Inhibition of ACE C-domain and Neprilysin as a New Therapy in Hypertension

Inhibition of ACE C-domain and Neprilysin as a New Therapy in Hypertension

• Autor
• Rheure Alves-Lopes
• Co-autores
• Augusto Montezano , Adam Harvey , Francisco Rios , Delyth Graham , Marko Poglitsch , Edward Sturrock , Rhian M Touyz
• Resumo

• Introduction:Dual inhibition of neutral endopeptidase (NEP) and angiotensin (Ang) converting enzyme (ACE) with omapatrilat was a promising antihypertensive drug but was associated with angioedema attributed to bradykinin (BK) accumulation. Here we assessed whether a C-domain specific ACE inhibitor, lisinopril-trp (LisW-S), which specifically inhibits Ang II production while maintaining BK metabolism, in combination with a NEP inhibitor (sacubitril), influences blood pressure, vascular function and permeability and the RAAS system in hypertension. Design and Methods:AngII was measured by LC-MS/MS (liquid chromatography). WT and Ang II-dependent hypertensive mice (male – 12-week old - TTRhRen) received vehicle, sacubitril, lisW-S, lisinopril, sacubitril+lisinopril, sacubitril+lisW-S and omapatrilat for 4 weeks. Blood pressure (BP) was measured by tail-cuff and vascular function/structure of mesenteric arteries and vascular permeability by myography and Evans Blue extravasation, respectively. This work was performed in accordance with the United Kingdom Animals Scientific Procedures Act 1986 (Licence No. 70/9021). Results: Increased AngII levels in TTRhRenmice (pg/g: WT 254.90±46.94vsTTRhRen623.70±58.21) was reduced by lisW-S (309±33.84), p<0.05. Systolic BP was increased in TTRhRenmice (WT 107.5±4.04 vsTTRhRen135.3±3.99) and reduced by sacubitril+lisW-S (117.0±1.08) and omapatrilat (113.6±2.52), p<0.05. Hypercontractility in TTRhRenmice (WT 9.42±0.20 vs TTRhRen10.84±0.19) was reversed by sacubitril+lisW-S (9.43±0.39 p<0.01), with no change in endothelial dysfunction (WT 92.72±5.1 vsTTRhRen65.05±3.21 vsTTRhRen+sacubitril+lisW-S61.04±6.89, p<0.05). Omapatrilat decreased contraction and improved vasodilation, followed by increased vascular permeability, which may contribute to angioedema. Additionally, sacubitril+lisW-S reversed hypertension-associated inward hypertrophic vascular remodelling (CSA mm2: LinA3 2832000 ± 248200 vs sacubitril+lisW-S 1693000 ± 199700). These effects were similar to those of omapatrilat (CSA mm2: 2286333 ± 44796.66). Conclusion: The combination of a C-domain selective ACEiplus a NEP inhibitor reduces blood pressure, normalises vascular contraction and prevents vascular remodelling in an endothelium-independent manner. 

• Palavras-chave
• Hypertension, Angiotensin Converting Enzyme, Neutral Endopeptidase
• Modalidade
• Comunicação oral
• Área Temática
• Disfunção endotelial