| Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms. | |
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MedLine Citation:
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PMID: 17577097 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Erythropoietin is known to stimulate red cell production and has recently been shown to protect the heart against injury from ischemia/reperfusion. However, it is unknown whether darbepoetin alfa (Dpa), a long-acting analog of erythropoietin, can play a protective role against myocardial infarction. We assessed the potential protective role of Dpa in an in vivo rat model of myocardial ischemia/reperfusion and the underlying mechanisms. We found that a single intravenous Dpa treatment immediately before 30 minutes of regional ischemia reduced myocardial necrosis following 120 minutes of reperfusion in a dose-dependent manner. Optimal protection with Dpa against myocardial infarction was manifest at a dose of 2.5 microg/kg. Dpa conferred cardioprotection when administered after the onset of ischemia and at the start of reperfusion. Dpa (2.5 microg/kg) also reduced infarct size and Troponin I leakage 24 hours after reperfusion. Inhibition of p42/44 MAPK (PD98059), p38 MAPK (SB203580), mitochondrial ATP-dependent potassium (KATP) channels (5-HD), sarcolemmal KATP channels (HMR 1098), but not phosphatidylinositol-3 (PI3) kinase/Akt (Wortmannin and LY 294002) abolished Dpa-induced cardioprotection. Dpa confers immediate and sustained cardioprotection in rats, suggesting a potential therapeutic role of this long-acting erythropoietin analog for the treatment of acute myocardial infarction. |
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Authors:
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John E Baker; Deborah Kozik; Anna K Hsu; Xiangping Fu; James S Tweddell; Garrett J Gross |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of cardiovascular pharmacology Volume: 49 ISSN: 0160-2446 ISO Abbreviation: J. Cardiovasc. Pharmacol. Publication Date: 2007 Jun |
Date Detail:
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Created Date: 2007-06-19 Completed Date: 2007-07-20 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 337-45 Citation Subset: IM |
Affiliation:
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Division of Cardiothoracic Surgery; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. jbaker@mcw.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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1-Phosphatidylinositol 3-Kinase
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antagonists & inhibitors,
metabolism Animals Cardiotonic Agents* / administration & dosage, pharmacology, therapeutic use Disease Models, Animal Dose-Response Relationship, Drug Enzyme Activation / drug effects Enzyme Inhibitors / pharmacology Erythropoietin / administration & dosage, analogs & derivatives*, pharmacology, therapeutic use Heart / drug effects Male Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors, metabolism Myocardial Infarction / etiology, prevention & control* Myocardial Reperfusion Injury / complications Myocardium / enzymology, metabolism, pathology Potassium Channels / metabolism Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
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HL 08311/HL/NHLBI NIH HHS; HL 54075/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cardiotonic Agents; 0/Enzyme Inhibitors; 0/Potassium Channels; 11096-26-7/Erythropoietin; 209810-58-2/darbepoetin alfa; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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