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The effect of K201 on isolated working rabbit heart mechanical function during pharmacologically induced Ca 2+ overload
Author(s) -
Kelly A,
Elliott EB,
Matsuda R,
Kaneko N,
Smith GL,
Loughrey CM
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01531.x
Subject(s) - contractility , preload , medicine , pressure overload , stroke volume , cardiac function curve , isoprenaline , ventricular pressure , cardiology , chemistry , volume overload , diastole , endocrinology , heart rate , blood pressure , hemodynamics , heart failure , stimulation , cardiac hypertrophy
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 .