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Title: Antihypertensive and antihypertrophic effects of omapatrilat in SHR.
Austin Authors: Burrell, Louise M ;Droogh, J;Man in't Veld, O;Rockell, M D;Farina, N K;Johnston, Colin I
Affiliation: Department of Medicine, The University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia
Issue Date: 1-Oct-2000
Publication information: American Journal of Hypertension; 13(10): 1110-6
Abstract: Vasopeptidase inhibitors, such as omapatrilat are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). In normotensive rats, a single dose of oral omapatrilat (10 mg/kg) and 1 mg/kg inhibited plasma ACE (P < .01) for 24 h and increased plasma renin activity for 8 h (P < .01). In vitro autoradiography using the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A showed omapatrilat (10 mg/kg) caused rapid and potent inhibition of renal NEP and ACE, respectively, for 24 h (P < .01). In spontaneously hypertensive rats, 10 days of oral omapatrilat (40 mg/kg/day) reduced blood pressure (vehicle 237 +/- 4 mm Hg; omapatrilat, 10 mg/kg, 212 +/- 4 mm Hg; omapatrilat 40 mg/kg, 197 +/- 4 mm Hg, P < .01) in a dose-dependent manner (10 v 40 mg/kg, P < .01). Left ventricular hypertrophy was significantly reduced by high-dose omapatrilat (vehicle 2.76 +/- 0.03 mg/g body weight; omapatrilat, 10 mg/kg, 2.71 +/- 0.02 mg/g; omapatrilat 40 mg/kg, 2.55 +/- 0.02 mg/g, P < .01) and omapatrilat also increased kidney weight compared to vehicle (both doses, P < .01). Omapatrilat caused significant inhibition of plasma ACE and increased plasma renin activity (both doses, P < .01), and in vitro autoradiographic studies indicated sustained inhibition of renal ACE and NEP (both doses, P < .01). Omapatrilat is a potent vasopeptidase inhibitor, and its antihypertensive effects are associated with inhibition of NEP and ACE at the tissue level and beneficial effects on cardiovascular structure. Relating the degree of tissue inhibition to physiologic responses may allow further definition of the role of local renin angiotensin and natriuretic peptide systems in the beneficial effects of vasopeptidase inhibitors.
Gov't Doc #: 11041166
Type: Journal Article
Subjects: Animals
Antihypertensive Agents.therapeutic use
Blood Pressure.drug effects
Cardiomegaly.drug therapy.pathology
Dose-Response Relationship, Drug
Hypertension.drug therapy.physiopathology
Neprilysin.antagonists & inhibitors
Organ Size.drug effects
Peptidyl-Dipeptidase A.blood.drug effects.metabolism
Protease Inhibitors.therapeutic use
Pyridines.therapeutic use
Rats, Inbred SHR.physiology
Rats, Sprague-Dawley
Thiazepines.therapeutic use
Time Factors
Appears in Collections:Journal articles

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