【作者】 曹中；

【导师】 王邦宁；

【作者基本信息】 安徽医科大学 ， 内科学， 2010， 硕士

【摘要】 目的研究缬沙坦、螺内酯合用对心力衰竭大鼠细胞因子、胶原的影响,观察二者在心脏方面的协同作用,并通过缬沙坦和螺内酯对细胞因子及其心肌信号转导通路的影响,探讨二者协同作用的可能机制。方法以Sprague-Dawlay大鼠为研究对象,采用腹主动脉缩窄法建立压力负荷心力衰竭大鼠模型。大鼠随机分为5组:正常组、模型组、缬沙坦组(缬沙坦20mg/ (kg·d))、螺内酯组(螺内酯40mg/ (kg·d))和缬沙坦+螺内酯组(缬沙坦20mg/ (kg·d)+螺内酯40mg/ (kg·d)),正常组和模型组予等容积蒸馏水每天灌胃一次。连续给药8周后,采集血液,ELISA法分别检测大鼠血清中白细胞介素6 ( IL-6)、肿瘤坏死因子α( TNF-α)、B型利钠肽(BNP),放免法检测Ⅲ型前胶原氨端肽(PⅢNP)水平。取正常组和模型组大鼠心脏及肺脏组织,通过HE染色,光学显微镜下观察心肺组织的细胞学改变。另外取各组大鼠心肌组织,使用RT-PCR法检测各组心肌组织核因子-κB (NF-κB ) mRNA的表达。结果①光学显微镜下,模型组大鼠心肌和肺组织HE染色显示:肺泡壁毛细血管扩张充血,肺泡壁纤维结缔组织增生显著,肺泡腔内可见少量水肿液,部分炎细胞及红细胞漏出,局部可见含铁血黄素沉着(肺泡壁毛细血管通透性增加),间质小血管扩张、充血;心肌纤维排列紊乱,大部分心肌细胞浊肿变性,心肌细胞呈肥大表现,细胞体积增大,细胞核体积增大、深染,胞浆内可见细颗粒物质,心肌间质可见少量慢性炎细胞浸润,部分心肌纤维溶解。②与模型组比较,缬沙坦组及联合给药组大鼠血清IL-6、TNF-α、BNP、PⅢNP水平均显著下降,螺内酯组大鼠血清TNF-α、BNP、PⅢNP水平均显著下降,而IL-6水平无明显改善。缬沙坦+螺内酯联合给药组与单独给药组比较,对各项指标的抑制作用更加明显。③模型组大鼠心肌组织内NF-κB mRNA表达量明显增加,与正常对照组比较差异具有显著性(P<0.01)。与模型组比较,缬沙坦可显著抑制心力衰竭大鼠心肌组织NF-κB mRNA的表达(P<0.05),且缬沙坦和螺内酯联合给药组具有协同效应(P<0.01)。螺内酯组NF-κB mRNA表达无明显变化。结论①在改善心力衰竭大鼠心功能和心室胶原重构方面,缬沙坦和螺内酯联合使用的作用大于二者单独使用。②缬沙坦联合螺内酯抑制心室胶原重构的机制,可能是通过减少心肌信号转导通路中NF-κB的表达,进而抑制炎症因子TNF-α、IL-6的含量,减少心肌细胞肥大和胶原产生,逆转心肌肥厚,最终改善左室重构和心脏功能。更多还原

【Abstract】 Objective To study the effect of valsartan, spironolactone combination on cardiac remodeling in mice with heart failure synergies and through valsartan and spironolactone on cardiac cell factor and its signal transduction pathway, and to explore the possible mechanism of synergy between the two. Methods Sprague-Dawlay mice were studied by using abdominal coarctation of the aorta was established by pressure overload mouse model of heart failure. Mice were randomly divided into five groups: normal group, model group, valsartan group (valsartan 20mg / (kg·d)), spironolactone (spironolactone 40mg / (kg·d)) and valsartan + spironolactone group (valsartan 20mg / (kg·d) + spironolactone 40mg / (kg·d)), the normal group and model group to equal volume of distilled water gavage once a day. Continuous administmouseion of 8 weeks, collecting blood, ELISA method were used to detect serum interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), B-type natriuretic peptide (BNP), radioimmunoassay ammonia terminal procollagenⅢpeptide (PⅢNP) level. Take the normal group and model group, mouse heart and lung tissues, by HE staining, observed under light microscope the cellular changes in heart and lung tissue. Also take myocardial tissue of mice in each group, using RT-PCR method to detect the myocardial nuclear factor-κB (NF-κB) mRNA expression.Results①optical microscope, model group, cardiac and lung tissue HE staining: capillary dilatation and congestion of alveolar wall, alveolar wall fibrous connective tissue prolifemouseion significantly, a small amount of alveolar edema fluid can be seen, some inflammatory cells and red blood cell leakage, local shows hemosiderosis (alveolar wall increased capillary permeability), interstitial expansion of the small blood vessels, congestive; myocardial fibers disorder, the majority of myocardial cells cloudy swelling degenemouseion, myocardial cells were mast performance, cell volume increases, nuclear volume increases, deep dyeing, the cytoplasm shows fine particulate matter, a small amount of myocardial interstitial chronic inflammatory cell infiltmouseion can be seen, some myocardial fibers dissolved.②Compared with model group, valsartan group and the joint administmouseion of serum IL-6, TNF-α, BNP, PⅢNP were significantly decreased, spironolactone of serum TNF-α, BNP, PⅢNP were significantly decreased , while the IL-6 level was not significantly improved. Valsartan + spironolactone combined dose group and individual treatment group compared to the more pronounced inhibition of the indicators.③model group, mouse heart tissue NF-κB mRNA expression was significantly increased compared with normal control group difference was significant (P <0.01). Compared with model group, valsartan could significantly inhibit myocardial tissue of mice with heart failure NF-κB mRNA expression (P <0.05), and valsartan and spironolactone has a synergistic effect of combined treatment group (P <0.01). Spironolactone group of NF-κB mRNA expression was not changed significantly.Conclusions①heart failure in improving cardiac function and ventricular remodeling in mice, the effect of valsartan and spironolactone on the role of joint use is greater than the two alone.②valsartan combined with spironolactone inhibiting left ventricular remodeling mechanism might be by reducing the myocardial signal transduction pathway in the expression of NF-κB, thus inhibiting inflammatory cytokines TNF-α, IL-6 levels, reducing cardiac myocyte hypertrophy and collagen production reverse ventricular enlargement, myocardial hypertrophy, left ventricular remodeling and ultimately improve cardiac function.更多还原