缬沙坦对糖尿病大鼠肾脏的保护作用

研究表明,血管紧张素转换酶抑制剂（ＡＣＥＩ）能够减少糖尿病肾病的尿蛋白、延缓肾小球硬化的发生［１］;然而血管紧张素Ⅱ受体１拮抗剂（ＡＴ１ＲＡ）对糖尿病肾病的作用尚不清楚。我们通过观察ＡＴＩＲＡ──缬纱坦（ｖａｌｓａｒｔａｎ）对糖尿病大鼠蛋白尿、血压及肾组织转化生长因子－β１（ＴＧＦ－β１）和原癌基因蛋白Ｃ－Ｆｏｓ的影响,探讨缬沙坦对糖尿病大鼠肾脏的保护作用和机理。 一、材料与方法 １．材料：（１）雄性ＳＤ大鼠４０只,体重２３０～２７０ ｇ（河南医科大学动物实验中心提供）;（２）链脲佐菌素（Ｓｔｒｅ…     

波生坦对肾大部切除大鼠红细胞生成素诱发高血压的作用

重组人红细胞生成素(rHuEPO)主要的副作用是诱发和(或)加重高血压,其机制尚未充分阐明。研究显示,内皮素(ET)可能起重要作用犤1,2犦。本实验拟用rHuEPO纠正5/6肾切除大鼠模型的贫血,并观察用内皮素受体拮抗剂波生坦(bosentan)干预后其血压的变化和探讨相关机制。一、材料与方法1.动物模型的建立:参照文献犤3犦方法建立5/6肾切除SD大鼠慢性肾衰模型及假手术动物。手术后4周Scr升高,证实慢性肾衰模型建立成功。2.实验分组:(1)假手术组(Sham组):术后4周开始每天灌注与bosentan(瑞士Actellion公司惠赠)溶液等量的自来水,隔日皮下注射与EP…     

非选择性内皮素受体拮抗剂波生坦对糖尿病大鼠内皮素系统的作用研究

目的：观察非选择性内皮素受体拮抗剂波生坦(Bosentan)对糖尿病大鼠内皮素系统的作用。方法：SD大鼠经链脲佐菌素诱导建立糖尿病大鼠模型，设非治疗组、Bosentan治疗组及正常对照组。4周后比较各组大鼠血浆及肾脏内皮素含量，并用RT—PCR及免疫组化法检测大鼠肾脏内皮素-1(ET-1)和内皮素A、B两种受体基因与蛋白的表达。结果：糖尿病大鼠的ET—1表达明显增加。非治疗组大鼠肾脏ET—A受体的表达显增多。而Bosentan治疗使其表达明显下降。三组大鼠肾组织ET—B受体的表达并无明显区别。结论：糖尿病大鼠肾组织中有内皮素系统的高度活跃。Bosentan不仅通过与ET-1竞争内皮素受体，而且能够下调肾组织中表达增多的ET—A受体，从而显干扰了ET-1的致病作用。     

维生素E对糖尿病大鼠肾脏的保护作用

维生素Ｅ对糖尿病大鼠肾脏的保护作用毛晓明王洪济王爱萍饶亚萍高血糖是引起糖尿病肾病等糖尿病微血管并发症的关键因素，但其发生机理目前尚未完全阐明。近年来的研究发现高血糖所诱导的二酰基甘油（ＤＡＧ）－蛋白激酶Ｃ（ＰＣＫ）代谢通路活性增高与糖尿病微血管并发症...     

缬沙坦对自发性高血压大鼠肾脏结构与功能的保护作用

目的探讨缬沙坦对自发性高血压大鼠(SHR)肾结构与功能的保护作用及其机制。方法将20只SHR随机分为3组,治疗组分别以苯那普利(10mg·kg     

银杏黄酮苷对实验性糖尿病大鼠肾脏保护作用的研究

目的:探讨银杏黄酮苷对糖尿病大鼠肾脏保护作用及其机制。方法:选择雄性SD大鼠24只,随机分为三 组,每组8只,即正常对照组(N组),糖尿病组(DM组),银杏黄酮苷治疗组(DG组)。DM、DG组腹腔注射链脲佐菌素 (STZ)制模成功后,DG组给予银杏黄酮苷灌胃,10周后观察各组血糖、血浆内皮素-1(ET-1)、24h尿白蛋白排泄率、肾 重等指标。用免疫组化方法观察肾脏基质金属蛋白酶-3(MMPs-3)、纤溶酶原激活物抑制物-1(PAI-1)的表达及肾脏 的病理形态学改变。结果:与DM相比,DG组ET-1、尿白蛋白排泄率降低(P<0.05,P<0.01),肾脏肥大指数DG明显 降低(P<0.05);肾组织PAI-1表达DG组低于DM组(P<0.01),MMPs-3DG组则高于N组及DM组(P<0.01)。结 论:STZ诱导的糖尿病大鼠存在纤溶系统功能紊乱、内皮细胞受损及与之平行的尿蛋白排泄率、ET-1的增加,PAI-1表达 增强、MMPs-3表达下调。应用银杏黄酮苷干预治疗,可以降低尿白蛋白排泄率、减少内皮素释放,使PAI-1的表达下 调,MMPs-3的表达上调,对糖尿病大鼠肾脏有部分保护作用。     

牛初乳短链胰岛素样生长因子-1对糖尿病大鼠肾脏的保护作用及其机制研究

目的观察牛初乳短链胰岛素样生长因子－１（ＢＣｔＩＧＦ－１）对糖尿病肾病的保护作用及探讨其可能的作用机制。方法采用生化法、放射免疫法、荧光分析法及逆转录－聚合酶链式反应（ＲＴ－ＰＣＲ）技术等进行研究。结果（１）糖尿病治疗组的空腹血糖、甘油三酯、果糖胺明显低于糖尿病对照组;（２）糖尿病治疗组２４ｈ尿白蛋白排泄率、２４ｈ尿量、２４ｈ内生肌酐清除率低于糖尿病对照组;（３）电镜观察大鼠肾脏病理切片发现ＢＣｔ     

二子合剂对糖尿病大鼠肾脏的保护作用

目的：探讨富含木脂素成分的中药牛蒡子、五味子组成的二子合剂对糖尿病大鼠肾脏的保护作用。方法：将SD大鼠建成链脲佐菌素诱导的糖尿病模型，设正常对照组、模型对照组、苯那普利治疗组、二子合剂大剂量治疗组及小剂量治疗组．4周后检测血糖、24h尿量、尿蛋白总量、尿白蛋白总量、血胆固醇、尿ET-1、TNF-α及肾组织病理变化。结果：与模型对照组相比，苯那普利组及二子合剂大剂量治疗组各项检测指标均有改善，两疗效近似。二子合剂小剂量治疗组仅见尿白蛋白总量及毛细血管襻面密度有减少。结论：牛蒡子、五味子合剂对糖尿病肾脏损害有一定的保护作用，其作用与剂量有相关性。     

内皮素受体阻断剂在高血压糖尿病鼠中的肾脏保护作用及其可能机制

目的；探讨核因子κB（NF－κB）和周期素激酶抑制剂（CKI）p21,p27在糖尿病高血压进展中的可能机制及非选择性内皮素受体阻断剂波生坦（bosentan)的干预作用。方法：自发性高血压大鼠经链脲佐菌素诱导成的糖尿病模型（SHR－DM），设非选择性内皮素受体阻断剂波生坦（bosentan)＋长效钙离拮抗剂氨氯地平（amlodipine)组，amlodipine组，血管紧张素转换酶抑制剂西拉普利（cilazapril)组和非治疗组，4周后用免疫组织化学方法和Wester blot方法观察肾脏NF－κB，p21,p27,与转化生长因子（TGF－β1）的变化，结果：bosentan可以明显抑制SHR－DM的组肾脏NF－κB，TGF－β1，p21和p27的表达，其肾脏保护作用与cilazapril 相似。结果：bosentan的肾脏保护作用可能与干预NF－κB－TGF－β1－p21,p27通路有关。     

血管紧张素Ⅱ受体拮抗剂对5/6肾切除鼠的肾脏保护作用

目的探讨血管紧张素Ⅱ受体拮抗剂氯沙坦对5/6肾切除大鼠肾脏病变的保护作用。方法将5/6肾切除鼠分为氯沙坦治疗组和对照组,设假手术组为正常对照。检测各组术后第2、4、6周的尿蛋白及第6周的血清尿素氮、肌酐、总蛋白、白蛋白,观察第6周肾组织病理改变,并应用免疫组织化学方法检测肾组织内纤维连接蛋白(FN)和Ⅳ型胶原在肾小球的沉积。结果氯沙坦治疗组比对照组尿蛋白排泄量明显减少(P<0.01),血肌酐、尿素氮水平下降(P<0.01),肾小球增生、硬化程度明显减轻;免疫组织化学显示,对照组肾小球内FN和Ⅳ型胶原沉积增多,治疗组FN和IV型胶原沉积比对照组减少(P<0.01)。结论氯沙坦对5/6肾切除鼠肾脏病变有部分保护作用。     

Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock

BACKGROUND: Cardiac dysfunction during septic shock is well described but the underlying mechanisms still remain to be resolved. This study was conducted to elucidate the involvement of endothelin in cardiac function during endotoxin shock by the use of endothelin receptor antagonism. METHODS: Anaesthetised and haemodynamically stable landrace pigs received the nonpeptide mixed endothelin receptor antagonist bosentan, two hours after onset of endotoxaemia (n=7). Cardiopulmonary vascular changes, including cardiac index, stroke work index, coronary artery blood flow, rate of change of left ventricular pressure (dp/dt), and arterial and coronary sinus plasma levels of endothelin-1-like immunoreactivity were compared to a control group only receiving endotoxin (n=7). RESULTS: Plasma endothelin-1-like immunoreactivity increased threefold in the control group. Bosentan effectively counteracted the endotoxin induced decrease in cardiac index. This was accompanied by a significant reduction of both right and left ventricular afterload. In addition, coronary artery blood flow increased and coronary vascular resistance decreased compared to controls. Dp/dt remained unaffected by endothelin receptor antagonism. A further increase in plasma endothelin-1-like immunoreactivity was seen in response to bosentan. CONCLUSION: These results indicate that the increased endothelin production during endotoxaemia contributes to a depressed cardiac performance and that endothelin receptor antagonism may counteract this development. Possible mechanisms for the improved cardiac performance include both a reduction of afterload and enhanced coronary blood flow.     

牛磺酸对糖尿病大鼠肾脏氧化应激和非酶糖基化的抑制作用

目的　研究牛磺酸对糖尿病大鼠肾脏氧化应激反应和非酶糖基化的抑制效果。方法　链脲佐菌素诱发的糖尿病大鼠用牛磺酸治疗１４ 周后,评价牛磺酸对糖尿病大鼠肾脏氧自由基代谢和非酶糖基化产物的影响。结果　与对照组大鼠比较,糖尿病大鼠肾皮质超氧化物岐化酶（ＳＯＤ）和过氧化氢酶（ＣＡＴ） 活性明显降低,而丙二醛含量明显增加;血清和肾皮质晚期糖基化终末产物（ＡＧＥｓ） 水平升高和肾小球ＡＧＥｓ 的形成增加。牛磺酸治疗可明显增加糖尿病大鼠肾脏ＳＯＤ 和ＣＡＴ活性,减低肾皮质ＭＤＡ含量,显著降低糖尿病大鼠血清、肾脏ＡＧＥｓ 水平,减少肾小球ＡＧＥｓ 的形成。结论　牛磺酸能明显抑制糖尿病大鼠肾脏氧化应激反应和非酶糖基化。     

Role of endothelin receptors and relationship with nitric oxide synthase in impaired erectile response in diabetic rats

To evaluate the protective role of bosentan (BOS), an endothelin‐1 (ET‐1) receptor antagonist, and to show the changes in rats with experimentally induced diabetic erectile dysfunction (ED), a total of 24 albino Wistar rats were allocated into four groups. Group 1 was the healthy group and Group 2 had diabetes mellitus (DM) induced by intraperitoneal injection of 60 mg kg^?1 streptozotocin (STZ). Following the establishment of DM, Group 3 and Group 4 were treated with oral BOS doses of 50 mg kg^?1 and 100 mg kg^?1, respectively, for 60 days. At the end of the treatment, we evaluated yawning and erection response to apomorphine treatment and then the animals were sacrificed. ET‐1, eNOS, iNOS, tumour necrosis factor (TNF)‐α, ET‐RA and ET‐RB mRNA expressions were analysed in cavernosal tissue. It was observed that yawning and erection response decreased in the diabetic group; however, both of these improved with BOS treatment. While ET‐1, TNF‐α and iNOS gene expressions increased, eNOS, ET‐RA and ET‐RB gene expressions decreased in the DM group compared to the healthy group. DM has a negative impact on cavernosal tissue blood flow through activating vasoconstrictor mediators in cavernosal tissue. BOS regulates significantly eNOS, iNOS and TNF‐α expressions in a dose‐dependent manner.     

Role of endothelin in the circulatory changes associated with small bowel strangulation obstruction in pigs: effects of the endothelin receptor antagonist bosentan

BACKGROUND: We have previously shown that experimental strangulation obstruction leads to increased release and concentration of endothelin-1 (ET-1) in venous blood from the strangulated bowel loop. The present study focuses on the microcirculatory effects of the released ET-1 in strangulation obstruction. METHODS: In anesthetized pigs strangulation obstruction was induced by increasing pressure in a baby pressure gasket placed around a loop of ileum until venous pressure reached 45 mm Hg. The pigs were randomly allocated into two groups. The nonselective ET(A)/ET(B) antagonist bosentan was administered intravenously (5 mg kg(-1)) to eight pigs (bosentan group) 30 min before strangulation, which was maintained for 90 min. Another eight pigs were treated in same manner except for the bosentan injection (control group). RESULTS: The concentration of ET in arterial and intestinal venous blood increased markedly after intravenous administration of bosentan. Intravenous infusion of bosentan was followed by a reduction in systemic arterial blood pressure. Bosentan reduced vascular resistance and increased blood flow in the normal intestinal mucosa. It also reduced muscularis blood flow in the beginning of the experiment. In strangulated small bowel bosentan inhibited the increase in vascular resistance usually caused by strangulation obstruction. Muscularis blood flow in strangulated small bowel was not affected by bosentan. CONCLUSION: Endothelin is involved in the normal regulation of arterial blood pressure. The increase in vascular resistance associated with strangulation obstruction is caused mainly by locally released endothelin.     

Renoprotective effects of tea catechin in streptozotocin- induced diabetic rats

Tea catechins, a class of flavonoids, are suggested to have biological effects, possibly mediated through their antioxidative properties. Recent data indicated that tea catechins suppressed proliferative changes in glomeruli and inhibited the development of glomerulosclerosis in partially nephrectomized rats. We thus sought to determine whether tea catechins may protect against renal dysfunction in streptozotocin-induced diabetic rats. Four groups of male Sprague-Dawley rats (n=11–15 per group), with and without streptozotocin-induced diabetes, were treated with and without catechins (5 mg/day) administered in the drinking water for 12 weeks. At the end of the treatment period, 24-hour urinary albumin excretion rate (AER), serum lipid peroxides as thiobarbituric acid reactive substrates (TBARS) and blood pressure were measured. Renal glomerular volume and interstitial fibrosis were assessed morphologically. Albuminuria developed progressively in untreated diabetic rats, resulting in a mean AER of 559±124 (mean±SE) versus 63±7 μg/day/100 g body weight in non-diabetic rats at 12 weeks (P<0.001). Catechin treatment significantly reduced AER to 287±56 μg/day/100 g body weight in diabetic rats (P=0.017 versus untreated diabetic rats). Increased interstitial fibrosis in the kidney, observed in untreated diabetic rats, was completely normalized with catechin treatment. Serum levels of TBARS and blood pressure were comparable among the four groups. In conclusion, administration of tea catechin retards the progression of functional and morphological changes in the kidney of streptozotocin-induced diabetic rats.