Relationship Between Myocardial Apoptosis And Endothelin-1 In Heart Failure Rats And Intervention Of β-Blockers

OBJECTIVE: Using over-afterloaded congestive heart failure rats as experimental model, to study the relationship between myocardial apoptosis and cardiac endothelin-1 gene expression and their effects on ventricular remodeling and heart function, and to investigate the intervention of carvedilol and atenolol on heart failure rats. METHODS: Partially banding abdominal aortic artery to achieve congestive heart failure rats model, 30 Wistar-Kyoto rats were randomly divided into three groups: ①heart failure group(n=10), ②atenolol group(n=10), ③carvedilol group(n=10). Sham-operated group(n=10) was set up as a control one. After 4 weeks of medicine intervention, hemodynamic parameters, left and right ventricular mass index, serum SOD and MDA, myocardial apoptosis and expression of preproendothelin-1 gene were determined in each group. RESULTS: (1)Compared with sham-operated group, hemodynamic parameters were deteriorated(P<0.01-0.05), and LVMI and RVMI were risen up by 19.8% and 40.7%, respectively, in heart failure group(p<0.001-0.01).　Under optical microscope, myocyte hypertrophy, myocardial cell degeneration, extensive areas of interstitial, inflammatory cell infiltrate were seen in heart failure rats; in heart failure rats, serum SOD activity was descended while MDA was ascended(P<0.01-0.05); myocardial apoptosis was increased significantly(p<0.001), and endothelin-1 gene was over-expressed(p<0.001). In addition, there was positive correlation betweenmyocardial apoptosis and endothelin-1 gene expression(r=0.698, p<0.05). (2)In heart failure group, there was a strong relationship between LVMI and endothelin-1(r=0.672, p<0.05), so between LVMI and myocyte apoptosis (r=0.767, P<0.01); cardiomyocyte apoptosis and endothelin-1 gene expression were associated with failured heart hemodynamic parameters(p<0.001-0.05); both cardiac apoptosis index and endothelin-1 gene expression were negatively related to SOD activity(r=-0.636, -0.744,P<0.02-0.05) and positively to MDA content(r=0.701,0.836,P<0.01-0.05). (3)In comparison with heart failure rats, HR, MBP and LVEDP were decreased and -dp/dtmax was increased after atenolol therapy(p<0.01-0.05); myocardial apoptosis index was reduced obviously(p<0.05). However, there were no significant difference on LVMI and RVMI, SOD and MDA, and cardiac endothelin-1 gene expression in atenolol group. (4)HR, MBP and LVEDP were descended, and LVSP and ±dp/dtmax were ascended (p<0.01-0.05); LVMI and RVMI were improved; serum MDA content was decreased while SOD activity was significantly increased in carvedilol group(p<0.01-0.05). After carvedilol intervention, myocyte apoptosis was on fallen and cardiac endothelin-1 gene was down-regulated(p<0.01-0.05). Besides, there was obvious difference between carvedilol group and atenolol group on myocardial apoptosis(p<0.01)CONCLUSIONS: (1)There are oxidation stress in congestive heart failure, and endothelin-1 gene expression and myocardial apoptosis are increased greatly. (2)Endothelin-1 may be a promotor for cardiac apoptosis, which indicates that interference of endothelin-1 production may be a novel therapeutic target for apoptosis. (3)Both cell apoptosis and endothelin-1 take part in ventricular remodeling. In addition, apoptosis and endothelin-1 have direct effects on the prognosis of heart failure. (4)Atenolol mainly improves diastolic function, and has prohibitive effect on myocardial apoptosis. (5)It is suggested that carvedilol, whose mechanism may be its elimination of oxygen radicals, attenuation of apoptosis and down-expression of endothelin-1 gene, has better protective effects than atenolol on heart failure and reverse of ventricular remodelling.