环硝酮抗氧化剂对内毒素休克和慢性菌血症动物模型的保护作用。

Circulatory shock Pub Date : 1994-07-01
J F French, C E Thomas, T R Downs, D F Ohlweiler, A A Carr, R C Dage
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引用次数: 0

摘要

在动物模型中发现了氧源性自由基在内源性休克病理生理中的作用的证据。然而,自由基在慢性细菌感染模型中的重要性尚未得到检验。本研究描述了一种新的硝基自旋陷阱,并探讨了其在内毒素休克和慢性菌血症动物模型中的活性。MDL 101,002是α -苯基n -叔丁基硝基(PBN)的环化变体,是一种已建立的自旋陷阱。经电子顺磁共振(EPR)谱分析证实,MDL 101002能与自由基反应生成持久性加合物。作为体外抗氧化剂和羟基自由基清除剂,该制剂的效力是PBN的10倍左右。在大鼠内毒素休克模型中,在内毒素治疗(30 mg/kg, i.p.)前30分钟给药MDL 101002 (3-30 mg/kg, i.p.)能以剂量依赖性方式降低死亡率。内毒素处理大鼠肝脏匀浆中过氧化氢增强的化学发光增加,表明氧化应激和抗氧化剂消耗增加。重要的是,内毒素治疗前30分钟和后120分钟,用MDL 101002 (30 mg/kg, i.p.)治疗,最小化了化学发光的增加。MDL 101,002也降低了慢性菌血症模型的死亡率,将感染的纤维蛋白凝块植入庆大霉素治疗的白细胞减少大鼠的腹腔。MDL 101,002 (2.5 mg/kg/hr)使这些大鼠的存活率从24%提高到52%。这些数据与自由基在内毒素休克病理生理中的作用一致,表明自由基也是慢性脓毒症模型的重要介质。
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Protective effects of a cyclic nitrone antioxidant in animal models of endotoxic shock and chronic bacteremia.

Evidence of a role for oxygen-derived free radicals in the pathophysiology of endotoxic shock has been found in animal models. However, the importance of free radicals in chronic models of bacterial infection has not been examined. In this study a novel nitrone radical spin trap is described and its activity in animal models of endotoxic shock and chronic bacteremia were explored. MDL 101,002 is a cyclized variant of alpha-phenyl N-tert-butyl nitrone (PBN), an established spin trap. MDL 101,002 can react with free radicals to form persistent adducts as demonstrated by electron paramagnetic resonance (EPR) spectroscopy. This agent is about 10 times more potent than PBN as an in vitro antioxidant and scavenger of hydroxyl radicals. In a rat endotoxic shock model MDL 101,002 (3-30 mg/kg, i.p.) administered 30 min prior to endotoxin (30 mg/kg, i.p.) treatment reduced mortality in a dose-dependent manner. Peroxide-enhanced chemiluminescence in hepatic homogenates from endotoxin treated rats was elevated indicating that oxidative stress and antioxidant depletion was increased. Importantly, treatment with MDL 101,002 (30 mg/kg, i.p.) 30 min prior to, and 120 min following endotoxin, minimized the increase in chemiluminescence. MDL 101,002 also reduced mortality in a model of chronic bacteremia employing implantation of infected fibrin clots into the peritoneal cavity of gentamicin-treated leukopenic rats. MDL 101,002 (2.5 mg/kg/hr) increased survival from 24% to 52% in these rats. These data are consistent with a role for free radicals in the pathophysiology of endotoxic shock and suggest free radicals are also important mediators in chronic models of sepsis.

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