果糖诱导高血压大鼠血管内皮素-1、内皮素受体-A和内皮源性一氧化氮合酶表达的变化

目的研究果糖诱导高血压和胰岛素抵抗大鼠血管内皮素-1(ET-1)及内皮素-A受体(ETA-R)和内皮源性一氧化氮合酶(eNOS)的变化,探讨内皮功能变化在果糖诱导高血压和胰岛素抵抗中的作用.方法雄性Sprague-Dawley(SD)大鼠饮用10%果糖水3周,尾套法测量血压,并留取血清及尿标本分别测定血清胰岛素、血脂、血糖及血和尿中血ET-1水平后,处死大鼠.ELISA法测定血清及尿中ET-1水平,RT-PCR法测定大鼠主动脉中ET-1及ETA-R表达,Western杂交检测eNOS的表达情况.结果与正常饮水大鼠相比,高果糖饮水3周后,大鼠血压明显升高[(132.8±1.49 vs 120.5±1.7)mmHg,P<0.01]、血胰岛素水平亦明显高于正常饮水组[(12.2±2.3 vs 9.5±1.2)mIu/L,P<0.05].两组间血清ET-1的水平并没有显著差异,但尿中ET-1的水平,果糖饮水组显著高于正常对照组.果糖饮水组大鼠主动脉ET-1和ETA-R的mRNA水平明显升高,而eNOS蛋白质水平显著低于正常组.结论ET-1和ETA-R高表达及eNOS表达的降低参与了果糖诱导高血压和高胰岛素血症的形成.     

胰岛素抵抗大鼠血糖正常阶段心肌内皮素1、内皮型一氧化氮合酶表达的改变

高糖饲料喂养SD大鼠建立胰岛素抵抗（In）模型。12周时IR大鼠心室肌内皮素（ET）-1蛋白及mRNA表达升高，内皮型一氧化氮合酶（eNOS）蛋白和mRNA表达降低。表明高糖膳食诱导的IR大鼠在IR早期已存在心肌ET-1与eNOS平衡的异常。     

内皮型一氧化氮合酶基因对果糖诱导高血压大鼠的降压效应

目的　研究静脉注射人内皮型一氧化氮合酶 (eNOS)基因对果糖诱导高血压大鼠的降压作用及其对胰岛素抵抗的影响。方法　通过给雄性Sprague Dawley大鼠饮用 10 %的果糖水诱导制成高血压动物模型 ,2周后经静脉注入含人eNOScDNA的pcDNA·eNOS重组质粒。每周测血压 2次 ,并于注入eNOS重组质粒后 2周与对照组同时取血 ,测定血糖、血脂及血胰岛素水平 ,并记录 2 4h尿量。结果　一次静脉注射含人eNOS基因的重组质粒后第 3天 ,大鼠升高的收缩压明显下降至 ( 12 2 80± 0 2 )mmHg( 1mmHg =0 133kPa) ,最大降压效应在导入基因后第 14天 ,血压下降至 ( 12 0 30± 1 6 )mmHg并持续 3周以上 ,而对照组血压 [( 12 5 80± 0 4 )mmHg]无变化 (P <0 0 0 1)。实验组在血压下降的同时 ,血胰岛素水平也明显降低。结论　人eNOS基因的导入可能有助于降低血压 ,并改善高血压伴胰岛素抵抗 ,提高患者的胰岛素敏感性。     

氯沙坦对高血压患者血清一氧化氮、内皮素-1和血管内皮功能的影响

目的 探讨氯沙坦对高血压患者血清一氧化氮（NO）、内皮素-1（ET-1）和血管内皮功能的影响.方法 入选108例首诊轻、中度高血压患者,给予氯沙坦50～100 mg,qd,共12周;另人选同期健康体检者为正常对照组（对照组100例）.观察高血压患者治疗前后血流介导的肱动脉内皮依赖性血管舒张功能（FMD）、ET-1和NO的变化.结果 随访12周后,与治疗前比较,高血压患者的血压下降,FMD提高,NO上升,ET-1降低（均P〈0.05）.多元线性逐步回归显示,校正年龄、血压、血脂、血糖等因素后,ET-1和NO是FMD的影响因素（均P〈0.05）.结论 氯沙坦改善高血压患者血管内皮功能可能与减少内皮素分泌,增加一氧化氮水平有关.     

原发性高血压分级与胰岛素抵抗、血浆内皮素-1的关系

目的探讨血浆内皮素-1(endothelin-1,ET-1)、胰岛素抵抗(insulin resistance,IR)和原发性高血压(高血压)分级之间的关系。方法入选150例门诊及体检科新发现的高血压患者,按照2010年《中国高血压防治指南》诊断标准和血压分级原则,分为高血压1级组(52例)、高血压2级组(50例)、高血压3级组(48例),分别检测患者的血浆ET-1、空腹血糖(fasting blood glucose,FBG)、空腹血清胰岛素(fasting serum insulin,FINS)浓度。IR检测采用HOMA法,计算胰岛素敏感指数(insulin sensitivity index,ISI)。结果高血压3级组ISI明显小于高血压2级组和高血压1级组,差异有统计学意义(0.31±0.07 vs.0.43±0.06 vs.0.52±0.03,P<0.05);高血压2级组ISI明显小于高血压1级组,差异有统计学意义(P<0.05)。高血压3级组血浆ET-1浓度明显高于高血压2级组和高血压1级组,差异有统计学意义[(166.27±10.58)ng.L-1vs.(156.74±12.11)ng.L-1vs.(148.62±11.45)ng.L-1,P<0.05];高血压2级组血浆ET-1浓度明显高于高血压1级组,差异有统计学意义(P<0.05)。相关分析结果显示,ISI与收缩压呈负相关(r=-0.58,P<0.05),与舒张压也呈负相关(r=-0.56,P<0.05);ET-1与收缩压呈正相关(r=0.60,P<0.05),与舒张压也呈正相关(r=0.59,P<0.05)。结论 IR及血浆ET-1浓度升高与高血压血压分级有密切关系。     

感觉神经损伤性盐敏感性高血压大鼠血浆血管紧张素Ⅱ和内皮素的变化

目的观察感觉神经损伤性盐敏感性高血压大鼠模型血浆血管紧张素Ⅱ和内皮素-1的变化,并探讨该模型形成的可能机制。方法新生Wistar大鼠皮下注射辣椒辣素（50mg／Kg）,对照组则皮下注射对照液,哺乳期后挑选出雄性大鼠分成4组分别给予含盐不同的饮食4周,检测鼠尾收缩压、体重、血浆血管紧张素Ⅱ浓度、内皮素-1浓度和24h尿量、饮水量、尿钠、尿钾。结果辣椒辣素新生处理大鼠在高盐饮食时鼠尾收缩压明显增高,肾排钠和水功能降低、血浆血管紧张素Ⅱ和内皮素-1浓度明显升高。结论感觉神经损伤性盐敏感性高血压大鼠新模型的形成可能与肾素一血管紧张素一醛固酮及内皮素系统有关。     

感觉神经损伤性盐敏感性高血压大鼠血浆血管紧张素Ⅱ和内皮素的变化

目的 观察感觉神经损伤性盐敏感性高血压大鼠模型血浆血管紧张素Ⅱ和内皮素-1的变化,并探讨该模型形成的可能机制.方法 新生Wistar大鼠皮下注射辣椒辣素(50 mg/Kg),对照组则皮下注射对照液,哺乳期后挑选出雄性大鼠分成4组分别给予含盐不同的饮食4周,检测鼠尾收缩压、体重、血浆血管紧张素Ⅱ浓度、内皮素-1浓度和24h尿量、饮水量、尿钠、尿钾.结果 辣椒辣素新生处理大鼠在高盐饮食时鼠尾收缩压明显增高,肾排钠和水功能降低、血浆血管紧张素Ⅱ和内皮素-1浓度明显升高.结论 感觉神经损伤性盐敏感性高血压大鼠新模型的形成可能与肾素-血管紧张素-醛固酮及内皮素系统有关.     

内皮型一氧化氮合酶和内皮素-2基因多态性与老年高血压关系的研究

目的 探讨内皮型一氧化氮合酶(eNOS)基因G894T多态性和内皮素-2(endothelin-2,ET-2)基因A985G多态性与老年高血压的关系.方法 测定高血压患者和年龄、性别相匹配的对照者的身高、体重、血脂、血糖等指标.采用基因芯片技术测定(230例高血压患者和186例健康人)的eNOS和ET-2基因多态性,并对测定的基因型和等位基因频率进行病例对照研究.应用logistic回归分析性别、体重指数、血脂、血糖及基因型对高血压的影响. 结果 高血压组eNOS基因G894T中GG、GT、TT基因型频率及G、T等位基因频率与对照组相比差异显著(分别为χ2=13.698及χ2=13.075,P均＜0.05);高血压组ET-2基因A985G中AA、AG、GG基因型频率及A、G等位基因频率与对照组相比差异显著(分别为χ2=19.358及χ2=20.452,P均＜0.05).Logistic回归分析显示性别、体重指数、血糖、血总胆固醇及eNOS、 ET-2基因型是高血压发病的危险因素,OR值分别为0.052、1.121、 1.323、4.006、0.294、3.423(P<0.01).结论 性别、体重指数、血糖、血总胆固醇是高血压的独立危险因素;eNOS 基因G894T和ET-2基因A985G可能是老年高血压发病的易感基因.     

自发性高血压大鼠内皮素A型受体基因的表达

应用反转录－聚合酶链式反应方法，测定大鼠ET－A型受体（endothelinareceptor，ETA－R）mRNA在体内的分布，证明ETA－RmRNA不仅存在于血管平滑肌细胞中，亦存在于内皮细胞中；而且广泛分布于脑、心、肾、肺等组织内。发现在原发性高血压大鼠的脑、心、肾组织中，ETA－RARNA水平明显升高，提示ETA－R基因表达增加，可能是高血压发病的一个重要因素。     

Role of Nitric Oxide and Endothelin-1 in a Portal Hypertensive Rat Model

Background: Portal hypertension is often accompanied by a hyperdynamic circulation state. Some reports have suggested that nitric oxide (NO) plays an important role in this hyperdynamic state. On the other hand, although endothelin (ET)-1, a powerful vasoconstrictor, was recently identified, little is known about its role in portal hypertension or about the interaction between NO and ET-1. The aim of this study was therefore to investigate whether or not the inhibitor of NO synthase (NOS) might improve portal hypertension, and also to clarify the relationship between NO and ET-1. Methods: Portal hypertensive (PHT) rats, in which hypertension was induced by a two-step ligation of the portal vein (PVL), were used. The mean arterial pressure (MAP), portal pressure (PP), visceral blood flow volume (BFV), and serum levels of NO and ET-1 were determined in PVL rats treated with two NOS inhibitors with different functions: NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG). Control (CTR) rats, treated by a sham operation (SO), were also studied. Results: Two-step PVL treatment induced a significant increase in the serum level of NO3- and ET-1 in the portal vein. L-NAME and AG administration significantly decreased PP at doses of 50 mg/kg in PHT rats after 60 min administration, while no inhibitor effected any modification in the CTR rats. Both NOS inhibitors increased MAP and decreased PP and BFV in the portal vein, gastric mucosa, and spleen, in addition to decreasing the serum levels of NO3- and ET-1 in the PHT rats, while neither blockade modified any parameters in the CTR rats. In PHT rats, L-arginine, a NO substance, reversed the effect of L-NAME, while it did not induce any recovery from the AG effect. Conclusions: In PHT rats, NO seems to contribute to portal hypertension. PVL increases not only the serum level of NO3-, but also that of ET-1 in the portal vein. Both L-NAME and AG reduce PP and BFV of the portal vein, spleen, gastric mucosa, and liver. In addition, the inhibition of NOS diminishes the serum level not only of NO, but also of ET-1. Use of an appropriate NOS inhibitor may therefore positively affect the hyperdynamic state in portal hypertension.     

内皮素和一氧化氮在心血管病中的作用

心血管疾病与血管内皮的关系已被医务界所认识 ,血管内皮所分泌的内皮素— 1及一氧化氮在心血管疾病的发病中起重要作用。所以 ,保护血管内皮功能可以预防心血管疾病     

慢性宫内缺氧对子代大鼠心脏诱导型一氧化氮合酶、血清内皮素1的影响

目的探讨慢性宫内缺氧对子代大鼠心脏诱导型一氧化氮合酶、血清内皮素1的影响。方法建立慢性宫内缺氧大鼠模型,实验分为缺氧组、空气模拟对照组、空白对照组,每组10只子鼠。监测出生1天龄子鼠体重、各脏器重量,免疫组织化学法检测心肌细胞诱导型一氧化氮合酶的表达,酶联免疫吸附法检测1天龄、6月龄子鼠血清内皮素1的表达。结果宫内缺氧引起仔鼠主要脏器不成比例生长。宫内缺氧组子代大鼠出生时心肌诱导型一氧化氮合酶表达显著高于空气模拟对照组及空白对照组(P<0.01),而空气模拟对照组与空白对照组比较差别无统计学意义。1天龄子鼠各组间血清内皮素1的表达差异无统计学意义,6月龄子鼠缺氧组显著高于空气模拟对照组及空白对照组(P<0.01),而空气模拟对照组与空白对照组比较差别无统计学意义。结论慢性宫内缺氧作为孕期不良生长环境应激因素,可引起子鼠低出生体重以及主要脏器不成比例生长,并导致心脏诱导型一氧化氮合酶、血清内皮素1表达增高,致使心血管病风险性增高。     

Big Endothelin-1 and Nitric Oxide in Hypertensive Elderly Patients with and without Obstructive Sleep Apnea-Hypopnea Syndrome

Background

The role of oxidative stress in hypertensive elderly patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) is unknown.

Objective

The purpose was to evaluate the levels of big endothelin-1 (Big ET-1) and nitric oxide (NO) in elderly hypertensive patients with and without moderate to severe OSAHS.

Methods

Volunteers were hospitalized for 24 h. We obtained the following data: body mass index (BMI); 24-ambulatory blood pressure monitoring; and current medication. Arterial blood was collected at 7pm and 7am for determining plasma NO and Big ET-1 levels. Pulse oximetry was performed during sleep. Pearson''s or Spearman''s correlation and univariate analysis of variance were used for statistical analysis.

Results

We studied 25 subjects with OSAHS (group 1) and 12 without OSAHS (group 2) aged 67.0 ± 6.5 years and 67.8 ± 6.8 years, respectively. No significant differences were observed between the groups in BMI; number of hours of sleep; 24-h systolic and diastolic BPs; awake BP, sleep BP and medications to control BP between groups. No differences were detected in plasma Big ET-1 and NO levels at 19:00 h, but plasma Big ET-1 levels at 7:00 h were higher in group 1 (p = 0.03). In group 1, a negative correlation was also observed between the mean arterial oxyhemoglobin saturation level, 24-h systolic BP (p = 0.03, r = −0.44), and Big ET-1 (p = 0.04, r = −0.41).

Conclusions

On comparing elderly hypertensive patients with and without OSAHS having similar BP and BMI, we observed higher Big ET-1 levels After sleep in the OSAHS group. NO levels did not differ between the hypertensive patients with or without OSAHS.     

Modulatory Role of Nitric Oxide/cGMP System in Endothelin-1-Induced Signaling Responses in Vascular Smooth Muscle Cells

Nitric oxide (NO) is an important vasoprotective molecule that serves not only as a vasodilator but also exerts antihypertrophic and antiproliferative effects in vascular smooth muscle cells (VSMC). The precise mechanism by which the antihypertrophic and antiproliferative responses of NO are mediated remains obscure. However, recent studies have suggested that one of the mechanisms by which this may be achieved includes the attenuation of signal transduction pathways responsible for inducing the hypertrophic and proliferative program in VSMC. Endothelin-1 is a powerful vasoconstrictor peptide with mitogenic and growth stimulatory properties and exerts its effects by activating multiple signaling pathways which include ERK 1/2, PKB and Rho-ROCK. Both cGMP-dependent and independent events have been reported to mediate the effect of NO on these pathways leading to its vasoprotective response. This review briefly summarizes some key studies on the modulatory effect of NO on these signaling pathways and discusses the possible role of cGMP system in this process.     

香烟烟雾对大鼠脑血管内皮细胞超微结构及内皮素1表达的影响

目的研究吸烟对大鼠脑血管内皮细胞超微结构及其内皮素1的影响。方法用免疫组织化学方法分别检测正常对照组、长期大量吸烟组、长期小量吸烟组、短期大量吸烟组及戒烟组大鼠脑血管内皮素1的表达;运用Westen-blotting法对以上各组脑内皮素1特异性受体进行定量分析。同时电镜观察其脑血管内皮细胞超微结构的变化。结果吸烟大鼠各组内皮素1及脑内皮素1特异性受体表达均明显高于正常对照组(P<0.01),长期大量吸烟组明显高于其他各吸烟组,戒烟组明显低于短期大量吸烟组。吸烟可致脑血管内皮细胞超微结构变化,并可见凋亡细胞,长期大量吸烟组较其他各吸烟组改变明显。结论吸烟可引起脑血管内皮细胞损伤,使内皮素1表达上调。戒烟可使上述改变明显恢复。内皮细胞损伤、内皮素1表达上调在吸烟对脑损伤中起重要作用,是吸烟引起脑血栓的重要途径之一。     

内皮素-1在血管平滑肌细胞增殖作用中的研究进展

血管重构是血管壁功能和结构异常改变的过程,涉及血管内皮细胞、血管平滑肌细胞和细胞外基质的病理改变。血管平滑肌细胞增殖在血管重构中起关键性的作用。内皮素-1是一种活性多肽,参与调控血管平滑肌细胞收缩、增殖、迁移和基因表达等多项细胞功能。内皮素-1在平滑肌细胞增殖的作用机制可能是防止血管重构的关键靶点。     

Molecular Analysis of Cocaine-Induced Endothelial Dysfunction: Role of Endothelin-1 and Nitric Oxide

Cocaine remains the most frequently used illicit substance. Although cocaine-induced atherosclerosis is well documented, its mechanism of action on human vascular endothelial cells has not been determined. Nitric oxide (NO) and endothelin-1 (ET-1) are involved in endothelial cell activation and leukocyte recruitment. The present study monitored the effects of cocaine on NO and ET-1 production in human aortic endothelial cells (HAECs) and the effects of sodium nitroprusside (SNP) and BQ-123 on leukocyte adhesion to HAECs. Acute exposure to cocaine (1 and 3 μM) significantly increased ET-1 production (2-fold) and ET-1 receptor type-A (ET_AR) protein expression, within 6–12 h. Cocaine exposure for a longer duration (24–72 h) showed a temporal decrease in both NO production and endothelial NO-synthase (eNOS) expression. The cocaine-mediated suppression of NO was ameliorated by co-treatment of cells with the ET_AR blocker, BQ-123 (5 μM). Furthermore, both short-term (24 h) and long-term (72 h) exposure to cocaine increased endothelial adhesion of monocytes (U937 cells) by 20% and 40%, respectively, which were also suppressed by BQ-123 and SNP co-treatment. These data suggest that a concomitant increase in both ET-1 and ET_AR expression in cocaine exposed HAECs may enhance signaling via the ET_AR which decreases eNOS expression and NO production, and ultimately results in endothelial activation and leukocyte adhesion. Our findings implicate a molecular mechanism of action of cocaine and a therapeutic effect of ET_AR-specific inhibitor in suppressing the cocaine-induced endothelial dysfunction.     

内皮素对大鼠主动脉血管平滑肌细胞骨桥蛋白表达的影响

目的观察内皮素1对培养的大鼠主动脉血管平滑肌细胞骨桥蛋白表达的影响。方法用含10％小牛血清DMEM培养基体外培养大鼠主动脉血管平滑肌细胞，随机分为对照组、不同浓度（10^-5、10^-6、10^-7和10^-8mol／L）及时间（6h、12h、24h和48h）干预组，应用逆转录聚合酶链反应及Westem blot技术结合吸光度扫描分析。观察内皮素1对血管平滑肌细胞骨桥蛋白表达的影响。结果不同浓度内皮素1均明显刺激血管平滑肌细胞骨桥蛋白mRNA和蛋白的表达，但无剂量依赖性促进作用；除6h干预组与对照组相比差异无显著性外，其他各不同时间干预组（12h、24h和48h）均明显刺激血管平滑肌细胞骨桥蛋白mRNA和蛋白的表达，且具有时间依赖性。结论内皮素1能促进血管平滑肌细胞骨桥蛋白的表达。