title: Mechanistic insight into the functional and toxic effects of Strophanthidin in the failing human myocardium.
abstract: BACKGROUND
  Cardiac glycosides are characterized by a narrow therapeutic range with Ca2+-overload and arrhythmias occurring at higher concentrations. Data on cardiac glycosides in isolated failing human myocardium are scarce and the frequency-dependent actions and toxicity of Strophanthidin have not yet been characterized.
  
  
  OBJECTIVE
  To determine inotropic responses and toxicity of Strophanthidin in failing human myocardium.
  
  
  RESULTS
  Experiments were performed in trabeculae from 64 end-stage failing hearts. Developed force, and intracellular [Ca2+]i and [Na+]i were recorded with Strophanthidin (0.01 to 1 micromol/L; 37 degrees C, 1 Hz) and compared to interventions with distinct mechanisms of action (elevated [Ca2+]o, Isoproterenol, and EMD57033). The effects of Strophanthidin on force-frequency behaviour were also assessed. Strophanthidin exerted concentration-dependent positive inotropic effects. These were paralleled by increases in intracellular [Na+] as well as increasing [Ca2+]i-transients and SR-Ca2+-load. At high concentrations (>0.5 micromol/L), Strophanthidin caused afterglimmers and aftercontractions, with declining developed force despite further increasing [Ca2+]i-transients. The force-frequency-relationship and diastolic function at higher pacing rates was worsened by Strophanthidin in a concentration-dependent manner.
  
  
  CONCLUSIONS
  Strophanthidin toxicity was dependent on concentration, calcium load, beating rate and beta-adrenergic receptor activation. Our data support the view that low doses, heart rate control and additional beta-adrenergic receptor blockade are essential in the use of cardiac glycosides in heart failure.
authors.affiliation: Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: von Lewinski
authors.forename: Egbert
authors.initials: E
authors.lastname: Bisping
authors.forename: Andreas
authors.initials: A
authors.lastname: Elgner
authors.forename: Jens
authors.initials: J
authors.lastname: Kockskämper
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
mesh_terms: D002316:Cardiotonic Agents / Q000494:pharmacology / Q000633:toxicity; D003971:Diastole / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000187:drug effects; D013327:Strophanthidin / Q000494:pharmacology* / Q000633:toxicity; D013599:Systole / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D019831:Sodium-Calcium Exchanger; D013327:Strophanthidin; D007545:Isoproterenol