Antihypertensive and antihypertrophic effects of omapatrilat in SHR

Vasopeptidase inhibitors, such as omapatrilat are single molecules that sim ultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). In normotensive rats, a single dose of oral omapatrilat (10 m g/kg) and 1 mg/kg inhibited plasma ACE (P <.01) for 24 h and increased plas ma renin activity for 8 h (P <.01). In vitro autoradiography using the spec ific NEP inhibitor radioligand I-125-RB104 and the specific ACE inhibitor r adioligand I-125-MK351A showed omapatrilat (10 mg/kg) caused rapid and pote nt inhibition of renal NEP and ACE, respectively, for 24 h (P <.01). In spontaneously hypertensive rats, 10 days of oral omapatrilat (40 mg/kg/d ay) 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/k g, 2.55 +/- 0.02 mg/g, P <.01) and omapatrilat also increased kidney weight compared to vehicle (both doses, P <.01). Omapatrilat caused significant i nhibition 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 e ffects are associated with inhibition of NEP and ACE at the tissue level an d beneficial effects on cardiovascular structure. Relating the degree of ti ssue inhibition to physiologic responses may allow further definition of th e role of local renin angiotensin and natriuretic peptide systems in the be neficial effects of vasopeptidase inhibitors. Am J Hypertens 2000; 13:1110- 1116 (C) 2000 American Journal of Hypertension, Ltd.