Document Detail


Sustained improvement of cardiac function and prevention of cardiac remodeling after long-term dual ECE-NEP inhibition in rats with congestive heart failure.
MedLine Citation:
PMID:  15085059     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Acute inhibition of endothelin converting enzyme (ECE) and neutral endopeptidase (NEP) exerts beneficial hemodynamic effects in chronic heart failure (CHF). However, the long-term effects of dual ECE-NEP inhibition are unknown. We evaluated, in rats with CHF, the long-term effects of the dual ECE-NEP inhibitor CGS 26303 (10 mg.kg(-1).day(-1)) on systemic and left ventricular (LV) hemodynamics and LV remodeling, and compared them to those induced by the selective NEP inhibitor CGS 24592 (10 mg.kg(-1).day(-1)), both administered subcutaneously by mini-pump for 30 days starting 7 days after left coronary artery ligation. After 30 days, CGS 26303, but not CGS 24592, reduced systolic blood pressure, while both drugs never affected heart rate. Echocardiographic studies showed that only CGS 26303 diminished LV end-diastolic and systolic diameters and increased LV fractional shortening and cardiac output. Moreover, CGS 26303, but not CGS 24592, reduced LV end-diastolic pressure, while LV dP/dtmax/min was not affected. Both drugs reduced collagen accumulation in the 'viable' part of the LV, but only CGS 26303 reduced LV weight. Thus, long-term treatment with CGS 26303 decreases both preload and afterload, increases cardiac output, and diminishes LV hypertrophy, dilatation, and cardiac fibrosis, suggesting that dual ECE-NEP inhibition might be beneficial in human CHF.
Authors:
Paul Mulder; Stephane Barbier; Christelle Monteil; Arco Y Jeng; Jean Paul Henry; Sylvanie Renet; Christian Thuillez
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  43     ISSN:  0160-2446     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2004 Apr 
Date Detail:
Created Date:  2004-04-15     Completed Date:  2004-07-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  489-94     Citation Subset:  IM    
Affiliation:
Rouen University Medical School, France. paul.mulder@univ-rouen.fr
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MeSH Terms
Descriptor/Qualifier:
Animals
Aspartic Acid Endopeptidases / antagonists & inhibitors*,  metabolism
Blood Pressure / drug effects,  physiology
Cardiac Output / drug effects,  physiology
Heart Failure / drug therapy*,  enzymology
Heart Rate / drug effects,  physiology
Male
Metalloendopeptidases
Neprilysin / antagonists & inhibitors*,  metabolism
Phenylalanine / analogs & derivatives*,  pharmacology,  therapeutic use
Phosphonic Acids / pharmacology,  therapeutic use
Rats
Rats, Wistar
Tetrazoles / pharmacology,  therapeutic use
Ventricular Remodeling / drug effects*,  physiology
Chemical
Reg. No./Substance:
0/CGS 24592; 0/Phosphonic Acids; 0/Tetrazoles; 154116-31-1/CGS 26303; 63-91-2/Phenylalanine; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.11/Neprilysin; EC 3.4.24.71/endothelin-converting enzyme

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


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