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K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum
In heart failure, intracellular Ca(2+) leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca(2+) 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 re...
Autores principales: | , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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D. Steinkopff-Verlag
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807967/ https://www.ncbi.nlm.nih.gov/pubmed/19718543 http://dx.doi.org/10.1007/s00395-009-0057-8 |
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author | Toischer, Karl Lehnart, Stephan E. Tenderich, Gero Milting, Hendrik Körfer, Reiner Schmitto, Jan D. Schöndube, Friedrich A. Kaneko, Noboru Loughrey, Christopher M. Smith, Godfrey L. Hasenfuss, Gerd Seidler, Tim |
author_facet | Toischer, Karl Lehnart, Stephan E. Tenderich, Gero Milting, Hendrik Körfer, Reiner Schmitto, Jan D. Schöndube, Friedrich A. Kaneko, Noboru Loughrey, Christopher M. Smith, Godfrey L. Hasenfuss, Gerd Seidler, Tim |
author_sort | Toischer, Karl |
collection | PubMed |
description | In heart failure, intracellular Ca(2+) leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca(2+) 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(2+) 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(2+)](e) 1.25 mM) 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 Ca(2+) load. At high [Ca(2+)](e) concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 μM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca(2+)](e) normalised to 1 mmol/L [Ca(2+)](e): control 1.26 ± 0.06, K201 1.01 ± 0.03, P < 0.01). In addition at high [Ca(2+)](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 Ca(2+) concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00395-009-0057-8) contains supplementary material, which is available to authorized users. |
format | Text |
id | pubmed-2807967 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | D. Steinkopff-Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-28079672010-01-22 K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum Toischer, Karl Lehnart, Stephan E. Tenderich, Gero Milting, Hendrik Körfer, Reiner Schmitto, Jan D. Schöndube, Friedrich A. Kaneko, Noboru Loughrey, Christopher M. Smith, Godfrey L. Hasenfuss, Gerd Seidler, Tim Basic Res Cardiol Original Contribution In heart failure, intracellular Ca(2+) leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca(2+) 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(2+) 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(2+)](e) 1.25 mM) 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 Ca(2+) load. At high [Ca(2+)](e) concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 μM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca(2+)](e) normalised to 1 mmol/L [Ca(2+)](e): control 1.26 ± 0.06, K201 1.01 ± 0.03, P < 0.01). In addition at high [Ca(2+)](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 Ca(2+) concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00395-009-0057-8) contains supplementary material, which is available to authorized users. D. Steinkopff-Verlag 2009-08-30 2010 /pmc/articles/PMC2807967/ /pubmed/19718543 http://dx.doi.org/10.1007/s00395-009-0057-8 Text en © The Author(s) 2009 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Original Contribution Toischer, Karl Lehnart, Stephan E. Tenderich, Gero Milting, Hendrik Körfer, Reiner Schmitto, Jan D. Schöndube, Friedrich A. Kaneko, Noboru Loughrey, Christopher M. Smith, Godfrey L. Hasenfuss, Gerd Seidler, Tim K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum |
title | K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum |
title_full | K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum |
title_fullStr | K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum |
title_full_unstemmed | K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum |
title_short | K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum |
title_sort | k201 improves aspects of the contractile performance of human failing myocardium via reduction in ca(2+) leak from the sarcoplasmic reticulum |
topic | Original Contribution |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807967/ https://www.ncbi.nlm.nih.gov/pubmed/19718543 http://dx.doi.org/10.1007/s00395-009-0057-8 |
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