K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum

Toischer, K. et al. (2010) K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum. Basic Research in Cardiology, 105(2), pp. 279-287. (doi:10.1007/s00395-009-0057-8)

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Publisher's URL: http://dx.doi.org/10.1007/s00395-009-0057-8

Abstract

In heart failure, intracellular Ca2+ leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca2+ from the sarcoplasmic reticulum (SR) potentially contributing to decreased function. Experimental data suggest that the 1,4-benzothiazepine K201 (JTV-519) may stabilise RyR2s and thereby reduce detrimental intracellular Ca2+ leak. Whether K201 exerts beneficial effects in human failing myocardium is unknown. Therefore, we have studied the effects of K201 on muscle preparations from failing human hearts. K201 (0.3 µM; extracellular [Ca2+]e 1.25mM) showed no effects on contractile function and micromolar concentrations resulted in negative inotropic effects (K201 1 µM; developed tension -9.8 ± 2.5% compared to control group; P < 0.05). Interestingly, K201 (0.3 µM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca2+ load. At high [Ca2+]e concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30s). Strikingly, treatment with K201 (0.3 µM) prevented diastolic dysfunction (diastolic tension at 5mmol/L [Ca2+]e normalised to 1mmol/L [Ca2+]e: control 1.26 ± 0.06, K201 1.01 ± 0.03, P < 0.01). In addition at high [Ca2+]e, K201 (0.3 µM) treatment significantly improved systolic function [developed tension +27 ± 8% (K201 vs. control); P < 0.05]. The beneficial effects on diastolic and systolic functions occurred throughout the physiological frequency range of the human heart rate from 1 to 3 Hz. Upon elevated intracellular Ca2+ concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201

Item Type:Articles
Keywords:Human, Heart failure, Contractile performance, Sarcoplasmic reticulum, Ryanodine receptor, K201
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Loughrey, Professor Christopher
Authors: Toischer, K., Lehnart, S., Tenderich, G., Milting, H., Körfer, R., Schmitto, J., Schöndube, F., Kaneko, N., Loughrey, C., Smith, G.L., Hasenfuss, G., and Seidler, T.
Subjects:R Medicine > RC Internal medicine
Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences
Journal Name:Basic Research in Cardiology
Publisher:Springer
ISSN:0300-8428
ISSN (Online):1435-1803
Published Online:30 August 2009

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