title: Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats.
abstract: Mast cell stimulation leads to an early response with histamine release and prostaglandin (PGD(2)) production but attempts to link these two events have been contradictory. In IgE-mediated mast cell activation, a late-phase PGD(2)-production is caused by increased cyclooxygenase-2 (COX-2) expression whereas a COX-2 involvement in the early response is uncertain. The present study compares the influence of four COX-inhibitors (NSAIDs) on the histamine release of mast cells from naïve and actively sensitized rats. NSAIDs of different COX-1 vs. COX-2 selectivity were used, i.e. acetylsalicylic acid (ASA), piroxicam, meloxicam, and NS-398, a selective COX-2-inhibitor. All could inhibit antigen-induced histamine release, with 64%, 34%, 27% and 85% inhibition by ASA (5 mM), piroxicam (100 microM), meloxicam (100 microM) and NS-398 (100 microM), respectively. Similar inhibition was found with compound 48/80 without calcium added to the medium whereas compound 48/80 with calcium was affected less by ASA and NS-398 and unaffected by the oxicams. Only small differences between the two kinds of mast cells were found, except with NS-398 which was a significantly more effective inhibitor of naïve than sensitized cells when exposed to compound 48/80 with calcium present. The results do not show any consistent relationship between the influence of the NSAIDs and their COX-2-selectivity. The high NSAID-concentrations required for inhibition cast doubt about an involvement of COX-inhibition and indicate additional or other targets. The results seem to exclude toxic effects on mast cell energy production but are consistent with an interference with the calcium disposition.
authors.affiliation: Department of Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. fing@farmakol.ku.dk
authors.forename: Nina
authors.initials: N
authors.lastname: Grosman
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D006736:Horses / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D000077239:Meloxicam; D009578:Nitrobenzenes / Q000494:pharmacology; D010894:Piroxicam / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044967:Serum / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D009578:Nitrobenzenes; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010894:Piroxicam; D003189:p-Methoxy-N-methylphenethylamine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin; D000077239:Meloxicam