Effects of inhibitors of arachidonic acid metabolism on endotoxin-induced ocular inflammation.
Rabbits were treated with the cyclooxygenase inhibitors indomethacin (2.5 and 10 mg/kg; IP) or flunixin meglumine (2.2 and 8.8 mg/kg; IM), or the dual cyclooxygenase/lipoxygenase inhibitor BW755C (10 and 30 mg/kg; IP) (administered 4 times over 25 hours). One hour following drug administration, 10 ng of E. coli endotoxin was injected into the vitreal chamber and the subsequent inflammatory response was measured 24 h later. Indomethacin was the most effective inhibitor of prostaglandin (PG) E2 and PGF 2 alpha accumulation in the aqueous humor and their ex vivo production by the lens. It was the only agent that decreased iridal hyperemia and protein concentration in the aqueous humor. Flunixin decreased PG production, although generally to a lesser degree than indomethacin. BW755C produced modest inhibition of PG production in the aqueous humor, but did not affect PG production by the lens. The high dose of BW755C also reduced 5-hydroxyeicosatetraenoic acid (5-HETE) levels in the aqueous humor, but did not alter production by the lens. The results indicate that despite drastic reductions in PG levels in the aqueous humor and PG production by the lens, only modest decreases in aqueous humor protein concentration and iridal hyperemia were achieved. Furthermore, 5-HETE does not appear to be important in the modulation of these inflammatory signs, although it is possible that larger decreases in its production could result in more dramatic effects.
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D003002:Clonixin / Q000031:analogs & derivatives / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D011453:Prostaglandins / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D014605:Uveitis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D004731:Endotoxins; D006893:Hydroxyeicosatetraenoic Acids; D011453:Prostaglandins; D011720:Pyrazoles; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; C014558:flunixin meglumine; D003002:Clonixin; D007213:Indomethacin