutrophil adherence to the vascular endothelium.
Wallace
J L
JL
Department of Pharmacology and Therapeutics, University of Calgary, Alberta, Canada.
McKnight
W
W
Wilson
T L
TL
Del Soldato
P
P
Cirino
G
G
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012771:Shock, Hemorrhagic / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*
D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; C102148:nitroaspirin; D005996:Nitroglycerin; D001241:Aspirin