Department of Physiology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.
PLoS One. 2010 Sep 7;5(9):e12622. doi: 10.1371/journal.pone.0012622.
Kinin B(1) receptor (B(1)R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B(1)R activation could perpetuate the oxidative stress which leads to diabetic complications.
Young Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8-12 weeks. A selective B(1)R antagonist (SSR240612) was administered acutely (3-30 mg/kg) or daily for a period of 7 days (10 mg/kg) and the impact was measured on systolic blood pressure, allodynia, protein and/or mRNA B(1)R expression, aortic superoxide anion (O(2)(-)) production and expression of superoxide dismutase (MnSOD) and catalase. SSR240612 reduced dose-dependently (3-30 mg/kg) high blood pressure in 12-week glucose-fed rats, but had no effect in controls. Eight-week glucose-fed rats exhibited insulin resistance (HOMA index), hypertension, tactile and cold allodynia and significant increases of plasma levels of glucose and insulin. This was associated with higher aortic levels of O(2)(-), NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B(1)R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O(2)(-) in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10-100 microM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without Sar[D-Phe(8)]des-Arg(9)-BK (20 microM; B(1)R agonist). Data show that the greater aortic O(2)(-) production induced by the B(1)R agonist was blocked only by apocynin.
Activation of kinin B(1)R increased O(2)(*-) through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B(1)R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B(1)R gene expression in this model.
激肽 B（1）受体（B（1）R）在糖尿病模型中的氧化应激诱导下产生。本研究旨在确定 B（1）R 激活是否会延续导致糖尿病并发症的氧化应激。
年轻的 Sprague-Dawley 大鼠喂食 10% D-葡萄糖或自来水（对照组）8-12 周。选择 B（1）R 拮抗剂（SSR240612）进行急性给药（3-30mg/kg）或每日给药（7 天，10mg/kg），并测量对收缩压、触痛和冷痛、蛋白和/或 mRNA B（1）R 表达、主动脉超氧阴离子（O（2）（-））生成以及超氧化物歧化酶（MnSOD）和过氧化氢酶的表达的影响。SSR240612 以剂量依赖性方式（3-30mg/kg）降低 12 周葡萄糖喂养大鼠的高血压，但对对照组没有影响。8 周葡萄糖喂养大鼠表现出胰岛素抵抗（HOMA 指数）、高血压、触觉和冷痛以及血糖和胰岛素水平显著升高。这与主动脉 O（2）（-）、NADPH 氧化酶活性、MnSOD 和过氧化氢酶表达的增加有关。所有这些异常，包括 B（1）R 过度表达（脊髓、主动脉、肝脏和腓肠肌），均通过长期 SSR240612 治疗得到纠正。还在存在和不存在 NADPH 氧化酶（apocynin）、黄嘌呤氧化酶（allopurinol）或一氧化氮合酶（L-NAME）抑制剂（10-100μM）的情况下，测量了葡萄糖喂养大鼠主动脉中 O（2）（-）的产生，以及有和没有 Sar[D-Phe（8）]des-Arg（9）-BK（20μM；B（1）R 激动剂）。数据表明，B（1）R 激动剂诱导的主动脉 O（2）（-）产生的增加仅被 apocynin 阻断。
激肽 B（1）R 的激活通过血管中 NADPH 氧化酶的激活增加了 O（2）（*-）。在该模型中，B（1）R 阻断的长期阻断通过降低氧化应激和 B（1）R 基因表达来恢复心血管、感觉和代谢异常。
