Document Detail

Beneficial effects of SR33805 in failing myocardium.
MedLine Citation:
PMID:  21467075     Owner:  NLM     Status:  MEDLINE    
AIMS: SR33805, a potent Ca(2+) channel blocker, increases cardiac myofilament Ca(2+) sensitivity in healthy rat cardiomyocytes. Therefore, the aim of the present study was to evaluate the effects of SR33805 on contractile properties in ischaemic failing hearts after myocardial infarction (MI) in vivo and in vitro at the cellular level.
METHODS AND RESULTS: The effect of SR33805 (10 µM) was tested on the excitation-contraction coupling of cardiomyocytes isolated from rat with end-stage heart failure. Cell shortening and Ca(2+) transients were measured in intact cardiomyocytes, while contractile properties were determined in Triton X-100 permeabilized myocytes. Acute treatment with SR33805 restored the MI-altered cell shortening without affecting the Ca(2+) transient amplitude, suggesting an increase of myofilament Ca(2+) sensitivity in MI myocytes. Indeed, a SR33805-induced sensitization of myofilament activation was found to be associated with a slight increase in myosin light chain-2 phosphorylation and a more significant decrease on troponin I (TnI) phosphorylation. Decreased TnI phosphorylation was related to inhibition of protein kinase A activity by SR33805. Finally, administration of a single intra-peritoneal bolus of SR33805 (20 mg/kg) improved end-systolic strain and fractional shortening of MI hearts.
CONCLUSION: The present study indicates that treatment with SR33805 improved contractility of ischaemic failing hearts after MI in the rat by selectively modulating the phosphorylation status of sarcomeric regulatory proteins, which then sensitized the myofilaments to Ca(2+). Our results gave a proof of concept that manipulation of the Ca(2+) sensitivity of sarcomeric regulatory proteins can be used to improve contractility of a failing heart.
Younss Ait Mou; Attila Toth; Cécile Cassan; Daniel Czuriga; Pieter P de Tombe; Zoltan Papp; Alain Lacampagne; Olivier Cazorla
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-04-04
Journal Detail:
Title:  Cardiovascular research     Volume:  91     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-20     Completed Date:  2011-11-23     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  412-9     Citation Subset:  IM    
INSERM U1046, Université Montpellier 1, Montpellier, France.
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MeSH Terms
Calcium Channel Blockers / pharmacology
Calcium Signaling / drug effects
Cardiac Myosins / metabolism
Cardiotonic Agents / administration & dosage,  pharmacology*
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors,  metabolism
Disease Models, Animal
Excitation Contraction Coupling / drug effects
Heart Failure / drug therapy*,  metabolism,  physiopathology,  ultrasonography
Indoles / administration & dosage,  pharmacology*
Injections, Intraperitoneal
Myocardial Contraction / drug effects*
Myocytes, Cardiac / drug effects*,  metabolism
Myofibrils / drug effects,  metabolism
Myosin Light Chains / metabolism
Protein Kinase Inhibitors / pharmacology
Rats, Wistar
Recovery of Function
Sulfones / administration & dosage,  pharmacology*
Time Factors
Troponin I / metabolism
Grant Support
Reg. No./Substance:
0/Calcium Channel Blockers; 0/Cardiotonic Agents; 0/Indoles; 0/Myosin Light Chains; 0/Protein Kinase Inhibitors; 0/Sulfones; 0/Troponin I; 0/myosin light chain 2; 121345-64-0/SR 33805; EC AMP-Dependent Protein Kinases; EC 3.6.1.-/Cardiac Myosins
Comment In:
Cardiovasc Res. 2011 Aug 1;91(3):371-2   [PMID:  21652598 ]

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

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