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 Ca<sup>2+</sup> leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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 [Ca<sup>2+</sup>]<sub>e</sub> 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; <i>P</i> < 0.05). Interestingly, K201 (0.3 µM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca<sup>2+</sup> load. At high [Ca<sup>2+</sup>]<sub>e</sub> 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 [Ca<sup>2+</sup>]<sub>e</sub> normalised to 1mmol/L [Ca<sup>2+</sup>]<sub>e</sub>: control 1.26 ± 0.06, K201 1.01 ± 0.03, <i>P</i> < 0.01). In addition at high [Ca<sup>2+</sup>]<sub>e</sub>, K201 (0.3 µM) treatment significantly improved systolic function [developed tension +27 ± 8% (K201 vs. control); <i>P</i> < 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 Ca<sup>2+</sup> concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201
Item Type: | Articles |
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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 > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health 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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