title: Effects of ACE inhibitor and AT1 blocker on dystrophin-related proteins and calpain in failing heart.
abstract: OBJECTIVE
  Genetic depletion of dystrophin-related protein (DRP) complex causes cardiomyopathy in animals and humans. We found in a previous study that some types of DRP were degraded and that calpain content was increased in rats with non-genetically induced heart failure. The present study was aimed at examining the effects of an angiotensin-I-converting enzyme inhibitor (ACEI) trandolapril (Tra) or an angiotensin II type 1 receptor blocker (ARB) candesartan (Can), both of which are known to improve the pathophysiology of chronic heart failure (CHF) on degradation of DRP in failing hearts.
  
  
  METHODS
  Coronary artery-ligated (CAL) and sham-operated rats (Sham rats) were treated orally with 3 mg/kg/day trandolapril (Tra) or 1 mg/kg/day candesartan (Can) from the 2nd to 8th week after surgery.
  
  
  RESULTS
  Hemodynamic parameters of CAL rats at the 8th week after CAL (8w-CAL) indicated heart failure. alpha-Sarcoglycan (SG) and dystrophin in the surviving left ventricle (surviving LV) of 8w-CAL rats decreased, whereas beta-, gamma-, and delta-SGs remained unchanged. Calcium-activated neutral proteases mu-calpain and m-calpain increased in the surviving LV at the 8th week of postmyocardial infarction. Proteolytic activity in the presence of 5 mM Ca2+ markedly increased at the 2nd and 8th weeks, whereas 50 microM Ca2+ slightly but significantly increased proteolysis of casein. Tra or Can treatment improved the hemodynamic parameters, attenuated changes in alpha-SG and dystrophin, and reversed both calpain contents and activities of the failing heart back to sham levels.
  
  
  CONCLUSIONS
  These results suggest that attenuation in calpain-induced degradation of DRP complex is a possible mechanism for the Tra- or Can-mediated improvement of the pathogenesis of CHF following myocardial infarction.
authors.affiliation: Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tanonaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Ryo
authors.initials: R
authors.lastname: Oikawa
authors.forename: Miki
authors.initials: M
authors.lastname: Koshimizu
authors.forename: Takuya
authors.initials: T
authors.lastname: Daicho
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Toyo-Oka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeo
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D015153:Blotting, Western / Q000379:methods; D002154:Calpain / Q000032:analysis / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049031:Sarcoglycans / Q000032:analysis / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007211:Indoles; D020033:Protein Isoforms; D044140:Receptor, Angiotensin, Type 1; D049031:Sarcoglycans; D013777:Tetrazoles; C052035:trandolapril; D002154:Calpain; C081643:candesartan