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      Role of Angiotensin-Converting Enzyme and Neutral Endopeptidase in Flow-Dependent Remodeling

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          Omapatrilat inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). We compared the effects of omapatrilat (40 mg/kg/day, p.o.) to fosinopril (40 mg/kg/day, p.o.) on flow-induced vascular remodeling in New Zealand genetically hypertensive (GH) rats. Both drugs equally reduced blood pressure (BP) initially, but systolic BP and pulse pressure were reduced more by omapatrilat after 1 week. Carotid remodeling was induced by partial ligation of the left common carotid artery (LCA). There was little remodeling in untreated GH rats – measured as outer diameter to body weight (OD/BW vs. before ligation): 97 ± 1% of initial LCA (low flow) and 107 ± 3% of initial right common carotid artery (RCA, high flow). In contrast, OD/BW increased to 118 ± 5% (p < 0.05) of initial RCA after omapatrilat versus 108 ± 2% (p = 0.96) after fosinopril. The major change was increased RCA lumen area which was significantly larger in omapatrilat-treated animals (127% vs. control) than fosinopril-treated animals (103% vs. control). The increase in outward remodeling after omapatrilat treatment correlated weakly with vascular cGMP levels and decreased systolic BP. The results suggest that dual inhibition of NEP/ACE may have greater effects than ACE inhibition alone on vessel remodeling in hypertension.

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          Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial

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            Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase.

            A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.
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              Bradykinin-stimulated protein tyrosine phosphorylation promotes endothelial nitric oxide synthase translocation to the cytoskeleton.

              Stimulation of bovine aortic endothelial cells (BAEC) with bradykinin produces cycles of tyrosine phosphorylation/dephosphorylation of a 90 kDa endothelial nitric oxide synthase (eNOS)-associated protein which we have termed ENAP-1 (for endothelial nitric oxide synthase-associated protein 1). ENAP-1 interacts specifically and tightly with eNOS in BAEC and is co-immunoprecipitated from cell lysates with anti-eNOS antibodies. In addition, anti-phosphotyrosine antibodies co-precipitate eNOS. Bradykinin-stimulated tyrosine phosphorylation of ENAP-1 is blocked by the tyrosine kinase inhibitor, tyrphostin. Dephosphorylation is blocked by the tyrosine phosphatase inhibitor, orthovanadate. Treatment of BAEC with bradykinin or the tyrosine phosphatase inhibitor, phenylarsine oxide promotes tyrosine phosphorylation of detergent-insoluble, cytoskeletal proteins accompanied by translocation of eNOS to the cytoskeletal subcellular compartment. Translocation is blocked by the tyrosine kinase inhibitor, geldanamycin and does not appear to alter enzyme catalytic activity. Tyrosine phosphorylation-dependent association of eNOS with the cytoskeleton may have a role in targeting NO production to specific subcellular locations.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2004
                21 April 2004
                : 41
                : 2
                : 148-156
                aCenter for Cardiovascular Research and Department of Medicine, University of Rochester, Rochester, N.Y., and bDepartment of Internal Medicine, University of Virginia Health System, Charlottesville, Va., USA
                77144 J Vasc Res 2004;41:148–156
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 9, Tables: 3, References: 28, Pages: 9
                Research Paper


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