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Title: In-vitro and in-vivo inhibition of rat neutral endopeptidase and angiotensin converting enzyme with the vasopeptidase inhibitor gemopatrilat.
Austin Authors: Hubner, R A;Kubota, E;Casley, David J;Johnston, Colin I;Burrell, Louise M 
Affiliation: Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia
Issue Date: 1-May-2001
Publication information: Journal of Hypertension; 19(5): 941-6
Abstract: Vasopeptidase inhibitors are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). The aim of this study was to characterize in-vitro and in-vivo inhibition of NEP and ACE in the rat with the vasopeptidase inhibitor gemopatrilat.In-vitro NEP and ACE inhibition was studied by radioinhibitory binding assay using rat renal membranes and the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A, respectively (n = 3 per curve). In-vivo NEP and ACE inhibition was studied using in-vitro autoradiography in rats that received oral gemopatrilat (1, 3, 10 mg/kg; n = 4 per dose) and were killed 1 h later, or received oral gemopatrilat (3, 10 mg/kg) and were killed at time points 1, 2, 4, 8, 18, 24 and 48 h (n = 4 per time point).Gemopatrilat caused a concentration-dependent displacement of specific radioligands from renal membrane NEP (IC50 305 +/- 5.4 nmol/I) and ACE (IC50 3.6 +/- 0.02 nmol/). In the dose-response study gemopatrilat (1, 3 and 10 mg/kg) caused significant inhibition of plasma ACE (P< 0.01), and renal ACE and NEP (3, 10 mg/kg, P < 0.01). In the time course experiment, gemopatrilat (10 mg/kg) increased plasma renin activity for 8 h (P< 0.01) and inhibited plasma ACE (P< 0.05), renal NEP (P< 0.01) and renal ACE (P< 0.05) for 48 h.Gemopatrilat is a potent in-vitro vasopeptidase inhibitor that also causes prolonged inhibition of circulating and renal ACE and renal NEP after a single oral dose. The data suggest that gemopatrilat may be a useful addition to existing vasopeptidase inhibitors in the treatment of cardiovascular disease.
Gov't Doc #: 11393678
Type: Journal Article
Subjects: Administration, Oral
Angiotensin-Converting Enzyme Inhibitors.pharmacology
Binding, Competitive
Dose-Response Relationship, Drug
Enzyme Inhibitors.pharmacology
In Vitro Techniques
Iodine Radioisotopes
Neprilysin.antagonists & inhibitors
Protease Inhibitors.pharmacology
Rats, Sprague-Dawley
Time Factors
gamma-Aminobutyric Acid.analogs & derivatives.metabolism
Appears in Collections:Journal articles

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