Nitric oxide-dependent down-regulation of angiotensin II type 2 receptors during experimental sepsis
Nitric oxide-dependent down-regulation of angiotensin II type 2 receptors during experimental sepsis
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DOI：
10.1097/00003246-200109000-00016
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发表时间：
2001-09-01
影响因子：
8.8
通讯作者：
Kurtz, A
中科院分区：
文献类型：
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作者：
Bucher, M;Hobbhahn, J;Kurtz, A
目的：脓毒性休克期间全身肾素-血管紧张素系统高度激活。这引起了人们对肾上腺血管紧张素 II 2 型受体 (AT(2)) 的调节的兴趣，该受体被认为是在体内实验性败血症期间介导血管紧张素 II 诱导的肾上腺儿茶酚胺释放的靶标。此外，应在体外研究脓毒症典型内源性介质（如促炎细胞因子和一氧化氮）对 AT(2) 受体表达的影响。设计：前瞻性动物试验，然后进行对照细胞培养研究。地点：麻醉科实验室。受试者：体重 200-250 g 的雄性 Sprague-Dawley 大鼠，PC12 细胞系。干预措施：给大鼠注射脂多糖以刺激革兰氏阴性败血症或脂磷壁酸刺激革兰氏阳性败血症。 AT(2) 受体表达、促炎细胞因子（白介素-1β、肿瘤坏死因子-α 和干扰素-γ）的丰度以及一氧化氮合酶 If 的表达已在肾上腺中测定。将大鼠肾上腺嗜铬细胞瘤细胞与这些细胞因子或一氧化氮供体硝普钠或 S-亚硝基-N-乙酰青霉胺一起孵育，以在细胞水平上研究严重炎症期间 AT(2) 受体的调节。测量和主要结果：在两种脓毒症模型中，肾上腺中 AT(2) 受体表达下调，而组织细胞因子浓度升高，并诱导一氧化氮合酶 II 表达。 PC12 细胞与促炎细胞因子一起孵育会导致 AT(2) 受体的表达呈剂量依赖性减少，这一现象通过与一氧化氮供体一起孵育来模拟。通过将 PC12 细胞与 N-G-硝基-L-精氨酸甲酯共孵育来阻断细胞因子诱导的一氧化氮合成，可防止 AT(2) 受体的下调。结论：这些发现表明，在我们的脓毒症模型中，肾上腺中 AT(2) 受体的表达以一氧化氮依赖性方式下调。由于 AT(2) 受体被认为以刺激方式参与肾上腺儿茶酚胺分泌，因此尽管全身肾素-血管紧张素系统被强烈激活，但 AT(2) 受体表达减少可能通过血管紧张素 II 诱导的肾上腺儿茶酚胺释放受损，在败血性休克的发病机制中发挥重要作用。
Objective: The systemic renin-angiotensin system is highly activated during septic shock. This has focused interest in regulation of the adrenal angiotensin II type 2 receptor (AT(2)) as the target thought to mediate angiotensin II-induced adrenal catecholamine release during experimental sepsis in vivo. In addition, the influence of typical endogenous mediators of sepsis, such as proinflammatory cytokines and nitric oxide, on AT(2) receptor expression should be investigated in vitro.Design: Prospective animal trial followed by a controlled cell culture study.Setting: Laboratory of the Department of Anesthesiology.Subjects: Male Sprague-Dawley rats weighing 200-250 g, PC12 cell line.Interventions: Rats were injected with lipopolysaccharide to stimulate Gram-negative sepsis or lipoteichoic acid to stimulate Gram-positive sepsis. AT(2) receptor expression, abundance of the proinflammatory cytokines (interteukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma), and nitric oxide synthase If expression have been determined in the adrenal gland. Rat adrenal pheochromocytoma cells were incubated with these cytokines or with the nitric oxide donors sodium nitroprusside or S-nitroso-N-acetylpenicillamine to investigate the regulation of AT(2) receptors during severe inflammation on a cellular level.Measurements and Main Results: In the adrenal gland, AT(2) receptor expression was down-regulated in both models of sepsis, whereas tissue cytokine concentrations were elevated and nitric oxide synthase II expression was induced. Incubation of PC12 cells with proinflammatory cytokines resulted in a dose-dependent diminished expression of AT(2) receptors, which was mimicked by incubation with nitric oxide donors. Blocking of cytokine-induced nitric oxide synthesis by co-incubation of PC12 cells with N-G-nitro-L-arginine methyl ester prevented down-regulation of AT(2) receptors.Conclusions: These findings show that in our model of sepsis, the expression of AT(2) receptors in the adrenal gland is down-regulated in a nitric oxide-dependent manner. Because AT(2) receptors are thought to be involved in adrenal catecholamine secretion in a stimulatory fashion, the diminished expression of AT(2) receptors could play an important role in the pathogenesis of septic shock via impaired angiotensin II-induced adrenal catecholamine release, despite a strong activation of the systemic renin-angiotensin system.