Document Detail


Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338 Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent Manner.
MedLine Citation:
PMID:  21339476     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by ≤46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media:lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-β1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-β1 expression.
Authors:
Philipp Kalk; Yuliya Sharkovska; Elena Kashina; Karoline von Websky; Katharina Relle; Thiemo Pfab; Markus Alter; Philippe Guillaume; Daniel Provost; Katrin Hoffmann; Yvan Fischer; Berthold Hocher
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-2-21
Journal Detail:
Title:  Hypertension     Volume:  -     ISSN:  1524-4563     ISO Abbreviation:  -     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-2-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Nephrology, Charité, Campus Benjamin Franklin, Berlin, Germany; Center for Cardiovascular Research/Institute of Pharmacology, Charité, Campus Mitte, Berlin, Germany; Institute for Nutritional Science, University of Potsdam, Potsdam, Germany; Porsolt and Partners Pharmacology, Le Genest-Saint-Isle, France; Abbott Products GmbH, Hannover, Germany; and Institute of Anatomy, Charité, Campus Mitte, Berlin, Germany.
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