Department of Pharmacology, Faculty of Pharmacy, Mersin University, Turkey.
Basic Clin Pharmacol Toxicol. 2011 Sep;109(3):186-94. doi: 10.1111/j.1742-7843.2011.00708.x. Epub 2011 May 6.
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.
诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）是内毒素引起的血管低反应性和低血压的原因，导致多器官衰竭。内毒素休克的特征还包括组成型环氧化酶（COX-1）、细胞色素 P450（CYP）4A 和内皮型一氧化氮合酶（eNOS）表达减少。我们之前的研究表明，使用选择性 COX-2 抑制剂 NS-398 或非选择性 COX 抑制剂吲哚美辛双重抑制 iNOS 和 COX，可恢复血压，这可能是由于内毒素血症大鼠 CYP4A 产生的花生四烯酸（AA）衍生的 20-羟二十碳四烯酸（20-HETE）增加所致。本研究旨在探讨吡罗昔康（一种优先 COX-1 抑制剂）对内毒素引起的血压变化、COX-1、诱导型 COX（COX-2）、CYP4A1、eNOS、iNOS 和热休克蛋白 90（hsp90）表达以及 PGI（2）、PGE（2）、20-HETE 和 NO 产生的影响。向雄性 Wistar 大鼠腹腔内注射内毒素（10mg/kg）可导致血压下降和心率加快，同时肾 6-酮-PGF（1α）和 PGE（2）水平升高，以及 COX-2 蛋白表达增加。内毒素还导致全身和肾亚硝酸盐水平升高，与肾 iNOS 蛋白表达增加有关。相比之下，内毒素血症大鼠的全身和肾 20-HETE 水平以及肾 eNOS、COX-1 和 CYP4A1 的表达降低。除肾 COX-1 和 eNOS 蛋白表达外，内毒素的其他作用均被吡罗昔康（10mg/kg，腹腔注射）预防，该药物在注射内毒素后 1 小时给予。内毒素不改变肾 hsp90 蛋白表达。这些数据表明，与 COX-2 和 iNOS 表达减少以及 CYP4A1 表达和 20-HETE 合成增加相关的作用，导致吡罗昔康预防大鼠内毒素血症低血压的发生。
