title: The effect of K201 on isolated working rabbit heart mechanical function during pharmacologically induced Ca2+ overload.
abstract: OBJECTIVE
  Reduced cardiac contractility has been associated with disrupted myocardial Ca(2+)  signalling. The 1,4 benzothiazepine K201 (JTV-519) acts on several Ca(2+)  handling proteins and improves cardiac contractility in vivo in a variety of animal models of myocardial dysfunction. However, it is unclear whether this improvement depends on the systemic effects of K201 or if K201 reverses the effects of Ca(2+)  dysregulation, regardless of the cause.
  
  
  METHODS
  The effect of K201 on cardiac mechanical function was assessed in isolated working hearts from adult rabbits, using a ventricular pressure-volume catheter. In separate experiments, the effect of K201 was investigated in hearts following pharmacologically induced Ca(2+)  overload using elevated extracellular [Ca(2+) ] ([Ca(2+) ](o) ) and β-adrenoceptor stimulation.
  
  
  RESULTS
  K201 induced a concentration-dependent decline in systolic function (peak pressure, dP/dt(max)  and preload recruitable stroke work), lusitropy (reduced dP/dt(min)  and increased end diastolic pressure) and stroke volume, independent of decreased heart rate. In separate experiments, mechanical function in hearts exposed to 4.5 mmol·L(-1) [Ca(2+) ](o)  and 150 nmol·L(-1)  isoprenaline declined until cessation of aortic flow (in 6 out of 11 hearts). However, all hearts perfused with the addition of 1 µmol·L(-1)  K201 maintained aortic flow and demonstrated significantly improved peak systolic pressures, dP/dt(max)  and dP/dt(min) .
  
  
  CONCLUSIONS
  K201 significantly improved mechanical function of the heart during Ca(2+)  overload. This suggests that K201 can limit the detrimental effects of elevated intracellular Ca(2+)  and exert beneficial effects on cardiac contractile function, independent of systemic effects previously observed in vivo.
authors.affiliation: Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: A
authors.initials: A
authors.lastname: Kelly
authors.forename: E B
authors.initials: EB
authors.lastname: Elliott
authors.forename: R
authors.initials: R
authors.lastname: Matsuda
authors.forename: N
authors.initials: N
authors.lastname: Kaneko
authors.forename: G L
authors.initials: GL
authors.lastname: Smith
authors.forename: C M
authors.initials: CM
authors.lastname: Loughrey
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D013841:Thiazepines; C109183:K201 compound; D002118:Calcium