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

Kelly, A., Elliott, E.B., Matsuda, R., Kaneko, N., Smith, G.L. and Loughrey, C.M. (2012) The effect of K201 on isolated working rabbit heart mechanical function during pharmacologically-induced Ca2+ overload. British Journal of Pharmacology, 165(4b), pp. 1068-1083. (doi: 10.1111/j.1476-5381.2011.01531.x)

Abstract

<p><b>Background and purpose</b>: Reduced cardiac contractility has been associated with disrupted myocardial Ca²⁺ signaling. The drug K201 acts on a number of Ca²⁺ handling proteins and in vivo improves cardiac contractility in a variety of animal models of myocardial dysfunction. However, it is unclear whether (i) this is dependent on the systemic effects of the drug or (ii) K201 acts to reverse the effects of Ca²⁺ dysregulation regardless of the cause.</p> <p><b>Experimental approach</b>: The effect of K201 on cardiac mechanical function was assessed in isolated adult rabbit working hearts 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-adrenergic stimulation.</p> <p><b>Key results</b>: K201 led to a concentration-dependent decline in systolic function (peak pressure, dP/dt_<i>max</i> and preload recruitable stroke work), lusitropy (reduced dP/dt_<i>min</i> and increased end diastolic pressure) and stroke volume independent of the observed decrease in heart rate. In separate experiments, mechanical function in hearts exposed to 4.5 mmol/L [Ca²⁺]_o and 150 nmol/L isoproterenol declined until cessation of aortic flow (in 6 out of 11 hearts). However, all hearts perfused with the addition of 1.0 µmol/L K201 maintained aortic flow and demonstrated significantly improved peak systolic pressures, dP/dt_<i>max</i> and dP/dt_<i>min</i></p>. <p><b>Conclusions and Implications</b>: 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.</p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Godfrey and Loughrey, Professor Christopher and Kelly, Dr Allen and Elliott, Dr Elspeth
• Authors: Kelly, A., Elliott, E.B., Matsuda, R., Kaneko, N., Smith, G.L., and Loughrey, C.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: British Journal of Pharmacology
• ISSN: 0007-1188
• ISSN (Online): 1476-5381