| 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<D.01) 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 in mean arterial blood and systolic blood pressure, with a decrease by50.6%in pressure at the end of ventricular diastolic; there is an increase by25.5%and31.3%(P<0.01) separately in the increase and decrease of ventricular pressure and maximum rate.(2) ISO has led to a high T wave in Ⅱ Lead ECG, together with an increase in ST. However, the T wave level in Ⅱ Lead ECG is much lower with YangXinTongMai and ST has been improved. Compared with low-dose-dependent of YangXinTongMai group, the improvement in high-dose dependent of YangXinTongMai is more obvious.(3) Pathology has revealed that, compared with control group, there is a large fibrosis area in the endocradial in ISO group, together with myocardial necrosis scattered locally. The remaining myocardial fiber has become thickening and arranged disorderly. There are signs of swelling, fracture, disappearing or even dissolving of striated muscle, thus lead to the occurrence of hyaline and fatty degeneration, interstitial tissue. Compared with ISO group, in the low-dose YangXinTongMai group, there is no obvious sign of thickening in myocardial fibers disorganized ventricular wall. The necrotic area has reduced greatly, in a small focal strip, with the remaining myocardial fibers arranged neatly in rows. In the high-dose YangXinTongMai group, cardiac muscle fibers is as normal, neatly arranged, with no swelling, fracture, dissolution and fatty degernation of phenomenon.(4) The result, detected by Western blot, of the analysis of myocardial apoptosis protein Bcl-2and Bax in protein expression shows that the level of myocardial apoptosis protein Bcl-2reduced significantly while Bax protein expression increased, which shows the rotio between Bcl-2/Bax decreased, with a difference of statistics significance (P<0.05). After YangXinTongMai being taken, there is an increase in the Bcl-2expression and a reduce in Bax expression. The ratio between Bcl-2/Bax increased. A significant difference can be seen compared with YangXinTongMai (P<0.01) especially for theHigh-dose YangXinTongMai group.(5) The result of myocardial tissue of Akt via Western blot shows that, compared with normal control group, ISO has reduced greatly the Akt level of protein expression. After Dealt with YangXinTongMai, the Akt level of protein expression increased greatly, especially in high-dose-dependent YangXinTongMai group (6) Compared with normal control group, in ISO group, the blood of Rats and Myocardial tissue superoxide dismutase (SOD) reduced respectively by59.7%and41.8%. Plasma and Myocardial tissue superoxide dismutase (SOD) in the two different dosed groups decrease by39.0%,19.6%and by24.8%,8.7%. There is significant defference in staticstics (average P<0.05). Compared with the model group, in both the low-dose and high-dose YangXinTongMai group, there is an increase in plasma and ventricular tissue superoxide dismutase (SOD) by14.7%,34%and by13.6%,41.8%, with a significant defference in staticstics (average P<0.05). Malondiadehyde (MDA) in Plasma and myocardial tissue has decreased respectively by29.7.4%,62.6%and103.5%,163%. with significant difference in staticstics (average P<0.01). Plasma lactate dehydrogenase (LDH) reduce by45.7%and68.1%, with significant difference in staticstics (average P<0.01). Compared with the lower-dose YangXinTongMai group, plasma and ventricular tissue superxide dismutase (SOD) in the high-dose YangXinTongMai group has increased respectively by16.1%and36.4%. MDA of plasma and Myocardial tissue decreased respectively by25.2%and29.3%; LDH has decreased by15.3%, with with significant difference in staticstics (average P<0.05).(7) The density of IMD of Plasma asnd the myocardial tissue in normal control group is divided into29.2±5.0pg/ml and1.58±0.23pg/mg. pro. After dealt with ISO, there is a largely decrease of secretion in IMD of plasma and myocardial tissue, with a comparative significant difference, compared with normal groups (P<0.05). Compared with ISO model group, it shows that there is an increase in IMD of plasma and myocardial tissue in low-dose group but with no statistics significance. After dealt with high-dose YangXinTongMai, there is an increase in both plasma and the IMD density (P<0.01). The density of plasma and myocardial tissue ET of the normal control group is32.2±9.3pg/ml and1.09±0.39pg/mg. pro. Compared with control group, the secretion of plasma and myocardial tissue ET increase greatly (P<0.01). After dealt with YangXintongMai, the density of both plasma and myocardial tissue ET has decreased (P<0.01).(8) The Na+-K+-ATPase activity of normal cardiac plasma membrane of Rats is0.57±0.01μmol Pi/mg pro. h; compared with control group, Na+-K+-ATPase activity of ISO treatment group decreased by138.5%(0.24±0.01vs0.57±0.01,P<0.01). YangXinTongMai can increase the Na+-K+-ATPase activity, which, compared with ISO model group, has increased separately by49.0%and55.6%, with a significant difference in statistics (average P<0.01). There is an obvious difference between high-dose and low-dose groups (P<0.01)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. |
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