Cargando…
Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion
INTRODUCTION: The present study determined whether late-ischemia/early reperfusion therapy with the β(1)-adrenergic receptor (AR) blocker esmolol and phosphodiesterase III inhibitor milrinone reduced left ventricular (LV) myocardial infarct size (IS). METHODS AND RESULTS: In an ischemia/reperfusion...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2011
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110274/ https://www.ncbi.nlm.nih.gov/pubmed/21562974 http://dx.doi.org/10.1007/s10557-011-6302-z |
_version_ | 1782205508077223936 |
---|---|
author | Huang, Ming-He Wu, Yewen Nguyen, Vincent Rastogi, Saurabh McConnell, Bradley K. Wijaya, Cori Uretsky, Barry F. Poh, Kian-Keong Tan, Huay-Cheem Fujise, Kenichi |
author_facet | Huang, Ming-He Wu, Yewen Nguyen, Vincent Rastogi, Saurabh McConnell, Bradley K. Wijaya, Cori Uretsky, Barry F. Poh, Kian-Keong Tan, Huay-Cheem Fujise, Kenichi |
author_sort | Huang, Ming-He |
collection | PubMed |
description | INTRODUCTION: The present study determined whether late-ischemia/early reperfusion therapy with the β(1)-adrenergic receptor (AR) blocker esmolol and phosphodiesterase III inhibitor milrinone reduced left ventricular (LV) myocardial infarct size (IS). METHODS AND RESULTS: In an ischemia/reperfusion rat model (30-min ischemia/4-hr reperfusion), esmolol, milrinone or esmolol + milrinone were intravenous (IV) infused over 10 min (from the last 5min of ischemia to the first 5min of reperfusion). LV-IS were 48.9 ± 8.9%, 41.5 ± 5.4%, 25.8 ± 7.7% and 16.8 ± 7.3% for saline, esmolol, milrinone, and esmolol + milrinone, respectively (n = 12/group). Esmolol + milrinone further reduced LV-IS compared with esmolol or milrinone alone (p < 0.05). LV-IS-reduction induced by esmolol + milrinone was eliminated in the presence of protein kinase A-(PKA)-inhibitor (Rp-cAMPS) or Akt-inhibitor (AKT 1/2 kinase inhibitor). In mixed rat ventricular cardiomyocyte cultures, intra-ischemic application of esmolol, milrinone or esmolol + milrinone reduced myocyte death rates by 5.5%, 13.3%, and 16.8%, respectively, compared with saline (p < 0.01). This cell protective effect by esmolol + milrinone was abrogated in the presence of PKA-inhibitor or Akt-inhibitor. Esmolol, milrinone or esmolol + milrinone increased myocardial PKA activity by 22%, 28% and 59%, respectively, compared with saline (n = 6, p < 0.01). No non-specific adverse effect of Rp-cAMPS on myocytes was identified in a purified myocyte preparation during hypoxia/re-oxygenation. Antiapoptotic pathways were assessed by measuring myocardial phosphorylated Akt (pAkt) levels combined with terminal dUTP nick-end labelling staining analysis. Ten minutes following infusion of esmolol, milrinone or esmolol + milrinone, there were 1.7-, 2.7-, and 6-fold increase in tissue pAkt levels, respectively. This esmolol + milrinone induced pAkt activation was abolished in the presence of PKA inhibitor. Esmolol, milrinone and esmolol + milrinone reduced myocyte apoptosis rates by 22%, 37% and 60%, respectively, compared with saline (p < 0.01). CONCLUSIONS: Late-ischemia/early reperfusion therapy with esmolol + milrinone additively reduces LV-IS associated with robust activation of myocardial PKA and subsequent Akt-antiapoptotic pathway. |
format | Online Article Text |
id | pubmed-3110274 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-31102742011-07-14 Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion Huang, Ming-He Wu, Yewen Nguyen, Vincent Rastogi, Saurabh McConnell, Bradley K. Wijaya, Cori Uretsky, Barry F. Poh, Kian-Keong Tan, Huay-Cheem Fujise, Kenichi Cardiovasc Drugs Ther Article INTRODUCTION: The present study determined whether late-ischemia/early reperfusion therapy with the β(1)-adrenergic receptor (AR) blocker esmolol and phosphodiesterase III inhibitor milrinone reduced left ventricular (LV) myocardial infarct size (IS). METHODS AND RESULTS: In an ischemia/reperfusion rat model (30-min ischemia/4-hr reperfusion), esmolol, milrinone or esmolol + milrinone were intravenous (IV) infused over 10 min (from the last 5min of ischemia to the first 5min of reperfusion). LV-IS were 48.9 ± 8.9%, 41.5 ± 5.4%, 25.8 ± 7.7% and 16.8 ± 7.3% for saline, esmolol, milrinone, and esmolol + milrinone, respectively (n = 12/group). Esmolol + milrinone further reduced LV-IS compared with esmolol or milrinone alone (p < 0.05). LV-IS-reduction induced by esmolol + milrinone was eliminated in the presence of protein kinase A-(PKA)-inhibitor (Rp-cAMPS) or Akt-inhibitor (AKT 1/2 kinase inhibitor). In mixed rat ventricular cardiomyocyte cultures, intra-ischemic application of esmolol, milrinone or esmolol + milrinone reduced myocyte death rates by 5.5%, 13.3%, and 16.8%, respectively, compared with saline (p < 0.01). This cell protective effect by esmolol + milrinone was abrogated in the presence of PKA-inhibitor or Akt-inhibitor. Esmolol, milrinone or esmolol + milrinone increased myocardial PKA activity by 22%, 28% and 59%, respectively, compared with saline (n = 6, p < 0.01). No non-specific adverse effect of Rp-cAMPS on myocytes was identified in a purified myocyte preparation during hypoxia/re-oxygenation. Antiapoptotic pathways were assessed by measuring myocardial phosphorylated Akt (pAkt) levels combined with terminal dUTP nick-end labelling staining analysis. Ten minutes following infusion of esmolol, milrinone or esmolol + milrinone, there were 1.7-, 2.7-, and 6-fold increase in tissue pAkt levels, respectively. This esmolol + milrinone induced pAkt activation was abolished in the presence of PKA inhibitor. Esmolol, milrinone and esmolol + milrinone reduced myocyte apoptosis rates by 22%, 37% and 60%, respectively, compared with saline (p < 0.01). CONCLUSIONS: Late-ischemia/early reperfusion therapy with esmolol + milrinone additively reduces LV-IS associated with robust activation of myocardial PKA and subsequent Akt-antiapoptotic pathway. Springer US 2011-05-12 2011 /pmc/articles/PMC3110274/ /pubmed/21562974 http://dx.doi.org/10.1007/s10557-011-6302-z Text en © The Author(s) 2011 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 | Article Huang, Ming-He Wu, Yewen Nguyen, Vincent Rastogi, Saurabh McConnell, Bradley K. Wijaya, Cori Uretsky, Barry F. Poh, Kian-Keong Tan, Huay-Cheem Fujise, Kenichi Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion |
title | Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion |
title_full | Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion |
title_fullStr | Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion |
title_full_unstemmed | Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion |
title_short | Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion |
title_sort | heart protection by combination therapy with esmolol and milrinone at late-ischemia and early reperfusion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110274/ https://www.ncbi.nlm.nih.gov/pubmed/21562974 http://dx.doi.org/10.1007/s10557-011-6302-z |
work_keys_str_mv | AT huangminghe heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT wuyewen heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT nguyenvincent heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT rastogisaurabh heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT mcconnellbradleyk heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT wijayacori heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT uretskybarryf heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT pohkiankeong heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT tanhuaycheem heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion AT fujisekenichi heartprotectionbycombinationtherapywithesmololandmilrinoneatlateischemiaandearlyreperfusion |