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


Quaschning, Thomas; d'Uscio, Livius V; Shaw, Sidney; Viswambharan, Hema; Ruschitzka, Frank T; Lüscher, Thomas F (2001). Chronic vasopeptidase inhibition restores endothelin‐converting enzyme activity and normalizes endothelin levels in salt‐induced hypertension. Nephrology, Dialysis, Transplantation, 16(6):1176-1182.

Abstract

Background. 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. Methods. 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. Results. 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. Conclusions. 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

Abstract

Background. 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. Methods. 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. Results. 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. Conclusions. 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

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Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Nephrology
Health Sciences > Transplantation
Language:English
Date:1 June 2001
Deposited On:20 Sep 2018 14:22
Last Modified:09 Apr 2020 00:04
Publisher:Oxford University Press
ISSN:0931-0509
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/ndt/16.6.1176
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101093ndt1661176 (Library Catalogue)

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