Effects Of Different Doses Of Perindopril On Cardiac Function And ACE2/Ang-(1-9)/Ang-(1-7) Axis Of Ischemic Cardiac Dysfunction Rabbits

Objective: To investigate the appropriate dose of perindopril in treatment of ischemic cardiac dysfunction and the mechanisms of different dose of perindopril on cardiac function improvement in rabbits with ischemic cardiac dysfunction.Methods:1 Fourty male rabbits were randomly divided into 4 groups(n=10): High dose perindopril group, Low dose perindopril group, Saline group and Control group. After ischemic cardiac dysfunction models were made, rabbits of the first two groups were treated with perindopril split normal saline solution 2ml/kg/d via intragastric administration(1mg/ml and 0.33mg/ml respectively), while rabbits in the last two groups were treated with normal saline.2 The left anterior descending coronary arterys of the rabbits were ligatured for model preparation. Rabbits with left ventricular enjection fraction <50% measured with echocardiography 2 weeks after myocardial infarction were enrolled, then they were administered drug of corresponding dose.3 Cardiac function were detected by cardiac uhrasonography after 4 weeks treatment, and left ventricular enjection fraction, left ventricle fractional shortening and left ventricular end diastolic diameter were recorded.4 Serum samples were collected and Ang-(1-9) and Ang-(1-7) level of the samples were further tested with ELISA after 4 weeks treatment.5 Angiotensin-Converting Enzyme 2 and Angiotensin Type 2 Receptor mRNA level of myocardial of the infracted border zone were determinated via Real-Time PCR after 4 weeks treatment.Results: 1 LVEF and LVFS of cardiac dysfunction rabbits significantly decrease(P < 0.001, P=0.003), but LVEDD invreases(P < 0.001); After Perindopril administered, cardiac dysfunction was significantly improved, and better effects were obtained in the high dose perindopril group(P=0.041). 2 ACE2 and AT2 R mRNA expression of the cardiac dysfunction rabbits were significantly higher compared with control group(P < 0.001); ACE2 and AT2 R mRNA expression of the infarct area were significantly higher with perindopril treatment(P<0.001), and significantly higher in the high dose perindopril group than the low dose perindopril group(P<0.001). 3 Serum Ang-(1-9) and Ang-(1-7) level of the cardiac dysfunction rabbits increased after perindopril administered; compared with low dose perindopril group, Ang-(1-9) level of high dose perindopril group was significantly higher(P=0.012), while no statistical difference of Ang-(1-7) level was found between the two groups. 4 Correlation analysis indicated that LVEF was positively correlated with ACE2(R=0.720, P=0.001), AT2R(R=0.613, P=0.007) and serum Ang-(1-9) level(R=0.683, P=0.002), but had no correlation with serum Ang-(1-7) level(P=0.067).Conclusion:1 ACE2/Ang-(1-9)/Ang-(1-7) axis is simultaneous activated with RAAS in cardiac dysfunction rabbits.2 Perindopril can improve cardiac function via ACE2/Ang-(1-9)/Ang-(1-7) axis activation.3 High dose perindopril can improve cardiac function of the ischemic cardiac dysfunction rabbits more effectively than low dose perindopril.4 High dose of perindopril can improve the serum Ang-(1-9) level, and enhance the expression of ACE2 and AT2 R mRNA of infarcted border zone.5 Further improvement of high dose of perindopril on cardiac function may be correlated with increased ACE2 expression and Ang-(1-9) level, leading to AT2 R activation.