Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102±2 to 181±12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189±3 mm Hg) or omapatrilat (184±8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6±0.2 vs. 0.5±0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9±0.4 pmol/day) compared to enalapril-treated (1.6±0.2 pmol/day) or untreated (1.5±0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production. © 2004 Elsevier Inc. All rights reserved.