Document Detail

Antihypertrophic effects of combined inhibition of the renin-angiotensin system (RAS) and neutral endopeptidase (NEP) in progressive, tachycardia-induced experimental heart failure.
MedLine Citation:
PMID:  22895639     Owner:  NLM     Status:  MEDLINE    
Vasopeptidase inhibition (VPI), a therapeutic strategy by dual inhibition of both ACE and neutral endopeptidase 24.11, has not shown a prognostic benefit over ACE inhibition in chronic severe heart failure (CHF). Nevertheless, the effects of early treatment by VPI on cardiac remodelling have not been well assessed. We analysed the effects of early chronic VPI (50 mg/kg/day Omapatrilat) on cardiac remodelling and neurohumoral function during the progression of rapid ventricular pacing-induced heart failure in rabbits (early left ventricular dysfunction [ELVD]: 10 days at 330 bpm, CHF: further 10 days at 360 bpm). VPI-treated animals (ELVD-VPI n = 6; CHF-VPI n = 8) and placebo treated animals (ELVD n = 6; CHF n = 7) were compared with control rabbits (CTRL n = 5). LV fractional shortening (FS) and enddiastolic diameter (LVEDD) were assessed by echocardiography (12 MHz probe). LV BNP- and LV IL-6 gene expression was analysed quantitatively by real time PCR. Neurohumoral function was assessed by ANP, cGMP, plasma renin activity (PRA) and Aldosterone. In ELVD, LVEDD and atrial mass were significantly increased (both p < 0.05). This increase was markedly attenuated by VPI (both p < 0.05 vs. placebo). CHF was associated with a further increase in atrial mass and an increase in LV mass (both p < 0.05), which was again attenuated by VPI (atrial mass, p < 0.05 vs. untreated). LV BNP mRNA was significantly increased in CHF (p < 0.05 vs. control), and chronic VPI completely abolished this increase in ELVD and significantly attenuated it in CHF (p < 0.05 vs. CHF-placebo). Beyond that, the increase of cGMP was augmented by chronic VPI (p < 0.05 vs. placebo in CHF) in heart failure and that of Aldosterone was attenuated (p < 0.05 vs. placebo in ELVD), whereas PRA was temporarily increased (p < 0.05 vs. placebo in ELVD). Combined inhibition of ACE and NEP by VPI significantly inhibits early cardiac remodelling and LV BNP gene expression. If initiated early enough, it may slow down cardiac remodelling and represents a promising therapeutic strategy in progressive heart failure.
Christoph Birner; Coskun Ulucan; Mona Bratfisch; Tobias Götz; Alexander Dietl; Frank Schweda; Günter A Riegger; Andreas Luchner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-16
Journal Detail:
Title:  Naunyn-Schmiedeberg's archives of pharmacology     Volume:  385     ISSN:  1432-1912     ISO Abbreviation:  Naunyn Schmiedebergs Arch. Pharmacol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-11     Completed Date:  2013-03-26     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0326264     Medline TA:  Naunyn Schmiedebergs Arch Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1117-25     Citation Subset:  IM    
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MeSH Terms
Aldosterone / blood
Angiotensin-Converting Enzyme Inhibitors / pharmacology
Cardiomegaly / prevention & control*
Cardiovascular Agents / pharmacology*
Disease Models, Animal
Gene Expression Regulation / drug effects
Heart Failure / drug therapy*,  physiopathology
Natriuretic Peptide, Brain / genetics
Neprilysin / antagonists & inhibitors
Pyridines / pharmacology*
RNA, Messenger / metabolism
Renin / blood
Renin-Angiotensin System / drug effects
Tachycardia / physiopathology
Thiazepines / pharmacology*
Ventricular Dysfunction, Left / physiopathology
Ventricular Remodeling / drug effects
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 0/Cardiovascular Agents; 0/Pyridines; 0/RNA, Messenger; 0/Thiazepines; 114471-18-0/Natriuretic Peptide, Brain; 36NLI90E7T/omapatrilat; 4964P6T9RB/Aldosterone; EC; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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