Abstract | BACKGROUND: 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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Authors | T Quaschning, L V d'Uscio, S Shaw, H Viswambharan, F T Ruschitzka, T F Lüscher |
Journal | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
(Nephrol Dial Transplant)
Vol. 16
Issue 6
Pg. 1176-82
(Jun 2001)
ISSN: 0931-0509 [Print] England |
PMID | 11390717
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Angiotensin-Converting Enzyme Inhibitors
- Endothelin-1
- Endothelins
- Enzyme Inhibitors
- Protein Precursors
- Pyridines
- Sodium, Dietary
- Thiazepines
- omapatrilat
- Captopril
- Ecel1 protein, rat
- Metalloendopeptidases
- Neprilysin
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Topics |
- Angiotensin-Converting Enzyme Inhibitors
(pharmacology)
- Animals
- Aorta
(metabolism)
- Captopril
(pharmacology)
- Endothelin-1
(metabolism)
- Endothelins
(pharmacology)
- Enzyme Inhibitors
(pharmacology)
- Hypertension
(genetics, physiopathology)
- Male
- Metalloendopeptidases
(antagonists & inhibitors, metabolism)
- Neprilysin
(antagonists & inhibitors)
- Protein Precursors
(pharmacology)
- Pyridines
(pharmacology)
- Rats
- Rats, Inbred Dahl
- Renal Artery
(metabolism)
- Sodium, Dietary
- Thiazepines
(pharmacology)
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