The Different Degrees Of The Heart Rate Reduction Induced By ?-blockers Therapy On Rats With Heart Failure

Heart failure constitutes the serious and final common pathway for most forms of cardiovascular diseases.In the worldwide,heart failure has become a growing health problem.Heart failure prevalence is expected to rise in the future because of an ageing population.In the early stages of heart failure,a decline in pump function prompts increased the sympathetic nervous system activation and heart rate.Heart rate acceleration is a compensatory mechanism to maintain cardiac output in the face of declining cardiac function.However,when heart rate increases to a certain limit,it may increase myocardial oxygen consumption? accelerate cardiac relaxation and decrease coronary blood flow,actually contributes to further deterioration of cardiac function in heart failure.A large-scale clinical trial showed that five-beat increases of resting heart rate increase the risk of cardiovascular death and heart failure hospitalizations by 16%.?-adrenergic receptor??-AR?blockers directly target ?₁-adrenergic receptor??₁-AR?? reduce heart rate ? decrease myocardial oxygen consumption?improve ventricular filling function,and have beneficial effects of heart function and the prognosis of heart failure patients.The results of our early experiments study showed that ?₁-AR blockers can reduce heart rate in heart failure rats with left ventricular ejection fraction?EF?<40%,increase the levels of ?₁-AR mRNA expression,improve cardiac function parameters.However,heart rate reduction and ?₁-ARmRNA expression increased to a certain extent,heart function has not been further improved.One study has shown that ?-Blockers have beneficial clinical outcomes in the era of myocardial infarction,regardless of the LVEF.We studied cardiac function?left ventricular mass index?LVMI??the levels of ?₁-AR mRNA expression and ?₁-AR protein expression in the rats of heart failure with 40% ?EF <60% at different magnitudes of heart rate reduction,in order to explore the relationship between heart rate reduction induced by the intervention of ?₁-AR blocker bisoprolol and cardiac function.Objective: To study the relationship among cardiac function?LVMI ?₁-AR mRNA expression levels??₁-AR protein expression levels and the different magnitudes of heart rate reduction induced by ?₁-AR blocker in heart failure rats.Methods: Heart failure model was made through surgical ligation of the left anterior descending coronary artery.Sham operation group only had thoracotomy,without ligature of the artery.Transthoracic echocardiography was performed at 4 weeks after surgery in all rats.The successful standard of heart failure model was 40% ?EF <60%.25 rats reached the standard of heart failure and randomly divided into control group?G0?or one of the three ?-blocker treatment groups.Heart rate was reduced to different magnitudes by ?-blocker bisoprolol,including G1 Group: heart rate reduction 35-45 bpm;G2 group: heart rate reduction 75-85 bpm;G3 group: heart rate reduction 115-125 bpm.The three ?-blocker treatment groups were given bisoprolol by intragastric administration,while the rats of sham group and G0 group received equal volume of saline in the same way.All of the rats received 6 weeks of treatment after reach the target heart rate.Then echocardiography was conducted to detect the cardiac function.Left ventricular mass index?LVMI?was calculated at the end of the study.Reverse reaction polymerase chain reaction?RT-PCR?and Western blot?WB?method was used for determining the levels of ?₁-AR mRNA expression??₁-AR protein expression of non-infarcted myocardial,respectively.Results:1.EchocardiographyEchocardiography was performed in all of the rats at four weeks after the surgery and six weeks after the intervention of bisoprolol.Four weeks after the surgery,compared with the sham group,ejection fraction?EF?and fractional shortening?FS?were lower?left ventricular end diastolic diameter?LVEDD?and left ventricular systolic diameter?LVESD?were higher in rats of G0?G1?G2?G3 group.The differences were statistically significant?P<0.01?.Compared with the sham group,left ventricular wall thickness at end-diastolic?LVPWd??interventricular septum thickness at end-diastolic?IVSd?in rats of G0?G1?G2?G3 group were increased.The differences were statistically significant?P<0.05?.Before the drug therapy,no significant differences were observed among the rats of G0?G1?G2 and G3 groups in all of these echocardiographic indices?P>0.05?.After six weeks of therapy,FS and EF in rats of G1 and G2 groups were higher than G0 group.The differences were statistically significant?P<0.05?.Compared G3 group with G0 group,FS?EF?LVEDD?LVESD were no significant differences?P>0.05?.Compared with G0 group,LVEDD ? LVESD in rats of G1 and G2 groups decreased.The differences were statistically significant?P<0.01?.There were no statistical significant among G1?G2?G3 and G0 groups,including IVSd and LVPWd?P>0.05?.2.Heart rate and blood pressureBefore drug intervention,heart rate and blood pressure were evaluated in all of the rats with heart failure.Before drug intervention,the levels of heart rate and blood pressure in rats of G1?G2?G3 and G0 groups were similar.There were no significant differences?P>0.05?.After six weeks of ?-blocker treatment,heart rate reductions in rats of G1?G2?G3 groups were 45.00 ± 6.99 bpm? 78.83 ± 7.60 bpm,119.50 ± 10.33 bpm,receptively.The differences were statistically significant?P<0.01?.After drug intervention,there were no significant differences among the rats of G0?G1?G2 and G3 groups,including systolic blood pressure?SBP?and diastolic blood pressure?DBP??P>0.05?.3.Left ventricular mass indexCompared with the sham group,LVMI in rats of G1?G2 and G3 groups increased,but was lower than G0 group.The difference was statistically significant?P<0.01?.4.Myocardium ?₁-AR mRNA and protein expression levelsThe levels of myocardial ?₁-AR mRNA and protein expression in rats of G0 group were lower than the sham group.The differences were statistically significant?P<0.01?.Compared with G0 group,the levels of myocardial ?₁-AR mRNA and protein expression of G1 and G2 groups increased?P<0.01?,but were still lower than the sham group?P<0.01?.There were no statistical differences about the levels of ?₁-AR mRNA and protein expression between G1 and G2 groups?P>0.05?.Compared with G0 group,?₁-AR mRNA in rats of G3 group increased.There was no significant difference?P>0.05?.?₁-AR protein expression of G3 group statistically increased?P<0.01?.The levels of ?₁-AR mRNA and protein expression in G3 group were lower than G1 and G2 groups,the differences were statistically significant?P<0.05?.Conclusions:When heart rate reductions were 35-45 bpm and 75-85 bpm,not only heart function was improved,but also the levels of ?₁-AR mRNA and protein expression were upregulated;however,with the continued decline in heart rate,as the heart rate decreased 115-125 bpm,cardiac function was no further improvement.Compared with G0 group,the levels of myocardial ?₁-AR mRNA and protein expression of G3 group increased,but still were lower than G1 and G2 groups.