title: Piroxicam reverses endotoxin-induced hypotension in rats: contribution of vasoactive eicosanoids and nitric oxide.
abstract: Nitric oxide (NO) produced by inducible NO synthase (iNOS) is responsible for endotoxin-induced vascular hyporeactivity and hypotension resulting in multiple organ failure. Endotoxic shock is also characterized by decreased expression of constitutive cyclooxygenase (COX-1), cytochrome P450 (CYP) 4A and endothelial NOS (eNOS). Our previous studies demonstrated that dual inhibition of iNOS and COX with a selective COX-2 inhibitor, NS-398, or a non-selective COX inhibitor, indomethacin, restores blood pressure presumably because of increased production of 20-hydroxyeicosatetraenoic acid (20-HETE) derived from arachidonic acid (AA) by CYP4A in endotoxaemic rats. The aim of this study was to investigate the effects of piroxicam, a preferential COX-1 inhibitor, on the endotoxin-induced changes in blood pressure, expression of COX-1, inducible COX (COX-2), CYP4A1, eNOS, iNOS and heat shock protein 90 (hsp90), and production of PGI(2), PGE(2), 20-HETE and NO. Injection of endotoxin (10 mg/kg, i.p.) to male Wistar rats caused a fall in blood pressure and an increase in heart rate associated with elevated renal 6-keto-PGF(1α) and PGE(2) levels as well as an increase in COX-2 protein expression. Endotoxin also caused an elevation in systemic and renal nitrite levels associated with increased renal iNOS protein expression. In contrast, systemic and renal 20-HETE levels and renal expression of eNOS, COX-1 and CYP4A1 were decreased in endotoxaemic rats. The effects of endotoxin, except for renal COX-1 and eNOS protein expression, were prevented by piroxicam (10 mg/kg, i.p.), given 1 hr after injection of endotoxin. Endotoxin did not change renal hsp90 protein expression. These data suggest that a decrease in the expression and activity of COX-2 and iNOS associated with an increase in CYP4A1 expression and 20-HETE synthesis contributes to the effect of piroxicam to prevent the hypotension during rat endotoxaemia.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Mersin University, Turkey.
authors.forename: C Kemal
authors.initials: CK
authors.lastname: Buharalioglu
authors.forename: Belma
authors.initials: B
authors.lastname: Korkmaz
authors.forename: Tuba
authors.initials: T
authors.lastname: Cuez
authors.forename: Seyhan
authors.initials: S
authors.lastname: Sahan-Firat
authors.forename: Ayse Nihal
authors.initials: AN
authors.lastname: Sari
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
authors.forename: Bahar
authors.initials: B
authors.lastname: Tunctan
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D042926:Cytochrome P-450 CYP4A / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D015777:Eicosanoids / Q000096:biosynthesis*; D004731:Endotoxins / Q000633:toxicity*; D011464:Epoprostenol / Q000096:biosynthesis; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007022:Hypotension / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010894:Piroxicam / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D004731:Endotoxins; D006893:Hydroxyeicosatetraenoic Acids; D010894:Piroxicam; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D042926:Cytochrome P-450 CYP4A; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone