苦碟子总黄酮对实验性心肌缺血的保护作用及其机制研究
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摘要
急性心肌梗死(AMI)是指冠状动脉急性闭塞,血流中断,所引起的局部心肌急性缺血性坏死,其死亡率高,反复发作易引起心律失常或者心力衰竭,受到医学界的广泛重视。因此,开发安全有效的抗急性心肌缺血药物是一项重要的课题。
苦碟子总黄酮(Total Flavonoids of Sowthistle-leafixeris seedling,TFS)系从菊科植物抱茎苦卖菜(Ixeris sonchifolia Hance)全草中提取的有效部位,拟按治疗冠心病心绞痛的中药五类新药开发。
本实验通过建立大鼠及犬急性心肌梗死模型,从形态学、心肌酶学、血液生化学、心外膜心电图、心功能、血流动力学、心肌氧代谢及分子水平探讨了TFS对实验性心肌缺血的保护作用及其机制。结果表明,TFS可明显缩小心肌梗死面积,降低心肌缺血程度及缺血范围;通过提高内源性抗氧化酶活性,减轻氧自由基的损伤,降低血小板粘附功能和聚集功能,纠正心肌缺血时FFA代谢紊乱,减少缩血管物质生成,保持PGI2/TXA2生理平衡,改善心肌代谢和血流动力学,平衡心肌供氧与需氧,改善心肌舒缩功能等多种途径发挥抗心肌缺血作用。此外,TFS能抑制急性心肌梗死早期原癌基因及凋亡基因的表达,并明显降低血浆ET及AngⅡ水平,提示其可能防治急性心肌梗死后心室重构。
Backgroud:
Myocardial ischemia is a clinical state referring to coronary blood flow reduce for a variety of reasons resulting in myocardial oxygen supply deficiency and less removal of metabolic products.Myocardial ischemia is a higher incidence cardiovascular disease,its mortality is high when acute attack, Recurrent myocardial ischemia easily cause arrhythmia or heart failure,Myocardial ischemia is an important disease harmful to human health,which aroused wide attention. Therefore, looking for safe and effective drug for the prevention and treatment of ischemic heart disease is one of the important issues.
It has been confirmed Sowthistle-leafixeris seedling has a better effect in anti-myocardial ischemia. Sowthistle-leafixeris seedling is Selected as“famous brand in Jilin Province”, However,the extraction process of Sowthistle-leafixeris seedling is still not perfect, the level of quality control standards is not high, the production cycle is long, active ingredient content is low, therefore, the cost of production not only greatly increased,but there is also occasionally fever response.In order to improve quality, lower production costs, under the national high-tech research development plan (863) project grants, we make a formulations change from injection to freeze-dried powde. The content of its effective part (TotaL FLavonoids of SowthistLe-Leafixeris seedling, TFS) rise from 15%to 90%.
In this paper, after the establishment of rat and dog myocardial infarction Model, we analyse protective effects of TFS on experimental myocardial ischemia and its mechanism on morphology, enzymes, blood biochemistry, epicar dial ECG, cardiac function, hemodynamics, myocardial oxygen metabolism and molecular levels to provide pharmaco dynamic basis for the development of five new Chinese medicine to the treatment of chest pain.
Methods:
1.Establish a rat Model of myocardial infarction and measure the following indicators:
(1)Determinate of ECGⅡlead by RM-6000-type multi-channel physiological recorder in rats;
(2)Determinate serum aspartate aminotransferase enzyme (AST), creatine phosphate kinase (CK) and lactate dehydro genase (LDH) activity By COBAS-FARA automatic analyzer;
(3)Draw 1ml Blood from the abdominal aorta, anticoagulate with 3.8% sodium citrate by ratio of 1:9, add the blood into platelet adhesion LBY-F5 Miriam ball, count the number of platelets after adhesion in the light microscope, calculate platelet adhesion rate (PAR);
(4)Draw 3mL blood from the abdominal aorta, anticoagulate with 3.8% sodium citrate by ratio of 1:9, utilize LBY-NJ2 to measure platelet aggregation platelet;
(5)Stain organizations with chlorination NBT (NB-T) to calculate myocardial infarct size (MIS) with the ratio of myocardial ischemia and ventricular wet weight;
(6)Draw blood from abdominal aorta, detect serum malondial dehyde (MDA) content, superoxide dismutase (SOD) and glutath ione peroxidase (GSH-Px) activity by kit;
(7)Detecte plasma endothelin (ET),angiotensinⅡ(AngⅡ) and the level of PGI2 and TXA2 by Radioimmunoassay;
(8)Measure free fatty acids (FFA) content in ischemia and non-ischemic myocardial by Colorimetry;
(9)Detecte mRNA expression of cardiac proto-oncogene c-fos, c-myc,c-jun,Ras and apoptosis gene Bcl-2,Bax,p53,Fas by RT-PCR.
2.Establish canine myocardial infarction Model, determinate the following indicators:
(1)Separate the right common carotid artery, connecte pressure transducer after intubation, measure systolic blood pressure (SBP) and diastolic blood pressure (DBP) by carrier amplifiers (AP-601G);
(2)Separate the left femoral artery, insert the catheter to the left ventricle, connecte carrier amplifier (AP-601G) to detect left ventricular pressure (LVP) and the maximum change rate of left ventricular pressure (±dp/dtmax);
(3)Separate the aortic root, place the suitable electromagne tic flowmeter probe, measure cardiac output (CO);
(4)Separate LCX, place the suitable diameter electromagnetic flowmeter probe to measure coronary flow (CBF);
(5)Connect ECG electrodes, recordⅡ-lead ECG and heart rate (HR) by AB-601 bioel- ectrical amplifier;
(6)Map the epicardial electrocardiogram in normal, the edge of infarction zone and the central area of infarction by wet-type multi-point adsorption;
(7)Draw blood from the coronary sinus and the left femoral artery at the same time, measure arterial and venous blood oxygen by the CORNIHG 178 blood gas analyzer, calculate myocardial oxygen consumption (COC), myocardial oxygen utilization (MOUR) and myocardial oxygen consumption index (MOCI);
(8)Draw Blood from the femoral artery, determinate serum aspartate aminotransferase enzyme (AST), creatine phosphor kinase (CK) and lactate dehydrogenase (LDH) activity by COBAS-FAARA automatic biochemical analyzer;
(9)Stain tissues with chlorination NBT (NB-T) to calculate myocardial infarct size (MIS) with the ratio of myocardial ischemia and ventricular wet weight.
Results
(1)TFS can significantly reduce the MIS in rats and dogs, as well as the extent of myocardial ischemia in dogs and ischemic area,and can alleviate the level of the acute myocardial ischemic electrocardiogram (ST segment elevation and tall T wave) changes;
(2)TFS can significantly reduce serum MDA content, increase SOD and GSH-Px activity in acute myocardial infarction rats;
(3)TFS can significantly reduce PAR of acute myocardial infarction in rats,as well as the level of ADP-induced PAG and MPAG;
(4)TFS can significantly reduce the level of FFA in myocardial infarct and non-infarct area in rats with acute myocardial infarction;
(5)TFS can significantly reduce levels of plasma ET, AngⅡand TXA2,increase plasma levels of PGI2 and PGI2/TXA2 ratio in rats with acute myocardial infarction;
(6)TFS could inhibit gene expression of c-myc,c-fos, c-jun, Ras, raise the ratio of Bcl-2/Bax, inhibit the expression of p53 and Fas 24h after the acute myocardial infarction;
(7)TFS can significantly reduce content of ET, AngⅡand TXA2, increase plasma levels of PGI2 and PGI2/TXA2 ratio in rats with acute myocardial infarction;
(8)TFS can significantly reduce oxygen utilization, reduce oxygen consumption and LVEDP in dogs with acute myocardial infarction;
(9)TFS can significantly prevent blood pressure (SBP, DBP and MAP) from decreasing, markly increase MBF, LVP,±dp/dtmax, CO and CI, and decrease LVEDP;
Conclusion
(1)TFS can significantly reduce myocardial infarction area, the extent of myocardial ischemia and ischemic area, lower electrocardiogram change and serum CK, LDH and AST activity, morphological changes and enzyme changes consistent indicating that its protective effect on ischemic myocardium;
(2)TFS can enhance endogenous antioxidant enzyme activity, reduce the oxygen free radical injury, significantly reduce platelet adhesion function and aggregation function, and have a protective effect on ischemic myocardium;
(3)TFS can improve myocardial FFA metabolism disorders, reduce myocardial damage of FFA, do favor to regain energy supply at the time of myocardial ischemia, improve myocardial metabolism;
(4)TFS could inhibite the increase of vasoconstrictor substances in vivo, maintain the physiological balance of PGI2/TXA2 in favor of expansion of blood vessels to increase myocardial blood supply;
(5)TFS has effect of anti- cardiomyocyte apoptosis;
(6)TFS can reduce cardiac work, reducing myocardial oxygen consumption, balance myocardial oxygen supply and consum ption;
(7)TFS can significantly increase blood flow in dogs with acute myocardial infarction, and improve myocardial systolic and diastolic function to help fight against pump failure after infarction.
To sum up, TFS can protect ischemic myocardium in many different ways.
In this paper, We discuss mechanism and effects of TFS on anti-myocardial ischemia, anti-free radical, anti-platelet aggregation, improving the myocardial oxygen metabolism and hemodynamics and anti-myocardial apoptosis. The experimental results laid a solid foundation for its clinical application in anti-myocardial ischemia, provide pharmaco dynamic basis for the development of five new Chinese medicine to the treatment of chest pain.
苦碟子总黄酮(Total Flavonoids of Sowthistle-leafixeris seedling,TFS)系从菊科植物抱茎苦卖菜(Ixeris sonchifolia Hance)全草中提取的有效部位,拟按治疗冠心病心绞痛的中药五类新药开发。
本实验通过建立大鼠及犬急性心肌梗死模型,从形态学、心肌酶学、血液生化学、心外膜心电图、心功能、血流动力学、心肌氧代谢及分子水平探讨了TFS对实验性心肌缺血的保护作用及其机制。结果表明,TFS可明显缩小心肌梗死面积,降低心肌缺血程度及缺血范围;通过提高内源性抗氧化酶活性,减轻氧自由基的损伤,降低血小板粘附功能和聚集功能,纠正心肌缺血时FFA代谢紊乱,减少缩血管物质生成,保持PGI2/TXA2生理平衡,改善心肌代谢和血流动力学,平衡心肌供氧与需氧,改善心肌舒缩功能等多种途径发挥抗心肌缺血作用。此外,TFS能抑制急性心肌梗死早期原癌基因及凋亡基因的表达,并明显降低血浆ET及AngⅡ水平,提示其可能防治急性心肌梗死后心室重构。
Backgroud:
Myocardial ischemia is a clinical state referring to coronary blood flow reduce for a variety of reasons resulting in myocardial oxygen supply deficiency and less removal of metabolic products.Myocardial ischemia is a higher incidence cardiovascular disease,its mortality is high when acute attack, Recurrent myocardial ischemia easily cause arrhythmia or heart failure,Myocardial ischemia is an important disease harmful to human health,which aroused wide attention. Therefore, looking for safe and effective drug for the prevention and treatment of ischemic heart disease is one of the important issues.
It has been confirmed Sowthistle-leafixeris seedling has a better effect in anti-myocardial ischemia. Sowthistle-leafixeris seedling is Selected as“famous brand in Jilin Province”, However,the extraction process of Sowthistle-leafixeris seedling is still not perfect, the level of quality control standards is not high, the production cycle is long, active ingredient content is low, therefore, the cost of production not only greatly increased,but there is also occasionally fever response.In order to improve quality, lower production costs, under the national high-tech research development plan (863) project grants, we make a formulations change from injection to freeze-dried powde. The content of its effective part (TotaL FLavonoids of SowthistLe-Leafixeris seedling, TFS) rise from 15%to 90%.
In this paper, after the establishment of rat and dog myocardial infarction Model, we analyse protective effects of TFS on experimental myocardial ischemia and its mechanism on morphology, enzymes, blood biochemistry, epicar dial ECG, cardiac function, hemodynamics, myocardial oxygen metabolism and molecular levels to provide pharmaco dynamic basis for the development of five new Chinese medicine to the treatment of chest pain.
Methods:
1.Establish a rat Model of myocardial infarction and measure the following indicators:
(1)Determinate of ECGⅡlead by RM-6000-type multi-channel physiological recorder in rats;
(2)Determinate serum aspartate aminotransferase enzyme (AST), creatine phosphate kinase (CK) and lactate dehydro genase (LDH) activity By COBAS-FARA automatic analyzer;
(3)Draw 1ml Blood from the abdominal aorta, anticoagulate with 3.8% sodium citrate by ratio of 1:9, add the blood into platelet adhesion LBY-F5 Miriam ball, count the number of platelets after adhesion in the light microscope, calculate platelet adhesion rate (PAR);
(4)Draw 3mL blood from the abdominal aorta, anticoagulate with 3.8% sodium citrate by ratio of 1:9, utilize LBY-NJ2 to measure platelet aggregation platelet;
(5)Stain organizations with chlorination NBT (NB-T) to calculate myocardial infarct size (MIS) with the ratio of myocardial ischemia and ventricular wet weight;
(6)Draw blood from abdominal aorta, detect serum malondial dehyde (MDA) content, superoxide dismutase (SOD) and glutath ione peroxidase (GSH-Px) activity by kit;
(7)Detecte plasma endothelin (ET),angiotensinⅡ(AngⅡ) and the level of PGI2 and TXA2 by Radioimmunoassay;
(8)Measure free fatty acids (FFA) content in ischemia and non-ischemic myocardial by Colorimetry;
(9)Detecte mRNA expression of cardiac proto-oncogene c-fos, c-myc,c-jun,Ras and apoptosis gene Bcl-2,Bax,p53,Fas by RT-PCR.
2.Establish canine myocardial infarction Model, determinate the following indicators:
(1)Separate the right common carotid artery, connecte pressure transducer after intubation, measure systolic blood pressure (SBP) and diastolic blood pressure (DBP) by carrier amplifiers (AP-601G);
(2)Separate the left femoral artery, insert the catheter to the left ventricle, connecte carrier amplifier (AP-601G) to detect left ventricular pressure (LVP) and the maximum change rate of left ventricular pressure (±dp/dtmax);
(3)Separate the aortic root, place the suitable electromagne tic flowmeter probe, measure cardiac output (CO);
(4)Separate LCX, place the suitable diameter electromagnetic flowmeter probe to measure coronary flow (CBF);
(5)Connect ECG electrodes, recordⅡ-lead ECG and heart rate (HR) by AB-601 bioel- ectrical amplifier;
(6)Map the epicardial electrocardiogram in normal, the edge of infarction zone and the central area of infarction by wet-type multi-point adsorption;
(7)Draw blood from the coronary sinus and the left femoral artery at the same time, measure arterial and venous blood oxygen by the CORNIHG 178 blood gas analyzer, calculate myocardial oxygen consumption (COC), myocardial oxygen utilization (MOUR) and myocardial oxygen consumption index (MOCI);
(8)Draw Blood from the femoral artery, determinate serum aspartate aminotransferase enzyme (AST), creatine phosphor kinase (CK) and lactate dehydrogenase (LDH) activity by COBAS-FAARA automatic biochemical analyzer;
(9)Stain tissues with chlorination NBT (NB-T) to calculate myocardial infarct size (MIS) with the ratio of myocardial ischemia and ventricular wet weight.
Results
(1)TFS can significantly reduce the MIS in rats and dogs, as well as the extent of myocardial ischemia in dogs and ischemic area,and can alleviate the level of the acute myocardial ischemic electrocardiogram (ST segment elevation and tall T wave) changes;
(2)TFS can significantly reduce serum MDA content, increase SOD and GSH-Px activity in acute myocardial infarction rats;
(3)TFS can significantly reduce PAR of acute myocardial infarction in rats,as well as the level of ADP-induced PAG and MPAG;
(4)TFS can significantly reduce the level of FFA in myocardial infarct and non-infarct area in rats with acute myocardial infarction;
(5)TFS can significantly reduce levels of plasma ET, AngⅡand TXA2,increase plasma levels of PGI2 and PGI2/TXA2 ratio in rats with acute myocardial infarction;
(6)TFS could inhibit gene expression of c-myc,c-fos, c-jun, Ras, raise the ratio of Bcl-2/Bax, inhibit the expression of p53 and Fas 24h after the acute myocardial infarction;
(7)TFS can significantly reduce content of ET, AngⅡand TXA2, increase plasma levels of PGI2 and PGI2/TXA2 ratio in rats with acute myocardial infarction;
(8)TFS can significantly reduce oxygen utilization, reduce oxygen consumption and LVEDP in dogs with acute myocardial infarction;
(9)TFS can significantly prevent blood pressure (SBP, DBP and MAP) from decreasing, markly increase MBF, LVP,±dp/dtmax, CO and CI, and decrease LVEDP;
Conclusion
(1)TFS can significantly reduce myocardial infarction area, the extent of myocardial ischemia and ischemic area, lower electrocardiogram change and serum CK, LDH and AST activity, morphological changes and enzyme changes consistent indicating that its protective effect on ischemic myocardium;
(2)TFS can enhance endogenous antioxidant enzyme activity, reduce the oxygen free radical injury, significantly reduce platelet adhesion function and aggregation function, and have a protective effect on ischemic myocardium;
(3)TFS can improve myocardial FFA metabolism disorders, reduce myocardial damage of FFA, do favor to regain energy supply at the time of myocardial ischemia, improve myocardial metabolism;
(4)TFS could inhibite the increase of vasoconstrictor substances in vivo, maintain the physiological balance of PGI2/TXA2 in favor of expansion of blood vessels to increase myocardial blood supply;
(5)TFS has effect of anti- cardiomyocyte apoptosis;
(6)TFS can reduce cardiac work, reducing myocardial oxygen consumption, balance myocardial oxygen supply and consum ption;
(7)TFS can significantly increase blood flow in dogs with acute myocardial infarction, and improve myocardial systolic and diastolic function to help fight against pump failure after infarction.
To sum up, TFS can protect ischemic myocardium in many different ways.
In this paper, We discuss mechanism and effects of TFS on anti-myocardial ischemia, anti-free radical, anti-platelet aggregation, improving the myocardial oxygen metabolism and hemodynamics and anti-myocardial apoptosis. The experimental results laid a solid foundation for its clinical application in anti-myocardial ischemia, provide pharmaco dynamic basis for the development of five new Chinese medicine to the treatment of chest pain.
引文
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