Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats.
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.
Grosman
Nina
N
Department of Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. fing@farmakol.ku.dk
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
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