Effects of Membrane Metallo-Endopeptidase Inhibitor Alone or in Combination with Azilsartan on Renin-Angiotensin-Aldosterone-System in Rats with Heart Failure

Abstract

Purpose: Renin-angiotensin-aldosterone-system activation associated with heart failure is one of the main determinants of health condition deterioration of the patients with heart failure. The aim of this study is to compare the effectiveness of the metallo-endopeptidase inhibitor Sacubitril alone and in combination with azilsartan in ameliorating syndromes of heart failure in rats. Materials and Methods: twenty four rats were divided into 4 groups, each of 6 rats. The first group served as the normal control group. Heart failure was induced in the rats of the other three groups with isoproterenol 5 mg/kg/day for one week, 2nd group rats served as appositive control group, rats in the 3rd, and 4th groups were administered daily oral doses of sacubitril, and sacubitril-azilsartan combination respectively for two weeks. Results: Heart failure induction in rats with isoproterenol showed a statistically significant increase in plasma concentration of NT-proBNP, MMP9, Renin, Troponin I, and CK-MB. A significant decrease in mean blood pressure, urine flow, glomerular filtration rate was observed. Administration of sacubitril-azilsartan combinations showed a significant fall of MMP9, NT-proBNP, serum urea, Troponin I and creatinine. Rats that have received Sacubitril alone did not show significant changes in the mentioned parameters except for NT-proBNP and serum creatinine. Combining sacubitril with azilsartan showed a significant increase in urine flow, glomerular filtration rate, and renin plasma level, whereas Sacubitril alone failed to show a significant change in the mentioned parameters. Conclusion: Combination of sacubitril with azilsartan showed better efficacy to sacubitril monotherapy in improving plasma levels of cardiac biomarkers: NT-proBNP, MMP9, and troponin I levels. It has ameliorated compromised renal function through increasing glomerular filtration rate, urine flow, creatinine clearance, and urea clearance. Results revealed that the combination (azilsartan-sacubitril) showed better ameliorating impacts on syndromes of heart failure induced by isoproterenol in rats.