title: Chronic erythropoietin treatment limits infarct-size in the myocardium in vitro.
abstract: It has been well established that erythropoietin (EPO) can limit myocardial ischemia/reperfusion injury in a variety of acute settings. However, despite EPO being used chronically to treat anemia the infarct limiting effects of long term treatment (chronic) have never been fully investigated. In this study we examined the effects of a 3 week treatment of EPO (5,000 IU/Kg) in male Sprague Dawley rats in limiting myocardial infarction after 35 min ischemia and 2 h reperfusion in an in vitro isolated heart perfusion model. Treating the animals 'once a week' failed to limit infarct size significantly compared to a saline control (54.1% +/- 3.5 v 52.3% +/- 4.4), whereas a '3 times a week' regime succeeded in significantly reducing infarct size (36.2% +/- 3.2 v 52.3% +/- 4.4, p < 0.05). To demonstrate that the effect was not due to improved oxygen supply caused by a raised hematocrit level, we also administered EPO 24 h prior to ischemia/reperfusion. This treatment again reduced infarct size compared to a saline control (39.9% +/- 4.4 v 58.4% +/- 5.0, p < 0.05). To examine the mechanism of protection we used the PI3K inhibitor wortmannin and the nitric oxide synthase inhibitor L-NAME to try to abrogate EPO mediated protection. Where wortmannin failed to block the effects of EPO (31.7% +/- 6.0 v 36.2% +/- 3.2), L-NAME did abrogate protection (51.6% +/- 5.6 v 36.2% +/- 3.2, p < 0.05). We demonstrate that chronic EPO treatment limits infarct size and that it does so in a nitric oxide dependent manner.
authors.affiliation: The Hatter Institute and Centre for Cardiology, University College London Hospital and Medical School, UK.
authors.forename: Anthony John
authors.initials: AJ
authors.lastname: Bullard
authors.forename: Derek Miles
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006400:Hematocrit; D066298:In Vitro Techniques; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester