The purpose of this study was to examine whether selective iNOS inhibition can restore the hemodynamic changes and reduce the nitrotyrosine levels in the cerebral cortex of rats with streptozotocin-induced diabetes during endotoxin-induced shock. The study was designed to include three sets of experiments: (1) measurement of changes in systemic hemodynamics, (2) measurement of biochemical variables, including iNOS activity and nitrotyrosine formation in the brain, and (3) assessment of mortality rate. Rats were randomly divided into four groups: group 1, control; group 2, LPS: Escherichia coli endotoxin, 10.0 mg/kg (i.v.) bolus; group 3 (i.v.) LPS and L-N6-(1-iminoethyl)-lysine (L-NIL), 4mg/kg (i.p.); and group 4, LPS and NG-nitro-L-arginine methyl ester (L-NAME), 5 mg/kg (i.p.). In nondiabetic rats, administration of L-NIL prevented the hemodynamic and biochemical changes, and increases in plasma nitrite and cerebral nitrotyrosine levels induced by LPS. Administration of L-NAME partially prevented these LPS-induced changes. On the other hand, in diabetic rats, administration of L-NIL only partially prevented the hemodynamic and biochemical changes, and increases in plasma nitrite and cerebral nitrotyrosine levels associated with LPS. Administration of L-NAME, however, had no effects on these LPS-induced changes in diabetic rats. There was a significant difference in nitrotyrosine levels between nondiabetic and diabetic rats in groups 2, 3, and 4 at 2 and 3 h after the treatment (at 3 h; nondiabetic--control, 4.6 +/- 0.4; LPS (i.v.), 8.9 +/- 1.0, LPS (i.v.) + L-NIL, 4.7 +/- 0.5; LPS (i.v.) + L-NAME, 7.1 +/- 0.9; diabetic--control, 5.5 +/- 0.4; LPS (i.v.), 13.6 +/- 1.2; LPS (i.v.) + L-NIL, 9.0 +/- 0.9; LPS (i.v.) + L-NAME, 13.0 +/- 1.0; densitometric units). Insulin therapy resulted in a decrease in iNOS activity (at 3 h: 1.0 +/- 0.5 fmol mg min), nitrotyrosine formation (at 3 h; 5.0 +/- 0.5, densitometric units), and mortality rates (30% at 6 h, 50% at 12 h) in the LPS (i.v.) + L-NIL group of diabetic rats. Selective iNOS inhibition in diabetic rats could not improve hemodynamic instability, chemical changes, iNOS activity, and nitrotyrosine formation during septic shock compared with the improvements observed in nondiabetic rats. Tight glucose control along with administration of L-NIL can result in more effective restoration of the biochemical changes of septicemia in diabetic rats. Thus, hyperglycemia may be one of the mechanisms related to the aggravation of endotoxin-induced shock.

译文

:本研究的目的是研究选择性内源性iNOS抑制能否在内毒素诱导的休克期间恢复链脲佐菌素诱发的糖尿病大鼠的血流动力学变化并降低其大脑皮质的硝基酪氨酸水平。该研究被设计为包括三组实验:(1)测量全身血流动力学的变化,(2)测量生化变量,包括iNOS活性和脑中硝基酪氨酸的形成,以及(3)死亡率评估。将大鼠随机分为四组:第1组,对照组;第2组,第2组。第2组,LPS:大肠埃希菌内毒素,每次推注10.0 mg / kg(i.v.);第3组(静脉)LPS和L-N6-(1-亚氨基乙基)-赖氨酸(L-NIL),4mg / kg(腹膜);第4组,LPS和NG-硝基-L-精氨酸甲酯(L-NAME),5 mg / kg(腹膜内)。在非糖尿病大鼠中,L-NIL的给药阻止了血流动力学和生化变化,并增加了LPS诱导的血浆亚硝酸盐和脑硝基酪氨酸水平。 L-NAME的管理部分阻止了这些LPS引起的变化。另一方面,在糖尿病大鼠中,L-NIL的施用仅部分阻止了血流动力学和生化变化,并增加了与LPS相关的血浆亚硝酸盐和脑硝基酪氨酸水平。但是,在糖尿病大鼠中,L-NAME的给药对这些LPS诱导的变化没有影响。第2、3和4组的非糖尿病和糖尿病大鼠在治疗后2和3 h的硝酸酪氨酸水平存在显着差异(3 h;非糖尿病对照组4.6 /-0.4; LPS(iv)8.9) /-1.0,LPS(iv)L-NIL,4.7 /-0.5; LPS(iv)L-NAME,7.1 /-0.9;糖尿病对照,5.5 /-0.4; LPS(iv),13.6 /-1.2; LPS(iv)L-NIL,9.0 /-0.9; LPS(iv)L-NAME,13.0 /-1.0;光密度单位)。胰岛素治疗导致iNOS活性(3 h:1.0 /-0.5 fmol mg min),硝基酪氨酸形成(3 h; 5.0 /-0.5,光密度单位)和死亡率(6h,50时30%)降低LPS(iv)L-NIL组的糖尿病大鼠在12 h时的%)。与非糖尿病大鼠相比,对糖尿病大鼠的选择性iNOS抑制不能改善败血性休克期间的血流动力学不稳定,化学变化,iNOS活性和硝基酪氨酸形成。严格的葡萄糖控制以及L-NIL的使用可以使糖尿病大鼠败血病的生化变化更有效地恢复。因此,高血糖症可能是与内毒素诱发的休克加重有关的机制之一。

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