Alves-Lopes R, Montezano AC, Neves KB, et al. - This study attempted to ascertain if lisinopril-tryptophan, a C-domain specific ACE inhibitor that preserves the N-domain catalytic activity, together with sacubitril (NEP inhibitor), differentially influences cardiovascular function and vascular permeability in hypertension compared with omapatrilat and lisinopril+sacubitril which inhibits both the ACE C- and N-domains. Vehicle, sacubitril, lisinopril-tryptophan (lisW-S), lisinopril, lisinopril+sacubitril, or lisW-S+sacubitril were administered to Ang II (angiotensin II)–dependent hypertensive mice (transgenic mice expressing active human renin in the liver [also known as LinA3]) for 4 weeks. This study’s findings demonstrate that the targeting ACE C-domain and NEP as a combination therapy may be as effective as omapatrilat in lowering systolic blood pressure, but without inducing vascular permeability and endothelial injury.