Antihypertensive and antihypertrophic effects of omapatrilat in SHR

被引:46
作者
Burrell, LM [1 ]
Droogh, J [1 ]
in't Veld, OM [1 ]
Rockell, MD [1 ]
Farina, NK [1 ]
Johnston, CI [1 ]
机构
[1] Univ Melbourne, Austin & Repatriat Med Ctr, Dept Med, Melbourne, Vic 3084, Australia
关键词
omapatrilat; genetic hypertension; vasopeptidase inhibitor; neutral endopeptidase; angiotensin converting enzyme; spontaneously hypertensive rat;
D O I
10.1016/S0895-7061(00)01185-7
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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 I-125-RB104 and the specific ACE inhibitor radioligand I-125-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. Am J Hypertens 2000; 13:1110-1116 (C) 2000 American Journal of Hypertension, Ltd.
引用
收藏
页码:1110 / 1116
页数:7
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