Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS: 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.