温肾方对亚临床甲状腺功能减退大鼠模型心脏损害的防治作用机理研究
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摘要
目的：目前对于“是否需要治疗亚临床甲状腺功能减退,该如何治疗?”,仍存在较大争议。中医药以其独特的理论体系应用在亚临床甲状腺功能减退的临床治疗上取得了一定效果。本课题拟以中医古籍理论为基础,结合导师陈如泉教授的临证经验,采用“甲状腺全切术+术后皮下注射L-T4”的方法制备亚临床甲状腺功能减退大鼠模型,观察亚临床甲状腺功能减退对心脏结构及功能的影响,探讨温肾方对亚临床甲状腺功能减退大鼠模型心脏损害的防治作用及其相关作用机制。为中药治疗亚临床甲状腺功能减退提供实验依据,提出用温阳补虚法治疗亚临床甲状腺功能减退的理论。
方法：(1)翻阅古籍经典,结合近现代关于亚临床甲状腺功能减退的临床观察及实验研究成果,从肾阳虚角度立论探讨亚临床甲状腺功能减退的辨治方法。(2)跟师临床,总结导师陈如泉教授辨治亚临床甲状腺功能减退的辩证思路及用药规律。(3)采用“甲状腺全切术+术后皮下注射L-T4”法制备亚临床甲状腺功能减退大鼠模型,设定空白对照组、模型组、中药低剂量组、西药组、中+西药组及中药高剂量组,空白对照组和模型组每日灌服蒸馏水5m1/kg,中药低剂量组每日按中药低剂量组予以温肾方药液,用量为11.25g/kg·d；西药组予以L-T4片混悬液,用量为4.5μg/kg·d;中+西药组予以温肾方药液(11.25g/kg·d)和小量L-T4混悬液(2.25μg/kg·d);中药高剂量组予以温肾方药液(16.88g/kg·d,即中药低剂量组的1.5倍)。共灌胃30天。灌胃期大鼠饲料及饮用水,L-T4针剂处理同前。灌胃期间观察大鼠体重、活动、皮色及大便等情况。第31天处死大鼠,处理方法如下：腹主动脉取血用化学发光法测定血清FT3、FT4及TSH水平,剖胸取心脏组织用ELISA法参照组织T3试剂盒说明测定心肌组织T3水平、甲状腺激素受体表达水平、心肌肌球蛋白重链基因表达、心肌细胞内钙离子浓度及细胞凋亡,观察心肌组织病理形态学变化,同时观察温肾方对其指标的干预情况。
结果：(1)不论先天禀赋还是后天失调,失治误治导致的肾阳亏虚均有可能导致亚临床甲状腺功能减退的发生及发展,提供从肾阳虚角度辨治亚临床甲状腺功能减退的理论依据。
(2)导师陈如泉教授从肾阳虚辨治亚临床甲状腺功能减退,运用温阳补肾药物治疗亚临床甲状腺功能减退也可取得较好疗效。
(3)实验研究发现：与空白对照组比较,各治疗组体重均有增加(P<0.01)；与模型组比较,西药组、中+西药组及中药高剂量组体重增加较多,具有显著意义(P<0.01)；与中药低剂量组比较,西药组及中药高剂量组体重有所增加(P<0.05),中+西药组体重变化则具有显著意义(P<0.01)。各治疗组中FT3及FT4较空白对照组变化无统计学意义(P>0.05)；与模型组比较,各治疗组TSH均有所降低,具有显著意义(P<0.01),与空白对照组比较无统计学意义(P>0.05)。
(4)实验研究发现：与空白对照组比较,模型组心肌组织T。显著降低(P<0.01)；与模型组比较,中药高剂量组心肌组织T3水平显著升高(P<0.05)；中药高剂量组心肌组织T3水平接近于空白对照组(P>0.05)。与空白对照组比较,模型组大鼠心肌组织中甲状腺激素受体亚型Tα1、Tβ1表达显著降低,Tα2表达显著增加,(P<0.01)；与模型组比较,中+西药组大鼠心肌组织中甲状腺激素受体亚型Tα1、Tβ1表达增加(P<0.05)；Tα2表达降低(P<0.05)；中药高剂量组在下调Tα2表达,上调Tβ1表达方面有效(P<0.05)；中+西药组及中药高剂量组心肌甲状腺激素受体Tα、Tβ1表达水平接近于空白对照组(P>0.05),中+西药组在Tα1表达调节上优于中药高剂量组。
(5)实验研究发现：与空白对照组比较,模型组大鼠心肌肌球蛋白重链α-MHCmRNA表达降低(P<0.05),β-MHCmRNA表达显著增加,(P<0.01)；与模型组比较,中+西药组和中药高剂量组在上调大鼠心肌α-MHCmRNA表达,下调大鼠心肌β-MHCmRNA表达方面效果明显(P<0.05)；中+西药组及中药高剂量组心肌α-MHCmRNA、β-MHCmRNA表达水平接近于空白对照组(P>0.05)。
(6)实验研究发现：与空白对照组比较,模型组大鼠心肌羟脯氨酸、胶原蛋白含量降低(P<0.01)；与模型组比较,西药组、中+西药组和中药高剂量组心肌羟脯氨酸、胶原蛋白含量明显增高(P<0.01)；中药高剂量组心肌羟脯氨酸及胶原蛋白水平接近于空白对照组(P>0.05)。大鼠心肌组织在×400放大后,HE染色后显示空白对照组心肌细胞排列整齐,横纹清楚。与空白对照组相比较模型组大鼠心肌细胞排列紊乱,部分细胞肿胀明显；中药低剂量组大鼠心肌细胞病理变化介于二者之间,可见少量肿胀肌细胞；西药组、中+西药组及中药高剂量组大鼠心肌病理变化接近空白对照组。空白对照组大鼠心肌组织在透射电镜下可见细胞核未见明显改变,胞质中胶原纤维排列良好,肌节中各带明显,线粒体不肿胀,肌质网不扩张；模型组大鼠心肌组织中心肌细胞核不规则,染色质边集,胞质中线粒体明显肿胀,线粒体嵴损伤、断裂,形成不规则的增大的间隙,线粒体基质溶解,肌质网肿胀,可见肌节,但肌节中各带不明显；中药低剂量组大鼠心肌组织中细胞核轻度不规则收缩,核周间隙增大,细胞质中肌原纤维未见明显改变,部分线粒体轻度肿胀,嵴间隙增宽,糖原减少或消失,肌质网轻度扩张；西药组、中+西药组及中药高剂量组大鼠心肌组织中细胞核不规则,核周间隙局部增大。胞质中肌原纤维排列良好,肌节尚明显,肌节中各带不明显,线粒体不肿胀,肌质网轻度扩张。
(7)与空白对照组比较,模型组心肌细胞Ca2+浓度显著升高(P<0.01)；与模型组比较,中药高剂量组心肌细胞Ca2+浓度降低(P<0.05)；中药高剂量组心肌细胞Ca2+浓度接近于空白对照组(P>0.05)。大鼠心肌组织切片,染色标记后在×400放大后,模型组可见棕黄色细胞核明显增多,空白对照组偶见,中药低剂量组及西药组颗粒低、中+西药组及中药高剂量组均较少。
结论：肾阳虚是亚临床甲状腺功能减退的病理基础,因此应用温阳补肾药物能够治疗亚临床甲状腺功能减退。从导师陈如泉教授临床辨治亚临床甲状腺功能减退角度进一步证实温阳补肾药物能够治疗亚临床甲状腺功能减退。实验研究证明亚临床甲状腺功能减退引起心肌组织T3水平的降低和甲状腺激素受体基因的异常表达,影响心肌肌球蛋白重链基因表达,改变心肌组织胶原含量及心肌细胞内钙离子浓度,从而影响心肌组织结构及舒缩功能。温肾方能够在一定程度上逆转这些变化,在治疗亚临床甲状腺功能减退的基础上温肾方能能显著改善亚临床甲状腺功能减退模型大鼠的体重、活动等一般状况,还能在不升高血清FT3及FT4的基础上,降低TSH至正常水平,达到其有效治疗亚临床甲状腺功能减退的作用；温肾方能提高心肌组织T3水平,调整大鼠心肌组织中甲状腺激素受体各亚型的表达；逆转心肌肌球蛋白基因的异常表达；能提高心肌胶原蛋白含量,改善心肌细胞病理变化；能减轻心肌细胞钙超载,减少心肌细胞凋亡,从而起到预防心肌损害、保护心脏的作用,为中药治疗亚临床甲状腺功能减退防治并发症提供实验依据,温阳补虚法可能为有效治疗亚临床甲状腺功能减退的方法之一
主题词：亚临床甲状腺功能减退；心肌组织T3；甲状腺激素受体；心肌肌球蛋白；心肌胶原；组织病理；细胞凋亡；温肾方；大鼠
Objective:It is constantly a controversy clinical focus on whether SCH needs therapy and how to treat it.TCM has effects on treating SCH by its special theory. This topic, based on the old thoery of chinese traditional medicine, linked professor Chen's clinical experience, will observe the heart impacts of SCH by experimental SCH rats, resected thyroid tissue and replaced therapy of L-T4. We will reseach the influence and affected principle about wenshenfang, and provide theory evidence for treating SCH and advance the theory of treating SCH by warming Yang Kidney tonifying therapy.
Methods:(1)To find out the treatment of SCH from the Deficiency of Kidney Yang, based on the old theory and the contemporary cl inical experience and the experimental research results.(2) To explore the effective methods and regulations of medicine usage in treating SCH by cl inical analyzing of Professor Chen Who treats them by syndrome differentiation.(3)48experimental SCH wistar rats,made by resected thyroid tissue and replaced therapy of L-T4, were divided into6groups, the blank control group and the model group are fed by distilled water(5ml/Kg)everyday, the group treated by low-dose wenshenfang(11.25g/Kg) everyday, the group treated by high-dose wenshenfang (16.88g/Kg) everyday, the group treated by L-T4(4.5μ g/Kg) everyday and the group treated by L-T4(2.25μg/Kg) and wenshenfang (11.25g/Kg) everyday. The forage, the water and the replaced therapy of L-T4are same as before during the gavage. The rats'weight,activity, coat colour and stool are observed.On31st days morning, the rats are killed for examinations:sampled blood from the abdominal aorta for analysis of serum FT3、FT4and TSH. Take out the hearts and examine T3with ELISA in the light of instruction of T3kit. The gene expression o f thyroid hormone receptor andmyosin heavy chain are examined. The concentration of calcium was assessed and cardiomyocyte apoptosisthe pathomorphological change of heart were researched. The effects on the index of Wenshenfang are observed as well.
Results:(1) Deficiency of Kidney Yang in spite of induced by congenital gift or acquired disorders can lead to the occurrence and development of SCH, the theory can be afforded that the treatment of SCH from the deficiency of Kidney Yang.
(2) Professor Chen has succeeded in treating SCH on the theory of deficiency of Kidney Yang.
(3) It is found that:Compared with the blank control group, the body weight of the other groups is increased; compared with the model group, the body weight of the group treated by L-T4everyday, the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday incresed markedly (P <0.01).The level of the rat's FT3、FT4of each treatment group has not significant changes compared with the blank control group (P>0.05), the level of TSH of each treatment group has reduce markedly (P<0.01), has no significant changes compared with the blank control group (P>0.05)
(4) It is found that:Compared with the blank control group, the T3of myocardial tissue of the model group reduced (P<0.01); compared with the model group, the T3of myocardial tissue of the group treated by high-dose wenshenfang everyday has raised markedly(P<0.05), approximately same as the blank control group's (P>0.05). Thyroid hormone receptor isoforms T α1、T β1gene expression of the model group reduced markedly and Tα2gene expression raised (P<0.01)compared with the blank control group. Compared with the model group, thyroid hormone receptor isoforms Tα1、T β1gene expression of the group treated by L-T4and wenshenfang everyday raised and Tα2gene expression reduced (P <0.05), wenshenfang has effect on reducing Tα2gene expression and raising Tβ1gene expression (P<0.05). The levels of Tα2、 Tβ1gene expression of the group treated by L-T4and wenshenfang and the group treated by high-dose wenshenfang everyday are approximately same as that of the blank control group's (P>0.05).The treatment of L-T4and wenshenfang is better than that of high-dose wenshenfang on reducing Tα1gene expression.
(5) It is found that:Compared with the blank control group, α-MHCmRNA expression reduced (P<0.05), β-MHCmRNA expression raised (P<0.01); compared with the model group, α-MHCmRNA expression of the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday has raised, β-MHCmRNA expression reduced(P<0.05), approximately same as the blank control group's (P>0.05)
(6) It is found that:Compared with the blank control group, the content of myocardial hydroxyproline and collagen reduced (P<0.01); compared with the model group, the content of myocardial hydroxyproline and collagen of the group treated by L-T4everyday, the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday has raised (P<0.01), and the content of the group treated by high-dose wenshenfang everyday approximately same as the blank control group1s (P>0.05)
The rat's myocardial tissue after he-stained enlarged400times through microscope, we inspected that the cardiac muscle cells arrangement is neat, the cell size is homogeneous, the cell muscle striations clearly in the blank control group. The myocardial cells derangement, in the model group, and some cells swell significantly compared with the blank control group. The change of the group treated by low-dose wenshenfang everyday falls in between the two groups mentioned, only several swelling cardiac muscle cells. The cells of the group treated by L-T4everyday, the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday are approximately same as that of the blank control group.
We inspected that the rat's the cardiac muscle cells nuclei of the blank control group had not apparent change through the transmission electron microscope, and cytokinesis in the arrangement of collagen fibers in good, myocardial cells each with apparent sarcomere, mitochondria swollen, sarcoplasmic reticulum without dilatation. The model group rats cardiac tissue muscle nuclei is irregular.Chromatin margination, cytokinesis in markedly swollen mitochondria, the mitochondrial cristae of injury, fracture, forming irregular enlargement of gap, mitochondrial matrix dissolution, sarcoplasmic reticulum swelling, visible sarcomere, but the band are not obvious myotome. The group treated by low-dose wenshenfang everyday in myocardial tissues of rats had mild irregular shrinkage of nucleus, the perinuclear space increases, no obvious changes in the cytoplasm of myof ibrils, part of the mitochondrial mild swelling, crest clearance broadening, glycogen decreased or disappeared, sarcoplasmic reticulum mild dilatation. The group treated by L-T4everyday, the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday in myocardial tissues of rats were with nuclei irregular, perinuclear space locally increasing, cytokinesis in myof ibrillar arrange good, sarcomere is obvious, the band is not obvious myotome, mitochondria swollen, sarcoplasmic reticulum mild dilatation.
(7) Compared with the blank control group,the model group of myocardial cells concentration of Ca2+raised markedly (P<0.01), and that of the group treated by high-dose wenshenfang everyday reduced markedly (P<0.05), approximately same as the blank control group's (P>0.05)
Rat cardiac tissue was cut into slices,after died marker, we inspected through microscope enlarged400times. It was found that the model group showed Brown nuclei increased significantly, the blank control group barely,and the other groups several.
Conclusion:Deficiency of Kidney Yang is pathological basis of SCH. Warming Yang Kidney tonifying therapy is a remedy of SCH. Professor Chen's clinical experience gave another evidence of treating SCH by Warming Yang Kidney tonifying therapy. The present experiments indicate that SCH associated with the reduction of the T3of myocardial tissue, abnormal expression of Thyroid hormone receptor, variation of the content of myocardial collagen, structure and function of myocardium in rats. The TCM of wenshenfang could reverse these changes to a certain degree, affected the growth and activity of experimental rats, regulate thyroid function. The TCM of wenshenfang can increase the T3of myocardial tissue, regulate the expression of thyroid hormone receptor, reverse the abnormal expression of of myosin heavy chain, improve the content of myocardial collagen, amend myocardial tissue pathological, relieve calcium overload, and decrease myocardial apoptosis. So wenshenfang has the effect of protecting myocardium. This topic are expected to afford the theory evidence for treating SCH and advance the theory of treating SCH by warming Yang Kidney tonifying therapy.
方法：(1)翻阅古籍经典,结合近现代关于亚临床甲状腺功能减退的临床观察及实验研究成果,从肾阳虚角度立论探讨亚临床甲状腺功能减退的辨治方法。(2)跟师临床,总结导师陈如泉教授辨治亚临床甲状腺功能减退的辩证思路及用药规律。(3)采用“甲状腺全切术+术后皮下注射L-T4”法制备亚临床甲状腺功能减退大鼠模型,设定空白对照组、模型组、中药低剂量组、西药组、中+西药组及中药高剂量组,空白对照组和模型组每日灌服蒸馏水5m1/kg,中药低剂量组每日按中药低剂量组予以温肾方药液,用量为11.25g/kg·d；西药组予以L-T4片混悬液,用量为4.5μg/kg·d;中+西药组予以温肾方药液(11.25g/kg·d)和小量L-T4混悬液(2.25μg/kg·d);中药高剂量组予以温肾方药液(16.88g/kg·d,即中药低剂量组的1.5倍)。共灌胃30天。灌胃期大鼠饲料及饮用水,L-T4针剂处理同前。灌胃期间观察大鼠体重、活动、皮色及大便等情况。第31天处死大鼠,处理方法如下：腹主动脉取血用化学发光法测定血清FT3、FT4及TSH水平,剖胸取心脏组织用ELISA法参照组织T3试剂盒说明测定心肌组织T3水平、甲状腺激素受体表达水平、心肌肌球蛋白重链基因表达、心肌细胞内钙离子浓度及细胞凋亡,观察心肌组织病理形态学变化,同时观察温肾方对其指标的干预情况。
结果：(1)不论先天禀赋还是后天失调,失治误治导致的肾阳亏虚均有可能导致亚临床甲状腺功能减退的发生及发展,提供从肾阳虚角度辨治亚临床甲状腺功能减退的理论依据。
(2)导师陈如泉教授从肾阳虚辨治亚临床甲状腺功能减退,运用温阳补肾药物治疗亚临床甲状腺功能减退也可取得较好疗效。
(3)实验研究发现：与空白对照组比较,各治疗组体重均有增加(P<0.01)；与模型组比较,西药组、中+西药组及中药高剂量组体重增加较多,具有显著意义(P<0.01)；与中药低剂量组比较,西药组及中药高剂量组体重有所增加(P<0.05),中+西药组体重变化则具有显著意义(P<0.01)。各治疗组中FT3及FT4较空白对照组变化无统计学意义(P>0.05)；与模型组比较,各治疗组TSH均有所降低,具有显著意义(P<0.01),与空白对照组比较无统计学意义(P>0.05)。
(4)实验研究发现：与空白对照组比较,模型组心肌组织T。显著降低(P<0.01)；与模型组比较,中药高剂量组心肌组织T3水平显著升高(P<0.05)；中药高剂量组心肌组织T3水平接近于空白对照组(P>0.05)。与空白对照组比较,模型组大鼠心肌组织中甲状腺激素受体亚型Tα1、Tβ1表达显著降低,Tα2表达显著增加,(P<0.01)；与模型组比较,中+西药组大鼠心肌组织中甲状腺激素受体亚型Tα1、Tβ1表达增加(P<0.05)；Tα2表达降低(P<0.05)；中药高剂量组在下调Tα2表达,上调Tβ1表达方面有效(P<0.05)；中+西药组及中药高剂量组心肌甲状腺激素受体Tα、Tβ1表达水平接近于空白对照组(P>0.05),中+西药组在Tα1表达调节上优于中药高剂量组。
(5)实验研究发现：与空白对照组比较,模型组大鼠心肌肌球蛋白重链α-MHCmRNA表达降低(P<0.05),β-MHCmRNA表达显著增加,(P<0.01)；与模型组比较,中+西药组和中药高剂量组在上调大鼠心肌α-MHCmRNA表达,下调大鼠心肌β-MHCmRNA表达方面效果明显(P<0.05)；中+西药组及中药高剂量组心肌α-MHCmRNA、β-MHCmRNA表达水平接近于空白对照组(P>0.05)。
(6)实验研究发现：与空白对照组比较,模型组大鼠心肌羟脯氨酸、胶原蛋白含量降低(P<0.01)；与模型组比较,西药组、中+西药组和中药高剂量组心肌羟脯氨酸、胶原蛋白含量明显增高(P<0.01)；中药高剂量组心肌羟脯氨酸及胶原蛋白水平接近于空白对照组(P>0.05)。大鼠心肌组织在×400放大后,HE染色后显示空白对照组心肌细胞排列整齐,横纹清楚。与空白对照组相比较模型组大鼠心肌细胞排列紊乱,部分细胞肿胀明显；中药低剂量组大鼠心肌细胞病理变化介于二者之间,可见少量肿胀肌细胞；西药组、中+西药组及中药高剂量组大鼠心肌病理变化接近空白对照组。空白对照组大鼠心肌组织在透射电镜下可见细胞核未见明显改变,胞质中胶原纤维排列良好,肌节中各带明显,线粒体不肿胀,肌质网不扩张；模型组大鼠心肌组织中心肌细胞核不规则,染色质边集,胞质中线粒体明显肿胀,线粒体嵴损伤、断裂,形成不规则的增大的间隙,线粒体基质溶解,肌质网肿胀,可见肌节,但肌节中各带不明显；中药低剂量组大鼠心肌组织中细胞核轻度不规则收缩,核周间隙增大,细胞质中肌原纤维未见明显改变,部分线粒体轻度肿胀,嵴间隙增宽,糖原减少或消失,肌质网轻度扩张；西药组、中+西药组及中药高剂量组大鼠心肌组织中细胞核不规则,核周间隙局部增大。胞质中肌原纤维排列良好,肌节尚明显,肌节中各带不明显,线粒体不肿胀,肌质网轻度扩张。
(7)与空白对照组比较,模型组心肌细胞Ca2+浓度显著升高(P<0.01)；与模型组比较,中药高剂量组心肌细胞Ca2+浓度降低(P<0.05)；中药高剂量组心肌细胞Ca2+浓度接近于空白对照组(P>0.05)。大鼠心肌组织切片,染色标记后在×400放大后,模型组可见棕黄色细胞核明显增多,空白对照组偶见,中药低剂量组及西药组颗粒低、中+西药组及中药高剂量组均较少。
结论：肾阳虚是亚临床甲状腺功能减退的病理基础,因此应用温阳补肾药物能够治疗亚临床甲状腺功能减退。从导师陈如泉教授临床辨治亚临床甲状腺功能减退角度进一步证实温阳补肾药物能够治疗亚临床甲状腺功能减退。实验研究证明亚临床甲状腺功能减退引起心肌组织T3水平的降低和甲状腺激素受体基因的异常表达,影响心肌肌球蛋白重链基因表达,改变心肌组织胶原含量及心肌细胞内钙离子浓度,从而影响心肌组织结构及舒缩功能。温肾方能够在一定程度上逆转这些变化,在治疗亚临床甲状腺功能减退的基础上温肾方能能显著改善亚临床甲状腺功能减退模型大鼠的体重、活动等一般状况,还能在不升高血清FT3及FT4的基础上,降低TSH至正常水平,达到其有效治疗亚临床甲状腺功能减退的作用；温肾方能提高心肌组织T3水平,调整大鼠心肌组织中甲状腺激素受体各亚型的表达；逆转心肌肌球蛋白基因的异常表达；能提高心肌胶原蛋白含量,改善心肌细胞病理变化；能减轻心肌细胞钙超载,减少心肌细胞凋亡,从而起到预防心肌损害、保护心脏的作用,为中药治疗亚临床甲状腺功能减退防治并发症提供实验依据,温阳补虚法可能为有效治疗亚临床甲状腺功能减退的方法之一
主题词：亚临床甲状腺功能减退；心肌组织T3；甲状腺激素受体；心肌肌球蛋白；心肌胶原；组织病理；细胞凋亡；温肾方；大鼠
Objective:It is constantly a controversy clinical focus on whether SCH needs therapy and how to treat it.TCM has effects on treating SCH by its special theory. This topic, based on the old thoery of chinese traditional medicine, linked professor Chen's clinical experience, will observe the heart impacts of SCH by experimental SCH rats, resected thyroid tissue and replaced therapy of L-T4. We will reseach the influence and affected principle about wenshenfang, and provide theory evidence for treating SCH and advance the theory of treating SCH by warming Yang Kidney tonifying therapy.
Methods:(1)To find out the treatment of SCH from the Deficiency of Kidney Yang, based on the old theory and the contemporary cl inical experience and the experimental research results.(2) To explore the effective methods and regulations of medicine usage in treating SCH by cl inical analyzing of Professor Chen Who treats them by syndrome differentiation.(3)48experimental SCH wistar rats,made by resected thyroid tissue and replaced therapy of L-T4, were divided into6groups, the blank control group and the model group are fed by distilled water(5ml/Kg)everyday, the group treated by low-dose wenshenfang(11.25g/Kg) everyday, the group treated by high-dose wenshenfang (16.88g/Kg) everyday, the group treated by L-T4(4.5μ g/Kg) everyday and the group treated by L-T4(2.25μg/Kg) and wenshenfang (11.25g/Kg) everyday. The forage, the water and the replaced therapy of L-T4are same as before during the gavage. The rats'weight,activity, coat colour and stool are observed.On31st days morning, the rats are killed for examinations:sampled blood from the abdominal aorta for analysis of serum FT3、FT4and TSH. Take out the hearts and examine T3with ELISA in the light of instruction of T3kit. The gene expression o f thyroid hormone receptor andmyosin heavy chain are examined. The concentration of calcium was assessed and cardiomyocyte apoptosisthe pathomorphological change of heart were researched. The effects on the index of Wenshenfang are observed as well.
Results:(1) Deficiency of Kidney Yang in spite of induced by congenital gift or acquired disorders can lead to the occurrence and development of SCH, the theory can be afforded that the treatment of SCH from the deficiency of Kidney Yang.
(2) Professor Chen has succeeded in treating SCH on the theory of deficiency of Kidney Yang.
(3) It is found that:Compared with the blank control group, the body weight of the other groups is increased; compared with the model group, the body weight of the group treated by L-T4everyday, the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday incresed markedly (P <0.01).The level of the rat's FT3、FT4of each treatment group has not significant changes compared with the blank control group (P>0.05), the level of TSH of each treatment group has reduce markedly (P<0.01), has no significant changes compared with the blank control group (P>0.05)
(4) It is found that:Compared with the blank control group, the T3of myocardial tissue of the model group reduced (P<0.01); compared with the model group, the T3of myocardial tissue of the group treated by high-dose wenshenfang everyday has raised markedly(P<0.05), approximately same as the blank control group's (P>0.05). Thyroid hormone receptor isoforms T α1、T β1gene expression of the model group reduced markedly and Tα2gene expression raised (P<0.01)compared with the blank control group. Compared with the model group, thyroid hormone receptor isoforms Tα1、T β1gene expression of the group treated by L-T4and wenshenfang everyday raised and Tα2gene expression reduced (P <0.05), wenshenfang has effect on reducing Tα2gene expression and raising Tβ1gene expression (P<0.05). The levels of Tα2、 Tβ1gene expression of the group treated by L-T4and wenshenfang and the group treated by high-dose wenshenfang everyday are approximately same as that of the blank control group's (P>0.05).The treatment of L-T4and wenshenfang is better than that of high-dose wenshenfang on reducing Tα1gene expression.
(5) It is found that:Compared with the blank control group, α-MHCmRNA expression reduced (P<0.05), β-MHCmRNA expression raised (P<0.01); compared with the model group, α-MHCmRNA expression of the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday has raised, β-MHCmRNA expression reduced(P<0.05), approximately same as the blank control group's (P>0.05)
(6) It is found that:Compared with the blank control group, the content of myocardial hydroxyproline and collagen reduced (P<0.01); compared with the model group, the content of myocardial hydroxyproline and collagen of the group treated by L-T4everyday, the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday has raised (P<0.01), and the content of the group treated by high-dose wenshenfang everyday approximately same as the blank control group1s (P>0.05)
The rat's myocardial tissue after he-stained enlarged400times through microscope, we inspected that the cardiac muscle cells arrangement is neat, the cell size is homogeneous, the cell muscle striations clearly in the blank control group. The myocardial cells derangement, in the model group, and some cells swell significantly compared with the blank control group. The change of the group treated by low-dose wenshenfang everyday falls in between the two groups mentioned, only several swelling cardiac muscle cells. The cells of the group treated by L-T4everyday, the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday are approximately same as that of the blank control group.
We inspected that the rat's the cardiac muscle cells nuclei of the blank control group had not apparent change through the transmission electron microscope, and cytokinesis in the arrangement of collagen fibers in good, myocardial cells each with apparent sarcomere, mitochondria swollen, sarcoplasmic reticulum without dilatation. The model group rats cardiac tissue muscle nuclei is irregular.Chromatin margination, cytokinesis in markedly swollen mitochondria, the mitochondrial cristae of injury, fracture, forming irregular enlargement of gap, mitochondrial matrix dissolution, sarcoplasmic reticulum swelling, visible sarcomere, but the band are not obvious myotome. The group treated by low-dose wenshenfang everyday in myocardial tissues of rats had mild irregular shrinkage of nucleus, the perinuclear space increases, no obvious changes in the cytoplasm of myof ibrils, part of the mitochondrial mild swelling, crest clearance broadening, glycogen decreased or disappeared, sarcoplasmic reticulum mild dilatation. The group treated by L-T4everyday, the group treated by L-T4and wenshenfang everyday and the group treated by high-dose wenshenfang everyday in myocardial tissues of rats were with nuclei irregular, perinuclear space locally increasing, cytokinesis in myof ibrillar arrange good, sarcomere is obvious, the band is not obvious myotome, mitochondria swollen, sarcoplasmic reticulum mild dilatation.
(7) Compared with the blank control group,the model group of myocardial cells concentration of Ca2+raised markedly (P<0.01), and that of the group treated by high-dose wenshenfang everyday reduced markedly (P<0.05), approximately same as the blank control group's (P>0.05)
Rat cardiac tissue was cut into slices,after died marker, we inspected through microscope enlarged400times. It was found that the model group showed Brown nuclei increased significantly, the blank control group barely,and the other groups several.
Conclusion:Deficiency of Kidney Yang is pathological basis of SCH. Warming Yang Kidney tonifying therapy is a remedy of SCH. Professor Chen's clinical experience gave another evidence of treating SCH by Warming Yang Kidney tonifying therapy. The present experiments indicate that SCH associated with the reduction of the T3of myocardial tissue, abnormal expression of Thyroid hormone receptor, variation of the content of myocardial collagen, structure and function of myocardium in rats. The TCM of wenshenfang could reverse these changes to a certain degree, affected the growth and activity of experimental rats, regulate thyroid function. The TCM of wenshenfang can increase the T3of myocardial tissue, regulate the expression of thyroid hormone receptor, reverse the abnormal expression of of myosin heavy chain, improve the content of myocardial collagen, amend myocardial tissue pathological, relieve calcium overload, and decrease myocardial apoptosis. So wenshenfang has the effect of protecting myocardium. This topic are expected to afford the theory evidence for treating SCH and advance the theory of treating SCH by warming Yang Kidney tonifying therapy.
引文
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