Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms.
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.
Baker
John E
JE
Division of Cardiothoracic Surgery; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. jbaker@mcw.edu
Kozik
Deborah
D
Hsu
Anna K
AK
Fu
Xiangping
X
Tweddell
James S
JS
Gross
Garrett J
GJ
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002316:Cardiotonic Agents; D000068256:Darbepoetin alfa; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels