Cuzzocrea S, Mazzon E, Costantino G, Serraino I, De Sarro A, Caputi A P
Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi, 98100, Messina, Italy.
Cardiovasc Res. 2000 Aug 18;47(3):537-48. doi: 10.1016/s0008-6363(00)00018-3.
Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of n-acetylcysteine (NAC), a free radical scavenger, in rats subjected to SAO shock.
Treatment of rats with NAC (applied at 20 mg/kg, 5 min prior to reperfusion, followed by an infusion of 20 mg/kg/h) attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. NAC also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine in the plasma of the SAO-shocked rats after reperfusion. Immunohistochemical analysis for nitrotyrosine and for poly(ADP-ribose) synthetase (PARS) revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine and PARS were markedly reduced in tissue sections obtained from SAO-shocked rats which had received NAC. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin, which was mainly localised in the vascular endothelial cells. Ileum tissue section obtained from SAO-shocked rats with anti-intercellular adhesion molecule (ICAM-1) antibody showed a diffuse staining. NAC treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue section from SAO-shocked rats. In addition, in ex vivo studies in aortic rings from shocked rats, we found reduced contractions to noradrenaline and reduced responsiveness to a relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). NAC treatment improved contractile responsiveness to noradrenaline, enhanced the endothelium-dependent relaxations and significantly improved survival.
Taken together, our results clearly demonstrate that NAC treatment exert a protective effect and part of this effect may be due to inhibition of the expression of adhesion molecule and peroxynitrite-related pathways and subsequent reduction of neutrophil-mediated cellular injury.
内脏动脉闭塞性休克（SAO）会导致活性氧（ROS）生成增加，这参与了休克的病理生理过程。在此，我们研究了自由基清除剂N-乙酰半胱氨酸（NAC）对遭受SAO休克大鼠的影响。
用NAC（以20mg/kg给药，在再灌注前5分钟给予，随后以20mg/kg/h输注）处理大鼠，可减轻SAO休克引起的平均动脉血压下降以及多形核白细胞（PMN）的迁移。NAC还减轻了回肠损伤（组织学）以及SAO休克引起的回肠组织中髓过氧化物酶（MPO）和丙二醛（MDA）水平的升高。再灌注后，SAO休克大鼠血浆中二氢罗丹明123氧化为罗丹明的程度显著增加。对硝基酪氨酸和聚（ADP-核糖）合成酶（PARS）的免疫组织化学分析显示，SAO休克大鼠的回肠呈阳性染色。在接受NAC的SAO休克大鼠获得的组织切片中，硝基酪氨酸和PARS的染色程度显著降低。SAO休克大鼠再灌注后的回肠组织切片显示P-选择素呈阳性染色，其主要定位于血管内皮细胞。用抗细胞间粘附分子（ICAM-1）抗体处理SAO休克大鼠获得的回肠组织切片显示弥漫性染色。NAC处理显著降低了SAO休克大鼠组织切片中P-选择素和ICAM-1的强度和程度。此外，在对休克大鼠主动脉环的离体研究中，我们发现对去甲肾上腺素的收缩反应降低，对乙酰胆碱的舒张效应反应性降低（分别为血管反应性降低和内皮功能障碍）。NAC处理改善了对去甲肾上腺素的收缩反应性，增强了内皮依赖性舒张，并显著提高了存活率。
综上所述，我们的结果清楚地表明，NAC处理具有保护作用，部分作用可能是由于抑制了粘附分子和过氧亚硝酸盐相关途径的表达，以及随后减少了中性粒细胞介导的细胞损伤。
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