title: Effects of cyclooxygenase inhibitors on nitric oxide production and survival in a mice model of sepsis.
abstract: The effects of selective ((5,5-dimethyl-3-(3-florophenyl)-4-(4-methylsulphonyl-2(5H)-furanon); DFU) and (N-(2-cyclohexyloxy-4-nitrophenyl)-methansulphonamide; NS 398)) or non-selective (diclophenac and proquazon) inducible cyclooxygenase (COX-2) inhibitors on the survival, nitrite (stable product of nitric oxide (NO) as an index for inducible NO synthase (iNOS) activity) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha), stable product of prostacyclin as an index for COX-2 activity) production in serum, lungs, brain and/or kidney were investigated in endotoxin-induced sepsis model in mice. Endotoxin (10 mg x kg(-1), i.p.)-induced mortality was prevented by DFU, NS 398 and proquazon (0.1, 10 and 1 mg x kg(-1), respectively) and enhanced 2.6-fold with 0.1mg x kg(-1) diclophenac. Endotoxin-induced increase in the serum levels of nitrite was only inhibited by 10 mg x kg(-1) diclophenac. Endotoxin caused a significant decrease only in the brain levels of nitrite without affecting 6-keto-PGF(1alpha) levels in all tissues. The decreased levels of nitrite induced by endotoxin is further reduced by 0.1mg x kg(-1) DFU and 1 and 10mg x kg(-1) diclophenac while 10 mg x kg(-1) DFU and 1mg x kg(-1) proquazon increased it. On the other hand, 1mg x kg(-1) diclophenac and proquazon, and 10 mg x kg(-1) NS 398 increased the endotoxin-induced lung levels of 6-keto-PGF(1alpha). The results suggest that the COX inhibitors may have different effects on the survival and NO production depending on tissue and dose.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey. btunctan@angelfire.com
authors.forename: Bahar
authors.initials: B
authors.lastname: Tunçtan
authors.forename: Sedat
authors.initials: S
authors.lastname: Altug
authors.forename: Orhan
authors.initials: O
authors.lastname: Uludag
authors.forename: Beray
authors.initials: B
authors.lastname: Demirkay
authors.forename: Nurettin
authors.initials: N
authors.lastname: Abacioglu
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004008:Diclofenac / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000401:mortality; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D008070:Lipopolysaccharides; D009573:Nitrites; D009578:Nitrobenzenes; D011799:Quinazolines; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D004008:Diclofenac; D009569:Nitric Oxide; C011385:proquazone; D015121:6-Ketoprostaglandin F1 alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011451:Prostaglandin-Endoperoxide Synthases