养心通脉方对异丙肾上腺素心衰大鼠防治机理的研究
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摘要
目的：(1)从维持内皮素(ET)/中介素(IMD)平衡的内源性细胞保护机制方面研究阻断神经内分泌因子过度激活的药物作用新靶点,为临床开发有效治疗心力衰竭(HF)的新药提供新思路；(2)观察养心通脉方对异丙肾上腺素(ISO)诱导HF大鼠心肌重构的防治作用及内源性细胞保护机制,为开发具有地方民族特色的,有效治疗HF的中药新药提供科学的实验依据。
方法：用1%的戊巴比妥钠20～25mg/kg给予大鼠腹腔注射麻醉,然后皮下注射ISO,170mg·kg-1,分2次,每次间隔24h,制备心力衰竭模型,心肌组织病理切片观察心肌损伤；采用左心室和股动脉插管法及四道生理记录仪记录平均动脉血压(MABP)、左室收缩压(LVSP)、左室舒张末压(LVEDP)、左室最大压力上升及心室内压的变化率(±dp/dt)和心电图；生物化学法检测血浆和心肌组织超氧化物歧化酶(SOD)和丙二醛(MDA)及血浆乳酸脱氢酶(LDH)；酶联免疫吸附法检测血浆和心肌组织中介素(IMD)和内皮素(ET)含量测定；采用生物化学方法测定组织Na+-K+-ATPase活性；采用免疫印迹法检测凋亡蛋白B细胞淋巴瘤(Bcl-2),Bcl-2相关X蛋白(Bax)和心肌蛋白激酶B(Akt)蛋白表达。
结果：
(1)与正常对照组相比,模型组大鼠的左室收缩压降低18.4%,舒张末压升高604.5%(P<0.01),平均动脉血压降低32.7%,心室内压升高最大变化速率和心室内压降低最大变化速率分别降低70%和143.5%(P<0.01)；养心通脉方低剂量组大鼠的左室收缩压没有显著变化,平均动脉血压降低16.8%,心室舒张末压升高200.5%(P<0.01),心室内压升高最大变化速率和心室内压降低最大变化速率分别降低25%和55.7%；养心通脉方高剂量组大鼠的平均动脉血压、左室收缩压、心室内压升高最大变化速率没有显著变化,心室舒张末压升高100%(P<0.01),心室内压降低最大变化速率降低18.6%。与模型组比较,养心通脉方低剂量组大鼠平均动脉血压和左室收缩压没有显著变化,心室舒张末压降低98.6%,心室内压升高最大变化速率和心室内压降低最大变化速率分别增加33.3%和56.3%(P<0.01)；养心通脉方高剂量组大鼠平均动脉血压和左室收缩压没有显著的变化,心室舒张末压降低148.6%,心室内压升高最大变化速率和心室内压降低最大变化速率分别增加62.7%和105.5%(P<0.01)。与养心通脉方低剂量组比较,养心通脉方高剂量组大鼠平均动脉血压和左室收缩压没有显著的变化,心室舒张末压降低50.6%,心室内压升高最大变化速率和心室内压降低最大变化速率分别增加25.5%和31.3%(P<0.01)。
(2)异丙肾上腺素导致HF大鼠Ⅱ导联心电图T波高耸,并伴有ST段抬高,而养心通脉方对Ⅱ导联心电图T波高耸显著降低,ST段抬高程度得到改善。与养心通脉方低剂量组比较,养心通脉方高剂量组改善程度最明显。
(3)心肌组织病理切片显示,与正常对照组比较,模型组心内膜下层有大片纤维化区域和散在的局部心肌坏死灶,剩余的心肌纤维增粗,排列紊乱,肿胀、断裂、横纹肌消失,甚至溶解,发生玻璃样变和脂肪变性,间质组织增生。与模型组比较,养心通脉方低剂量组心肌纤维排列紊乱心室壁无明显增厚,心内膜下层有散在的纤维化区,坏死区域显著减小,呈小灶状和条状,剩余的心肌纤维排列整齐。养心通脉方高剂量组心肌纤维基本正常,排列较整齐,无肿胀、断裂、溶解和脂肪变性现象出现。
(4) Western blot检测心肌组织凋亡蛋白Bcl-2,Bax的蛋白表达显示,模型组凋亡蛋白表达Bcl-2水平显著降低,而Bax蛋白表达增加,Bcl-2/Bax比值降低,差异有显著性(P<0.05)。养心通脉方处理后,Bcl-2表达增加,Bax表达降低,Bcl-2/Bax比值升高,与模型组相比有显著性差异(P<0.01)。养心通脉方高剂量组最显著。
(5) Western blot检测心肌组织Akt,结果显示,与正常对照组比较,模型组显著减低了Akt蛋白的表达水平；养心通脉方处理后,Akt蛋白的表达水平明显增加,以养心通脉方高剂量组最为显著。
(6)与正常对照组相比较,模型组大鼠血浆和心肌组织的超氧化物歧化酶(SOD)分别降低59.7%和41.8%,养心通脉方高低剂量组血浆和心肌组织的超氧化物歧化酶(SOD)分别降低39.0%、19.6%和24.8%、8.7%,统计学均有显著性差异(均P<0.05)；与模型组比较,养心通脉方低高剂量组大鼠血浆和心肌组织的超氧化物歧化酶(SOD)分别增加14.7%、34%和13.6%、41.8%,统计学均有显著性差异(均P<0.05)；血浆和心肌组织的丙二醛(MDA)分别降低29.7%、62.6%和103.5%、163%,统计学均有显著性差异(均P<0.01)；血浆乳酸脱氢酶(LDH)分别降低45.7%和68.1%,统计学均有显著性差异(均P<0.01)。与养心通脉方低剂量组比较,养心通脉方高剂量组大鼠血浆和心肌组织的超氧化物歧化酶(SOD)分别增加16.1%和36.4%；血浆和心肌组织的丙二醛(MDA)分别降低25.2%和29.3%；血浆乳酸脱氢酶(LDH)降低15.3%,统计学均有显著性差异(均P<0.05)。
(7)正常对照组大鼠血浆和心肌组织IMD的浓度分别为29.2±5.Opg/ml和1.58±0.23pg/mg·pro。ISO处理后,血浆和心肌组织IMD的分泌显著减少,与正常对照组比较有显著性差异(P<0.05)。与模型组比较,养心通脉方低剂量组血浆和心肌组织IMD均增加,但无统计学意义；高剂量养心通脉方处理后,无论血浆和心肌组织IMD浓度均增加(P<0.01)。正常对照组大鼠血浆和心肌组织ET的浓度分别为32.2±9.3pg/ml和1.09±0.39pg/mg·pro。与正常对照组相比较,ISO处理后血浆和心肌组织ET的分泌显著增加(P<0.01),养心通脉方处理后,无论血浆和心肌组织ET浓度均减低(P<0.01)
(8)正常对照组大鼠心肌质膜Na+-K+-ATP酶活性是0.57±0.01μmolPi/mg pro·h。与正常对照组比较,模型组Na+-K+-ATP酶活性降低138.5%(0.24±0.01vs0.57±0.01,P<0.01)。养心通脉方处理后能够明显增加Na+-K+-ATP酶活性,分别比模型组增加49.0%和55.6%,有显著性差异(均P<0.01)。高剂量组与低剂量组比较有显著性差异(P<0.01)。
结论：(1)HF时ET升高,IMD下降,ET/IMD平衡失调,维持ET/IMD平衡关系在HF的防治中可作为新的药物作用靶点。(2)养心通脉方能够改善异丙肾上腺素诱导的心力衰竭大鼠的血流动力学,能减少脂质过氧化物MDA、LDH的生成和增加SOD活性,拮抗HF时氧化应激损伤。(3)养心通脉方防治HF的作用与增加Akt蛋白的表达水平,诱导Bcl-2蛋白的表达,减少促凋亡基因Bax蛋白的表达,从而降低心肌细胞的凋亡有关。(4)养心通脉方能够降低HF大鼠内源性损伤物质ET,增加心脏内源性保护物质IMD,维持细胞内源性防护机制的平衡,增加Na+-K+-ATP酶活性,使心肌细胞内外离子分布正常,保护细胞的正常兴奋性。
Objects:(1) To provide new ideas for the clinical development to new drugs with effective treatment for heart failure(HF) through research on new targets in drug action by blocking the excessive activation of neuroendocrine factors via the mechanism of endogenous cytoprotective maintaining the balance of endothelin(ET)/intermediary factor (IMD);(2) To provide scientific experimental evidence for developing new Chinese medicine, with local ethnic characteristics to effectively treat HF, through research on prevention and treatment mechanism of Prescription YangXinTongMai on Rats with myocardial remodeling caused by Isoproterenol (ISO).
Method:To give20-25mg/kg intraperitoneal injection of anesthesia with1%of Sodium Pentobarbital to Rats, and then Subcutaneous Injection of ISO,170mg. kg-1twice separately in24hours interval, to prepare model of myocardial ischemia so as to observe myocardial injury pathologically. To record the Mean Arterial Blood Pressure(MABP), Left Ventricular Systolic Pressure(LVSP),Left Ventricular End Diastolic Pressure(LVEDP), Left Ventricular and Diastolic Pressure and the maximum rise of Left Ventricular, the rate of change (±dp/dt) and ECG through left vertricle, femoral artery and four physiological redorder. To detect plasma and myocardial tissue superoxide dismutase (SOD) and malondialdehyde (MDA) and plasma lactate dehydrogenase(LDH) through biochemical method; to determine the IMD and ET content in plasma and tissue via enzyme-linked immunosorbent assay; to determine the organization of Na+-K+-ATPase activity via biochemical methods; and to detect apoptosis protein Bcl-2Bax and myocardial Akt protein via western blot.
Results:(1) Compared with the control group, there is an decrease by18.4%in systolic blood pressure of left ventricular of Rats in Isoproterenol (ISO), an increase by605.4%(P<0.01) in end-diastolic pressure, a decrease by32.7%in mean arterial blood, and a decrease by70%and143.5%(P<0.01) separately in the increase and decrease in ventricular pressure and maximum rate. There is no significant change in systolic blood pressure of left ventricular of Rat with low-dose YangXinTongMai, with a decrease by16.8%in mean arterial blood, an increase by200.5%(P<0.01) in pressure at the end of ventricular diastolic and a decrease by25%and55.7%separately in the increase and decrease in ventricular pressure and maximum rate. There is no significant change in mean arterial blood, in systolic blood pressure of left ventricular and heart rate of Rat with high-dose YangXinTongMai. The pressure at the end of ventricular diastol ic has increased100%(P<0.01), with a decrease by18.6%in the ventricular pressure to reduce the maximum rate of change. Compared with the Isoproterenol group, there is no significant change for Rats with low-dose YangXinTongMai, in mean arterial blood and systolic blood pressure, with a decrease by98.6%in pressure at the end of ventricular diastolic; there is an increase by33.3%and56.3%separately in the increase and decrease of ventricular pressure and maximum rate. There is no significant change for Rats with high-dose YangXinTongMai, in mean arterial blood and systolic blood pressure, with a decrease by148.6%in pressure at the end of ventricular diastolic; there is an increase by62.7%and105.5%(P<0.01) separately in the increase and decrease of ventricular pressure and maximum rate. Compared with Rats in low-dose YangXinTongMai group,there is no significant change for Rats in high-dose group, in mean arterial blood and systol ic blood pressure, with a decrease by50.6%in pressure at the end of ventricular diastolic; there is an increase by25.5%and31.3%(P Conclusion:(1) During HF, ET/IMD balance will be losing as ET will increase while IMD decreases. Maintaining balance between ET/IMD can be set up as new drug target in prevention and treatment of HF.(2) YangXinTongMai can improve Hemodynamics in rats with heart failure caused by ISO, reduce chances of generating Lipid peroxides MDA and LDH as well as it can increase SOD activity and resist oxidative stress injury when HF happens.(3) The role of YangXinTongMai s anti-HF and increase the expression level of Akt protein leads to the protein expression of Bcl-2, reduce the pro=aproptotic genes Bax protein expression, thus reduce myocardial apoptosis.(4) YangXinTongMai can reduse the substances of ET in dndogenous damage in the HF rats, increase the protective substances of IMD and keep the balance of the protective activitie, increase Na+-K+-ATPase so as to keep at normal the ion cells distribution inside and outside the Myocardial cells and generate the lactate dehydrogenase.
方法：用1%的戊巴比妥钠20～25mg/kg给予大鼠腹腔注射麻醉,然后皮下注射ISO,170mg·kg-1,分2次,每次间隔24h,制备心力衰竭模型,心肌组织病理切片观察心肌损伤；采用左心室和股动脉插管法及四道生理记录仪记录平均动脉血压(MABP)、左室收缩压(LVSP)、左室舒张末压(LVEDP)、左室最大压力上升及心室内压的变化率(±dp/dt)和心电图；生物化学法检测血浆和心肌组织超氧化物歧化酶(SOD)和丙二醛(MDA)及血浆乳酸脱氢酶(LDH)；酶联免疫吸附法检测血浆和心肌组织中介素(IMD)和内皮素(ET)含量测定；采用生物化学方法测定组织Na+-K+-ATPase活性；采用免疫印迹法检测凋亡蛋白B细胞淋巴瘤(Bcl-2),Bcl-2相关X蛋白(Bax)和心肌蛋白激酶B(Akt)蛋白表达。
结果：
(1)与正常对照组相比,模型组大鼠的左室收缩压降低18.4%,舒张末压升高604.5%(P<0.01),平均动脉血压降低32.7%,心室内压升高最大变化速率和心室内压降低最大变化速率分别降低70%和143.5%(P<0.01)；养心通脉方低剂量组大鼠的左室收缩压没有显著变化,平均动脉血压降低16.8%,心室舒张末压升高200.5%(P<0.01),心室内压升高最大变化速率和心室内压降低最大变化速率分别降低25%和55.7%；养心通脉方高剂量组大鼠的平均动脉血压、左室收缩压、心室内压升高最大变化速率没有显著变化,心室舒张末压升高100%(P<0.01),心室内压降低最大变化速率降低18.6%。与模型组比较,养心通脉方低剂量组大鼠平均动脉血压和左室收缩压没有显著变化,心室舒张末压降低98.6%,心室内压升高最大变化速率和心室内压降低最大变化速率分别增加33.3%和56.3%(P<0.01)；养心通脉方高剂量组大鼠平均动脉血压和左室收缩压没有显著的变化,心室舒张末压降低148.6%,心室内压升高最大变化速率和心室内压降低最大变化速率分别增加62.7%和105.5%(P<0.01)。与养心通脉方低剂量组比较,养心通脉方高剂量组大鼠平均动脉血压和左室收缩压没有显著的变化,心室舒张末压降低50.6%,心室内压升高最大变化速率和心室内压降低最大变化速率分别增加25.5%和31.3%(P<0.01)。
(2)异丙肾上腺素导致HF大鼠Ⅱ导联心电图T波高耸,并伴有ST段抬高,而养心通脉方对Ⅱ导联心电图T波高耸显著降低,ST段抬高程度得到改善。与养心通脉方低剂量组比较,养心通脉方高剂量组改善程度最明显。
(3)心肌组织病理切片显示,与正常对照组比较,模型组心内膜下层有大片纤维化区域和散在的局部心肌坏死灶,剩余的心肌纤维增粗,排列紊乱,肿胀、断裂、横纹肌消失,甚至溶解,发生玻璃样变和脂肪变性,间质组织增生。与模型组比较,养心通脉方低剂量组心肌纤维排列紊乱心室壁无明显增厚,心内膜下层有散在的纤维化区,坏死区域显著减小,呈小灶状和条状,剩余的心肌纤维排列整齐。养心通脉方高剂量组心肌纤维基本正常,排列较整齐,无肿胀、断裂、溶解和脂肪变性现象出现。
(4) Western blot检测心肌组织凋亡蛋白Bcl-2,Bax的蛋白表达显示,模型组凋亡蛋白表达Bcl-2水平显著降低,而Bax蛋白表达增加,Bcl-2/Bax比值降低,差异有显著性(P<0.05)。养心通脉方处理后,Bcl-2表达增加,Bax表达降低,Bcl-2/Bax比值升高,与模型组相比有显著性差异(P<0.01)。养心通脉方高剂量组最显著。
(5) Western blot检测心肌组织Akt,结果显示,与正常对照组比较,模型组显著减低了Akt蛋白的表达水平；养心通脉方处理后,Akt蛋白的表达水平明显增加,以养心通脉方高剂量组最为显著。
(6)与正常对照组相比较,模型组大鼠血浆和心肌组织的超氧化物歧化酶(SOD)分别降低59.7%和41.8%,养心通脉方高低剂量组血浆和心肌组织的超氧化物歧化酶(SOD)分别降低39.0%、19.6%和24.8%、8.7%,统计学均有显著性差异(均P<0.05)；与模型组比较,养心通脉方低高剂量组大鼠血浆和心肌组织的超氧化物歧化酶(SOD)分别增加14.7%、34%和13.6%、41.8%,统计学均有显著性差异(均P<0.05)；血浆和心肌组织的丙二醛(MDA)分别降低29.7%、62.6%和103.5%、163%,统计学均有显著性差异(均P<0.01)；血浆乳酸脱氢酶(LDH)分别降低45.7%和68.1%,统计学均有显著性差异(均P<0.01)。与养心通脉方低剂量组比较,养心通脉方高剂量组大鼠血浆和心肌组织的超氧化物歧化酶(SOD)分别增加16.1%和36.4%；血浆和心肌组织的丙二醛(MDA)分别降低25.2%和29.3%；血浆乳酸脱氢酶(LDH)降低15.3%,统计学均有显著性差异(均P<0.05)。
(7)正常对照组大鼠血浆和心肌组织IMD的浓度分别为29.2±5.Opg/ml和1.58±0.23pg/mg·pro。ISO处理后,血浆和心肌组织IMD的分泌显著减少,与正常对照组比较有显著性差异(P<0.05)。与模型组比较,养心通脉方低剂量组血浆和心肌组织IMD均增加,但无统计学意义；高剂量养心通脉方处理后,无论血浆和心肌组织IMD浓度均增加(P<0.01)。正常对照组大鼠血浆和心肌组织ET的浓度分别为32.2±9.3pg/ml和1.09±0.39pg/mg·pro。与正常对照组相比较,ISO处理后血浆和心肌组织ET的分泌显著增加(P<0.01),养心通脉方处理后,无论血浆和心肌组织ET浓度均减低(P<0.01)
(8)正常对照组大鼠心肌质膜Na+-K+-ATP酶活性是0.57±0.01μmolPi/mg pro·h。与正常对照组比较,模型组Na+-K+-ATP酶活性降低138.5%(0.24±0.01vs0.57±0.01,P<0.01)。养心通脉方处理后能够明显增加Na+-K+-ATP酶活性,分别比模型组增加49.0%和55.6%,有显著性差异(均P<0.01)。高剂量组与低剂量组比较有显著性差异(P<0.01)。
结论：(1)HF时ET升高,IMD下降,ET/IMD平衡失调,维持ET/IMD平衡关系在HF的防治中可作为新的药物作用靶点。(2)养心通脉方能够改善异丙肾上腺素诱导的心力衰竭大鼠的血流动力学,能减少脂质过氧化物MDA、LDH的生成和增加SOD活性,拮抗HF时氧化应激损伤。(3)养心通脉方防治HF的作用与增加Akt蛋白的表达水平,诱导Bcl-2蛋白的表达,减少促凋亡基因Bax蛋白的表达,从而降低心肌细胞的凋亡有关。(4)养心通脉方能够降低HF大鼠内源性损伤物质ET,增加心脏内源性保护物质IMD,维持细胞内源性防护机制的平衡,增加Na+-K+-ATP酶活性,使心肌细胞内外离子分布正常,保护细胞的正常兴奋性。
Objects:(1) To provide new ideas for the clinical development to new drugs with effective treatment for heart failure(HF) through research on new targets in drug action by blocking the excessive activation of neuroendocrine factors via the mechanism of endogenous cytoprotective maintaining the balance of endothelin(ET)/intermediary factor (IMD);(2) To provide scientific experimental evidence for developing new Chinese medicine, with local ethnic characteristics to effectively treat HF, through research on prevention and treatment mechanism of Prescription YangXinTongMai on Rats with myocardial remodeling caused by Isoproterenol (ISO).
Method:To give20-25mg/kg intraperitoneal injection of anesthesia with1%of Sodium Pentobarbital to Rats, and then Subcutaneous Injection of ISO,170mg. kg-1twice separately in24hours interval, to prepare model of myocardial ischemia so as to observe myocardial injury pathologically. To record the Mean Arterial Blood Pressure(MABP), Left Ventricular Systolic Pressure(LVSP),Left Ventricular End Diastolic Pressure(LVEDP), Left Ventricular and Diastolic Pressure and the maximum rise of Left Ventricular, the rate of change (±dp/dt) and ECG through left vertricle, femoral artery and four physiological redorder. To detect plasma and myocardial tissue superoxide dismutase (SOD) and malondialdehyde (MDA) and plasma lactate dehydrogenase(LDH) through biochemical method; to determine the IMD and ET content in plasma and tissue via enzyme-linked immunosorbent assay; to determine the organization of Na+-K+-ATPase activity via biochemical methods; and to detect apoptosis protein Bcl-2Bax and myocardial Akt protein via western blot.
Results:(1) Compared with the control group, there is an decrease by18.4%in systolic blood pressure of left ventricular of Rats in Isoproterenol (ISO), an increase by605.4%(P<0.01) in end-diastolic pressure, a decrease by32.7%in mean arterial blood, and a decrease by70%and143.5%(P<0.01) separately in the increase and decrease in ventricular pressure and maximum rate. There is no significant change in systolic blood pressure of left ventricular of Rat with low-dose YangXinTongMai, with a decrease by16.8%in mean arterial blood, an increase by200.5%(P<0.01) in pressure at the end of ventricular diastolic and a decrease by25%and55.7%separately in the increase and decrease in ventricular pressure and maximum rate. There is no significant change in mean arterial blood, in systolic blood pressure of left ventricular and heart rate of Rat with high-dose YangXinTongMai. The pressure at the end of ventricular diastol ic has increased100%(P<0.01), with a decrease by18.6%in the ventricular pressure to reduce the maximum rate of change. Compared with the Isoproterenol group, there is no significant change for Rats with low-dose YangXinTongMai, in mean arterial blood and systolic blood pressure, with a decrease by98.6%in pressure at the end of ventricular diastolic; there is an increase by33.3%and56.3%separately in the increase and decrease of ventricular pressure and maximum rate. There is no significant change for Rats with high-dose YangXinTongMai, in mean arterial blood and systolic blood pressure, with a decrease by148.6%in pressure at the end of ventricular diastolic; there is an increase by62.7%and105.5%(P<0.01) separately in the increase and decrease of ventricular pressure and maximum rate. Compared with Rats in low-dose YangXinTongMai group,there is no significant change for Rats in high-dose group, in mean arterial blood and systol ic blood pressure, with a decrease by50.6%in pressure at the end of ventricular diastolic; there is an increase by25.5%and31.3%(P
引文
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