The combination of valsartan and sacubitril does not improve effectiveness against AngII-induced AAAs

Abstract

Abdominal aortic aneurysm (AAA) is defined as permanent dilation of the abdominal aorta by more than 50% of its normal diameter. As AAAs grow progressively, the aorta can rupture and cause life-threatening bleeding. Preliminary data demonstrates that angiotensin II (AngII), which can induce AAA, plus testosterone were powerful stimulants for expression of neprilysin in abdominal aortic smooth muscle cells from male mice. Neprilysin is a metalloendopeptidase, which can cleave and inactivate AngII and natriuretic peptides. Because natriuretic peptides might be beneficial for reducing the growth of AAAs through decreasing blood pressure, inhibition of neprilysin along with blocking AngII receptor would be predicted to decrease AAA formation. Sacubitril is a competitive inhibitor of neprilysin and has been utilized with valsartan, an AngII receptor blocker, in the treatment of heart failure; however, this combination has not been tested against AAA formation. Therefore, in this study we evaluated the effects of valsartan, sacubitril, and their combination on the formation of AngII-induced AAAs. We treated the male mice with either solvent (control), valsartan (0.3, 0.5, 1, 6, or 20 mg/kg/day), sacubitril (1, 6, and 9 mg/kg/day), or the combination, which were 0.3 mg/kg/day valsartan with 1 mg/kg/day sacubitril or 0.5 mg/kg/day valsartan with 9 mg/kg/day sacubitril. All the treatments were infused (sc) for seven days prior to administering AngII and then along with AngII infusion for 28 days. We found that valsartan, except for the 0.3 mg/kg/day dose, dose-dependently inhibited AngII-infused AAA formation compared to the control. Sacubitril did not inhibit AAA formation at any dose examined. Combinational drug therapy also showed no additional effect on reducing AAA formation beyond that of valsartan alone