Chronic vasopeptidase inhibition restores endothelin-converting enzyme activity and normalizes endothelin levels in salt-induced hypertension.

Abstract

Vasopeptidase inhibition (VPI) represents a new therapeutic principle including both inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The present study investigated the effect of the vasopeptidase inhibitor omapatrilat on endothelin-1 (ET-1)-mediated vascular function in salt-induced hypertension. Dahl salt-sensitive rats (n=6/group) on standard or salt-enriched (4% NaCl) chow were treated for 8 weeks with either omapatrilat (36+/-4 mg/kg/day), captopril (94+/-2 mg/kg/day) or placebo. Aortic and renal artery segments were isolated and suspended in organ chambers for isometric tension recording. Functional endothelin-converting enzyme (ECE) activity was assessed in native segments and after preincubation with omapatrilat. Furthermore, vascular ECE protein levels as well as plasma and tissue ET-1 levels were determined. The increase in systolic blood pressure of salt-fed rats was prevented by omapatrilat and captopril to a comparable degree. In salt-induced hypertension, functional ECE activity (calculated as the ratio of the contraction to big ET-1 divided by the contraction to ET-1) in renal arteries (0.46+/-0.05) and in aorta (0.68+/-0.05) was reduced as compared with control animals (0.9+/-0.05 and 0.99+/-0.04, respectively; P<0.05). While omapatrilat in vitro blunted the response to big endothelin-1 (big ET-1) and diminished ECE activity further (P<0.01 vs native segments), chronic treatment with omapatrilat in vivo restored contractions to ET-1 (120+/-6%) and big ET-1 (98+/-9%) in renal arteries, and therefore normalized renovascular ECE activity. In addition, omapatrilat normalized plasma ET-1 concentrations (12.9+/-1.2 vs 16.6+/-1.4 pg/ml on high salt diet; P<0.05) and renovascular ECE protein levels. In salt-induced hypertension, vasopeptidase inhibition restores alterations in the endothelin system, such as renovascular ECE activity and responsiveness to ET-1 and big ET-1 with chronic but not acute in vitro application. Thus, the beneficial effects of vasopeptidase inhibition may reflect a resetting of cardiovascular control systems and therefore may be particularly suited to treat hypertension and heart failure.