高糖对系膜细胞金属蛋白酶表达的影响及肝素的干预作用

目的:研究高糖对正常人类系膜细胞(NHMc)增殖及金属蛋白酶2(MMP2)和金属蛋白酶9(MMP9)表达的影响及肝素对其的干预作用.方法:NHMC在含和(或)不含肝素的高糖培养基中培养,以正常糖培养基作对照.采用WST-1法测定NHMC增殖状况;用Western Blot技术分析MMP2、MMP9表达情况.结果:高糖组NHMC增殖明显高于对照组,二组间有显著性差异(P＜0.05).用肝素干预后,高糖组肝素浓度为50μg/ml时,NHMC增殖开始受到抑制,且随着肝素浓度递增,NHMC增殖抑制更明显(肝素50～400μg/ml浓度组与未加肝素组比较,均P＜0.05或P＜0.01).而对照组肝素浓度为200μg/ml时,NHMC增殖才出现抑制(肝素200～400μg/ml组与未加肝素组比较,均P＜0.05).另外,高糖与对照组NHMC均有一定量MMP2、MMP9表达,加入肝素后MMP2、MMP9出现高表达,特别是在高糖组尤为明显.结论:肝素能抑制高糖刺激下NHMC增殖并能使体外NHMC中的MMP2、MMP9出现高表达,推测MMPs可能参与了高糖状态下NHMC的细胞外基质的降解过程并且肝素有肾保护作用.     

金属基质蛋白酶9及其组织抑制物1在肾组织中的表达和调控

目的:观察STZ鼠肾组织及高糖状态下正常人类系膜细胞(NHMC)中金属基质蛋白酶9(MMP-9)、金属基质蛋白酶组织抑制物1(TIMP-1)表达状况及磷酸肌酸激酶(PKC)抑制剂对其表达的影响,探讨糖尿病肾病(DN)时PKC抑制剂在细胞外基质降解中的作用。方法:Wistar大鼠随机分为正常对照组、DN模型组、PKC抑制剂组。PKC抑制剂组采用根皮素10mg/(kg.d)混悬液灌胃进行干预。第8周处死大鼠(每组6只)。检测24h尿蛋白定量、血肌酐水平。用免疫组化方法检测肾脏组织MMP-9、TIMP-1的表达。用ELISA方法检测肾脏组织PKC活性。体外实验,将NHMC置37℃,5%CO2培养箱中进行培养。并将NHMC分为N组(对照组):糖浓度5mmol/L,H组(高糖组):糖浓度30mmol/L,P组(高糖加PKC抑制剂):糖浓度30mmol/L加chelery thrine chloride 10-5mmol/L,M组(甘露醇组):甘露醇30mmol/L。于培养24、48、72h后用MTT法测定细胞增值。采用ELISA方法检测四组PKC活性。分别用RT-PCR及Western Blot检测各组MMP-9、TIMP-1mRNA及蛋白表达。结果:DN模型组尿蛋白排泄明显增加(P<0.01),血肌酐上升(P<0.05),PKC活性明显增高,MMP-9和TIMP-1出现表达,MMP-9/TIMP-1比值降低。PKC抑制剂干预后其尿蛋白排泄明显减少,血肌酐水平降低,PKC活性下降,MMP-9、TIMP-1表达上调,其MMP-9/TIMP-1比值增高。体外实验中,高糖能促进NHMC增殖,且NHMC的增殖状况随时间的递增而明显增加。高糖(30mmol/L)能增加系膜细胞PKC的活性,MMP-9、TIMP-1较高表达,MMP-9/TIMP-1比值降低。而PKC抑制剂使PKC的活性降低同时,MMP-9、TIMP-1表达上调,MMP-9/TIMP-1比值增高。结论:高糖可诱导PKC活性,PKC抑制剂能使MMP-9、TIMP-1表达上调,MMP-9/TIMP-1表达比值升高,推测PKC的活性状况可影响DN细胞外基质降解过程。     

螺内酯对高糖培养大鼠肾小球系膜细胞增殖及TGF-β1、FN分泌的影响

目的探讨螺内酯对高糖培养大鼠肾小球系膜细胞（GMCs）增殖的抑制作用及转化生长因子β1（TGF-β1）、纤维黏连蛋白（FN）分泌的影响。方法将大鼠GMCs置于低糖、高糖及高糖＋不同浓度螺内酯中传代培养,并以此分组。采用噻唑蓝法检测各组大鼠GMCs增殖情况,采用ELISA法检测各组TGF-β1、FN分泌情况。结果高糖培养组大鼠GMCs增殖明显高于低糖培养组（P〈0.05）。加入螺内酯后,GMCs增殖受到抑制,与低糖、高糖组比较P〈0.05或〈0.01,且随着螺内酯剂量增加细胞增殖抑制递增。螺内酯可明显减少TGF-β1、FN的分泌（P〈0.05或〈0.01）,并随浓度增高、时间延长抑制作用增强。结论高糖能刺激大鼠GMCs增殖;螺内酯能抑制大鼠GMCs增殖,并可抑制TGF-β1、FN分泌。     

缬沙坦对2型糖尿病大鼠肾脏保护作用的研究

目的　了解血管紧张素受体拮抗剂缬沙坦对 2型糖尿病大鼠肾脏病变的保护作用及其机制。　方法　高糖、高脂饮食加小剂量链脲佐菌素 (STZ) 30mg/kg制作 2型糖尿病动物模型 ,将实验动物分为正常对照组、糖尿病组及缬沙坦治疗组 ,检测各组大鼠的血糖、血胰岛素、血肌酐、尿素氮、尿白蛋白、肾脏肥大指数的变化 ,免疫组化检测PAI 1的蛋白表达水平。　结果　缬沙坦治疗组较非治疗组尿白蛋白明显减少 (P <0 .0 1) ,尿素氮水平下降 (P <0 .0 5 ) ,肾脏肥大指数改善 (P <0 .0 5 ) ,免疫组化显示 ,糖尿病组大鼠肾小球PAI 1蛋白表达增多 ,治疗组PAI 1蛋白表达明显降低。　结论　缬沙坦对 2型糖尿病肾脏病变有一定的保护作用 ,其机制可能是通过下调糖尿病大鼠PAI 1的表达     

肾上腺髓质素对高糖培养的肾小球系膜细胞增殖和凋亡的影响及其机制的研究

目的观察肾上腺髓质素(AM)对高糖培养的肾小球系膜细胞HBZY-1增殖和凋亡的影响及其可能的作用机制。方法采用MTT法和流式细胞仪测定观察AM干预对HBZY-1细胞增殖和凋亡的影响,同时采用Western blot观察分裂素激活蛋白激酶(MAPK)信号传导途径中ERK和P38MAPK蛋白活性的变化。结果高糖状态下HBZY-1细胞增殖明显增强,凋亡轻度增加;AM干预后HBZY-1细胞增殖明显抑制,平均下降38.8%,同时凋亡明显增强。AM干预后,ERK1/2活性明显抑制,与高糖组比较平均下降约30%,而P38MAPK活性明显增强,较高糖组平均增高约70%。结论AM对高糖培养HBZY-1细胞增殖增强具有抑制作用,并促进其凋亡。这种作用是可能是通过MAPK信号传导途径所介导的。     

大肠癌和大肠腺瘤COX-2和Bcl-2的基因表达及其意义

目的　探讨COX 2及Bcl 2基因在大肠癌和大肠腺瘤组织中的表达及其意义。方法　应用免疫组化ABC法检测 2 8例大肠癌、2 8例大肠腺瘤和 10例正常黏膜中COX 2及Bcl 2表达 ,应用TUNEL法检测细胞凋亡。结果　在大肠癌、大肠腺瘤及正常黏膜中COX 2的阳性表达分别为 82 1%、85 7%和 0 0 %。Bcl 2的阳性表达分别为 75 0 %、78 6%和 2 0 0 %。大肠癌与腺瘤的COX 2及Bcl 2表达均无显著性差异 (P >0 0 5) ,但均显著高于正常黏膜 (P <0 0 1)。大肠癌中凋亡指数明显高于大肠腺瘤 (χ2 =8 80 ,P <0 0 5) ,COX 2和Bcl 2的表达均与大肠腺瘤及大肠癌的细胞凋亡指数呈显著负相关 (腺瘤P <0 0 1;癌P <0 0 5) ,两者均与临床病理特征无相关性 (P >0 0 5) ,大肠癌高、中、低分化各组间及不同Dukles分期 (A、B期和C、D期 )各组间凋亡指数无显著性差异 (P>0 0 5)。结论　COX 2和Bcl 2在大肠腺瘤及大肠癌中表达增强 ,从而抑制了细胞凋亡 ,在大肠腺瘤恶变及大肠癌的发生和发展过程中起到重要作用     

胰高血糖素样肽-1类似物对高糖诱导下肾小管上皮细胞Toll样受体4、骨桥蛋白表达的影响

目的 研究胰高血糖素样肽-1(GLP-1)类似物对高糖诱导下的肾小管上皮细胞中Toll样受体4(TLR4)、骨桥蛋白(OPN)表达的影响.方法 体外培养人肾小管上皮细胞HK-2,将其分为低糖组、高糖组、高渗透压组、低剂量干预组、中剂量干预组、高剂量干预组.干预48 h后采用细胞免疫化学法、RT-PCR法分别检测各组细胞中TLR4、OPN蛋白和mRNA的表达情况.结果 低糖组和高渗透压组TLR4、OPN蛋白和mRNA呈低表达,且表达无明显差异;高糖组TLR4、OPN蛋白及mRNA表达较低糖组明显增高;Exendin-4干预后TLR4、OPN的蛋白及mRNA的表达明显降低,且呈剂量依赖性,明显低于高糖组,但仍高于低糖组.结论 GLP-1类似物可通过抑制TLR4、OPN的表达来抑制免疫炎症反应对肾脏的损害,且GLP-1类似物的这种保护作用呈剂量依赖性.     

心脏成纤维细胞缺氧预处理对心肌细胞的保护作用

目的 :探讨大鼠心脏成纤维细胞缺血预处理 (IPC)对成纤维细胞及心肌细胞的保护作用。方法 :实验分为 6组 [对照 (CON) 1组、CON 2组 ,预处理 (PC) 1组、PC 2组、SMT组、NS3 98组 )。用Westernblotting法测定心肌细胞的环氧化酶 2 (COX2 )、分泌型一氧化氮合酶 (iNOS)表达量。心肌细胞损伤程度以乳酸脱氢酶 (LDH)释放和台盼蓝排斥试验判断 ,成纤维细胞损伤程度以台盼蓝排斥试验判断。结果 :PC 1组的细胞存活率与CON1组差异无显著性意义 (P >0 .0 5 )。PC2组LDH释放较CON2组明显减少 ,细胞存活率明显增加 (P <0 .0 1)。SMT组和NS3 98组LDH释放、细胞存活率与CON2组相当 (P >0 .0 5 )。PC2组COX2 表达量明显增加 ,与CON2组比较差异有极显著性意义 (P <0 .0 1) ,SMT组与CON2组间COX2 量差异无显著性意义 (P >0 .0 5 )。PC2组和NS3 98组的iNOS表达量较CON2组明显增加 ,差异有极显著性意义 (P <0 .0 1)。结论 :IPC不能对心脏成纤维细胞产生保护作用。心脏成纤维细胞在缺氧后可能释放某些“保护性递质” ,触发心肌细胞产生类似IPC的保护效应 ,而且与iNOS ,COX2 的表达有关 ,在信号传导中iNOS是COX2 的上游     

缬沙坦与吲达帕胺治疗原发性高血压的对比研究

目的 :评价缬沙坦 (valsartan)降压疗效的同时 ,探讨其降压外的其它作用。方法 :入选的原发性高血压患者被随机分为缬沙坦组和吲达帕胺 (indapamide)组。用药前后进行诊所血压、心脏超声多普勒及血浆一氧化氮 (NO)、血管紧张素Ⅱ (AngⅡ )、血浆醛固酮、空腹胰岛素及血脂 ,血清尿酸、血电解质、空腹血糖、肝肾功能及血尿常规检查 ,并计算空腹胰岛素 /空腹血糖值作为胰岛素抵抗指标。对已婚男性患者进行关于性功能障碍的问卷调查。结果 :治疗后 ,缬沙坦组和吲达帕胺组血压均有所下降 ,降压疗效相似 (总有效率分别为 6 7 5 %和 6 6 7% ) ,左心房指数均改善 ,有显著性差异 (P <0 0 5 ) ,舒张功能指标 (A/E)好转 ,有显著性差异 (P <0 0 1和P <0 0 5 ) ;缬沙坦组患者的AngⅡ和NO均升高 ,有显著性差异 (P <0 0 5和P <0 0 1) ,空腹胰岛素 /空腹血糖值降低 ,有显著性差异 (P <0 0 1) ,左心室心肌重量指数减低 ,有显著性差异 (P <0 0 5 ) ;此外 ,缬沙坦组患者的性活动增加 ,有显著性差异 (P <0 0 5 )。结论 :除了确切而缓和的降压作用外 ,缬沙坦具有良好的依从性和靶器官保护作用     

岩藻聚糖硫酸酯对高糖培养肾小球系膜细胞的影响

目的 探讨岩藻聚糖硫酸酯(FPS)对高糖培养大鼠肾小球系膜细胞(GMCs)增殖和细胞外基质(ECM)积聚的影响.方法 购自威海地区的干海带,经过水提取、层析分离制备FPS.体外培养大鼠GMCs并分为正常组、高糖损伤组、缬沙坦(Val)对照组、FPS治疗组.通过MTT法观察药物对GMCs增殖的影响,ELISA法检测TGF-β1的含量,免疫组化法检测IV-胶原(Col-Ⅳ)表达量.结果 FPS提取率为1.01%,平均分子量为83万D,总糖含量为67.03%,硫酸根的含量为38.29%.与正常对照组相比:自行制备的FPS高剂量组能够显著抑制高糖培养的大鼠GMCs的增殖(P＜0.01),抑制TGF-β1的过量分泌(P＜0.01)和Col-Ⅳ的过多表达(P＜0.01).与阳性对照组相比,其效果没有差异.结论 FPS能显著抑制GMCs增殖、TGF-β1的过量分泌和Col-Ⅳ的过多表达,对糖尿病肾病具有保护作用.     

缬沙坦和卡托普利对兔血管平滑肌细胞组织因子和组织因子途径抑制物表达及活性的影响

目的观察氧化修饰低密度脂蛋白（ox-LDL）、血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂对血管平滑肌细胞组织因子（TF）和组织因子途径抑制物（TFPI）表达和活性的影响。方法采用组织贴块法培养兔主动脉平滑肌细胞,进行形态学和α-肌动蛋白（actin）免疫组化鉴定。在细胞水平,采用免疫组化、免疫荧光法检测ox-LDL和缬沙坦对TF、TFPI蛋白表达的影响,激光共聚焦法检测ox-LDL和缬沙坦对TF蛋白表达的影响,ELISA法检测ox-LDL、缬沙坦和卡托普利对TF、TFPI抗原表达的影响,发色底物法检测ox-LDL、缬沙坦和卡托普利对TF活性的影响,RT—PCR检测ox-LDL和缬沙坦对TF mRNA表达的影响。结果ox-LDL可增加兔血管平滑肌细胞TF抗原活性和mRNA的表达,在mRNA水平调节TF的表达。ox-LDL可降低兔血管平滑肌细胞TFPI抗原的表达。不同浓度的缬沙坦和卡托普利可明显减少ox-LDL刺激的平滑肌细胞TF抗原表达及活性,缬沙坦对TF表达的影响呈浓度依赖性,同时缬沙坦还可明显减少ox-LDL刺激的TF mRNA表达,证明缬沙坦在mRNA水平上调节TF的表达。不同浓度的缬沙坦和卡托普利可增加ox-LDL刺激的血管平滑肌细胞TFPI抗原的表达,缬沙坦对TFPI表达的影响呈浓度依赖性,该结果由ELISA法得出。结论本实验在细胞水平观察到ox-LDL对血管平滑肌细胞TF表达和活性有促进作用,血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂对其有抑制作用,但这两种药对TFPI的表达有促进作用。从一个新的角度说明这两种药对动脉粥样硬化斑块特别是斑块促凝性的影响,它们可能是通过部分调节TF和TFPI的表达水平而发挥作用的。     

Cardioprotective effect of angiotensin II type 1 receptor antagonist associated with bradykinin-endothelial nitric oxide synthase and oxidative stress in Dahl salt-sensitive hypertensive rats

OBJECTIVES: The interactions between eNOS or oxidative stress and bradykinin under long-term treatment of angiotensin II type 1 receptor antagonists (ATRA) remain unknown. To elucidate the molecular mechanisms of the cardioprotective effect of ATRA, we evaluated whether valsartan affects the bradykinin-eNOS and nicotinamide adenine dinucleotide (NAD(P)H) oxidase pathway. METHODS: After 5 weeks of feeding an 8% NaCl diet to 6-week-old Dahl salt-sensitive hypertensive (DS) rats, a distinct stage of concentric left ventricular hypertrophy (LVH) was noted. Six-week-old DS rats were treated with one of the following drug combinations for 5 weeks until the onset of LVH: vehicle; bradykinin B2 receptor antagonist FR172,357 alone; high-dose hydralazine; low-dose hydralazine; high-dose valsartan; low-dose valsartan; high and low-dose valsartan plus FR172,357. Age-matched Dahl salt-resistant rats fed the same diet served as controls. RESULTS: eNOS expression and activity, which was decreased in hypertrophy, was increased by high or low-dose valsartan, but not by high and low-dose valsartan plus FR172,357 or FR172,357 alone or high and low-dose hydralazine. The increased expression of NAD(P)H oxidase p22phox, p47phox, p67phox, and gp91phox in DS rats was suppressed by high or low-dose valsartan, but not by high or low-dose valsartan plus FR172,357 or FR172,357 alone or high and low-dose hydralazine. Valsartan effectively inhibited vascular lesion formation and suppressed the expression of transforming growth factor-beta1, connective tissue growth factor, and type I collagen, but not valsartan plus FR172,357 or FR172,357 alone or high and low-dose hydralazine. CONCLUSION: These findings suggest that valsartan may have cardioprotective effects in this model, partly associated with the bradykinin-eNOS and oxidative stress pathway.     

Angiotensin II type 2 receptor expression after vascular injury: differing effects of angiotensin-converting enzyme inhibition and angiotensin receptor blockade

It has been suggested that the effects of angiotensin II type 1 receptor (AT1R) blockers are in part because of angiotensin II type 2 receptor (AT2R) signaling. Interactions between the AT2R and kinins modulate cardiovascular function. Because AT2R expression increases after vascular injury, we hypothesized that the effects on vascular remodeling of the AT1R blocker valsartan and the ACE inhibitor benazepril require AT2R signaling through the bradykinin 1 and 2 receptors (B1R and B2R). To test this hypothesis, Brown Norway rats were assigned to 8 treatments (n=16): valsartan, valsartan+PD123319 (AT2R inhibitor), valsartan+des-arg9-[Leu8]-bradykinin (B1R inhibitor), valsartan+HOE140 (B2R inhibitor), benazepril, benazepril+HOE140, amlodipine, and vehicle. After 1 week of treatment, carotid balloon injury was performed. Two weeks later, carotids were harvested for morphometry and analysis of receptor expression by immunohistochemistry and Western blotting. Valsartan and benazepril significantly reduced the intima:media ratio compared with vehicle. Blockade of AT2R, B1R, or B2R in the presence of valsartan prevented the reduction seen with valsartan alone. B2R blockade inhibited the effect of benazepril. Injury increased AT1R, AT2R, B1R, and B2R expression. Treatment with valsartan but not benazepril significantly increased intima AT2R expression 2-fold compared with vehicle, which was not reversed by inhibition of AT2R, B1R, and B2R. Functionally, valsartan increased intimal cGMP levels compared with vehicle, and this increase was inhibited by blocking the AT2R, B1R, and B2R. Results suggest that AT2R expression and increased cGMP represent a molecular mechanism that differentiates AT1R blockers, such as valsartan, from angiotensin-converting enzyme inhibitors like benazepril.     

缬沙坦对氧化低密度脂蛋白诱导的人内皮细胞基质金属蛋白酶-1表达的影响

目的观察缬沙坦对氧化低密度脂蛋白(ox-LDL)诱导的人内皮细胞基质金属蛋白酶-1(MMP-1)表达的影响。方法体外培养人脐静脉内皮细胞,待细胞生长到融合状态时,将细胞分为4组:对照组;OX-LDL组(加ox-LDL 100 mg/L);低浓度组(先加ox-LDL 100 mg/L,再加缬沙坦10 μmol/L);高浓度组(先加ox-LDL 100mg/L,再加缬沙坦30μmol/L)。RT-PCR测定MMP-1 mRNA的表达。结果与对照组比较,ox-LDL组MMP-1mRNA的表迭明显增多(P<0.05),与ox-LDL组比较,低、高浓度组抑制MMP-1 mRNA的表达(P<0.05),并呈浓度依赖性。结论缬沙坦的抗炎及稳定动脉粥样硬化斑块的作用,可能与抑制内皮细胞MMP-1的表达有关。     

Effects of AT1 Antagonist on MMP2, MMP9 Expression and Collagen Remodeling in Left Ventricle of Rabbit Undergoing Chronic Pressure Overload

Objectives To study the effects of AT1 antagonist on MMP2, MMP9 expression and collagen remodeling in left ventricle of rabbit undergoing chronic pressure overload. Methods 30 rabbits were randomly divided into 3 groups (n= 10,each group), including sham operation group, abdominal aorta banded group(banded group), abdominal aorta banded valsartan group (valsartan group).Twelve weeks after operation,hemodynamic parame-ters were acquired, then collagen volume fraction(CVF) and MMP2, MMP9 expression of left ventricle were measured by using VG and immunohistochemical stain. Results Compared with sham operation group, both MMP2 and MMP9 expression were enhanced in banded group; meanwhile, LVW/BW,LVEDP and CVF increased significantly. Compared with banded group, both MMP2 and MMP9 expression were weakened in valarstan group; simultaneously,LVW/BW, LVEDP and CVF decreased significantly.Conclusions Expression of MMP2 and MMP9 was enhanced in left ventricle of rabbit undergoing chronic pressure overload, which may be associated with collagen proliferation, ventricule remodeling and impaired heart function; Valsartan could inhibit collagen proliferation, prevent ventricule remodeling and preserve heart function by inhibiting abnormal expression of MMP2 and MMP9.     

Mechanism for blockade of angiotensin subtype 1 receptors to lower plasma glucose in streptozotocin-induced diabetic rats

AIMS: We investigated the mechanism(s) by which valsartan, a selective antagonist of angiotensin subtype 1 (AT(1)) receptor, decreased plasma glucose in streptozotocin (STZ)-induced diabetic rats. METHODS: The plasma glucose concentration was assessed by the glucose oxidase method. The concentration of beta-endorphin in plasma or medium incubating adrenal medulla was measured using an enzyme-linked immunosorbent assay. The mRNA levels of the subtype 4 form of glucose transporter (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in the liver were detected by Northern blotting analysis, while the protein levels of GLUT4 in isolated soleus muscle and hepatic PEPCK were investigated using Western blotting analysis. RESULTS: A single intravenous injection of valsartan dose-dependently increased plasma beta-endorphin-like immunoreactivity (BER) in parallel with the lowering of plasma glucose concentration in STZ-induced diabetic rats. Naloxone and naloxonazine inhibited the plasma glucose-lowering action of valsartan at doses sufficient to block opioid micro-receptors. In contrast to its action in wild-type diabetic mice, valsartan failed to modify plasma glucose in opioid micro-receptor knockout diabetic mice. Bilateral adrenalectomy in STZ-induced diabetic rats eliminated both the plasma glucose-lowering action and the plasma BER-elevating action of valsartan. In the isolated adrenal medulla of STZ-induced diabetic rats, angiotensin II (Ang II) or valsartan did not affect spontaneous BER secretion. Activation of cholinergic receptors by 1.0 micromol/l acetylcholine (ACh) enhanced BER secretion from the isolated adrenal medulla of STZ-induced diabetic rats, but not in the presence of 1.0 nmol/l Ang II, while valsartan reversed this inhibition by Ang II in a concentration-dependent manner. Treatment of STZ-induced diabetic rats with valsartan (0.2 mg/kg) three times daily for 3 days resulted in an increase in gene expression of GLUT4 in soleus muscle and impeded the reduction of elevated mRNA or protein level of hepatic PEPCK. Both of these effects were blocked by opioid micro-receptor antagonist. CONCLUSIONS: The results suggest that blockade of AT(1) receptor by valsartan may enhance the adrenal beta-endorphin secretion induced by ACh, activating the opioid micro-receptors to increase glucose utilization and/or to decrease hepatic gluconeogenesis, resulting in the reduction of plasma glucose in STZ-induced diabetic rats.     

缬沙坦对不同浓度C-反应蛋白诱导的单核细胞白细胞介素-6合成的影响

目的通过研究缬沙坦对C-反应蛋白(CRP)诱导的正常人外周血单核细胞合成白细胞介素-6(IL-6)的影响,观察缬沙坦的抗炎作用。方法采用密度梯度离心法分离人外周血单核细胞,应用酶联免疫吸附试验分别观察CRP(15、、10及20 mg/L)刺激单核细胞产生IL-6的时间及剂量效应,其峰值与缬沙坦抑制剂进行比较。结果CRP刺激单核细胞IL-6合成呈时间依赖性和剂量依赖性,20 mg/L CRP与5 mg/L CRP诱导IL-6合成开始的时间是4 h,在24 h达高峰,其峰值分别是(904±77)ng/L和(698±52)ng/L。高浓度缬沙坦(≥10-3mol/L)能抑制20 mg/LCRP诱导的单核细胞IL-6合成,较低浓度缬沙坦(1×10-6mol/L~1×10-3mol/L)能抑制5 mg/L CRP诱导的单核细胞IL-6合成。结论缬沙坦可用于轻度炎症时抗细胞因子治疗。     

Disparate effects of angiotensin II antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension: potential role of nephrin

OBJECTIVE AND DESIGN: To explore the effects of various antihypertensive regimes which achieve similar blood pressure control using a range of agents including the angiotensin II type 1 receptor antagonist, valsartan, as monotherapy or in combination with two subclasses of calcium channel blockers (CCBs) (the dihydropyridine, amlodipine and the phenylalkylamine, verapamil) on the progression of renal disease and the expression of the podocyte slit pore protein, nephrin in an accelerated model of diabetic nephropathy. RESULTS: Valsartan treatment reduced systolic blood pressure as assessed by radiotelemetry (135 +/- 3 versus diabetic 153 +/- 6 mmHg) as well as retarding the increase in albumin excretion rate by approximately 50%. Combination therapy of valsartan with either amlodipine or verapamil was equally effective in reducing blood pressure to valsartan monotherapy (valsartan + amlodipine 129 +/- 4 valsartan + verapamil 133 +/- 6 mmHg;) but was not as effective at reducing albuminuria. A reduction in glomerulosclerosis was observed with valsartan monotherapy with less reduction in injury with the valsartan + amlodipine combination, despite a similar reduction in blood pressure. The decrease in nephrin, in diabetic rats was attenuated by valsartan monotherapy, but not by other treatments. CONCLUSIONS: The results of this study demonstrate that despite a similar reduction in blood pressure, the addition of the CCB amlodipine to the AII antagonist failed to provide similar renoprotection to that observed with an equihypotensive regimen of valsartan as monotherapy. Furthermore, the depletion in glomerular nephrin expression in diabetic animals was only abrogated by valsartan treatment, the therapy which was most effective at retarding the development of albuminuria in this model.     

复方缬沙坦治疗轻中度原发性高血压患者的疗效观察

目的评价复方缬沙坦（缬沙坦80mg／氢氯噻嗪12．5mg复方制剂）治疗经单用缬沙坦80mg控制不良的轻、中度原发性高血压患者疗效和安全性。方法采用多中心、双盲、双模拟、随机、活性药物对照、平行试验方法。对经2周洗脱期的轻、中度原发性高血压患者[坐位舒张压≥95mmHg（1mmHg=0．133kPa）且〈110mmHg]采用单药缬沙坦80mg／d治疗4周,在单药导入结束后,坐位舒张压仍〉190mmHg的864例患者按1：1随机、双盲分为复方缬沙坦组或缬沙坦80mg／d组,继续治疗8周。在治疗4周和结束时评估药物安全性及有效性。结果在轻、中度原发性高血压患者中复方缬沙坦每日1次比单用缬沙坦80mg／d血压进一步下降、达标率提高。治疗结束时平均坐位收缩压多降低3．5mmHg,平均坐位舒张压多下降2．2mmHg,血压控制〈140／90mmHg的患者在复方缬沙坦组和单用缬沙坦80mg／d组分别为53．9％及40．9％。结论轻、中度原发性高血压患者采用复方缬沙坦治疗组降压有效率及达标率均优于每日1次服用缬沙坦80mg／d组。复方缬沙坦适用于缬沙坦单药控制不良的轻、中度原发性高血压患者。