The effect of K201 on isolated working rabbit heart mechanical function during pharmacologically induced Ca²⁺ overload

BACKGROUND AND PURPOSE

Reduced cardiac contractility has been associated with disrupted myocardial Ca²⁺ signalling. The 1,4 benzothiazepine K201 (JTV‐519) acts on several Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ overload using elevated extracellular [Ca²⁺] ([Ca²⁺]_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[Ca²⁺]_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 Ca²⁺ overload. This suggests that K201 can limit the detrimental effects of elevated intracellular Ca²⁺ and exert beneficial effects on cardiac contractile function, independent of systemic effects previously observed in vivo.

DOI: 10.1111/j.1476-5381.2011.01531.x

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