Protective effects of PF-10040 in experimental NSAID-gastritis: role of leukocytes, leukotrienes and PAF.
The effects and mechanism of action of PF-10040, a quinoline derivative, were examined in an experimental model of NSAID-gastritis. Oral pretreatment with PF-10040 dose-dependently reduced the severity of indomethacin-induced gastric damage, with a significant protective effect being observed with doses of 10 mg/kg or greater. The protective effects of this compound persisted for as long as 6 h after administration. PF-10040 also significantly reduced the severity of aspirin- or naproxen-induced gastric damage. At protective doses, PF-10040 did not significantly affect gastric LTB4 synthesis, LTB4-induced granulocyte recruitment to intradermal injection sites, or LTD4-induced changes in gastric blood flow. The free radical scavenging effects of PF-10040 were examined using an in vitro assay, in which it failed to exert significant effects at concentrations of up to 10 mM. PF-10040 had no significant effect on gastric acid secretion. In rat mesenteric venules, PF-10040 inhibited PAF-, but not LTB4-induced leukocyte adherence and emigration. These results suggest that the protective effects of PF-10040 are not attributable to scavenging of free radicals, inhibition of leukotriene synthesis, blockade of LTB4 or LTD4 receptors or inhibition of LTB4-mediated leukocyte endothelial cell adhesion.
Wallace
J L
JL
Gastrointestinal Research Group, University of Calgary, Alberta, Canada.
McKnight
G W
GW
Donigi-Gale
D
D
Shoupe
T S
TS
Granger
D N
DN
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D016166:Free Radical Scavengers; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D005756:Gastritis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D007546:Isoquinolines / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology*; D007975:Leukotriene B4 / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013270:Stomach / Q000098:blood supply / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016166:Free Radical Scavengers; D007546:Isoquinolines; D010972:Platelet Activating Factor; C077682:PF 10040; D007975:Leukotriene B4