Piroxicam reverses endotoxin-induced hypotension in rats: contribution of vasoactive eicosanoids and nitric oxide
| Autor: | C Kemal, Buharalioglu, Belma, Korkmaz, Tuba, Cuez, Seyhan, Sahan-Firat, Ayse Nihal, Sari, Kafait U, Malik, Bahar, Tunctan |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Time Factors Nitric Oxide Synthase Type II Blood Pressure Nitric Oxide Epoprostenol Dinoprostone Article Rats Endotoxins Vasodilation Piroxicam Cyclooxygenase 2 Vasoconstriction Hydroxyeicosatetraenoic Acids Cyclooxygenase 1 Animals Eicosanoids Cyclooxygenase Inhibitors Cytochrome P-450 CYP4A Hypotension Rats Wistar |
| Zdroj: | Basicclinical pharmacologytoxicology. 109(3) |
| ISSN: | 1742-7843 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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