Faculty Collaboration Database

Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms. J Cardiovasc Pharmacol 2007 Jun;49(6):337-45

Date

06/20/2007

Pubmed ID

17577097

DOI

10.1097/FJC.0b013e318040cf81

Scopus ID

2-s2.0-34347212063 (requires institutional sign-in at Scopus site)   43 Citations

Abstract

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.

Author List

Baker JE, Kozik D, Hsu AK, Fu X, Tweddell JS, Gross GJ

Author

John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cardiotonic Agents
Darbepoetin alfa
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Activation
Enzyme Inhibitors
Erythropoietin
Heart
Male
Mitogen-Activated Protein Kinase Kinases
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
Phosphatidylinositol 3-Kinases
Potassium Channels
Rats
Rats, Sprague-Dawley