降糖三黄片对糖尿病大鼠心肌保护作用及对BRADYKININ β1调控机制的影响
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摘要
文献研究
近年来,全球糖尿病心脏病(Diabetic Cardiopathy, DC)发病率增长迅速。心脏病变是DM最严重而突出的问题,约占DM患者死亡原因70%,在近三十年中,特别因为DM造成的心肌影响被广泛的研究。Ledet于1979年首先提出DC的病名,目前在内分泌界得到普遍公认。其包括冠状动脉粥样硬化性心脏病(冠心病)、DM性心肌病、微血管病变和植物神经功能紊乱所致的心率及心功能失常等。DCM首先由Rubler提出。在解剖患有充血性心衰的DM人尸体时提出的,这些死者均无冠状动脉粥样硬化的迹象,病理研究显示左心室肥大并纤维化伴有不同程度的小血管病变。其发病机制至今未能阐明,诸多因素如代谢紊乱、心肌纤维化、小血管病变,胰岛素抵抗、心脏自主神经病变和干细胞改变等都参与了DCM的发生发展。DC治疗防治方法仍以饮食治疗和合适的体育锻炼为基础,视具体情况予药物治疗。目前,人们针对防治DC进行了大量的研究工作,但收效甚为,研究发现血管紧张素转化酶抑制剂(Angiotensin Converting Enzyme Inhibitor,ACEI)、血管紧张素受体拮抗剂(Angiotensin Receptor Blocker, ARB)、缓激肽β1受体阻滞剂、DPP-4I等对DC有一定的防治作用。目前的治疗方式还是以一般心力衰竭指南为主。中药在防治慢性疾病特别是在对DM慢性并发症这种多因素参与的疾病中现有独特的优势。尽管中医古代文献无DC概念,但对DC的认识由来已久,因此从中药开发防治DC的新药将具有非常广阔的前途。
糖尿病心脏病在古代中医学属于“消渴病”并发“心痛”等范畴。其发病多与寒邪内侵、饮食不当、情志失调、年老体虚有关。中医对糖尿病心脏病的病机有不同看法,即为肺脾肾阴虚燥热,不断耗伤气阴,进而涉及于心,或脾气虚弱,痰湿内生,痰气互阻,心脉不通,或肺脉瘀阻、三焦不利、水饮停聚,或阴盛阳微,阴寒内盛及瘀和毒。降糖三黄片是以广州中医药大学熊曼琪教授研究课题组以气阴两虚、瘀血内阻为病机及《伤寒论》之桃核承气汤为底方,所研究成院内制剂的中成药。熊曼琪在《内经》“二阳结,谓之消”理论的指导下,认为胃肠燥热是糖尿病及其并发症的基本病机,提出痰热互结、气阴两虚是糖尿病及其并发症的主要证型。临床上糖尿病并发的心脏病往往在胸痹基础上兼见消渴病胃肠燥热的病机特点,推其病理,乃是消渴病胃肠燥热,易耗津灼液,血运不畅,日久则血疾结于心(心主血脉),属于心胃相关的子病犯母,表现为痰热互结,导致消渴病胸痹的发生。降糖三黄片在临床和实验研究上已取得很好成果,它具有降糖、降脂、改善胰岛素抵抗、保护肾脏、改善心脏功能及肝细胞脂肪变性。
实验研究
研究目的
拟通过降糖三黄片干预糖尿病心脏病大鼠,从免疫学、组织病理学、分子生物学角度,探讨降糖三黄片对糖尿病心脏病的保护作用及对Bradykinin β1调控机制的影响。
研究内容及方法
1.糖尿病大鼠糖代谢：将58只大鼠随机分为正常组10只与造模组(含模型组与给药组)。造模前将所有造模组大鼠禁食但不禁水12小时,造模组按40mg/kg剂量腹腔内注射STZ。1周后,尾缘静脉采血测定空腹血糖。连续两次空腹血糖>11.1mmol/L,且出现多饮、多尿、多食现象,确认为2型糖尿病模型。药物性糖尿病造模成功的大鼠进一步随机分为模型组、降糖三黄片组(高剂量)、降糖三黄片组(低剂量)、二甲双胍组、丹参滴丸组、DPP-4I组,各组8只。继续给予高糖高脂饮食2周。2周后,各治疗组开始给予中药及西药灌胃治疗5周,即为正常组：普通饲料喂养,模型组：高糖高脂饮食,降糖三黄片组(高剂量)：高糖高脂饮食+降糖三黄片(药量按787.5mg/kg/d的剂量),降糖三黄片组(低剂量)：高糖高脂饮食+降糖三黄片(药量按400mg/kg/d的剂量),二甲双胍组：高糖高脂饮食+二甲双胍(药量按照52.5mg/kg/d的剂量),丹参滴丸组：高糖高脂饮食+丹参滴丸(药量按26.25mg/kg/d的剂量),DPP-4I组：高糖高脂饮食+捷诺维(Januvia)(药量按照10.5mg/kg/d的剂量),实验期间,每周监测体重及空腹血糖。
2.S-T波及T波检测：使用垂体后叶素(Pit)注射液1U/kg经下肢静脉注射后成功建立心肌缺血动物模型以Ⅱ导联心电图(Electrocardiography, EKG)(?)记录1、2、5、20、25、30分钟ST波和T波改变。腹主动脉采血,提取含药血清及心脏组织,-70℃冰箱冻存,为分配执行GHbAlc1、NO、CK-MB测定。取心脏组织为行组织病理切片分析及PCR检测Bradykinin β1mRNA表达。
3.大鼠全血GHbAlc测定：血红蛋白中具有酮胺键的GHbAlc在酸性环境中加热,使己糖部分脱水,生成5一羟甲基醛(5-HMF)化合物,后者可与TBA反应呈黄色,然后进行比色定量。
4.大鼠全血NO测定：用双抗体夹心法测定标本中大鼠一氧化氮(N0)水平。用酶标仪在450nm波长下测定OD值,通过标准曲线计算样品中大鼠一氧化氮(N0)浓度。
5.大鼠血清CK-MB测定：用纯化过的抗体包被酶标板,制备固相载体,往包被抗CK-MB抗体的微孔中依次加入样本或标准品、生物素化的抗CK-MB抗体、HRP标记的亲和素,经过彻底洗涤后用底物TMB显色。用酶标仪在450nm波长下测定0D值计算样品浓度。
6.心肌缺血面积检测：心脏组织标本经取材、固定、HE染色、封片,把制作好的HE染色切片置于光学显微镜下计算心肌缺血面积。
7. Bradykinin β1mRNA表达PCR测定法：提取大鼠心脏总RNA,并进行RT-PCR分析Bradykinin β1mRNA表达
实验结果
1.降糖三黄片具能控制体重、降血糖和GHbAlc作用,虽然中西药在实验结束后未能降血糖调至正常值但总体显示中西药均有效干预糖代谢异常。DPP-4I有效地快速降低GHbAlc的作用,降糖三黄片、二甲双胍、丹参滴丸不能快速控制GHbAlc。
2.EKG结果显示,降糖三黄片高和低剂量组及丹参滴丸组均显著降低pit诱导心肌缺血ST段和T波偏移高度至0.2mV,而DPP-4I有效减少T波抬高至0.2mV,与正常组及模型组相比有显著差异(P<0.05),表明各中西药均有保护心肌作用,以降糖三黄片高剂量为优效,其次为丹参滴丸、降糖三黄片低剂量和DPP-4I。
3.正常组N0含量稍比模型组高但两组之间无统计学意义(P>0.05)；降糖三黄片高剂量组N0含量较正常组高,有统计学意义(P<0.05),而丹参滴丸组N0含量与正常组比较有更明显差别(P<0.01)；降糖三黄片低剂量组、二甲双胍组、DPP-4I组N0含量与模型组有显著差别(P<0.05),降糖三黄片高剂量组及丹参滴丸组N0含量较模型组高,之间有统计学意义(P<0.01)。
4.进行心肌缺血造模后之模型组大鼠血CK-MB高于正常组,有统计学意义(P<0.05),各治疗组大鼠血CK-MB浓度与正常组相比无统计学意义(P>0.05)；降糖三黄片高剂量组、丹参滴丸组和DPP-4I组大鼠血CK-MB浓度与模型组相比有统计学意义(P<0.05),降糖三黄片低剂量和二甲双胍组大鼠血CK-MB浓度与模型组相比无统计学意义(P>0.05)。
5.正常组与模型组均出现广泛心肌缺血,且面积大于治疗组,各治疗组均未发现广泛心肌缺血,降糖三黄片高低剂量组心肌缺血区面积与模型组、正常组比较无显著差异(P>0.05),二甲双胍、DPP-4I组心脏心肌缺血区面积与模型组、正常组比较显著降低(P<0.05)。二甲双胍组、DPP-4I组药物对SD大鼠心脏心肌缺血治疗效果最佳。
6.降糖三黄片高剂量组、二甲双胍组、丹参滴丸组、DPP-4I组的Bradykinin β1mRNA表达明显低于模型组(P<0.05)。模型组与正常组、降糖三黄片低剂量组无统计学意义(P>0.05)。模型组与各治疗组与正常组相比无统计学意义(P>0.05)。
结论
1.降糖三黄片控制体重和降血糖,有效干预糖代谢异常,但其未能观察到其降低GHbAlc,可能与观察疗程未达到2个月有关。
2.降糖三黄片具有提升血NO和降低CK-MB含量的作用,减少心肌缺血面积,降低心脏组织中Bradykinin β1基因表达量,说明中药降糖三黄片对心肌要保护作用。
Literature study
In recent years, the global Diabetic Cardiopathy (DC) incidence has grown rapidly. Cardiac pathological changes is DM most serious and prominent problem caused of70%mortality rate for DM patients, therefore in nearly30years, extensive research of impact of myocardial pathological changes caused by DM has been widely conducted. The name of the DC first proposed by Ledet in1979and it has been widely recognized in the world endocrine community, which including arrythmia and cardiac disfunction due to Coronary Atherosclerotic Heart Disease (CHD), Diabetic Cardiomyopathy (DCM), microvascular disease and autonomic dysfunction disorders. The name of DCM was first proposed by Rubler after no signs of coronary atherosclerosis found in the anatomy of the dead bodies of people with diabetes suffer from congestive heart failure, its pathological studies have shown left ventricular hypertrophy and fibrosis with varying degrees of micro vessel pathological changes. Its pathogenesis has so far failed to clarify, but numbers of factors, such as metabolic disorders, myocardial fibrosis, micro vessel pathological changes, insulin resistance, cardiac autonomic neuropathy and stem cells alteration were involved in the development of DCM. DC treatment and prevention methods still based on diet therapy and appropriate sport exercises, combined with drug treatments according to one's condition. Lots of research works deal with the effective drugs for prevention and treatment of DC, such as ACEI, ARB, bradykinin β1receptor blocker, DPP-4I. Current treatment still based on general heart failure treatment guidelines. Chinese medicine has unique advantage in the prevention and treatment of chronic diseases, especially in the chronic complications of DM. Although the concept of DC was not found in the ancient Chinese literature, but the knowledge of DC was exist for a many years, therefore the new drugs exploitation of traditional Chinese medicine for the prevention and treatment of DC has a very promising future.
DC in ancient Chinese medicine belongs to the "Xiao Ke" with "heartache" etc complication. The etiological factors were the invasion of cold pathogen, poor diet, emotional disorders, the aged and weak physical condition. Chinese medicine have different views on the pathogenesis of DC, such as dry hot defficiency yin of the lung-spleen-kidney and the hot constantly consume qi-yin, thus involving the heart; or weak spleen produces endogenous phlegm, thus sputum stagnation and blocked heart pulse; or the pulmonary vein stasis blocked triple burner and adverse water; or excessive Yin defficiency Yang and stasis and poison. Jiang-Tang-San-Huang Tablets (JTSHT) is made by Guangzhou University of Traditional Chinese Medicine Research Group of Professor Xiong Man Qi,based on Tao-He-Cheng-Qi decoction as basic prescription, and qi-yin defficiency and blood statis resistance as Pathogenesis according to Shang-flan theory. According to the statement of two Yang knot caused Xiao in Nei-Jing, Xiong Man Qi considered that gastrointestinal heat is the basic mechanism of DM and its complications the main syndrome of DM and its complication were hot phlegm static and defficiency qi-yin. Gastrointestinal heat as the pathogenesis characteristic of DC often occur in clinic based on the thoracic obstruction manifestation. thus it can be inferred that Xiao Ke gastrointestinal heat may consume and burning body liquid, that caused static blood circulation, finally falling into the blood disease knot in the heart; this mmechanism belongs to the heart and stomach related of child illness offends mother; the manifestations were node heat phlegm leading to the occurrence of DM thoracic obstruction. JTSHT on the clinical and experimental studies have been achieved very good results in reducing blood glucose and lipid, improving insulin resistance, protecting the kidney, improving cardiac function and hepatic steatosis.
Experimental study
Research purposes
Using JTSHT in DC rats treatment derived from immunology, histopatholo gy, molecular biology; to investigate the cardioprotective and Bradykinin β1gene regulatory mechanisms effect of JTSHT in DC rats model.
Methods
1. Glucose metabolism observation in DM rats:58rats were randomly d ivided into normal group of10rats and the DM group (including the model group and treatment group). All model group rats were only food fasted (liquid consumption permitted) for12hours before modeling, the models w ere given40mg/kg dose STZ intraperitoneal injection. Blood fasting glucos e withdrawed from tail vein after1week. Models were verified as type2DM model after twice fasting blood glucose>11.1mmol/L result with polyd ipsia, polyuria, polyphagia phenomenon symptoms. STZ-induced DM models wer e further randomly divided into model group, and treatment group, such as high dose JTSHT group, low dose JTSHT group, metformin group, Danshen Dri pping Pill (DSDW) group, DPP-4I group, with8rats in each group. DM rat s were given high-sugar high-fat diet (HSHFD) for2weeks. After2weeks, each treatment groups was given oral treatment of traditional Chinese me dicine and western medicine for5weeks. Normal group was given normal di et, model group was given high-sugar and high-fat diet, high dose JTSHT g roup was given HSHFD+JTSHT (dossage787.5mg/kg/d), low dose JTSHT grou p was given HSHFD+JTSHT (dossage400mg/kg/d), metformin group was give n HSHFD+metformin (dossage52.5mg/kg/d), DSDW groups wasn given HSHFD+DSDW (dossage26.25mg/kg/d), DPP-4I group was given HSHFD+Januvia (d ossage10.5mg/kg/d) during the experimental period, body weight and fast ing blood sugar were monitored weekly.
2. ST and T wave detection:acute myocardial ischemia models were on structed using pit injection1U/kg through lower limb venous, the ECG reco rding1,2,5,20,25,30minutes II lead ST and T wave changes. Abdominal aor tic blood extraction containing serum, frozen in-70℃refrigerator assi gned to perform GHbAlc, NO, CK-MB determination. Heart tissues were kept for histopathology and PCR detection of Bradykinin β1mRNA expression.
3. Whole blood GHbAlc Determination:hemoglobin has GHbAlc keto amide bond heated in an acidic environment,caused hexose portion dehydration, to form5-hydroxymethyl aldehyde Compound (5-HMF), which can be reacted with TBA yellow, and then carry out a quantitative colorimetric.
4. Whole blood NO determination:NO levels in the specimens was measu red with ELISA method.OD value of the standard curve was measured at450nm wavelength with a microplate reader to calculate NO concentration.
5. Serum CK-MB determination:by using purified antibody-coated micro titer plates to prepare a solid phase carrier, samples, biotinylated anti CK-MB antibody and HRP-labeled pro-biotin were added in turn into micropo rous bound by the anti CK-MB antibody,then washed thoroughly with TMB sub strate color. OD value of the standard curve was measured at450nm wavele ngth with a microplate reader to calculate NO concentration.
6. Detection of myocardial ischemia area:heart tissue samples withdr awning, fixing, HE staining, sealing, placed HE staining sample under an optical microscope to calculate myocardial ischemia area.
7. Bradykinin β1mRNA expression by PCR assays:the extraction of tot al RNA from rat heart and then carry out RT-PCR to analyze the Bradykinin β1mRNA expression.
Results
1. JTSHT is effective in controlling weight gain, reducing blood gluco se and GHbAlc, although chinese and western medicine was unable to suppre ss blood glucose to normal level but whole medicine were effective in abn ormal glucose metabolism intervention. Short term DPP-4I usage were effec tively and rapidly reduced GHbAlc, but JTSHT, metformin, DSDW were unable to controlled GHbAlc.
2. EKG results showed pit induced myocardial ischemia ST and T wave i n high and low dose JTSHT and DSDW group were significantly lower with he ight up to0.2mV, while the DPP-4I effectively reduced the T wave elevati on up to0.2mV, there significant difference (P<0.05) compared with the normal group and model group. This indicates that both Chinese and Wester n medicine has cardioprotective effect,the optimal drug is high dose JTSH T, followed by DSDW, low dose JTSHT and DPP-4I.
3. Normal group NO level was slightly higher than the model group but statistically significance was not found between both groups (P>0.05); th ere was statistically significance between normal and high dose JTSHT gro up(P<0.05)also between DSDW and normal group (P<0.01); NO level of low dose JTSHT, metformin and DPP-4I group compared to model group were signi ficantly different (P<0.05), also between high dose JTSHT, DSDW group and model group (P<0.01).
4. CK-MB level in rats after myocardial ischemia modeling was higher t han the normal group and was statistically significant (P<0.05), CK-MB1evel of whole treatment group was not statistically significant compared to normal group(P>0.05); CK-MB of high dose JTSHT, DSDW and DPP-4I group was statistically significant compared to model group(P<0.05), while CK-MB of low dose JTSHT and metformin group were not statistically significa nt compared to model group (P>0.05).
5. Extensive myocardial ischemia occured in normal group and model gr oup and the area was larger than the treatment groups, no extensive myoca rdial ischemia were found in the treatment groups, high and low dose JTSH T group ischemic area showed no significant difference compared with the model and normal group (P>0.05), myocardial ischemic area metformin, DPP-41group was significantly lower compared with the model and normal grou p (P<0.05). Metformin and DPP-4I are the most effective drug for myocard ial ischemia.
5. The Bradykinin β1mRNA expression of high dose JTSHT, metformin, D SDW and DPP-4I group was significantly lower than the model group (P<0.05). No statistical difference found between model, normal and low dose JTS HT group (P>0.05). The Bradykinin β1mRNA expression of model and whole t reatment group was not statistically significant compared with normal gro up(P>0.05)
Conclusion
1JTSHT is effective in controlling weight gain, reducing blood glucose, and abnormal glucose metabolism intervention, but failed to control GHbAlc, the reason may be due to short term treatment observation, which did not reach2month period.
2JTSHT has cardioprotective effect by elevating NO level, reducing CK-MB level and myocardial ischemia area, significantly supressing the expression cardiac tissue Bradykinin β1mRNA.
近年来,全球糖尿病心脏病(Diabetic Cardiopathy, DC)发病率增长迅速。心脏病变是DM最严重而突出的问题,约占DM患者死亡原因70%,在近三十年中,特别因为DM造成的心肌影响被广泛的研究。Ledet于1979年首先提出DC的病名,目前在内分泌界得到普遍公认。其包括冠状动脉粥样硬化性心脏病(冠心病)、DM性心肌病、微血管病变和植物神经功能紊乱所致的心率及心功能失常等。DCM首先由Rubler提出。在解剖患有充血性心衰的DM人尸体时提出的,这些死者均无冠状动脉粥样硬化的迹象,病理研究显示左心室肥大并纤维化伴有不同程度的小血管病变。其发病机制至今未能阐明,诸多因素如代谢紊乱、心肌纤维化、小血管病变,胰岛素抵抗、心脏自主神经病变和干细胞改变等都参与了DCM的发生发展。DC治疗防治方法仍以饮食治疗和合适的体育锻炼为基础,视具体情况予药物治疗。目前,人们针对防治DC进行了大量的研究工作,但收效甚为,研究发现血管紧张素转化酶抑制剂(Angiotensin Converting Enzyme Inhibitor,ACEI)、血管紧张素受体拮抗剂(Angiotensin Receptor Blocker, ARB)、缓激肽β1受体阻滞剂、DPP-4I等对DC有一定的防治作用。目前的治疗方式还是以一般心力衰竭指南为主。中药在防治慢性疾病特别是在对DM慢性并发症这种多因素参与的疾病中现有独特的优势。尽管中医古代文献无DC概念,但对DC的认识由来已久,因此从中药开发防治DC的新药将具有非常广阔的前途。
糖尿病心脏病在古代中医学属于“消渴病”并发“心痛”等范畴。其发病多与寒邪内侵、饮食不当、情志失调、年老体虚有关。中医对糖尿病心脏病的病机有不同看法,即为肺脾肾阴虚燥热,不断耗伤气阴,进而涉及于心,或脾气虚弱,痰湿内生,痰气互阻,心脉不通,或肺脉瘀阻、三焦不利、水饮停聚,或阴盛阳微,阴寒内盛及瘀和毒。降糖三黄片是以广州中医药大学熊曼琪教授研究课题组以气阴两虚、瘀血内阻为病机及《伤寒论》之桃核承气汤为底方,所研究成院内制剂的中成药。熊曼琪在《内经》“二阳结,谓之消”理论的指导下,认为胃肠燥热是糖尿病及其并发症的基本病机,提出痰热互结、气阴两虚是糖尿病及其并发症的主要证型。临床上糖尿病并发的心脏病往往在胸痹基础上兼见消渴病胃肠燥热的病机特点,推其病理,乃是消渴病胃肠燥热,易耗津灼液,血运不畅,日久则血疾结于心(心主血脉),属于心胃相关的子病犯母,表现为痰热互结,导致消渴病胸痹的发生。降糖三黄片在临床和实验研究上已取得很好成果,它具有降糖、降脂、改善胰岛素抵抗、保护肾脏、改善心脏功能及肝细胞脂肪变性。
实验研究
研究目的
拟通过降糖三黄片干预糖尿病心脏病大鼠,从免疫学、组织病理学、分子生物学角度,探讨降糖三黄片对糖尿病心脏病的保护作用及对Bradykinin β1调控机制的影响。
研究内容及方法
1.糖尿病大鼠糖代谢：将58只大鼠随机分为正常组10只与造模组(含模型组与给药组)。造模前将所有造模组大鼠禁食但不禁水12小时,造模组按40mg/kg剂量腹腔内注射STZ。1周后,尾缘静脉采血测定空腹血糖。连续两次空腹血糖>11.1mmol/L,且出现多饮、多尿、多食现象,确认为2型糖尿病模型。药物性糖尿病造模成功的大鼠进一步随机分为模型组、降糖三黄片组(高剂量)、降糖三黄片组(低剂量)、二甲双胍组、丹参滴丸组、DPP-4I组,各组8只。继续给予高糖高脂饮食2周。2周后,各治疗组开始给予中药及西药灌胃治疗5周,即为正常组：普通饲料喂养,模型组：高糖高脂饮食,降糖三黄片组(高剂量)：高糖高脂饮食+降糖三黄片(药量按787.5mg/kg/d的剂量),降糖三黄片组(低剂量)：高糖高脂饮食+降糖三黄片(药量按400mg/kg/d的剂量),二甲双胍组：高糖高脂饮食+二甲双胍(药量按照52.5mg/kg/d的剂量),丹参滴丸组：高糖高脂饮食+丹参滴丸(药量按26.25mg/kg/d的剂量),DPP-4I组：高糖高脂饮食+捷诺维(Januvia)(药量按照10.5mg/kg/d的剂量),实验期间,每周监测体重及空腹血糖。
2.S-T波及T波检测：使用垂体后叶素(Pit)注射液1U/kg经下肢静脉注射后成功建立心肌缺血动物模型以Ⅱ导联心电图(Electrocardiography, EKG)(?)记录1、2、5、20、25、30分钟ST波和T波改变。腹主动脉采血,提取含药血清及心脏组织,-70℃冰箱冻存,为分配执行GHbAlc1、NO、CK-MB测定。取心脏组织为行组织病理切片分析及PCR检测Bradykinin β1mRNA表达。
3.大鼠全血GHbAlc测定：血红蛋白中具有酮胺键的GHbAlc在酸性环境中加热,使己糖部分脱水,生成5一羟甲基醛(5-HMF)化合物,后者可与TBA反应呈黄色,然后进行比色定量。
4.大鼠全血NO测定：用双抗体夹心法测定标本中大鼠一氧化氮(N0)水平。用酶标仪在450nm波长下测定OD值,通过标准曲线计算样品中大鼠一氧化氮(N0)浓度。
5.大鼠血清CK-MB测定：用纯化过的抗体包被酶标板,制备固相载体,往包被抗CK-MB抗体的微孔中依次加入样本或标准品、生物素化的抗CK-MB抗体、HRP标记的亲和素,经过彻底洗涤后用底物TMB显色。用酶标仪在450nm波长下测定0D值计算样品浓度。
6.心肌缺血面积检测：心脏组织标本经取材、固定、HE染色、封片,把制作好的HE染色切片置于光学显微镜下计算心肌缺血面积。
7. Bradykinin β1mRNA表达PCR测定法：提取大鼠心脏总RNA,并进行RT-PCR分析Bradykinin β1mRNA表达
实验结果
1.降糖三黄片具能控制体重、降血糖和GHbAlc作用,虽然中西药在实验结束后未能降血糖调至正常值但总体显示中西药均有效干预糖代谢异常。DPP-4I有效地快速降低GHbAlc的作用,降糖三黄片、二甲双胍、丹参滴丸不能快速控制GHbAlc。
2.EKG结果显示,降糖三黄片高和低剂量组及丹参滴丸组均显著降低pit诱导心肌缺血ST段和T波偏移高度至0.2mV,而DPP-4I有效减少T波抬高至0.2mV,与正常组及模型组相比有显著差异(P<0.05),表明各中西药均有保护心肌作用,以降糖三黄片高剂量为优效,其次为丹参滴丸、降糖三黄片低剂量和DPP-4I。
3.正常组N0含量稍比模型组高但两组之间无统计学意义(P>0.05)；降糖三黄片高剂量组N0含量较正常组高,有统计学意义(P<0.05),而丹参滴丸组N0含量与正常组比较有更明显差别(P<0.01)；降糖三黄片低剂量组、二甲双胍组、DPP-4I组N0含量与模型组有显著差别(P<0.05),降糖三黄片高剂量组及丹参滴丸组N0含量较模型组高,之间有统计学意义(P<0.01)。
4.进行心肌缺血造模后之模型组大鼠血CK-MB高于正常组,有统计学意义(P<0.05),各治疗组大鼠血CK-MB浓度与正常组相比无统计学意义(P>0.05)；降糖三黄片高剂量组、丹参滴丸组和DPP-4I组大鼠血CK-MB浓度与模型组相比有统计学意义(P<0.05),降糖三黄片低剂量和二甲双胍组大鼠血CK-MB浓度与模型组相比无统计学意义(P>0.05)。
5.正常组与模型组均出现广泛心肌缺血,且面积大于治疗组,各治疗组均未发现广泛心肌缺血,降糖三黄片高低剂量组心肌缺血区面积与模型组、正常组比较无显著差异(P>0.05),二甲双胍、DPP-4I组心脏心肌缺血区面积与模型组、正常组比较显著降低(P<0.05)。二甲双胍组、DPP-4I组药物对SD大鼠心脏心肌缺血治疗效果最佳。
6.降糖三黄片高剂量组、二甲双胍组、丹参滴丸组、DPP-4I组的Bradykinin β1mRNA表达明显低于模型组(P<0.05)。模型组与正常组、降糖三黄片低剂量组无统计学意义(P>0.05)。模型组与各治疗组与正常组相比无统计学意义(P>0.05)。
结论
1.降糖三黄片控制体重和降血糖,有效干预糖代谢异常,但其未能观察到其降低GHbAlc,可能与观察疗程未达到2个月有关。
2.降糖三黄片具有提升血NO和降低CK-MB含量的作用,减少心肌缺血面积,降低心脏组织中Bradykinin β1基因表达量,说明中药降糖三黄片对心肌要保护作用。
Literature study
In recent years, the global Diabetic Cardiopathy (DC) incidence has grown rapidly. Cardiac pathological changes is DM most serious and prominent problem caused of70%mortality rate for DM patients, therefore in nearly30years, extensive research of impact of myocardial pathological changes caused by DM has been widely conducted. The name of the DC first proposed by Ledet in1979and it has been widely recognized in the world endocrine community, which including arrythmia and cardiac disfunction due to Coronary Atherosclerotic Heart Disease (CHD), Diabetic Cardiomyopathy (DCM), microvascular disease and autonomic dysfunction disorders. The name of DCM was first proposed by Rubler after no signs of coronary atherosclerosis found in the anatomy of the dead bodies of people with diabetes suffer from congestive heart failure, its pathological studies have shown left ventricular hypertrophy and fibrosis with varying degrees of micro vessel pathological changes. Its pathogenesis has so far failed to clarify, but numbers of factors, such as metabolic disorders, myocardial fibrosis, micro vessel pathological changes, insulin resistance, cardiac autonomic neuropathy and stem cells alteration were involved in the development of DCM. DC treatment and prevention methods still based on diet therapy and appropriate sport exercises, combined with drug treatments according to one's condition. Lots of research works deal with the effective drugs for prevention and treatment of DC, such as ACEI, ARB, bradykinin β1receptor blocker, DPP-4I. Current treatment still based on general heart failure treatment guidelines. Chinese medicine has unique advantage in the prevention and treatment of chronic diseases, especially in the chronic complications of DM. Although the concept of DC was not found in the ancient Chinese literature, but the knowledge of DC was exist for a many years, therefore the new drugs exploitation of traditional Chinese medicine for the prevention and treatment of DC has a very promising future.
DC in ancient Chinese medicine belongs to the "Xiao Ke" with "heartache" etc complication. The etiological factors were the invasion of cold pathogen, poor diet, emotional disorders, the aged and weak physical condition. Chinese medicine have different views on the pathogenesis of DC, such as dry hot defficiency yin of the lung-spleen-kidney and the hot constantly consume qi-yin, thus involving the heart; or weak spleen produces endogenous phlegm, thus sputum stagnation and blocked heart pulse; or the pulmonary vein stasis blocked triple burner and adverse water; or excessive Yin defficiency Yang and stasis and poison. Jiang-Tang-San-Huang Tablets (JTSHT) is made by Guangzhou University of Traditional Chinese Medicine Research Group of Professor Xiong Man Qi,based on Tao-He-Cheng-Qi decoction as basic prescription, and qi-yin defficiency and blood statis resistance as Pathogenesis according to Shang-flan theory. According to the statement of two Yang knot caused Xiao in Nei-Jing, Xiong Man Qi considered that gastrointestinal heat is the basic mechanism of DM and its complications the main syndrome of DM and its complication were hot phlegm static and defficiency qi-yin. Gastrointestinal heat as the pathogenesis characteristic of DC often occur in clinic based on the thoracic obstruction manifestation. thus it can be inferred that Xiao Ke gastrointestinal heat may consume and burning body liquid, that caused static blood circulation, finally falling into the blood disease knot in the heart; this mmechanism belongs to the heart and stomach related of child illness offends mother; the manifestations were node heat phlegm leading to the occurrence of DM thoracic obstruction. JTSHT on the clinical and experimental studies have been achieved very good results in reducing blood glucose and lipid, improving insulin resistance, protecting the kidney, improving cardiac function and hepatic steatosis.
Experimental study
Research purposes
Using JTSHT in DC rats treatment derived from immunology, histopatholo gy, molecular biology; to investigate the cardioprotective and Bradykinin β1gene regulatory mechanisms effect of JTSHT in DC rats model.
Methods
1. Glucose metabolism observation in DM rats:58rats were randomly d ivided into normal group of10rats and the DM group (including the model group and treatment group). All model group rats were only food fasted (liquid consumption permitted) for12hours before modeling, the models w ere given40mg/kg dose STZ intraperitoneal injection. Blood fasting glucos e withdrawed from tail vein after1week. Models were verified as type2DM model after twice fasting blood glucose>11.1mmol/L result with polyd ipsia, polyuria, polyphagia phenomenon symptoms. STZ-induced DM models wer e further randomly divided into model group, and treatment group, such as high dose JTSHT group, low dose JTSHT group, metformin group, Danshen Dri pping Pill (DSDW) group, DPP-4I group, with8rats in each group. DM rat s were given high-sugar high-fat diet (HSHFD) for2weeks. After2weeks, each treatment groups was given oral treatment of traditional Chinese me dicine and western medicine for5weeks. Normal group was given normal di et, model group was given high-sugar and high-fat diet, high dose JTSHT g roup was given HSHFD+JTSHT (dossage787.5mg/kg/d), low dose JTSHT grou p was given HSHFD+JTSHT (dossage400mg/kg/d), metformin group was give n HSHFD+metformin (dossage52.5mg/kg/d), DSDW groups wasn given HSHFD+DSDW (dossage26.25mg/kg/d), DPP-4I group was given HSHFD+Januvia (d ossage10.5mg/kg/d) during the experimental period, body weight and fast ing blood sugar were monitored weekly.
2. ST and T wave detection:acute myocardial ischemia models were on structed using pit injection1U/kg through lower limb venous, the ECG reco rding1,2,5,20,25,30minutes II lead ST and T wave changes. Abdominal aor tic blood extraction containing serum, frozen in-70℃refrigerator assi gned to perform GHbAlc, NO, CK-MB determination. Heart tissues were kept for histopathology and PCR detection of Bradykinin β1mRNA expression.
3. Whole blood GHbAlc Determination:hemoglobin has GHbAlc keto amide bond heated in an acidic environment,caused hexose portion dehydration, to form5-hydroxymethyl aldehyde Compound (5-HMF), which can be reacted with TBA yellow, and then carry out a quantitative colorimetric.
4. Whole blood NO determination:NO levels in the specimens was measu red with ELISA method.OD value of the standard curve was measured at450nm wavelength with a microplate reader to calculate NO concentration.
5. Serum CK-MB determination:by using purified antibody-coated micro titer plates to prepare a solid phase carrier, samples, biotinylated anti CK-MB antibody and HRP-labeled pro-biotin were added in turn into micropo rous bound by the anti CK-MB antibody,then washed thoroughly with TMB sub strate color. OD value of the standard curve was measured at450nm wavele ngth with a microplate reader to calculate NO concentration.
6. Detection of myocardial ischemia area:heart tissue samples withdr awning, fixing, HE staining, sealing, placed HE staining sample under an optical microscope to calculate myocardial ischemia area.
7. Bradykinin β1mRNA expression by PCR assays:the extraction of tot al RNA from rat heart and then carry out RT-PCR to analyze the Bradykinin β1mRNA expression.
Results
1. JTSHT is effective in controlling weight gain, reducing blood gluco se and GHbAlc, although chinese and western medicine was unable to suppre ss blood glucose to normal level but whole medicine were effective in abn ormal glucose metabolism intervention. Short term DPP-4I usage were effec tively and rapidly reduced GHbAlc, but JTSHT, metformin, DSDW were unable to controlled GHbAlc.
2. EKG results showed pit induced myocardial ischemia ST and T wave i n high and low dose JTSHT and DSDW group were significantly lower with he ight up to0.2mV, while the DPP-4I effectively reduced the T wave elevati on up to0.2mV, there significant difference (P<0.05) compared with the normal group and model group. This indicates that both Chinese and Wester n medicine has cardioprotective effect,the optimal drug is high dose JTSH T, followed by DSDW, low dose JTSHT and DPP-4I.
3. Normal group NO level was slightly higher than the model group but statistically significance was not found between both groups (P>0.05); th ere was statistically significance between normal and high dose JTSHT gro up(P<0.05)also between DSDW and normal group (P<0.01); NO level of low dose JTSHT, metformin and DPP-4I group compared to model group were signi ficantly different (P<0.05), also between high dose JTSHT, DSDW group and model group (P<0.01).
4. CK-MB level in rats after myocardial ischemia modeling was higher t han the normal group and was statistically significant (P<0.05), CK-MB1evel of whole treatment group was not statistically significant compared to normal group(P>0.05); CK-MB of high dose JTSHT, DSDW and DPP-4I group was statistically significant compared to model group(P<0.05), while CK-MB of low dose JTSHT and metformin group were not statistically significa nt compared to model group (P>0.05).
5. Extensive myocardial ischemia occured in normal group and model gr oup and the area was larger than the treatment groups, no extensive myoca rdial ischemia were found in the treatment groups, high and low dose JTSH T group ischemic area showed no significant difference compared with the model and normal group (P>0.05), myocardial ischemic area metformin, DPP-41group was significantly lower compared with the model and normal grou p (P<0.05). Metformin and DPP-4I are the most effective drug for myocard ial ischemia.
5. The Bradykinin β1mRNA expression of high dose JTSHT, metformin, D SDW and DPP-4I group was significantly lower than the model group (P<0.05). No statistical difference found between model, normal and low dose JTS HT group (P>0.05). The Bradykinin β1mRNA expression of model and whole t reatment group was not statistically significant compared with normal gro up(P>0.05)
Conclusion
1JTSHT is effective in controlling weight gain, reducing blood glucose, and abnormal glucose metabolism intervention, but failed to control GHbAlc, the reason may be due to short term treatment observation, which did not reach2month period.
2JTSHT has cardioprotective effect by elevating NO level, reducing CK-MB level and myocardial ischemia area, significantly supressing the expression cardiac tissue Bradykinin β1mRNA.
引文
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