Effect Of DAA-â…  And Danshensu On Ventricular Remodeling During Heart Failure Induced By Adriamycin In Rat

ObjectiveBy through the model rats of heart failure induced with adriamycin(ADR),to investigate the function of angiotensinâ…¡(Angâ…¡),Matrix metalloproteinase(MMP-9) and tissue inhibitor of metalloproteinase(TIMP-1) in extracellular matrix remodeling,to explore the influence and possible mechanisms of desasparticacid angiotensinâ… (DAA-â… ),Danshensu and captopril which may be contributed to improve the LV remodeling.Methods1.Model of heart failure and Sub-agents:98 male SD rats were randomly divided into ten groups:normal control,model control,best concentration of DAA-â… ,high concentration of DAA-â… ,low concentration of DAA-â… ,best concentration of DAA-â… +Indomethacin,Danshensu, Danshensu+best concentration of DAA-â… ,Danshensu+high concentration of DAA-â… ,captopril. There were eight rats in normal control group accompanied by ten rats in every group of others. We established the experimental model of heart failure in rats by intraperitoneal injection of ADR.The dosage of 2mg/kg must be applied for a total medication of seven weeks that had been injected every three days for Ex-five times and the fllowing every seven days for once.Five weeks later,it began to give intervention on corresponding groups with drugs for four weeks in accordance with the following amount:best concentration of DAA-â… 1013pmol/kg·d,high concentration of DAA-â… 4053pmol/kg·d,low concentration of DAA-â… 506pmol/kg·d, indomethacin 25mg/kg·d,Danshensu 50mg/kg·d,captopril 10mg/kg·d.2.Hemodynamics measurement:Functional biology systems had been made use of evaluating cardiac function of rats by the hemodynamic changes.PE50 pipe connected to biological system through the pressure transducer was intubated from right common carotid artery to Left ventricular,and then,the computer in real-time scanning made the analysis of heart rate(HR),left ventricular systolic pressure(LVSP),left ventricular end-diastolic pressure (LEVDP),the largest increase in the rate of left ventricular pressure(+dp/dtmax) and fall rate (-dp/dtmax).3.Angâ…¡levels in plasma:Angâ…¡level in plasma was detected by RIA kit in order to compare the changes in the level of Angâ…¡for different medication.4.Gene expression of MMP-9 and TIMP-1:MRNA expression of MMP-9 and TIMP-1 was detected by RT-PCR in order to compare the effects of drugs intervention on MMP-9 and TIMP-1 in myocardial tissue. 5.VG staining of myocardial tissue:Myocardial pathology was observed by VG staining.In staining slices,it can be seen bright red collagen fibers,brown muscle fibers and dark blue nucleus.Basic structure of myocardial fibers and proliferation of collagen fibers were observed in each group.Results1.Mortality:The rats of normal control group had all survived.There was serious depletion of the model group that the mortality rate of 40%was much higher than the other treatment groups,and but best concentration of DAA-â… +indomethacin had the same grievous condition of death.Particularly in the treatment groups Danshensu+best concentration of DAA-â… had the most significant effect for the mortality rate at 20%,and the remaining groups were reduced in varying degrees.2.Cardiac function:Compared with the normal group,HR and LVEDP of model group showed a clear upward trend,and LVSP,±dp/dtmax decreased,however the differences are obvious(P＜0.01).Compared with model group,HR and LVEDP of best concentration of DAA-â… group and low concentration of DAA-â… group were in lower levels.LVSP and±dp/dtmax increased.Simultaneously the five indicators were significant differences(P＜0.01).By contrast, high concentration of DAA-â… group and best concentration of DAA-â… +indomethacin group did not have differences with model group.It's most apparent of danshensu+best concentration of DAA-â… group that HR and LVEDP decreased as well as LVSP and±dp/dtmax increased during the groups concerned about danshensu.The other two groups had significant differences (P＜0.05)with model group though the range of changes was inferiorer than the former group.At the same time,captopril can significantly decrease HR and LVEDP,still increase LVSP and±dp /dtmax(P＜0.01).3.Angâ…¡levels in plasma:Compared with normal group,Angâ…¡level of model group was at 525.40±43.15 pg/ml that woule be in a high position(P＜0.01).Compared with model group, with the exception of DAA-â… +indomethacin group for 522.17±42.09 pg/ml,the other treatment groups had significant differences(P＜0.01).Separately at 342.21±32.69 pg/ml and 338.62±36.76 pg/ml of Angâ…¡level,best concentration of DAA-â… group and Danshensu+ DAA-â… concentration group were superior to high concentration of DAA-â… group and low concentration of DAA-â… group(P＜0.01),while there was no significant difference between best concentration of DAA-â… group and Danshensu+ DAA-â… group(P＞0.05) that it illustrates that their therapeutic effects are analogous.Captopril group reduced the concentration of Angâ…¡more well at 315.59±28.93 pg/ml than Danshensu+best concentration of DAA-â… and best concentration of DAA-â… (P＜0.01).4.Myocardium pathology:In model group,microscopic observation showed that the nucleus was located in the edge of muscle fiber.Then,the thickening myofibril completely appeared irregular shape with scattered disorder,still there was edema,proliferation of connective tissue and infiltration of inflammatory cells.Best concentration of DAA-â… +indomethacin group and high concentration of DAA-â… group were still in the doldrums.The other treatment groups had improved in varying degrees.5.Expression of MMP-9 mRNA:Compared with normal group,MMP-9 mRNA expression for 0.87±0.18 of model group had significantly increased by 314.28%(P＜0.01),and the other treatment groups that increased in varying degrees had significant statistical significances (P＜0.01).Compared with the model group,with the exception of best concentration of DAA-â… + indomethacin group for 0.86±0.11,MMP-9 mRNA expressions of the other treatment groups that reduced in varying degrees had significant differences(P＜0.01).6.Expression of TIMP-1 mRNA:Compared with normal group,TIMP-1 mRNA expression for 0.42±0.11 of model group had slightly increased by 23.52%(P＜0.05),and the other treatment groups that increased in varying degrees had significant statistical significances (P＜0.01).Compared with the model group,In addition to best concentration of DAA-â… + indomethacin group for 0.42±0.14,TIMP-1 mRNA expressions of the other treatment groups that increased in varying degrees had significant differences(P＜0.01).Conclusion1.In the premise of the cumulative dose,the CHF model in rats induced by ADR rat is reliable and effective.In the process of experiment,there would be to emerge a series of signs and symptoms of CHF such as drowsy,diarrhea,lip-week cyanosis,difficulty breathing,haggard hair,ascites,individual death.2.Pathophysiology process of heart failure is closely related to ventricular remodeling. Thence it would be of important clinical significance to take measures in time for improving cardiac function and coping with remodeling on the delay of malignant transformation.3.The function of DAA-â… is not positively correlated with the dose.DAA-â… in the dosage of 1013pmol/kg can maximize the effectiveness that it can reverse ventricular remodeling and block the development process of CHF because of blocking the cardiovascular effects of Angâ…¡,relieving CHF symptoms,improving cardiac function,reducing the expression of MMP-9 and enhancing the expression of TIMP-1.4.DAA-â… in dosage of 4053pmol/kg would be unable to have an impact on ventricular remodeling because the cardiovascular protective effect is reversed and even more Angâ…¡is not effectively blocked.5.DAA-â… in dosage of 506pmol/kg is difficult to form a most effectiveness against ventricular remodeling obviously.6.Indomethacin sensitived for AT1R plays a important role in the cardiovascular system for preventing DAA-â… effectively.7.Danshensu is known as the role of anti-myocardial fibrosis.It applied Individually has a weak effect to heart that is far less than DAA-â… .It can significantly improve matrix remodeling which affect on heart with DAA-â… ,and however there is a prerequisite that the dosage of DAA-â… is 1013pmol/kg.When the dose has achieved 4053pmol/kg,the protective effect of heart weaker than the former and but stronger than alone application of Danshensu.Therefore,Danshensu combined with DAA-â… can have synergy in the confrontation of ventricular remodeling.8.There is a genuine role for Captopril that it can reverse the effects of cardiac hypertrophy,improve symptoms of heart failure and slow down the process of heart failure. However,DAA-â… in the dosage of 1013pmol/kg has advantages more than captopril on improving cardiac function and incremental regulation of TIMP-1 to achieve a balance with MMP-9.The other effects of cardiovascular protection from ventricular remodeling are similar.9.DAA-â… combined with the AT1 receptor may be confronted with the cardiovascular effects of Angâ…¡potentially along with blocking AT1 receptor on induction of downstream to MMPs.At the same time,a high level of Angâ…¡in local tissue and circulation excited type 2 receptor indirectly through the feedback cycle after that Angâ…¡combining with AT1 has been blocked.Thus the stimulation of AT2 gives rise to the phosphorylation of modulator protein because of Angâ…¡combining with AT2 so that it will be vasodilatation,inhibiting growth and differentiation of cells and moreover promoting the endothelial cells to produce NO,PGI₂, bradykinin.Ventricular remodeling would be taken a favorable turn eventually.