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Sivelestat Attenuates Myocardial Reperfusion Injury during Brief Low Flow Postischemic Infusion
The neutrophil elastase inhibitor sivelestat (ONO-5046) possesses unknown mechanisms of cardioprotection when infused following global ischemia, even in the absence of neutrophils. Since myocardial ischemia-reperfusion injury is strongly associated with endothelial dysfunction and reactive oxygen sp...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674745/ https://www.ncbi.nlm.nih.gov/pubmed/23766850 http://dx.doi.org/10.1155/2013/279847 |
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author | Aune, Sverre E. Yeh, Steve T. Kuppusamy, Periannan Kuppusamy, M. Lakshmi Khan, Mahmood Angelos, Mark G. |
author_facet | Aune, Sverre E. Yeh, Steve T. Kuppusamy, Periannan Kuppusamy, M. Lakshmi Khan, Mahmood Angelos, Mark G. |
author_sort | Aune, Sverre E. |
collection | PubMed |
description | The neutrophil elastase inhibitor sivelestat (ONO-5046) possesses unknown mechanisms of cardioprotection when infused following global ischemia, even in the absence of neutrophils. Since myocardial ischemia-reperfusion injury is strongly associated with endothelial dysfunction and reactive oxygen species (ROS) generation during reperfusion, we have tested the hypothesis that infusion of sivelestat during postischemic low flow would preserve endothelial and contractile function and reduce infarct size through an ROS-mediated mechanism. Isolated male rat hearts, subjected to global ischemia of 25 minutes, were reperfused with low flow with or without sivelestat followed by a full flow reperfusion. Hearts treated with sivelestat showed a significant improvement of LV contractile function and a reduction in infarct size. Infusion of L-NAME (nonspecific blocker of endothelial nitric oxide synthase (eNOS)) along with sivelestat during reperfusion reversed the preservation of contractile function and infarct size. In vitro EPR spin trapping experiments showed that sivelestat treatment decreased superoxide adduct formation in bovine aortic endothelial cells (BAECs) subjected to hypoxia-reoxygenation. Similarly, dihydroethidine (DHE) staining showed decreased superoxide production in LV sections from sivelestat-treated hearts. Taken together, these results indicate that sivelestat infusion during postischemic low flow reduces infarct size and preserves vasoreactivity in association with decreased ROS formation and the preservation of nitric oxide. |
format | Online Article Text |
id | pubmed-3674745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-36747452013-06-13 Sivelestat Attenuates Myocardial Reperfusion Injury during Brief Low Flow Postischemic Infusion Aune, Sverre E. Yeh, Steve T. Kuppusamy, Periannan Kuppusamy, M. Lakshmi Khan, Mahmood Angelos, Mark G. Oxid Med Cell Longev Research Article The neutrophil elastase inhibitor sivelestat (ONO-5046) possesses unknown mechanisms of cardioprotection when infused following global ischemia, even in the absence of neutrophils. Since myocardial ischemia-reperfusion injury is strongly associated with endothelial dysfunction and reactive oxygen species (ROS) generation during reperfusion, we have tested the hypothesis that infusion of sivelestat during postischemic low flow would preserve endothelial and contractile function and reduce infarct size through an ROS-mediated mechanism. Isolated male rat hearts, subjected to global ischemia of 25 minutes, were reperfused with low flow with or without sivelestat followed by a full flow reperfusion. Hearts treated with sivelestat showed a significant improvement of LV contractile function and a reduction in infarct size. Infusion of L-NAME (nonspecific blocker of endothelial nitric oxide synthase (eNOS)) along with sivelestat during reperfusion reversed the preservation of contractile function and infarct size. In vitro EPR spin trapping experiments showed that sivelestat treatment decreased superoxide adduct formation in bovine aortic endothelial cells (BAECs) subjected to hypoxia-reoxygenation. Similarly, dihydroethidine (DHE) staining showed decreased superoxide production in LV sections from sivelestat-treated hearts. Taken together, these results indicate that sivelestat infusion during postischemic low flow reduces infarct size and preserves vasoreactivity in association with decreased ROS formation and the preservation of nitric oxide. Hindawi Publishing Corporation 2013 2013-05-22 /pmc/articles/PMC3674745/ /pubmed/23766850 http://dx.doi.org/10.1155/2013/279847 Text en Copyright © 2013 Sverre E. Aune et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Aune, Sverre E. Yeh, Steve T. Kuppusamy, Periannan Kuppusamy, M. Lakshmi Khan, Mahmood Angelos, Mark G. Sivelestat Attenuates Myocardial Reperfusion Injury during Brief Low Flow Postischemic Infusion |
title | Sivelestat Attenuates Myocardial Reperfusion Injury during Brief Low Flow Postischemic Infusion |
title_full | Sivelestat Attenuates Myocardial Reperfusion Injury during Brief Low Flow Postischemic Infusion |
title_fullStr | Sivelestat Attenuates Myocardial Reperfusion Injury during Brief Low Flow Postischemic Infusion |
title_full_unstemmed | Sivelestat Attenuates Myocardial Reperfusion Injury during Brief Low Flow Postischemic Infusion |
title_short | Sivelestat Attenuates Myocardial Reperfusion Injury during Brief Low Flow Postischemic Infusion |
title_sort | sivelestat attenuates myocardial reperfusion injury during brief low flow postischemic infusion |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674745/ https://www.ncbi.nlm.nih.gov/pubmed/23766850 http://dx.doi.org/10.1155/2013/279847 |
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