Effects of cyclooxygenase-1/cyclooxygenase-2 inhibition on leukocyte/endothelial cell interactions in the rat mesentery.
Nonsteroidal anti-inflammatory drugs (NSAID) inhibit cyclooxygenase activity and cause gastrointestinal damage in part by promoting leukocyte accumulation in the mucosa. Our aim was to evaluate the effects of selective blockade of the isoenzymes cyclooxygenase-1 and cyclooxygenase-2 on leukocyte adhesion in vivo. Leukocyte/endothelial cell interactions were examined in rat mesenteric venules before and after treatment with indomethacin, SC-560 (5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole, cyclooxygenase-1 inhibitor), DFP (5,5-dimethyl-3-(2-propoxy)-4-(4-methanesulfonyl)-2(5H)-furanone, cyclooxygenase-2 inhibitor), or SC-560 plus DFP (20 mg/kg, i.v. each). Indomethacin increased leukocyte-rolling flux, reduced rolling velocity and elicited significant leukocyte adhesion. Neither SC-560 nor DFP induced these effects although their co-administration reproduced the indomethacin response. Indomethacin and SC-560, but not DFP, abolished cyclooxygenase-1 activity in blood. Plasma from indomethacin- or DFP-, but not from SC-560-treated rats abolished cyclooxygenase-2 activity in activated A549 cells. Specific blockade of cyclooxygenase-1 or cyclooxygenase-2 does not induce any inflammatory event in the rat mesentery and the inflammatory response observed with non-selective NSAIDs seems to be due to the inhibition of both isoenzymes.
Calatayud
Sara
S
Unidad Mixta de Investigación, Facultad de Medicina-Hospital Clínico Universitario, Universidad de Valencia, Blasco Ibañez 17, 46010, Valencia, Spain. sara.calatayud@uv.es
Mitchell
Jane A
JA
Perretti
Mauro
M
Giuliano
Francesco
F
Warner
Timothy D
TD
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001555:Benzene Derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005663:Furans / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects* / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D008565:Membrane Proteins; D008643:Mesentery / Q000187:drug effects* / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014407:Tumor Cells, Cultured
C404485:3-2(-propyloxy)-(4-methylsulfonylphenyl)-(5,5-dimethyl)furanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001555:Benzene Derivatives; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; C115461:SC 560; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D007213:Indomethacin