The effect of K201 on isolated working rabbit heart mechanical function during pharmacologically induced Ca 2+ overload

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. © 2011 The Authors. British Journal of Pharmacology.