Document Detail


Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033.
MedLine Citation:
PMID:  10704173     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Myofilament Ca(2+) sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca(2+) concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca(2+) sensitization in vivo with the use of EMD-57033 enhances both systolic and diastolic function in failing hearts at minimal energetic cost. METHODS AND RESULTS: Pressure-dimension data were measured with sonomicrometry/micromanometry in conscious dogs before (CON, n=9) and after tachycardia-induced heart failure (HF, n=11). In contrast to blunted dobutamine (DOB) responses in HF, low-dose EMD-57033 (0.4 mg. kg(-1). min(-1) for 20 minutes) markedly enhanced contractility, doubling end-systolic elastance and raising fractional shortening similarly in CON-treated and HF hearts. EMD-57033 effects were achieved at a reduced heart rate, without vasodilation. EMD-57033 augmented blunted heart rate-dependent contractility responses in HF at a rate of twice that of DOB, despite matched basal inotropic responses. EMD-57033 also improved diastolic function, lowering left ventricular end-diastolic pressure and increasing the filling rate. At equipotent inotropic doses and matched preload, EMD-57033 lowered the oxygen cost of contractility by -11.4+/-5.8%, whereas it rose 64+/-18% with DOB (P=0.001) and 28+/-11% with milrinone. Doubling EMD-57033 dose further augmented positive inotropy in CON and HF, accompanied by vasodilation, increased heart rate, and other changes consistent with PDE3I coactivity, but the oxygen cost of contractility remained improved compared with the use of DOB. CONCLUSIONS: Selective Ca(2+) sensitization with minimal PDE3I in vivo is achieved with the use of EMD-57033, improving basal and rate-stimulated contractility and mechanoenergetics of HF without compromising diastolic function. Despite PDE3I activity at higher doses, energetic benefits persist.
Authors:
H Senzaki; T Isoda; N Paolocci; U Ekelund; J M Hare; D A Kass
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Circulation     Volume:  101     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2000 Mar 
Date Detail:
Created Date:  2000-03-23     Completed Date:  2000-03-23     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1040-8     Citation Subset:  AIM; IM    
Affiliation:
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Pressure / drug effects
Calcium / physiology*
Cardiac Output, Low / physiopathology*
Cardiotonic Agents / pharmacology*
Coronary Circulation / drug effects
Diastole
Dobutamine / pharmacology
Dogs
Female
Heart / drug effects*,  physiopathology*
Male
Myocardial Contraction / drug effects
Myocardium / metabolism
Oxygen Consumption / drug effects
Quinolines / pharmacology*
Rest
Thiadiazines / pharmacology*
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Quinolines; 0/Thiadiazines; 120223-04-3/EMD 53998; 34368-04-2/Dobutamine; 7440-70-2/Calcium

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


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