Therapeutic assessment of combination therapy with a neprilysin inhibitor and angiotensin type 1 receptor antagonist on angiotensin II-induced atherosclerosis, abdominal aortic aneurysms, and hypertension.

Combined neprilysin (NEP) inhibition (sacubitril) and angiotensin type 1 receptor (AT1R) antagonism (valsartan) is used in the treatment of congestive heart failure and is gaining interest for other angiotensin II (AngII)-related cardiovascular diseases. In addition to heart failure, AngII promotes hypertension, atherosclerosis and abdominal aortic aneurysms (AAAs). Similarly, NEP substrates or products have broad effects on the cardiovascular system. In this study we examined NEP inhibition (with sacubitril) and AT1R antagonism (with valsartan) alone or in combination on AngII-induced hypertension, atherosclerosis or AAAs in male low density lipoprotein receptor (Ldlr) deficient mice. Preliminary studies assessed drug delivery via osmotic minipumps for simultaneous release of sacubitril and/or valsartan with AngII over 28 days. Mice were infused with AngII (1,000 ng/kg/min) in the absence (vehicle, VEH) or presence of sacubitril (1, 6 or 9 mg/kg/day), valsartan (0.3, 0.5, 1, 6 or 20 mg/kg/day), or the combination thereof (1 and 0.3, or 9 or 0.5 mg/kg/day of sacubitril and valsartan, respectively). Plasma AngII and renin concentrations increased 4-fold at higher valsartan doses indicative of removal of AngII negative feedback on renin. Sacubitril doubled plasma AngII concentrations at lower doses (1 mg/kg/day). Valsartan dose-dependently decreased systolic blood pressure, aortic atherosclerosis and AAAs of AngII-infused mice, while sacubitril had no effect on atherosclerosis or AAAs, but reduced blood pressures of AngII-infused mice. Combination therapy with sacubitril and valsartan did not provide additive benefits. These results suggest limited effects of combination therapy with NEP inhibition and AT1R antagonism against AngII-induced hypertension, atherosclerosis or AAAs. Significance Statement The combination of valsartan (AT1R antagonist) and sacubitril (NEP inhibitor) did not provide benefit above valsartan alone on AngII-induced hypertension, atherosclerosis or AAAs in Ldlr-/- mice. These results do not support this drug combination in therapy of these AngII-induced cardiovascular diseases.