氨基胍对糖尿病大鼠心脏功能及心肌超微结构的影响

目的 :探讨非酶糖化抑制剂 氨基胍 (amin oguanidine ,AG)对链尿佐菌素 (streptozotocin ,STZ)糖尿病大鼠心肌的保护作用 ,为糖尿病心肌病的防治提供参考。方法 :建立STZ糖尿病大鼠模型 ,随机分为对照组、糖尿病组和氨基胍治疗组 ,AG剂量为15 0mg·kg-1·d-1。 12周时测定大鼠血清果糖胺含量、心脏重量指数、左室内压最大上升和下降率 (±dp dtmax)值 ,电镜观察心肌超微结构 ,测量心肌毛细血管基底膜厚度。结果 :糖尿病组大鼠血清果糖胺含量、心脏重量指数明显增高 ,±dp dtmax降低 ;超微结构显示心肌肌原纤维排列紊乱 ,线粒体肿胀变性 ,间质胶原增生 ,微血管内皮细胞肿胀、基底膜明显增厚。氨基胍治疗组血清果糖胺含量降低、心脏重量指数明显下降、±dp dtmax 值上升 ,微血管基底膜增厚减轻 ,间质胶原减少 ,心肌细胞超微结构异常减轻。结论 :糖尿病时存在心脏功能异常、心肌肥厚和超微结构的改变 ,早期应用AG在一定程度上可阻抑糖尿病心肌病变的发展。     

黄芪降低糖尿病大鼠心肌黏附分子表达并保护心肌细胞超微结构

目的观察黄芪对糖尿病大鼠心肌细胞间黏附分子(ICAM)-1、血管黏附分子(VCAM)-1表达的影响。方法链脲佐菌素(STZ)诱导糖尿病大鼠模型。实验分正常对照组(n=8)、糖尿病对照组(n=11)、黄芪组(n=11,4.2g·kg-1·d-1),用药8周。测血糖、体重、糖化血红蛋白(HbA1c)、心脏重量;透射电镜观察心肌细胞超微结构变化;免疫组织化学检测心肌ICAM-1、VCAM-1表达,图像分析软件对其结果进行半定量分析。结果糖尿病组心重指数明显高于正常组(P<0.05);与糖尿病组比较,黄芪组心重指数下降(P<0.05)。正常组大鼠心肌细胞器完好;糖尿病组心肌细胞内线粒体水肿、肌原纤维溶解、肌浆网扩张、肌纤维间水肿等变化;黄芪组大鼠心肌细胞肌原纤维排列整齐,肌节较完整,线粒体量多,偶见肌原纤维断裂及线粒体肿胀。免疫组织化学显示:与正常组比较,糖尿病组心肌ICAM-1、VCAM-1强着色(P<0.05),胞质均呈棕黄色颗粒强,心肌组织间微动脉壁、毛细血管基底膜有棕黄色物质沉积;而黄芪组呈中等度染色,毛细血管基底膜着色,ICAM-1、VCAM-1表达明显下降(P<0.05)。结论黄芪降低糖尿病大鼠心肌ICAM-1、VCAM-1表达,同时保护糖尿病心肌细胞超微结构。     

链脲佐菌素糖尿病大鼠心肌超微结构观察

目的观察1周、4周、8周和12周链脲佐菌素(STZ)糖尿病大鼠心肌超微结构的动态变化。方法制备STZ糖尿病大鼠模型,分别于1周、4周、8周和12周,取左室心肌组织行透射电镜观察。结果病程1周时心肌肌原纤维疏松水肿,部分区域线粒体肿胀,形状不规则。4周时心肌肌原纤维间隙增宽。线粒体肿胀,数量增多。偶见粗细肌丝排列紊乱,闰盘间隙周围水肿。间质毛细血管内皮增生。8周时肌原纤维灶性溶解,肌丝排列稀疏,肌浆网扩张。线粒体大小不一,嵴减少或消失,甚至空泡变性。间质中毛细血管内皮细胞突向管腔。12周时肌原纤维呈大片状溶解,肌小节失去正常结构。线粒体断嵴、空泡变性现象更明显。间质纤维增多,糖原颗粒及脂滴沉积。结论糖尿病在心肌病变的发病机制中有重要作用。     

转化生长因子β_1在糖尿病心肌病变中作用的研究

目的:观察链脲佐菌素(STZ)诱导的1型糖尿病(T1DM)大鼠体内血清和心肌局部转化生长因子β1(TGFβ1)在糖尿病心肌病变发生发展病程中含量的变化和心肌结构的改变,探讨TGFβ1在糖尿病心肌病变中的作用。方法:采用双抗体夹心ELISA法进行血清TGFβ1测定,用免疫组织化学测定心肌TGFβ1的变化,光镜下观察心肌细胞形态学改变,电镜下观察心肌线粒体的超微结构变化及毛细血管基底膜的改变。结果:糖尿病大鼠较正常大鼠血清和心肌组织中TGFβ1含量增加(P<0.01),且随着病程的进展而升高;光镜下可见心肌细胞肿胀,排列紊乱;电镜下可见心肌细胞线粒体肿胀,毛细血管内皮细胞基底膜增厚。结论:糖尿病大鼠TGFβ1浓度变化趋势与心肌病变程度相一致,其浓度变化可反映T1DM心肌病的病变程度,在T1DM心肌病变中起促进作用。     

银杏叶提取物对糖尿病大鼠心肌线粒体呼吸控制率的影响

目的观察银杏叶提取物(EGb)对糖尿病大鼠心肌线粒体呼吸控制率的影响。方法30只SD大鼠随机分为正常对照组、糖尿病组和银杏叶治疗组,观察各组大鼠心肌线粒体超微结构,心肌线粒体呼吸控制率的变化。结果糖尿病大鼠心肌线粒体主要表现为肿胀,嵴变短,空泡化;呼吸控制率3态呼吸降低,呼吸控制率降低。银杏叶治疗组病变较糖尿病组明显减轻,治疗组心肌线粒体呼吸控制率3态呼吸及呼吸控制率与正常对照组无明显差异。结论EGb能提高心肌线粒体的呼吸控制率,从而对糖尿病大鼠心肌起保护作用。     

蜂胶总黄酮对大鼠心肌缺血-再灌注损伤诱导细胞凋亡的影响

目的研究蜂胶总黄酮对大鼠心肌缺血-再灌注损伤诱导细胞凋亡的影响。方法用TUNEL、流式细胞技术及电镜观察细胞超微结构研究细胞凋亡。结果TUNEL结果表明:蜂胶总黄酮对大鼠心肌缺血-再灌注损伤诱导细胞凋亡有改善作用。流式细胞仪检测:根据PI法流式细胞技术检测二倍体亚峰分析,蜂胶总黄酮对细胞凋亡亦有明显改善。电镜观察:假手术组心肌细胞超微结构未见明显异常;模型组心肌细胞可见线粒体肿胀,线粒体嵴不同程度溶解破坏,遗留较多空泡,核染色质边集,核皱缩,核膜表面凹凸不平等形态学改变,但未见到典型的凋亡小体,蜂胶总黄酮组心肌线粒体排列尚规整,线粒体嵴无明显破坏,肌丝排列整齐,无明显破坏。结论蜂胶总黄酮对大鼠心肌缺血-再灌注损伤诱导细胞凋亡具有改善作用。     

不同ACEI类药物对糖尿病大鼠心肌间质纤维化的影响

目的通过研究卡托普利、贝那普利、福辛普利对糖尿病大鼠心肌转化生长因子β1（TGF—β1）及基质金属蛋白酶（MMPs）的影响,探讨这3种药物对糖尿病大鼠心肌的抗纤维化作用。方法50只SD大鼠分为10只正常组,40只糖尿病组,糖尿病组链脲佐菌素注射建模。建模成功后将成功的糖尿病鼠（37只,未成功2只,死亡1只）随机分糖尿病组（n=9）、卡托普利治疗组（n=9）、贝拉普利治疗组（n=9）、福辛普利治疗组（n=10）,免疫组化法测Ⅰ、Ⅲ型胶原的表达,TGF-β1、基质金属蛋白酶特异性抑制物（TIMP—1）和MMP-1蛋白的表达。RT—PCR法测TIMP-1和MMP-1 mRNA的表达。结果糖尿病组心脏指数心室指数显著大于正常组（P〈0．05）,Ⅰ、Ⅲ型胶原的表达也增加（P〈0．05）,存在着心肌间质纤维化,胶原Ⅰ、胶原Ⅲ、TGF—β1、TIMP-1蛋白及TIMP-1 mRNA的表达增高（P〈0．05）,MMP—1蛋白及mRNA的表达减少（P〈0．05）。经过卡托普利、福辛普利、贝那普利后,上述各异常指标均有所改善。结论3组药物通过对TGF-β1和MMPs的影响可明显改善糖尿病心肌间质纤维化。卡托普利的疗效比贝那普利与福辛普利稍差,贝那普利与福辛普利之间无差异。     

TNF-α在糖尿病心肌病变中的表达

目的:观察链脲佐菌素(STZ)糖尿病大鼠肿瘤坏死因子-α(TNF-α)在血清、心肌组织中的表达水平及心肌细胞结构改变,探讨TNF-α在糖尿病心肌病变发生、发展中的作用。方法:建立糖尿病大鼠模型(实验组),分别于6周、10周、14周,在光镜、电镜下观察心肌结构,酶联免疫吸附法(ELISA)测定血清TNF-α水平,免疫组化方法检测心肌组织TNF-α表达,并与对照组对比。结果:TNF-α在实验组较对照组表达增加(P<0.01),并随病程进展增加。光镜、电镜下可见糖尿病心肌细胞肿胀、肌丝稀疏,线粒体肿胀、破裂。结论:TNF-α在糖尿病大鼠心肌中表达增强,促进糖尿病心肌病变进展。     

福辛普利联用金水宝治疗早期2型糖尿病肾病临床观察

目的:探讨福辛普利联用金水宝对早期2型糖尿病肾病微量白蛋白尿的影响。方法:68例早期2型糖尿病肾病患者随机分为两组,联合用药组35例,福辛普利组33例。联合用药组给予福辛普利联用金水宝,福辛普利组给予福辛普利,用药6周,测定患者治疗前后24 h尿微量白蛋白排泄率(UAE)及内生肌酐清除率(CCr)。结果:联合用药组降低UAE总有效率94.3%,明显优于福辛普利组的60.6%(P<0.05)。联合用药组的CCr明显低于福辛普利组(P<0.01)。结论:福辛普利与金水宝联合治疗早期糖尿病肾病,可降低尿微量白蛋白和内生肌酐清除率,延缓糖尿病肾病发展,效果显著。     

2型糖尿病大鼠心肌细胞超微结构改变及灵芝孢子的干预

目的:探讨2型糖尿病大鼠心肌细胞超微结构的改变情况及灵芝孢子对其改变的影响。方法:选Wistar大鼠50只,随机分3组(正常对照组,模型组,灵芝孢子组)。模型组及灵芝孢子组用链脲佐菌素(STZ)诱导成糖尿病大鼠动物模型,成功者改喂高脂高糖饮食,灵芝孢子组另加喂灵芝孢子粉(250m g.kg/d)持续10周。实验结束前一天做糖耐量试验,断头取血,用透射电镜观察糖尿病大鼠心肌细胞病理变化。结果:模型组肌原纤维边界不清,排列乱,有融解消失,线粒体肿胀变性,数目多,微血管内皮细胞肿胀,管腔窄;灵芝孢子组电镜下病变明显减轻。结论:灵芝孢子可以抑制糖尿病性心肌病时心肌细胞超微结构的改变,对心肌具有保护作用。     

福辛普利与氯沙坦对实验性糖尿病大鼠肾病的防治作用与转化生长因子β_1的关系

目的探讨转化生长因子β1(TGFβ1)与糖尿病肾病之间的关系及血管紧张素转换酶抑制剂福辛普利和血管紧张素Ⅱ受体拮抗剂氯沙坦对肾小球病变的保护作用与机制。方法建立糖尿病大鼠模型,分为正常对照(A组)、糖尿病组(B组)、福辛普利治疗组(C组)、氯沙坦治疗组(D组),检测第1、2、4、12周血糖、24h尿TGFβ1排泄率以及Alb排泄率。于第4周、第12周处死大鼠获取肾,计算肾脏肥大指数,分离皮髓质,检测肾皮质TGFβ1蛋白水平及皮质TGFβ1mRNA水平。结果①尿Alb排泄率与尿TGFβ1排泄率:各实验组尿Alb排泄率与尿TGFβ1排泄率随病程延长进一步增加,二种药物治疗均可使尿Alb排泄率与尿TGFβ1排泄率明显减少,但不能使其恢复正常。②免疫组化结果显示各实验组大鼠肾皮质TGFβ1蛋白含量较对照组显著增加,随病程延长增加更加明显,二种药物治疗组大鼠肾皮质TGFβ1蛋白含量较B组明显减少。③各时期肾皮质TGFβ1mRNA的表达量B组最高,C、D组大鼠肾皮质TGFβ1蛋白含量较B组明显减少,早期以C组减少更为明显。肾皮质TGFβ1mRNA的表达量与尿TGFβ1排泄率呈正相关。结论肾脏TGFβ1mRNA及其蛋白表达的上调可能是糖尿病肾病的发生机制之一,尿TGFβ1排泄率可以作为诊断早期糖尿病肾病和评价病变程度的标志物之一。福辛普利、氯沙坦具有确切肾脏保护作用,且福辛普利早期作用较氯沙坦更为明显。这种作用部分与其抑制肾脏TGFβ1过度表达有关。     

福辛普利对去窦弓神经大鼠器官损伤的保护作用

目的研究血压波动性在福辛普利治疗去窦弓神经大鼠器官保护中的重要作用。方法在去窦弓神经(SAD)大鼠饲料中给予福辛普利15 mg·kg^-1·d^-1（根据体重和每日消耗的饲料总量计算，每周调整1次），16周后在清醒状态下记录24　h血压波动性，用光镜和计算机图象分析技术观察心脏、肾脏和胸主动脉的组织病理学改变。结果与SAD大鼠相比，福辛普利治疗组大鼠的血压波动性明显降低，左心室壁厚、肾小球硬化积分、心肌胶原容积分数与血压波动性呈正相关，福辛普利可明显减轻去窦弓神经大鼠引起的器官损伤。结论福辛普利长期治疗可有效减轻去窦弓神经大鼠的器官损伤。降低血压波动性在福辛普利的器官保护中可能具有重要的作用。     

The influence of sulindac on diabetic cardiomyopathy: a non-invasive evaluation by Doppler echocardiography in streptozotocin-induced diabetic rats

The aim of the present study was to investigate the cardioprotective activity of sulindac as an aldose reductase inhibitor in the development of cardiomyopathy by non-invasive techniques; M-mode and Doppler echocardiography. Diabetes was induced by streptozotocin (45 mg/kg, iv) in the Sprague-Dawley rats. Echocardiography, biochemical and histological studies were carried out in normal control, diabetic untreated, diabetic vehicle (sodium carboxy methyl cellulose, 1%, po) and sulindac (6 mg/kg and 20 mg/kg, po) treated animals at varying time intervals. In the diabetic untreated and vehicle treated rats at 12 weeks after induction of diabetes, there was a significant decrease in the E-wave, an increase in the A-wave and corresponding decrease in the E/A ratio was observed. Significant decrease in the Eat was found after 12 weeks (P < 0.05). Whereas systolic function variables; ejection fraction and fractional shortening were significantly decreased (P < 0.05) after 12 weeks compared to their baseline data. In the sulindac treated animals, there were no significant alterations in the systolic and diastolic parameters were found throughout the study period. Myocardial fructose levels were significantly increased in the diabetic untreated animals compared to normal control rats (P < 0.05), whereas these were significantly decreased in the sulindac (6 mg/kg and 20 mg/kg) treated animals (301.11+/-37.98, 214.11+/-25.31, vs. 914.88+/-56.01 nmol/g) compared to diabetic vehicle treated group (P < 0.05). Extensive focal ischemic myocyte degeneration was observed in the diabetic untreated and vehicle treated rats, whereas in the sulindac (6 mg/kg) treated rats, minimal necrosis was found, with no evidence of necrosis in sulindac (20 mg/kg) group. Our results show for the first time that sulindac has a cardioprotective activity as this agent prevented the development of left ventricular dysfunction in STZ-induced diabetic rats in the 12-week chronic study.     

Effects of probucol on impaired cardiac performance and lipid metabolism in streptozotocin-induced diabetic rats.

Plasma lipids and cardiac performance were studied in diabetic rats treated with probucol. Male Wistar rats were rendered diabetic with a single intraperitoneal injection of streptozotocin (STZ, 75 mg/kg). Nondiabetic control rats received the vehicle alone. Two weeks after STZ or vehicle injection, control and diabetic rats were randomly assigned to probucol-treated or untreated groups. The rats in the two probucol-treated groups (control- and diabetic-probucol groups) were fed a diet containing 1% probucol (w/w) for 4 weeks. Blood was drawn, and then cardiac performance was assessed by the isolated perfused working heart technique. Probucol treatment had no effect on the cardiac performance of the nondiabetic control rats. The peak left ventricular developed pressure and maximum rate of change in left ventricular pressure during systole were significantly greater in the probucol-treated diabetic rats than in the untreated diabetic rats (p less than 0.05), although cardiac performance did not improve to the level in the nondiabetic rats. Plasma cholesterol, free fatty acid, and phospholipid were significantly elevated in the untreated diabetic rats, and probucol treatment decreased significantly the plasma cholesterol and free fatty acid concentrations (p less than 0.05). These data suggest that probucol treatment improves plasma lipids and cardiac performance in rats with experimental diabetes and may prevent diabetic cardiomyopathy.     

福辛普利对去窦弓神经大鼠肠系膜阻力血管结构改变的影响

目的:研究血管紧张素转换酶(ACE)抑制药福辛普利对去窦弓神经(SAD)大鼠肠系膜阻力血管结构改变的逆转作用。方 法:大鼠行SAD术后随机分为SAD组、福辛普利治疗组,另设假手术对照组,给药和(或)饲养16wk后处死大鼠,取肠系膜动脉二 级分枝,应用光镜和计算机图像分析技术观察组织病理学改变。结果:与SAD组大鼠相比,福辛普利治疗组大鼠肠系膜阻力血管的 壁厚、壁厚／内径比率、壁面积、平滑肌细胞核数／视野明显减小,而平滑肌相对面积比未发生显著改变。结论:福辛普利可明显抑制 SAD大鼠肠系膜阻力血管的结构改变。     

有机铬对实验性糖尿病大鼠胰腺保护作用的观察

目的：观察有机铬对实验性糖尿病大鼠胰腺的保护作用。方法：用灌胃的方式增加糖尿病大鼠体内的有机铬含量,观察灌胃12周后糖尿病大鼠的血糖浓度、血清胰岛素浓度及胰腺的病理改变。并与正常大鼠及未治疗组大鼠加以比较。结果：治疗组大鼠血糖浓度及血清胰岛素浓度与未治疗组相比具有明显差异。胰腺组织结构改善明显。结论：有机铬能保护糖尿病鼠胰腺组织．增加血清胰岛素,降低血糖。     

Pioglitazone improves left ventricular diastolic function and decreases collagen accumulation in prediabetic stage of a type II diabetic rat.

This study investigated the effect of pioglitazone, an insulin sensitizer, on metabolic abnormalities and oxidative stress as a cause of myocardial collagen accumulation in prediabetic rat hearts. Twenty male diabetic rats and 9 male nondiabetic age-matched rats were used. The diabetic rats were divided into two groups: diabetic treated and untreated. Pioglitazone was mixed in rat chow fed to the diabetic treated group (0.01%). Treatment duration was 5 weeks. At baseline (15 weeks) and 20 weeks of age, blood glucose, lipid, insulin, and plasma malondialdehyde-thiobarbituric acid (MDA) levels were measured and Doppler echocardiography was tracked. At 20 weeks of age, left ventricular collagen content was studied. Blood glucose, plasma insulin, and triglyceride levels in the diabetic treated group were significantly lower than those in the untreated diabetic group. Deceleration time (ms) of early diastolic inflow in the treated diabetic group decreased significantly compared with the untreated diabetic group (65 +/- 8 vs. 77 +/- 8, p < 0.01). Ratio of left ventricular weight to body weight (mg/g) and ratio of left ventricular collagen content to dry weight (mg/100 mg) were decreased in the treated diabetic group (1.5 +/- 0.1, 1.3 +/- 0.3) compared with the untreated diabetic group (1.7 +/- 0.2, p < 0.01; 1.7 +/- 0.3, p < 0.05). Plasma MDA concentration (nmol/ml) significantly decreased (2.9 +/- 0.3 at baseline to 2.3 +/- 0.3 at 20 weeks, p = 0.001) in the treated diabetic group, and was lower than that in the untreated diabetic group (3.2 +/- 0.7 at 20 weeks, p < 0.05). Pioglitazone improved glucose and lipid metabolism and reduced oxidative stress in the left ventricle, which decreased left ventricular collagen accumulation and improved left ventricular diastolic function of prediabetic rat hearts.     

The effects of the sulfonylurea glyburide on glutathione peroxidase, superoxide dismutase and catalase activities in the heart tissue of streptozotocin-induced diabetic rat

Oxygen free radicals have been suggested to be a contributory factor in diabetes complications. The aim of this study was to examine the effects of glyburide on the antioxidant enzyme activities in the heart tissue of diabetic rats. We investigated the activities of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) in the hearts of both control and streptozotocin-induced diabetic rats. In the heart of diabetic rats, the activity of total superoxide dismutase decreased significantly (p < 0.005), whereas the activity of catalase and glutathione peroxidase increased to a large extent (p < 0.0001 and p = 0.05, respectively) at the end of the fourth week compared with the control group. Glyburide treatment of diabetic rats for 4 weeks corrected the changes observed in diabetic heart. In addition, blood glucose levels of untreated diabetic rats decreased following the glyburide treatment. These results demonstrate that the sulfonylurea glyburide is capable of exerting direct insulin-like effect on heart superoxide dismutase, catalase and glutathione peroxidase activities of diabetic rats in vivo.