Comparison of the effects of indomethacin, RHC80267 and R59022 on superoxide production by 1,oleoyl-2,acetyl glycerol and A23187 in human neutrophils.
1 Indomethacin (10(-4)M) causes marked augmentation of O-2 release from human neutrophils when these are stimulated by either 1,oleoyl-2,acetylglycerol or the divalent cation ionophore, A23187, the concentration-response curve for each agent being shifted to the left and the maximum response to each increased. 2 The diacylglycerol kinase inhibitor, R59022 (10(-5)M) has effects very similar to those of indomethacin on both the 1,oleoyl-2,acetylglycerol-induced and the A23187-induced concentration-response curves for O-2 generation. 3 The diacylglycerol lipase inhibitor, RHC80267 (10(-5 M) on the other hand, has a similar effect to indomethacin on 1,oleoyl-2,acetylglycerol-induced O2- generation but, unlike indomethacin, has no effect on A23187-induced O2- generation. Comparison of the effects of these three agents provides a clue to the locus of the action of indomethacin in increasing superoxide release, suggesting that it may act as a diacylglycerol kinase inhibitor. A component of diacylglycerol lipase inhibition may also be present. It is suggested that these results could have relevance for the use of indomethacin as an anti-inflammatory agent in chronic rheumatoid diseases.
Dale
M M
MM
Department of Pharmacology, University College London.
Penfield
A
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology*; D003510:Cyclohexanes / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D004075:Diglycerides / Q000494:pharmacology*; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D007700:Kinetics; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D011744:Pyrimidinones / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D003510:Cyclohexanes; D003512:Cyclohexanones; D004075:Diglycerides; D005989:Glycerides; D010972:Platelet Activating Factor; D011744:Pyrimidinones; D013844:Thiazoles; D013481:Superoxides; D000001:Calcimycin; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; C038237:1-oleoyl-2-acetylglycerol; C047505:R 59022; D007213:Indomethacin