title: Beneficial effects of SR33805 in failing myocardium.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM U1046, Université Montpellier 1, Montpellier, France. yaitmou@lumc.edu
authors.forename: Younss
authors.initials: Y
authors.lastname: Ait Mou
authors.forename: Attila
authors.initials: A
authors.lastname: Toth
authors.forename: Cécile
authors.initials: C
authors.lastname: Cassan
authors.forename: Daniel
authors.initials: D
authors.lastname: Czuriga
authors.forename: Pieter P
authors.initials: PP
authors.lastname: de Tombe
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Papp
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D024722:Cardiac Myosins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D019210:Troponin I / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D007211:Indoles; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D019210:Troponin I; C107184:myosin light chain 2; C084255:SR 33805; D017868:Cyclic AMP-Dependent Protein Kinases; D024722:Cardiac Myosins