Vascular protective actions of a nitric oxide aspirin analog in both in vitro and in vivo models of diabetes mellitus
Vascular protective actions of a nitric oxide aspirin analog in both in vitro and in vivo models of diabetes mellitus
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DOI：
10.1016/s0891-5849(02)00832-8
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发表时间：
2002-06-01
影响因子：
7.4
通讯作者：
Del Soldato, P
中科院分区：
文献类型：
--
作者：
Pieper, GM;Siebeneich, W;Del Soldato, P
背景：在实验和人类糖尿病中观察到内皮依赖性松弛缺陷。这种缺陷的性质尚不完全清楚，但可能涉及由于活性氧（ROS）的产生增强而导致一氧化氮（NO）生物活性降低。在本文中，我们研究了一种名为2-乙酰氧基苯甲酸2-（2-硝基氧甲基）苯基酯（标记为NCX4016）的新型no供体抗氧化剂对暴露于急性血糖升高的正常动脉或来自慢性糖尿病动物的动脉中no介导的内皮依赖性松弛的益处和作用。材料与方法：利用电子顺磁共振（EPR）光谱和5,5-二甲基-1-吡咯啉- n -氧化物（DNIPO）自旋俘获技术，研究了NO-NSAIDs对溶液中本质自由基的清除作用。在急性研究中，正常大鼠主动脉在组织培养中暴露18小时至5.5 mM或40 mM，存在或不存在NCX4016， NCX4016是一种与阿司匹林无关的非捐献性非甾体抗炎药（NCX2216）或阿司匹林。测定了体外胸主动脉环对乙酰胆碱内皮依赖性松弛的血管反应性。对慢性高血糖大鼠，静脉注射链脲佐菌素诱导糖尿病。在未治疗或长期使用NCX4016的动物中，8周后测定胸主动脉环对体外乙酰胆碱内皮依赖性松弛的血管反应性。体内抗氧化作用通过测定血浆异前列腺素和测定主动脉核部分nf - κ b的核结合活性来确定。结果：NCX4016和NCX2216对dpo - oh形成产生浓度依赖性抑制，表明清除羟基自由基（HO.）。相反，对超氧阴离子自由基的清除效果不明显。葡萄糖浓度升高的正常动脉急性孵育引起对乙酰胆碱的正常松弛抑制。与NCX4106共孵育可预防这种损伤，但甘露醇、母体化合物（阿司匹林）或NCX2216不能预防这种损伤。此外，用NCX4016进行慢性治疗可以防止内皮依赖性乙酰胆碱松弛的缺陷，这种保护不是由于血糖浓度或血红蛋白糖化的任何变化而发生的。用NCX4016治疗确实降低了血浆异前列腺素的升高，并使糖尿病引起的主动脉组织核组分中NF-kappaB结合活性的升高正常化。结论：总的来说，这些研究表明，使用no供体非甾体抗炎药进行抗氧化干预可能为保护糖尿病内皮提供一种重要的新治疗策略。(C) 2002爱思唯尔科学有限公司
Background: Defective endothelium-dependent relaxation is observed in experimental and human diabetes mellitus. The nature of this defect is not fully understood but may involve decreased nitric oxide (NO) bioactivity due to enhanced production of reactive oxygen species (ROS). In this paper, we examine the benefits and actions of a novel NO-donating, antioxidant called 2-acetoxybenzoic acid 2-(2-nitrooxymethyl) phenyl ester, and denoted as NCX4016, on NO-mediated endothelium-dependent relaxation in normal arteries exposed to acute elevations in glucose or in arteries derived from chronic diabetic animals. Material and Methods: Intrinsic free radical scavenging by NO-NSAIDs in solution were evaluated using electron paramagnetic resonance (EPR) spectroscopy and spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DNIPO). In acute studies, normal rat aortas were exposed in tissue culture for 18 h to 5.5 mM or 40 mM in the presence or absence of NCX4016, a NO-donating NSAID unrelated to aspirin (NCX2216) or aspirin. Vascular reactivity of thoracic aortic rings to endothelium-dependent relaxation to acetylcholine in vitro was determined. For chronic hyperglycemia, diabetes was induced in rats by intravenous injection with streptozotocin. Vascular reactivity of thoracic aortic rings to endothelium-dependent relaxation to acetylcholine in vitro was determined after 8 wks in untreated animals or animals chronically-treated with NCX4016. Antioxidant efficacy in vivo was determined by measurement of plasma isoprostanes and by nuclear binding activity of NF-kappaB in nuclear fractions of aortae. Results: Incubation with NCX4016 and NCX2216 produced a concentration-dependent inhibition of DMPO-OH formation indicating scavenging of hydroxyl radicals (HO.). In contrast, little efficacy to scavenge superoxide anion radicals was noted. Acute incubation of normal arteries with elevated glucose concentration caused inhibition of normal relaxation to acetylcholine. This impairment was prevented by coincubation with NCX4106 but not by mannitol, the parent compound (aspirin) or by NCX2216. In addition, chronic treatment with NCX4016 prevented die development of defective endothelium-dependent relaxation to acetylcholine, This protection did not occur as a result to any changes in blood glucose concentration or hemoglobin glycation. Treatment with NCX4016 did decrease the elevation in plasma isoprostanes and normalized the diabetes-induced increase in NF-kappaB binding activity in nuclear fractions derived from aortic tissue. Conclusions: Collectively, these studies suggest that antioxidant interventions using NO-donating NSAIDs may provide an important novel therapeutic strategy to protect the diabetic endothelium. (C) 2002 Elsevier Science Inc.