罗格列酮对2型糖尿病大鼠主动脉内皮依赖性血管舒张功能的影响

目的观察2型糖尿病（T2DM）大鼠胸主动脉内皮依赖性血管舒张功能和一氧化氮（NO）、一氧化氮合酶（eNOS）的变化及罗格列酮（RSG）治疗对其内皮功能的影响。方法SD大鼠经高糖高脂喂养6周后予小剂量链脲佐菌素腹腔注射建立T2DM大鼠模型，糖尿病大鼠又分为对照（DM）组和RSG治疗组，RSG组用RSG干预8周，另选正常大鼠为正常对照（NC）组。实验终止时用正常葡萄糖高胰岛素钳夹技术的葡萄糖输注率（GIR）评价胰岛素抵抗，观察大鼠离体主动脉内皮依赖性血管舒张反应和主动脉NO、eNOS的变化。结果T2DM大鼠GIR、胸主动脉内皮依赖性血管舒张反应、主动脉NO含量及eNOS阳性表达较NC组显著降低（P〈0、01），RSG治疗后上述指标均显著升高（P〈0．05）。结论T2DM大鼠存在内皮依赖性血管舒张功能紊乱，RSG治疗可改善内皮功能，增强NO水平和eNOS的活性。     

胰岛素抵抗和2型糖尿病大鼠主动脉内皮依赖性舒张功能及相关活性物质的变化

目的观察胰岛素抵抗和2型糖尿病大鼠胸主动脉内皮依赖性血管舒张功能和内皮型一氧化氮合酶（eNOS）、磷脂酰肌醇-3激酶（PBK）、蛋白激酶B（PKB）的变化,探讨胰岛素抵抗和高血糖状态下内皮功能障碍的发生机制。方法4～6周龄雄性SD大鼠高糖高脂喂养6周,建立胰岛素抵抗模型（IR组）,再从中取20只予小剂量链脲佐菌素（STZ）腹腔注射建立2型糖尿病大鼠模型（DM组）,喂养8周后用正常血糖高胰岛素钳夹技术的葡萄糖输注率评价胰岛素抵抗,用大鼠离体主动脉环对乙酰胆碱的血管舒张反应来评价大鼠的内皮依赖性血管舒张功能,Gress重氮化反应法检测主动脉NO含量,免疫组化法检测主动脉eNOS阳性表达,RT—PCR方法检测主动脉PBK、PKB、eNOSmRNA表达,透射电镜检测大鼠主动脉超微结构变化,并检测空腹血糖、空腹胰岛素、甘油三酯和胆固醇水平,计算胰岛素敏感指数。结果（1）IR和DM组大鼠体重、空腹胰岛素、甘油三酯和胆固醇均较正常对照组显著高（P〈0．01）,胰岛素敏感指数、葡萄糖输注率显著低（P〈0．01）。（2）IR和DM组大鼠胸主动脉内皮依赖性血管舒张功能显著低于NC组（P〈0．05）,DM组又低于IR组,大鼠主动脉对乙酰胆碱诱导的最大舒张反应与空腹血糖、甘油三酯、胆固醇和空腹胰岛素呈显著负相关,与胰岛素敏感指数显著正相关（P均〈0．01）。（3）IR、DM组大鼠离体主动脉NO浓度及PBK、PKB、eNOSmRNA相对光密度较正常对照组显著低（P〈0．01）,而DM组上述指标又低于IR组（P〈0．05）。免疫组化显示IR、DM组主动脉eNOS阳性表达较正常对照组显著低（P〈0．01）。（4）IR和DM组大鼠胸主动脉透射电镜检查均可见内皮细胞和内皮下超微结构的病理改变。结论胰岛素抵抗和2型糖尿病大鼠存在内皮依赖性血管舒张功能下降和主动脉超微结构的病理改变,同时主动脉NO浓度、eNOS免疫组化阳性表达、PBK、PKB、eNOSmRNA表达也下降,提示PI-3K、PKB、eNOS表达下降致NO产生减少可能是胰岛素抵抗和高血糖内皮功能障碍的机制之一。     

注射用血栓通对2型糖尿病大鼠血管内皮功能的保护作用

目的观察注射用血栓通对2型糖尿病(T2DM)大鼠血管内皮细胞功能的保护作用。方法根据随机原则,35只大鼠平均分为5组:正常对照(NC)组,糖尿病模型(DM)组和血栓通低、中、高剂量组(5、10、20 g.kg-1.d-1),除NC组外,其余各组小剂量链脲佐菌素(STZ)和高脂喂养诱导T2DM大鼠模型,血栓通组每日腹腔注射血栓通,NC组和DM组每日腹腔注射同体积蒸馏水。连续给药4 w后麻醉,腹主动脉采血,测血清一氧化氮(NO)、内皮型一氧化氮合酶(eNOS)、内皮素(ET)-1,然后迅速分离胸主动脉,连接张力传感器,将血管张力变化用生物信号定量记录分析系统对进行分析。于浴槽中加入浓度为5×10-8mol/L的去甲肾上腺素(NE),待动脉环收缩达峰值后,分别加入不同浓度的乙酰胆碱(ACh),观察血管的舒张反应,以占NE收缩值的百分比表示(%)。结果与NC组比较,DM组NO水平、eNOS活性降低,ET-1水平升高(P<0.01)。与DM组比较,血栓通治疗组NO水平、eNOS活性升高,ET-1水平降低,其中中剂量组和大剂量组改善明显(P<0.05)。与NC组比较,DM组大鼠胸主动脉对ACh的内皮依赖性舒张反应明显减弱(P<0.01);与DM组相比,血栓通治疗组对ACh累积剂量舒张百分率有所提高,中剂量和大剂量组明显提高(P<0.05)。结论血栓通能够改善2型糖尿病大鼠内皮依赖的血管舒张功能。     

吡咯烷二硫代氨基甲酸酯对2型糖尿病大鼠大血管损伤的保护作用

目的 观察吡咯烷二硫代氨基甲酸酯(PDTC)的降糖作用,以及对2型糖尿病(T2DM)大鼠主动脉血管内皮诱生型一氧化氮合酶(iNOS)表达及硝基酪氨酸(NT)生成的影响.方法 雄性WistarA大鼠,随机分为两组,正常对照组(NC组)和高脂饮食组(HFD组),喂养8 w后,HED组腹腔注射小剂量链脲佐菌素(STZ),诱导成功的T2DM大鼠随机分为糖尿病组(DM组)和PDTC治疗组(PDTC组),PDTC治疗组接受PDTC(50 mg/kg)治疗,持续1周,断头处死后留取血浆检测血糖及各种生化指标;留取主动脉组织,检测主动脉组织匀浆中丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)的含量;HE染色观察主动脉组织形态学变化,免疫组化观察各组大鼠主动脉内皮iNOS、NT的表达.结果 PDTC治疗1w后,PDTC组大鼠空腹血糖、MDA水平明显低于DM组;SOD和GSH-Px水平明显高于DM组(P<0.01).免疫组化结果显示:iNOS、NT在DM组大鼠主动脉内皮表达水平明显高于NC组;在PDTC治疗组大鼠主动脉内皮表达水平明显低于DM组.结论 PDTC不仅具有降血糖作用,而且可以减少iNOS的表达,进而减少过氧亚硝基阴离子(ONOO<'->)及NT的产生,延缓了糖尿病大血管并发症的发生.早期应用PDTC可预防T2DM因"代谢记忆"所致的大血管损伤.     

2型糖尿病患者血浆护骨素浓度与内皮依赖性血管舒张功能关系的研究

目的探讨T2DM患者血浆护骨素(OPG)浓度与内皮依赖性血管舒张功能的关系。方法选取T2DM患者(T2DM组)154例和健康对照(NC)者46名,分别测定其血浆OPG浓度,并采用高分辨血管外超声法检测肱动脉血流介导的内皮依赖性血管舒张功能和硝酸甘油介导的非内皮依赖性血管舒张功能。结果 T2DM组血流介导的内皮依赖性血管舒张功能为(3.56±0.64)%,低于NC组(5.32±0.55)%(P<0.01)。多元回归分析显示,内皮依赖性血管舒张功能、24hUAlb均与血浆OPG水平相关。Pearson相关分析显示,OPG浓度与内皮依赖性血管舒张功能呈负相关(r=-0.284,P=0.000)。结论血浆OPG水平在T2DM患者中升高,其水平与内皮依赖性血管舒张功能呈负相关。     

肿瘤坏死因子相关的凋亡诱导配体对2型糖尿病大鼠内皮依赖性血管舒张功能的影响

目的 观察TNF相关的凋亡诱导配体（TRAIL）对T2DM大鼠主动脉内皮依赖性血管舒张功能的影响及其可能的机制. 方法 选取4周龄雄性SD大鼠,分为正常对照组（NC,n=10）与模型组（n=40）,随机将模型组分为T2DM亚组（n=10）与TRAIL亚组（TRAIL,n=10）.TRAIL干预6周后,检测各组FPG及FIns水平,计算ISI.检测NC组与TRAIL亚组血清TRAIL水平.观察大鼠离体主动脉内皮依赖性血管舒张反应,并检测主动脉一氧化氮（NO）含量、内皮型一氧化氮合酶活性（eNOS）.结果 与NC组比较,T2DM亚组FPG、FIns水平升高（P＜0.01）,ISI降低（P＜0.01）,血清TRAIL水平降低（P＜0.01）;血管内皮功能失调,乙酰胆碱（Ach）引起的血管最大舒张率降低（P＜0.01）,血管中NO含量及eNOS阳性表达降低（P＜0.01或P＜0.01）.TRAIL亚组血管Ach的舒张反应改善（P＜0.01）;血管中NO含量增加且eNOS阳性表达上调（P＜0.05或P＜0.01）;FPG、FIns降低,ISI提高（P＜0.01）. 结论 TRAIL改善T2DM大鼠内皮依赖性血管舒张功能的同时,可促进具有血管保护作用的NO生成.     

胰岛素强化治疗对新诊断2型糖尿病患者内皮脂肪酶的影响

目的观察胰岛素强化治疗前后初发2型糖尿病(T2DM)患者血清内皮脂肪酶水平的变化。方法健康成人20例为正常对照组(NC组),新诊断2型糖尿病30例为DM组,DM组胰岛素强化治疗2周,治疗前后采用酶联免疫吸附法检测血清内皮脂肪酶水平,同时测定治疗前后超敏C反应蛋白、空腹血糖、餐后2小时血糖。结果与NC组比,DM组血清内皮脂肪酶水平显著增高(P<0.01);DM组治疗前与治疗后比较血清内皮脂肪酶水平显著降低(P<0.01),超敏C反应蛋白、空腹血糖、餐后2小时血糖明显降低(P均<0.01)。结论 2型糖尿病患者体内存在轻度炎症,胰岛素强化治疗可减轻炎症反应,降低血清内皮脂肪酶的水平。     

脂联素对2型糖尿病大鼠主动脉内皮功能影响的研究

目的观察APN对T2DM大鼠主动脉内皮功能的影响。方法采用高脂饮食加腹腔注射STZ建立T2DM大鼠模型。造模成功后随机分为DM组9只和APN组8只,另设正常对照(NC)组10只。APN组给予尾静脉注射腺病毒重组APN(0.71×109 IU/只),DM组和NC组给予同等剂量生理盐水注射。测定各组胸主动脉内皮功能,核因子-κB(NF-κB)表达及一氧化氮(NO)水平。结果与DM组相比,APN组高敏C反应蛋白(hsC-RP)[(1.85±0.56)vs(3.13±0.38)mg/L]和丙二醛水平[(2.44±0.28)vs(4.80±0.59)mg/L]降低,APN水平[(273.50±21.20)vs(94.97±25.12)μg/L]升高(P0.01)。NC组主动脉环最大舒张率高于其他两组[(81.7±5.2)%vs(65.9±9.9)%vs(36.0±8.9)%,P0.05]。DM组主动脉NF-κB表达高于APN组和NC组,且APN组表达高于NC组(P0.05)。NC组器官池中NO水平高于DM组和APN组[(125.6±17.7)vs(103.5±20.3)vs(72.5±9.1)μmol/g,P0.05]。结论 APN能改善T2DM大鼠主动脉内皮功能,其机理可能与通过减少氧化应激和炎症反应,增加NO的产生有关。     

急性高血糖对肱动脉内皮依赖性血管舒张功能影响的研究

目的 探讨葡萄糖负荷试验所致急性高血糖对血管内皮功能的影响。方法 选择正常健康人（NC）、糖耐量减低（IGT）患者和2型糖尿病（T2DM）患者各10例。所有对象均做OGTT，分别于0、60、120min采用高分辨血管外超声检测肱动脉血流介导的内皮依赖性血管舒张功能和硝酸甘油（GNT）介导的内皮非依赖性血管舒张功能。结果 IGT组和T2DM组0、60、120min的内皮依赖性血管舒张功能均明显低于NC组（P〈0．05）。与0min相比，IGT组和T2DM组60min内皮依赖性血管舒张功能明显降低，120min又回升，明显高于60min者（P〈0．05）。IGT组和T2DM组在基础状态下，LDL-C、Lp（a）、FPG、HbA-C与内皮依赖性血管舒张功能呈负相关（P〈0．01）。在OGTT中，这两组血糖与内皮依赖性血管舒张功能呈负相关（P〈0．001）。结论 高血糖快速抑制内皮依赖性血管舒张功能。提示餐后高血糖在糖尿病血管并发症的发生与发展中起重要作用。     

生长分化因子11对2型糖尿病小鼠胰岛β细胞保护作用的研究

目的探讨生长分化因子11(GDF11)对T2DM小鼠胰岛β细胞的作用。方法选取C57BL/6J野生型小鼠,通过高脂饮食及STZ制备T2DM模型并随机均分为糖尿病rGDF11干预组(DM+rGDF11)和糖尿病对照组(DM),同时将普通饲料喂养的C57BL/6J小鼠随机分为正常rGDF11干预组(Con+rGDF11,n=10)和正常对照组(Con,n=10),观察GDF11对小鼠生理生化指标、胰岛β细胞功能及含量指标的影响。结果干预6周后,Con组与Con+rGDF11组各糖脂代谢指标比较,差异无统计学意义(P0.05)。与DM组比较,DM+rGDF11组FBG、HbA1c、胰升血糖素及血脂水平降低(P0.05),且rGDF11干预后上调胰岛β细胞重要基因表达,促进胰岛素分泌,改善胰岛形态及β细胞含量(均P0.05)。结论 GDF11可改善胰岛β细胞功能及维持β细胞含量,进而延缓糖尿病的发生发展。     

胰岛素抵抗和2型糖尿病大鼠主动脉内皮功能的变化及罗格列酮的影响

目的观察罗格列酮对胰岛素抵抗（IR）和2型糖尿病大鼠胸主动脉内皮依赖性舒张功能和一氧化氮（NO）的影响。方法SD大鼠高脂高糖喂养建立IR模型,链脲佐菌素（STZ）腹腔注射建立2型糖尿病大鼠模型,各模型又分为对照组和治疗组：IR对照（IRC）组、IR治疗（IRT）组、糖尿病对照（DMC）组和糖尿病治疗（DMT）组,另选正常大鼠为正常对照（NC）组和正常治疗（NT）组,治疗组用罗格列酮干预8周。检测各组大鼠空腹血糖（FPG）、空腹胰岛素（FINS）、甘油三酯（TG）和胆固醇（TC）水平,用正常葡萄糖高胰岛素钳夹技术的葡萄糖输注率（GIR）评价IR,观察大鼠离体主动脉乙酰胆碱依赖性血管舒张功能和NO浓度的变化。结果IRC、DMC组大鼠体质量、FINS、TG、TC及C反应蛋白（CRP）显著升高（P〈0．05）,IRT、DMT组大鼠FINS、TG及CRP降低（P〈0．01）;IRC、DMC组大鼠GIR、NO及各浓度的内皮依赖性舒张反应（EDVR）降低（P〈0．01）,NT、IRT和DMT组大鼠GIR、NO及ED—VR升高（P〈0．05）。EDVR与NO含量、胰岛素敏感指数（ISI）呈显著正相关（r=0．561,r=0．351）,与FPG、TG、TC及CRP呈显著负相关（r=-0．356、r=-0．451、r=-0．402、r=-0．391）。结论IR和2型糖尿病大鼠存在NO水平下降和内皮依赖性血管舒张功能紊乱,罗格列酮治疗可以升高NO水平,改善内皮功能。     

Chronic angiotensin IV treatment reverses endothelial dysfunction in ApoE-deficient mice

AIMS: Endothelial dysfunction is considered a surrogate marker for cardiovascular disease. Angiotensin II, the principal hormone of the renin angiotensin system, is known to promote atherogenesis. However, other angiotensin peptide fragments such as angiotensin IV possess biological activity that may in fact counter-regulate the actions of angiotensin II. Therefore, we investigated the role of angiotensin IV on the development of endothelial dysfunction in apolipoprotein E-deficient (ApoE-/-) mice. METHODS AND RESULTS: In contrast to their wild-type control, ApoE-/- mice that were fed a high-fat diet had exacerbated endothelial dysfunction, evidenced by impaired endothelium-dependent vasodilation. Chronic infusion of angiotensin IV (1.44 mg/kg per day) in ApoE-/- mice for 2 weeks resulted in significant improvements in endothelial function. Angiotensin IV treatment markedly decreased superoxide levels (dihydroethidium staining fluorescence and L-012 chemiluminescence) and increased endothelial nitric oxide synthase expression (immunoreactivity and western blotting) in aortic tissue. Co-treatment of angiotensin IV with either AT4 receptor antagonist divalinal-Ang IV or AT2 receptor antagonist PD123319 attenuated these changes, indicating involvement of both the AT4 and the AT2 receptors. CONCLUSION: Chronic angiotensin IV treatment in ApoE-/- mice evoked a marked vasoprotective effect that appeared to be mediated by improved NO bioavailability as a result of AT4 and/or AT2 receptor stimulation.     

2型糖尿病早期内皮依赖性血管舒张功能的临床研究

目的探讨2型糖尿病（T2DM）早期患者血管内皮功能的变化及其临床意义。方法选择44例新诊断无并发症的T2DM早期患者和40名年龄、性别等匹配的正常对照者。采集空腹静脉血测定FPG、Fins、HbA,c、TC、TG、HDL—C、LDL-C、UA、NO、内皮素1（ET～1）等,并行75g葡萄糖耐量试验测定2hPG。采用高分辨率血管外彩超测定肱动脉、颈动脉的血管内径及颈动脉内膜中层厚度（IMT）,以反应性充血前后血管内径变化百分比反映血管舒张功能。对IMT与各项指标的变化进行相关性分析。结果T2DM组与对照组之间FPG、Fins、2hPG、HbA1C、TG、TC、HDL—C、LDL-C、H（）MAIR、NO、ET-1差异均有统计学意义（P〈0．05或P〈0．01）,而性别、年龄、BMI、收缩压、舒张压、UA差异无统计学意义（P〉0．05）。T2DM组基础血管内径、血流介导的内皮依赖性舒张功能和硝酸甘油介导的非内皮依赖性舒张功能与对照组之间差异有统计学意义（P〈0．01）。基础血流在两组问差异无统计学意义（P〉0．05）。不同部位IMT在不同人群中的密切相关因素是不同的。结论T2DM早期患者就有血管内皮功能损伤,不仅存在内皮依赖性血管舒张功能障碍,而且存在非内皮依赖性血管舒张功能障碍。     

植物雌激素α-玉米赤霉醇内皮依赖性舒张效应的机制研究

目的探讨植物雌激素α-玉米赤霉醇(α-ZAL)对大鼠胸主动脉环内皮依赖性舒张效应中一氧化氮合酶(NOS)-NO-环磷酸鸟苷(cGMP)系统的作用。方法采用体外血管环灌流的方法,先用10-6mol/L苯肾上腺素预收缩血管。观察10-10～10-5mol/L6个不同浓度α-ZAL对内皮完整和去除内皮的大鼠胸主动脉环的舒张作用。α-ZAL10-10～10-8mol/L为低浓度组,α-ZAL10-7～10-5mol/L为高浓度组,0.1%乙醇浓度为对照组。在高浓度组中分别预先加用10-5mol/L左旋硝基精氨酸甲酯(L-NAME组)和亚甲蓝(MB组)并观察其影响,测定动脉环中内皮型一氧化氮合酶(eNOS)和cGMP含量及灌流液中NO含量变化。结果L-NAME组和MB组均可减弱高浓度组中α-ZAL的内皮依赖性胸主动脉环舒张作用(P<0.05,P<0.01);与对照组比较,高浓度组胸主动脉环中eNOS、cGMP含量及灌流液中NO含量增高(P<0.05,P<0.01);与高浓度组比较,L-NAME组可降低灌流液中NO含量及胸主动脉环中cGMP含量(P<0.05,P<0.01);MB组可降低胸主动脉环中cGMP含量(P<0.01)。结论α-ZAL的内皮依赖性舒张作用与NOS-NO-cGMP系统的激活有关。     

The effect of the phytoestrogen genistein on plasma nitric oxide concentrations,endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women

The phytoestrogen genistein improves endothelial dysfunction in ovariectomized rats through a nitric oxide-dependent mechanism. We investigated whether genistein alters the balance between the nitric oxide products and endothelin-1 and influences endothelium-dependent vasodilation in postmenopausal women. Sixty healthy postmenopausal women were enrolled in the study. A double-blind, placebo controlled, randomized design was employed. After a 4-week stabilization on a standard fat-reduced diet, participants to the study were randomly assigned to receive either genistein (n=30; 54 mg/day) or placebo (n=30). Flow-mediated, endothelium-dependent vasodilation of the brachial artery, plasma nitric oxide breakdown products and endothelin-1 levels were measured at baseline and after 6 months of genistein therapy. The mean baseline level of nitrites/nitrates was 22+/-10 micromol/l and increased to 41+/-10 micromol/ml after 6 months of treatment. The mean baseline plasma endothelin-1 level was 14+/-4 pg/ml and decreased to 7+/-1 pg/ml following 6 months of treatment with genistein. The mean baseline ratio of nitric oxide to endothelin also significantly increased at the end of treatment. Flow-mediated, endothelium-dependent vasodilation of the brachial artery was 3.9+/-0.8 mm at baseline and increased to 4.4+/-0.7 mm after 6 months of treatment. Placebo-treated women showed no changes in plasma nitrites/nitrates, endothelin-1 levels and flow-mediated vasodilation. Genistein therapy improves flow-mediated endothelium dependent vasodilation in healthy postmenopausal women. This improvement may be mediated by a direct effect of genistein on the vascular function and could be the result of an increased ratio of nitric oxide to endothelin.     

Improvement of endothelial function by systemic transfusion of vascular progenitor cells

Endothelial dysfunction is characterized by abnormalities in vasoreactivity and is a marker of the extent of atherosclerosis. Cellular repair by circulating progenitor cells of ongoing vascular injury may be essential for vascular integrity and function and may limit abnormalities in vasoreactivity. Apolipoprotein E-deficient (apoE-/-) mice were splenectomized and treated with high-cholesterol diet for 5 weeks, resulting in marked impairment of endothelium-dependent vasodilation of aortic segments as compared with wild-type mice. Intravenous transfusion of 2x10(7) spleen-derived mononuclear cells (MNCs) isolated from wild-type mice on 3 consecutive days restored endothelium-dependent vasodilation in the apoE-/- mice, as measured 7, 14, and 45 days after transfusion. Histological analyses of aortic tissue identified fluorescent-labeled, exogenously applied progenitor cells that expressed the endothelial cell marker CD31 in the endothelial cell layer of atherosclerotic lesions. Progenitor cell treatment led to increased vascular nitric oxide synthase activity. Transfusion of either in vitro-differentiated Dil-Ac-LDL/lectin-positive endothelial progenitor cells, CD11b-positive (monocyte marker), CD45R-positive (B-cell marker), or Sca-1-positive (stem cell marker) MNC subpopulations significantly improved endothelium-dependent vasodilation, although these treatments were not as effective as transfusion of total MNCs. Depletion of MNCs of either CD11b-positive, CD45R-positive, or Sca-1-positive cells resulted in significant attenuation of endothelium-dependent vasodilation as compared with nondepleted MNCs; however, vasoreactivity was still significantly improved as compared with saline-treated apoE-/- mice. Intravenous transfusion of spleen-derived MNCs improves endothelium-dependent vasodilation in atherosclerotic apoE-/- mice, indicating an important role of circulating progenitor cells for the repair of ongoing vascular injury. More than 1 subpopulation of the MNC fraction seems to be involved in this effect.     

Effects of different levels of exercise volume on endothelium-dependent vasodilation: roles of nitric oxide synthase and heme oxygenase

The objective of this study was to examine the effects of moderate and high levels of exercise volume on endothelium-dependent vasodilation and associated changes in vascular endothelial/inducible nitric oxide synthase (eNOS and iNOS) and heme oxygenase (HO). Male Sprague-Dawley rats were assigned to sedentary control, acute (2 weeks), or chronic (6 weeks) treadmill running at moderate intensity (50% maximal aerobic velocity) with different durations of exercise episodes: 2 h/d (endurance training, moderate volume) and 3 h/d (intense training, high volume). Endothelium-dependent vascular function was examined in isolated thoracic aorta. Co-localization and contents of aortic eNOS/iNOS and HO-1/HO-2 were determined with immunofluorescence and Western blotting. Compared with sedentary controls, rats subjected to acute and chronic endurance training showed enhanced endothelium-dependent relaxation (p<0.01). Whereas acetylcholine-induced dilation was inhibited completely by NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) in sedentary controls, the dilation in the training groups was only partly blocked by L-NAME (inhibition was 98+/-3%, 79+/-6%, and 77+/-5% in sedentary control, acute, and chronic training groups, respectively, p<0.01). The remnant dilation in the training groups was further inhibited by HO inhibitor protoporphyrin IX zinc, with concomitant elevation in aortic eNOS as well as HO-1 and HO-2. In contrast to endurance exercise, high-volume intense training resulted in mild hypertension with significant impairment in endothelium-dependent vasodilation and profuse increases in aortic iNOS and eNOS (p<0.01). In conclusion, endothelium-dependent vasodilation is improved by endurance exercise but impaired by chronic intense training. Elevations of vascular eNOS and HO-1/HO-2 may contribute to enhanced vasodilation, which can be offset by intense training and elevation in vascular iNOS.     

Estradiol enhances endothelium-dependent vasodilation via a nitric oxide pathway

BACKGROUND AND AIM: The mechanisms by which estradiol dilates arterial vessels are still unclear. Our aim was to study if estradiol enhances endothelium-dependent vasodilation in an experimental model of human arteries in vitro, and if this effect is nitric oxide mediated. METHODS: Using organ bath chambers, we studied 18 arterial rings obtained from left internal mammary arteries during coronary artery bypass grafting surgery. Response to acetylcholine was evaluated at baseline and after the addition of estradiol 10-6 mol/l to the medium, both in the presence or absence of a nitric oxide synthase inhibitor (L-NNA 10-4 mol/l). RESULTS: Estradiol significantly enhanced the relaxation of the arterial rings in response to acetylcholine (52 +/- 20% after estradiol versus 42 +/- 22% at baseline; n = 10; p = 0.02). However, endothelium-dependent vasodilation relaxation after estradiol addition was not enhanced in the presence of L-NNA (47 +/- 25% after estradiol versus 38 +/- 22% at baseline; n = 8; p = NS). CONCLUSIONS: Estradiol in vitro enhances endothelium-dependent vasodilation of internal human mammary artery rings; this effect is blunted after the addition to the medium of a nitric oxide inhibitor. Therefore, the vasodilator properties of estradiol at the studied dosage depend on the nitric oxide pathway.