title: Enalapril treatment increases cardiac performance and energy reserve via the creatine kinase reaction in myocardium of Syrian myopathic hamsters with advanced heart failure.
abstract: BACKGROUND
  Converting enzyme inhibitor treatment of congestive heart failure slows progression to failure and reduces mortality rate. It is known whether these benefits are due solely to improved hemodynamics or also to improved myocyte energetics. This study examines the effect of enalapril treatment on both isovolumic contractile performance and its biochemical correlate, flux through the creatine kinase (CK) system, in an animal model of severely failing myocardium.
  
  
  RESULTS
  Seven-month-old Syrian cardiomyopathic (TO-2 strain) and normal golden Syrian (FIB strain) hamsters were each randomly assigned to one of three groups supplied daily with either no, low (25 mg/kg body wt), or high (100 mg/kg body wt) doses of enalapril for 12 to 14 weeks. At 10 months of age, all substrates and products and flux through the CK reaction were measured in isolated perfused hearts by 31P magnetization transfer and chemical assay. Compared with normal hamsters, the myopathic hamsters exhibited significantly lower body weights and higher biventricular heart weights, which were partially reversed by drug treatment. The Langendorff-perfused hearts showed decreased isovolumic contractile performance with identical load conditions. This was partially reversed by drug treatment. In the failing hearts, the following substrate and product concentrations and enzyme activities were decreased compared with nonfailing hearts but were unchanged by drug treatment: ATP (-28%), phosphocreatine (-48%), free creatine (-64%), ADP (-51%), and CK (-34%, primarily MM isoenzyme). Flux through the CK reaction for the untreated cardiomyopathic hamster hearts was decreased by 67%, and this decrease was almost completely reversed by enalapril treatment. The increased CK flux is due to an increase in the rate constant for the reaction, since substrate concentrations are unchanged, and is not predicted by the rate equation. In enalapril-treated failing hearts, phosphoryl transfer via the CK reaction increased with contractile performance. This was not observed in the nonfailing hearts, in which energy reserve is adequate to support changes in contractile performance.
  
  
  CONCLUSIONS
  Decreased flux through CK reaction leads to decreased capacity for ATP synthesis and may contribute to decreased contractile performance in cardiomyopathic hamster hearts. Enalapril treatment results in increased phosphoryl transfer through the CK reaction in failing myocardium, and this increase is coupled to improved cardiac performance. Decreased CK flux in failing hearts is due to a combination of decreased Vmax and lower guanidino pool; this mechanism fails to explain changes in CK flux in enalapril-treated failing hearts.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Mass 02115.
authors.forename: L
authors.initials: L
authors.lastname: Nascimben
authors.forename: J
authors.initials: J
authors.lastname: Friedrich
authors.forename: R
authors.initials: R
authors.lastname: Liao
authors.forename: P
authors.initials: P
authors.lastname: Pauletto
authors.forename: A C
authors.initials: AC
authors.lastname: Pessina
authors.forename: J S
authors.initials: JS
authors.lastname: Ingwall
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism*; D006224:Cricetinae; D004656:Enalapril / Q000627:therapeutic use*; D004734:Energy Metabolism / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D007527:Isoenzymes; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008647:Mesocricetus; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects
chemical_list: D007527:Isoenzymes; D004656:Enalapril; D003402:Creatine Kinase