益气舒心颗粒治疗兔DHF模型疗效的实验研究
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摘要
背景 舒张性心力衰竭(DHF)是指在心室收缩功能正常(射血分数正常EF＞45％)的情况下，心室松弛性和顺应性减低使心室充盈量减少和充盈压升高，从而导致肺循环和体循环淤血的综合征。二十世纪80年代住院患者的回顾性研究证明，DHF患者大约占全部心力衰竭患者的30％～40％。DHF的治疗大多是经验性的，现在还缺少大规模多中心的随机对照临床试验，DHF的诊治已成为心血管病领域中急需解决的重要课题。
目标 对益气舒心颗粒冲剂治疗新西兰白兔DHF药效的实验观察、分析，进一步探讨益气舒心颗粒治疗DHF的疗效及作用机制，冀其为中医研究DHF规范化和客观化提供依据。
研究方法 应用高脂饲料喂养新西兰白兔12周的方法建立兔DHF的模型，使用日本RW—6000光电八导生理仪检测左心室舒张、收缩功能，左心室内压(LVP)、左心室舒张末期压(LVEDP)、左心室等容舒张期压力最大上升速率(+dp／dtmax)、左心室等容舒张期压力下降速率(—dp／dtmax)、心率(HR)、心电图Ⅱ导(ECG)、动脉收缩压(SBP)、舒张压(DBP)计算左室松弛时间常数左室收缩指数、利用左心室重量与体重之比(LVW／BW)定量心肌肥厚程度。同时检测血ET、AngⅡ、ANP。治疗组用益气舒心颗粒(由具有益气宣肺活血利水的中草药制成)治疗，对照组用合心爽、开搏通，治疗8周后再用日本RW—6000光电八导生理仪检测左心室舒张、收缩功能，进行比较。评价益气舒心颗粒治疗DHF的疗效。
结论 应用高脂饲料喂养新西兰白兔12周的方法能够建立兔DHF的模型。益气舒心颗粒能够降低左心室等容舒张期压力下降速率(—dp／dtmax)、左心室舒张末期压(LVEDP)、左心室内压(LVP)、舒张压(DBP)、血ET、ATⅡ、ANP、CHO、LDL-C、TG。治疗效果与合心爽、开搏通相当，部分指标(CHO，LDL-C，TG，ET、LVSP)的改善优于合心爽、开搏通。证明益气舒心颗粒通过多靶点治疗DHF，最主要的机制可能为阻断钙离子通道，改善了心肌细胞内的钙超负荷，并能够降低血脂、调整紊乱的神经内分泌，特别是降低了血ET、ATⅡ、ANP，阻止了DHF的进一步的发展。
Background: Diastolic heart failure (DHF) is a clinical syndrome characterized by the symptoms and signs of heart failure, a preserved ejection fraction (EF>45%), and abnormal diastolic function. From a conceptual perspective, diastolic heart failure occurs when the ventricular chamber is unable to accept an adequate volume of blood during diastole, at normal diastolic pressures and at volumes sufficient to maintain an appropriate stroke volume. These abnormalities are caused by a decrease in ventricular relaxation and/or an increase in ventricular stiffness and give rise to the left ventricular filling pressure elevating, the left ventricular filling capacity decreasing, systemic and pulmonary circulation congesting goring. It has been proofed that 35% to 40% of all the patients with heart failure are the DHF by reviewing the hospitalized patients in the 80's 20th century .The treatment of DHF is most experiencing and still short of large scale multiplicity centers random control clinical trial now. Therefore the diagnosis and treatment of the DHF is a most important project which is urgent to resolved in the fields of cardiology.
Objective: This test is to systematically study the effective of the YiQiShuXin granular medicine in treating DHF of the rabbit and to enucleate what is it's probability functionary mechanism. Methods: The model of the rabbit DHF is established by feeding the New Zealand white rabbit 12 weeks with Cholesterol-Rich fodder. Treating groups are treated with the YiQiShuXin granular medicine(Chinese medicine with the effective of YiQiXuanfeiHuoxueLiShui), while control groups are treated with Cardizen and Captopril for 8 weeks. Such parameters as the left ventricle diastolic pressure (LVDP), contractility index and the left ventricle pressure (LVP) etc, are tested by the eight leads electricity physiology instrument (Japan, RW-6000) to evaluate the curative effect of the YiQiShuXin granular medicine on the DHF treatment. Results and Conclusions:
1: The model of the rabbit DHF is successfully established by feeding the New Zealand white rabbit 12 weeks with Cholesterol-Rich fodder.
2: The YiQiShuXin granular medicine can cut down the peak descending maximal rate in period of isovolumic contraction (-dp/dtmax), the left ventricle pressure (LVP), the left ventricle end diastole pressure (LVEDP), diastolic pressure (DBP), the level of the ET, XT, ANP, CHO, LDL-C and TG in blood.
3: Such parameters as CHO, LDL-C, TG, ET and LVSP for the YiQiShuXin granular medicine
are superior to Cardizen and Captopril, while its curative effect of is parallel with that of Cardizen
and Captopril.
4: The main mechanism is probably to obstruct the calcium ion passageway, decrease calcium overload inner the myocardium cell and cut down the blood grease and come back chaotic nerve endocritic level in some extent, particularly blood ET, AT and ANP, therefore stop further the development of DHF .
目标 对益气舒心颗粒冲剂治疗新西兰白兔DHF药效的实验观察、分析，进一步探讨益气舒心颗粒治疗DHF的疗效及作用机制，冀其为中医研究DHF规范化和客观化提供依据。
研究方法 应用高脂饲料喂养新西兰白兔12周的方法建立兔DHF的模型，使用日本RW—6000光电八导生理仪检测左心室舒张、收缩功能，左心室内压(LVP)、左心室舒张末期压(LVEDP)、左心室等容舒张期压力最大上升速率(+dp／dtmax)、左心室等容舒张期压力下降速率(—dp／dtmax)、心率(HR)、心电图Ⅱ导(ECG)、动脉收缩压(SBP)、舒张压(DBP)计算左室松弛时间常数左室收缩指数、利用左心室重量与体重之比(LVW／BW)定量心肌肥厚程度。同时检测血ET、AngⅡ、ANP。治疗组用益气舒心颗粒(由具有益气宣肺活血利水的中草药制成)治疗，对照组用合心爽、开搏通，治疗8周后再用日本RW—6000光电八导生理仪检测左心室舒张、收缩功能，进行比较。评价益气舒心颗粒治疗DHF的疗效。
结论 应用高脂饲料喂养新西兰白兔12周的方法能够建立兔DHF的模型。益气舒心颗粒能够降低左心室等容舒张期压力下降速率(—dp／dtmax)、左心室舒张末期压(LVEDP)、左心室内压(LVP)、舒张压(DBP)、血ET、ATⅡ、ANP、CHO、LDL-C、TG。治疗效果与合心爽、开搏通相当，部分指标(CHO，LDL-C，TG，ET、LVSP)的改善优于合心爽、开搏通。证明益气舒心颗粒通过多靶点治疗DHF，最主要的机制可能为阻断钙离子通道，改善了心肌细胞内的钙超负荷，并能够降低血脂、调整紊乱的神经内分泌，特别是降低了血ET、ATⅡ、ANP，阻止了DHF的进一步的发展。
Background: Diastolic heart failure (DHF) is a clinical syndrome characterized by the symptoms and signs of heart failure, a preserved ejection fraction (EF>45%), and abnormal diastolic function. From a conceptual perspective, diastolic heart failure occurs when the ventricular chamber is unable to accept an adequate volume of blood during diastole, at normal diastolic pressures and at volumes sufficient to maintain an appropriate stroke volume. These abnormalities are caused by a decrease in ventricular relaxation and/or an increase in ventricular stiffness and give rise to the left ventricular filling pressure elevating, the left ventricular filling capacity decreasing, systemic and pulmonary circulation congesting goring. It has been proofed that 35% to 40% of all the patients with heart failure are the DHF by reviewing the hospitalized patients in the 80's 20th century .The treatment of DHF is most experiencing and still short of large scale multiplicity centers random control clinical trial now. Therefore the diagnosis and treatment of the DHF is a most important project which is urgent to resolved in the fields of cardiology.
Objective: This test is to systematically study the effective of the YiQiShuXin granular medicine in treating DHF of the rabbit and to enucleate what is it's probability functionary mechanism. Methods: The model of the rabbit DHF is established by feeding the New Zealand white rabbit 12 weeks with Cholesterol-Rich fodder. Treating groups are treated with the YiQiShuXin granular medicine(Chinese medicine with the effective of YiQiXuanfeiHuoxueLiShui), while control groups are treated with Cardizen and Captopril for 8 weeks. Such parameters as the left ventricle diastolic pressure (LVDP), contractility index and the left ventricle pressure (LVP) etc, are tested by the eight leads electricity physiology instrument (Japan, RW-6000) to evaluate the curative effect of the YiQiShuXin granular medicine on the DHF treatment. Results and Conclusions:
1: The model of the rabbit DHF is successfully established by feeding the New Zealand white rabbit 12 weeks with Cholesterol-Rich fodder.
2: The YiQiShuXin granular medicine can cut down the peak descending maximal rate in period of isovolumic contraction (-dp/dtmax), the left ventricle pressure (LVP), the left ventricle end diastole pressure (LVEDP), diastolic pressure (DBP), the level of the ET, XT, ANP, CHO, LDL-C and TG in blood.
3: Such parameters as CHO, LDL-C, TG, ET and LVSP for the YiQiShuXin granular medicine
are superior to Cardizen and Captopril, while its curative effect of is parallel with that of Cardizen
and Captopril.
4: The main mechanism is probably to obstruct the calcium ion passageway, decrease calcium overload inner the myocardium cell and cut down the blood grease and come back chaotic nerve endocritic level in some extent, particularly blood ET, AT and ANP, therefore stop further the development of DHF .
引文
1. Dougherty AH, Naccarelli GV, Gray EL, et al. Congestive heart failure with normal systolic function.Am J Cardiol, 1984,54: 778-782.
2. Morgan JP, Erny RE, Allen PD, et al.Abnormal intracellular calcium handling, a major cause of systolic and diasolic dysfunction in ventricular myocardium from patients with heart failure. Circulation, 1980,81 (suppl Ⅲ)Ⅲ21—31.
3. Lorell BH, Isoyama S, Grice WN, et al. Effects of ouabain and isoproterenol on left ventricular diastolic function during low flow ischemia in isolated, blood-perfused rabbit hearts. Circulation Research, 1988,63:457-467.
4. Brutsaert DL, Fransen P. Andries LJ, et al. Cardiac endothelium and myocardial function. Cardiovasc Res. 1998; 38: 281-290.
5. Paulus WJ. Beneficial effects of nitric oxide on cardiac diastolic function: "the flip side of the coin." Heart Failure Rev. 2000; 5: 337-344.
6．张子彬 左室舒张功能障碍性心力衰竭的诊断修订标准(中国心力衰竭协会 CHFA)心血管病学进展；2002，109(3)：封二。
7. Working group report. How to diagnose heart failure. European study group on diastolic heart failure. Eur Heart J, 1998,19: 990-1003.
8. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000; 101: 2118-2121.
9. Feldman AM, Weinberg EO, Ray PE, et al. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation on rats with chronic aortic banding. Circulation Research, 1993,73 : 184-192.
10. Kiss E, Ball NA, Kranias EG, et al. Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca~(2+)- ATPase protein levels Effects on Ca~(2+) transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure Circulation Research. 1995.77:759-764.
11. Schwinger RH,Bohm M, Schmidt U, et al.Unchanged protein levels of SERCA 11 and phospholamban but reduced uptake and-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts .Circulation, 1995,92:3220-3228.
12. Gandhi SK , Powers JC , Normal A, et al. The pathogenesis of acute pulmonary edema associated with hypertension [J] N England J Med,2001,344:17～22.
13. Zile MR, Gaasch WH ,Carroll JD, et al. Heart failure with a normal ejection fraction: Is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? [J] Circulation ,2001,104:779～782.
14. Kupferema R, Mitrapp, Hohenberg-PC, et al. Analytical calculation of intracellular calcium wave characteristics, Biophys J, 1997,72:2430～2444.
15. Wckenedn-AD, Kaprielian-R, Kassiri-Z, et al. The role of action potential prolongation and altered intracellular calcium handing in the pathogenesis of heart failure. Cardiovascular Research, 1998,37:312～313.
16. Hartman-A, et al. Persisting effect of Ca~(2+) channel blockers on left ventricular function in hypertrophic cardiomyopathy after 14years treatment. Angiology, 1996. 47: 765
17. Yalcin F, Aksoy F G; Muderrisoglu H, et al. Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function. Clin Cardiol, 2000,23(6):437—41
18．陈晓瑞，崔宛华贝那普利对高血压病和冠心病 左室舒张功能不全的影响．中国新药与临床杂志，2001，20(3)：196—198
19．胡大一慢性充血性心力衰竭药物治疗的现代观点与最新进展．中国实用内科杂志，2000，20(1)：6
20. Wachtell K, Bella J N, Rokkedal), et al. Change in diastolic left ventricular filling after one year of antihypertensive treatment: the losartan intervention for endpoint reduction in hypertension (LIFE)study. Circulation, 2002, 105(9):
21．张梅，张运，徐新生，等小剂量多巴酚丁胺负荷超声心动图对二尖瓣反流左室舒张功能的研究．中华超声影像学杂志，2000，9(3)：158-160
22. Zierhat W, et al. Left Ventricular wall stress and sarcoplasmic reticulum Ca~(2+)—ATPase gene expression in renal hypertensive rats dose-dependent effects of ACE inhibition and AT_(1_)receptor blockade. Cardio Res 1996.31:758-768
23. John Hyole, et al Cardio vascular Therapy Today, 2000, 4 (4): 5—7
24. Spinale FG, et al. Concomitant Endothelin Receptor Subtype A Blockade during the Progression of Pacing induced congestive heart failure in rabbits :Beneficial effects on left ventricular and myocyte function. circulation, 1997,95:1918-1929
25. Yu C M, Wang Q, Lau C P, et al. Reversible impairment of left and right ventricular systolic and diastolic function during short-lasting atrial fibrillation in patients with an implantable atrial defibrillator: a tissue Doppler imaging study. Pacing Clin Electrophysiol, 2001,24(6):979—988
26. Szatkowski M L, Westfall M V, Gomez C A, et al. In vivo acceleration of heart relaxation performance by parvalbumin gene delivery. J Clin Invest, 2001, 107(2): 191—198
27. Nishimura RA, Mechanism of hemodynamic improvement by dual-chamber pacing for left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study [J] Jam Coll Cardiol ,1995,25:281～288
2. Morgan JP, Erny RE, Allen PD, et al.Abnormal intracellular calcium handling, a major cause of systolic and diasolic dysfunction in ventricular myocardium from patients with heart failure. Circulation, 1980,81 (suppl Ⅲ)Ⅲ21—31.
3. Lorell BH, Isoyama S, Grice WN, et al. Effects of ouabain and isoproterenol on left ventricular diastolic function during low flow ischemia in isolated, blood-perfused rabbit hearts. Circulation Research, 1988,63:457-467.
4. Brutsaert DL, Fransen P. Andries LJ, et al. Cardiac endothelium and myocardial function. Cardiovasc Res. 1998; 38: 281-290.
5. Paulus WJ. Beneficial effects of nitric oxide on cardiac diastolic function: "the flip side of the coin." Heart Failure Rev. 2000; 5: 337-344.
6．张子彬 左室舒张功能障碍性心力衰竭的诊断修订标准(中国心力衰竭协会 CHFA)心血管病学进展；2002，109(3)：封二。
7. Working group report. How to diagnose heart failure. European study group on diastolic heart failure. Eur Heart J, 1998,19: 990-1003.
8. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000; 101: 2118-2121.
9. Feldman AM, Weinberg EO, Ray PE, et al. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation on rats with chronic aortic banding. Circulation Research, 1993,73 : 184-192.
10. Kiss E, Ball NA, Kranias EG, et al. Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca~(2+)- ATPase protein levels Effects on Ca~(2+) transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure Circulation Research. 1995.77:759-764.
11. Schwinger RH,Bohm M, Schmidt U, et al.Unchanged protein levels of SERCA 11 and phospholamban but reduced uptake and-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts .Circulation, 1995,92:3220-3228.
12. Gandhi SK , Powers JC , Normal A, et al. The pathogenesis of acute pulmonary edema associated with hypertension [J] N England J Med,2001,344:17～22.
13. Zile MR, Gaasch WH ,Carroll JD, et al. Heart failure with a normal ejection fraction: Is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? [J] Circulation ,2001,104:779～782.
14. Kupferema R, Mitrapp, Hohenberg-PC, et al. Analytical calculation of intracellular calcium wave characteristics, Biophys J, 1997,72:2430～2444.
15. Wckenedn-AD, Kaprielian-R, Kassiri-Z, et al. The role of action potential prolongation and altered intracellular calcium handing in the pathogenesis of heart failure. Cardiovascular Research, 1998,37:312～313.
16. Hartman-A, et al. Persisting effect of Ca~(2+) channel blockers on left ventricular function in hypertrophic cardiomyopathy after 14years treatment. Angiology, 1996. 47: 765
17. Yalcin F, Aksoy F G; Muderrisoglu H, et al. Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function. Clin Cardiol, 2000,23(6):437—41
18．陈晓瑞，崔宛华贝那普利对高血压病和冠心病 左室舒张功能不全的影响．中国新药与临床杂志，2001，20(3)：196—198
19．胡大一慢性充血性心力衰竭药物治疗的现代观点与最新进展．中国实用内科杂志，2000，20(1)：6
20. Wachtell K, Bella J N, Rokkedal), et al. Change in diastolic left ventricular filling after one year of antihypertensive treatment: the losartan intervention for endpoint reduction in hypertension (LIFE)study. Circulation, 2002, 105(9):
21．张梅，张运，徐新生，等小剂量多巴酚丁胺负荷超声心动图对二尖瓣反流左室舒张功能的研究．中华超声影像学杂志，2000，9(3)：158-160
22. Zierhat W, et al. Left Ventricular wall stress and sarcoplasmic reticulum Ca~(2+)—ATPase gene expression in renal hypertensive rats dose-dependent effects of ACE inhibition and AT_(1_)receptor blockade. Cardio Res 1996.31:758-768
23. John Hyole, et al Cardio vascular Therapy Today, 2000, 4 (4): 5—7
24. Spinale FG, et al. Concomitant Endothelin Receptor Subtype A Blockade during the Progression of Pacing induced congestive heart failure in rabbits :Beneficial effects on left ventricular and myocyte function. circulation, 1997,95:1918-1929
25. Yu C M, Wang Q, Lau C P, et al. Reversible impairment of left and right ventricular systolic and diastolic function during short-lasting atrial fibrillation in patients with an implantable atrial defibrillator: a tissue Doppler imaging study. Pacing Clin Electrophysiol, 2001,24(6):979—988
26. Szatkowski M L, Westfall M V, Gomez C A, et al. In vivo acceleration of heart relaxation performance by parvalbumin gene delivery. J Clin Invest, 2001, 107(2): 191—198
27. Nishimura RA, Mechanism of hemodynamic improvement by dual-chamber pacing for left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study [J] Jam Coll Cardiol ,1995,25:281～288