Document Detail

Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms.
MedLine Citation:
PMID:  17577097     Owner:  NLM     Status:  MEDLINE    
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.
John E Baker; Deborah Kozik; Anna K Hsu; Xiangping Fu; James S Tweddell; Garrett J Gross
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  49     ISSN:  0160-2446     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-06-19     Completed Date:  2007-07-20     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  337-45     Citation Subset:  IM    
Division of Cardiothoracic Surgery; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
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MeSH Terms
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
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors,  metabolism
Myocardial Infarction / etiology,  prevention & control*
Myocardial Reperfusion Injury / complications
Myocardium / enzymology,  metabolism,  pathology
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism
Potassium Channels / metabolism
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/Cardiotonic Agents; 0/Enzyme Inhibitors; 0/Potassium Channels; 11096-26-7/Erythropoietin; 15UQ94PT4P/darbepoetin alfa; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Protein Kinase Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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