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Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury

Omecamtiv mecarbil (OM) is a first-in-class myosin activator. It was developed as a new inotropic therapy option for heart failure and is currently the object of a phase 3 clinical trial program. OM activates ryanodine receptors, which were shown to be involved in cardioprotection induced by conditi...

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Autores principales: Stroethoff, Martin, Behmenburg, Friederike, Meierkord, Simon, Bunte, Sebastian, Mayer, Felix, Mathes, Alexander, Heinen, André, Hollmann, Markus W., Huhn, Ragnar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463149/
https://www.ncbi.nlm.nih.gov/pubmed/30889854
http://dx.doi.org/10.3390/jcm8030375
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author Stroethoff, Martin
Behmenburg, Friederike
Meierkord, Simon
Bunte, Sebastian
Mayer, Felix
Mathes, Alexander
Heinen, André
Hollmann, Markus W.
Huhn, Ragnar
author_facet Stroethoff, Martin
Behmenburg, Friederike
Meierkord, Simon
Bunte, Sebastian
Mayer, Felix
Mathes, Alexander
Heinen, André
Hollmann, Markus W.
Huhn, Ragnar
author_sort Stroethoff, Martin
collection PubMed
description Omecamtiv mecarbil (OM) is a first-in-class myosin activator. It was developed as a new inotropic therapy option for heart failure and is currently the object of a phase 3 clinical trial program. OM activates ryanodine receptors, which were shown to be involved in cardioprotection induced by conditioning strategies. We hypothesize that OM exerts a concentration-dependent cardioprotective effect through pre- and postconditioning. Isolated male Wistar rat hearts underwent 33 min of global ischemia and 60 min of reperfusion. OM was administered in various concentrations (1, 3, 10, and 30 µM) over 10 min prior to ischemia. Based on these results, in subsequent experiments 3 and 10 µM OM were given over 10 min after ischemia. Infarct sizes were determined by TTC staining. In controls, the infarct size was 60% ± 10% and 59% ± 12%, respectively. Ten micromolar OM before ischemia reduced the infarct size to 33% ± 8%. The lower concentrations did not initiate cardioprotection, and the next highest concentration did not enhance the protective effect. Even if 10 μM OM was given in the early reperfusion phase, it significantly reduced the infarct size (31% ± 6%), whereas 3 μM OM did not trigger a protective effect (58% ± 15%). This study shows for the first time that OM induces cardioprotection by pre- and postconditioning with a binary phenomenon, which is either ineffective or has a maximal effect.
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spelling pubmed-64631492019-04-19 Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury Stroethoff, Martin Behmenburg, Friederike Meierkord, Simon Bunte, Sebastian Mayer, Felix Mathes, Alexander Heinen, André Hollmann, Markus W. Huhn, Ragnar J Clin Med Article Omecamtiv mecarbil (OM) is a first-in-class myosin activator. It was developed as a new inotropic therapy option for heart failure and is currently the object of a phase 3 clinical trial program. OM activates ryanodine receptors, which were shown to be involved in cardioprotection induced by conditioning strategies. We hypothesize that OM exerts a concentration-dependent cardioprotective effect through pre- and postconditioning. Isolated male Wistar rat hearts underwent 33 min of global ischemia and 60 min of reperfusion. OM was administered in various concentrations (1, 3, 10, and 30 µM) over 10 min prior to ischemia. Based on these results, in subsequent experiments 3 and 10 µM OM were given over 10 min after ischemia. Infarct sizes were determined by TTC staining. In controls, the infarct size was 60% ± 10% and 59% ± 12%, respectively. Ten micromolar OM before ischemia reduced the infarct size to 33% ± 8%. The lower concentrations did not initiate cardioprotection, and the next highest concentration did not enhance the protective effect. Even if 10 μM OM was given in the early reperfusion phase, it significantly reduced the infarct size (31% ± 6%), whereas 3 μM OM did not trigger a protective effect (58% ± 15%). This study shows for the first time that OM induces cardioprotection by pre- and postconditioning with a binary phenomenon, which is either ineffective or has a maximal effect. MDPI 2019-03-18 /pmc/articles/PMC6463149/ /pubmed/30889854 http://dx.doi.org/10.3390/jcm8030375 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Stroethoff, Martin
Behmenburg, Friederike
Meierkord, Simon
Bunte, Sebastian
Mayer, Felix
Mathes, Alexander
Heinen, André
Hollmann, Markus W.
Huhn, Ragnar
Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury
title Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury
title_full Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury
title_fullStr Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury
title_full_unstemmed Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury
title_short Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury
title_sort cardioprotective properties of omecamtiv mecarbil against ischemia and reperfusion injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463149/
https://www.ncbi.nlm.nih.gov/pubmed/30889854
http://dx.doi.org/10.3390/jcm8030375
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