title: Altered myocardial thin-filament function in the failing Dahl salt-sensitive rat heart: amelioration by endothelin blockade.
abstract: BACKGROUND
  Dahl salt-sensitive rats fed a high-salt diet develop compensated left ventricular hypertrophy followed by a transition to myocardial failure. We previously reported an increase in a troponin T isoform (TnT3) and a decrease in TnT phosphorylation in failing Dahl salt-sensitive rat hearts compared with low-salt controls. The present study was undertaken to determine whether the thin filament plays a role in depression of the contractile machinery in this model.
  
  
  RESULTS
  Native thin filaments (NTFs) were isolated intact from rats with compensated left ventricular hypertrophy and failing hearts and compared with age-matched controls. NTF velocity was measured as a function of free calcium in the in vitro motility assay. Maximal velocity was similar in all groups. However, NTFs from failing hearts demonstrated a reduction in calcium sensitivity compared with controls, as reflected in the pCa50 (5.88+/-0.05 versus 6.22+/-0.05, respectively, P<0.001). No difference in thin-filament motility (pCa50, V(max)) was observed in rats with compensated left ventricular hypertrophy compared with controls. Protein kinase A treatment of NTFs from control and failing hearts had no effect on thin-filament calcium sensitivity. However, the endothelin receptor blocker bosentan prevented the reduction in thin-filament calcium sensitivity found in failing hearts.
  
  
  CONCLUSIONS
  The thin filament is a key modulator of contractile performance in the transition to failure in the Dahl salt-sensitive rat model. The alteration in thin-filament function may be mediated by an endothelin-triggered pathway potentially affecting protein kinase C signaling.
authors.affiliation: Cardiology Unit, Department of Medicine, University of Vermont, Burlington, Vt 05405, USA.
authors.forename: Teruo
authors.initials: T
authors.lastname: Noguchi
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kihara
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Begin
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gorga
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Palmiter
authors.forename: Martin M
authors.initials: MM
authors.lastname: LeWinter
authors.forename: Peter
authors.initials: P
authors.lastname: VanBuren
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000077300:Bosentan; D002118:Calcium / Q000494:pharmacology; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009210:Myofibrils / Q000737:chemistry; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D020107:Troponin T / Q000378:metabolism
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D020033:Protein Isoforms; D013449:Sulfonamides; D020107:Troponin T; D011493:Protein Kinase C; D000077300:Bosentan; D002118:Calcium