Document Detail

Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry.
MedLine Citation:
PMID:  10525103     Owner:  NLM     Status:  MEDLINE    
The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.
J H McElmurray; R Mukherjee; R B New; A C Sampson; M K King; J W Hendrick; A Goldberg; T J Peterson; H Hallak; M R Zile; F G Spinale
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  291     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1999 Nov 
Date Detail:
Created Date:  1999-11-24     Completed Date:  1999-11-24     Revised Date:  2013-06-04    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  799-811     Citation Subset:  IM; S    
Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
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MeSH Terms
Angiotensin-Converting Enzyme Inhibitors / pharmacology*
Blood Chemical Analysis
Disease Models, Animal
Heart Ventricles / anatomy & histology,  drug effects*,  enzymology
Hemodynamics / drug effects*
Hydroxamic Acids / pharmacology*
Matrix Metalloproteinase Inhibitors*
Microscopy, Electron, Scanning
Oligopeptides / pharmacology*
Peptidyl-Dipeptidase A / metabolism*
Random Allocation
Time Factors
Grant Support
Reg. No./Substance:
0/(R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid; 0/Angiotensin-Converting Enzyme Inhibitors; 0/Hydroxamic Acids; 0/Matrix Metalloproteinase Inhibitors; 0/Oligopeptides; EC A
M R Zile / Med U SC, Charleston

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