Protective effects of PF-10040 in experimental NSAID-gastritis: role of leukocytes, leukotrienes and PAF.

Abstract

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.

• Authors: J L Wallace, G W McKnight, D Donigi-Gale, T S Shoupe, D N Granger
• Journal: Journal of lipid mediators (J Lipid Mediat) Vol. 7 Issue 2 Pg. 183-96 (Jun 1993) ISSN: 0921-8319 [Print] Netherlands
• PMID: 8400119 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Free Radical Scavengers
• Isoquinolines
• Platelet Activating Factor
• PF 10040
• Leukotriene B4

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use, toxicity)
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Disease Models, Animal
• Free Radical Scavengers
• Gastric Acid (metabolism)
• Gastric Mucosa (blood supply, drug effects, metabolism)
• Gastritis (blood, chemically induced, prevention & control)
• Isoquinolines (therapeutic use)
• Leukocytes (drug effects, physiology)
• Leukotriene B4 (pharmacology, physiology)
• Male
• Platelet Activating Factor (antagonists & inhibitors, pharmacology, physiology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Stomach (blood supply, drug effects)
• Vasoconstriction (drug effects)