Study Of A Combination Therapy With Enalipril And Losartan In Modification Of Myocardial Fibrosis And Cell Apoptosis In Spontaneous Hypertension Rats

Objective:To observe changes in cardiac myocyte apoptosis and myocardial fibrosis in spontaneous hypertension rats (SHR) that received either enalapril, an angiotensin converting enzyme inhibitor (ACEI), and losartan, an angiotensin II receptor antagonist, alone or combination of two chemicals. To further detect the influence on left ventricular hypertrophy of the above-mentioned three regimens and to analyze the difference between single and combined therapy. To provide rationale experimentally for potential application of this combined therapy. Methods:Forty male SHR of 18 weeks old were randomly assigned to the following 4 groups. Group A, 10 rats for blank control; Group B, 10 rats received enalapril (30mg/kg.d); Group C, 10 that received losartan (20mg/kg/d);Group D, 10 that received a combination of enalapril and losartan (enalapril 15mg/kg.d+losartan 10mg/kg.d). A fifth group of 8 Wistar Kyoto rats aged 18 weeks was set up as normal control. All these 5 groups of rats were fed with standard diet under same condition (temperature: 20-22.C; humidity 50-60%) and were decapitated after 16 weeks following peritoneal injection of barbital (50mg/kg). Cardiac index, left ventricular index, left ventricle wall thickness and diameter of myocardial cell were recorded. Blood samples were drawn for determination of plasma concentration of endothlin (ET), atrial natriureticpeptide(ANP), epinephrine(E), norepinenephrine(NE), hyaline acid (HA) and plasma renin activity (PRA). TUNEL method was applied to detect cells of apoptosis and calculate apoptosis index (AI). S-P staining was used to detect expression of bcl-2 and fas. Automatic imaging analysis system was used in quantitating myocardial fibrosis. Results:Each of three regimens has similar effect in modulating plasma concentration of ET, ANP, NE and in enhancing plasma renin activity. The combination therapy seemed to be superior to either of two drugs alone in reversing left ventricular hypertrophy (LVH). The superiority of combined therapy can also be seen in reducing cardiac apoptosis and an over-expression of fas and enhancing expression of bcl-2 protein. The combined therapy has a further benefit over losartan alone in reducing myocardial fibrosis, which is similar to enalapril alone. Conclusions:The combined therapy of enalapril and losartan is more effective in reversing left ventricular hypertrophy and modulating apoptosis-related gene expression than either of the two drugs alone.