INHIBITION OF ACE C-DOMAIN AND NEPRILYSIN AS A NEW THERAPY IN HYPERTENSION

Abstract

Objective: Dual inhibitors of neutral endopeptidase (NEP) and ACE (omapatrilat) have potent blood pressure-lowering actions, with angioedema as a side effect, due to bradykinin accumulation. Here we assessed whether a C-domain specific ACE inhibitor, lisinopril-trp (lis-trp), which specifically inhibits Ang II production while maintaining bradykinin metabolism, in combination with a NEP inhibitor (sacubitril), influences blood pressure, vascular function and the RAAS system in hypertension. Design and method: Ang II was measured by LC-MS/MS (liquid chromatography). WT and AngII-dependent hypertensive mice (TTRhRen) received vehicle, sacubitril, lis-trp, lisinopril, sacubitril + lisinopril, sacubitril + lis-trp and omapatrilat for 4 weeks. Blood pressure (BP) was measured by tail-cuff and vascular function/structure of mesenteric arteries by myography. Results: Increased AngII levels in TTRhRen mice (pg/g: WT 254.90 ± 46.94 vs TTRhRen 623.70 ± 58.21) was reduced by lis-trp (309 ± 33.84), p < 0.05. Systolic BP was increased in TTRhRen mice (WT 107.5 ± 4.04 vs TTRhRen 135.3 ± 3.99) and reduced by sacubitril + lis-trp (117.0 ± 1.08) and omapatrilat (113.6 ± 2.52), p < 0.05. Hypercontractility in TTRhRen mice (WT 9.42 ± 0.20 vs TTRhRen 10.84 ± 0.19) was reversed by sacubitril + lis-trp (9.43 ± 0.39 p < 0.01), with no change in endothelial dysfunction (WT 92.72 ± 5.1 vs TTRhRen 65.05 ± 3.21 vs TTRhRen + sacubitril + lis-trp 61.04 ± 6.89, p < 0.05). Omapatrilat decreased contraction and improved vasodilation, which may contribute to angioedema. Additionally, sacubitril + lis-trp reversed hypertension-associated inward hypertrophic vaxscular remodelling (CSA um2: LinA3 2832000 ± 248200 vs sacubitril + lis-trp 1693000 ± 199700). These effects were similar to those of omapatrilat (CSA um2: 2286333 ± 44796.66). Conclusions: The combination of a C-domain selective ACEi plus a NEP inhibitor reduces blood pressure, normalises vascular contraction and prevents vascular remodelling in an endothelium-independent manner.