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

这项研究的目的是检查在内毒素诱导的休克期间,选择性iNOS抑制是否可以恢复链脲佐菌素诱导的糖尿病大鼠的血液动力学变化并降低大脑皮层中的硝基酪氨酸水平。该研究旨在包括三组实验 :( 1) 测量全身血液动力学的变化,(2) 测量生化变量,包括大脑中的iNOS活性和硝基酪氨酸形成,以及 (3) 评估死亡率。将大鼠随机分为四组: 第1组,对照组; 第2组,LPS: 大肠杆菌内毒素,10.0 mg/kg (i.v.) 推注; 第3组 (i.v.)LPS和L-N6-(1-亚氨基乙基)-赖氨酸 (L-NIL),4 mg/kg (i.p.); 和第4组,LPS和NG-硝基-L-精氨酸甲酯 (L-NAME),5 mg/kg (i.p.)。在非糖尿病大鼠中,给予L-NIL可防止血液动力学和生化变化,并增加LPS诱导的血浆亚硝酸盐和脑硝基酪氨酸水平。给予L-NAME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的给药仅部分阻止了血液动力学和生化变化,并增加了与LPS相关的血浆亚硝酸盐和脑硝基酪氨酸水平。L-NAME的给药对糖尿病大鼠的这些LPS诱导的变化没有影响。治疗后2小时和3小时,第2、3和4组的非糖尿病和糖尿病大鼠之间的硝基酪氨酸水平存在显着差异 (在3小时; 非糖尿病-对照,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; 糖尿病控制,5.5 +/- 0.4; LPS (i.v.),13.6 +/- 1.2; LPS (i.v.) + L-NIL,9.0 +/- 0.9; LPS (i.v.) + L-名称,13.0 +/- 1.0; 光密度测量单位)。胰岛素治疗导致iNOS活性降低 (3小时: 1.0 +/- 0.5 fmol mg min),硝基酪氨酸形成 (3小时; 5.0 +/- 0.5,光密度单位) 和死亡率 (6小时30%,在LPS (i.v.) 中50% 12 h)+ L-NIL组糖尿病大鼠。与非糖尿病大鼠相比,在败血性休克期间选择性抑制iNOS不能改善血流动力学不稳定性,化学变化,iNOS活性和硝基酪氨酸形成。严格的血糖控制以及L-NIL的给药可以更有效地恢复糖尿病大鼠败血症的生化变化。因此,高血糖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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