title: Enhanced preservation of the rat heart after prolonged hypothermic ischemia with erythropoietin-supplemented Celsior solution.
abstract: BACKGROUND
  The cardioprotective efficacy of erythropoietin (EPO) has been widely documented in rodent models of acute coronary syndrome. We sought to evaluate its cardioprotective potential as an adjunct to Celsior cardioplegia in a rodent model of prolonged hypothermic global ischemia-reperfusion injury.
  
  
  METHODS
  Isolated working rat hearts were subjected to 6 or 10 hours of hypothermic ischemic storage in Celsior cardioplegic solution. Celsior was supplemented with EPO over a dose range of 0 to 5 units/ml, as well as with glyceryl trinitrate (0.1 mg/ml) and zoniporide (1 µmol/liter). Myocardial functional recovery was determined after 45 minutes of reperfusion, then left ventricular tissue was prepared for Western blotting.
  
  
  RESULTS
  The presence of EPO in Celsior dose-dependently improved recovery of myocardial function after 6 hours ischemic storage time (cardiac output recovery: 52.5 ± 11.3% vs 2.5 ± 0.4%; EPO: 5 units/ml vs 0 units/ml; p < 0.05). This functional benefit was associated with decreased lactate dehydrogenase released into coronary effluent and enhanced phosphorylation of STAT3, all of which were completely abrogated by pre-treatment with stattic, a selective inhibitor of STAT3 activation. When the ischemic storage time was extended to 10 hours, additive beneficial effects on myocardial function were seen when EPO was used in combination with the cardioprotective agents glyceryl trinitrate and zoniporide.
  
  
  CONCLUSIONS
  EPO has demonstrated cardioprotective efficacy in a rodent model of ischemia-reperfusion injury simulating cardiac allograft preservation, which appears to be mediated via activation of the SAFE cytoprotective signaling pathway.
authors.affiliation: Transplant Program, Victor Chang Cardiac Research Institute, Sydney, Australia.
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Watson
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Jireh
authors.initials: J
authors.lastname: Tsun
authors.forename: Andrew
authors.initials: A
authors.lastname: Jabbour
authors.forename: Min
authors.initials: M
authors.lastname: Ru Qiu
authors.forename: Paul C
authors.initials: PC
authors.lastname: Jansz
authors.forename: Mark
authors.initials: M
authors.lastname: Hicks
authors.forename: Peter S
authors.initials: PS
authors.lastname: Macdonald
mesh_terms: D000818:Animals; D002314:Cardioplegic Solutions / Q000494:pharmacology / Q000627:therapeutic use*; D050377:Cold Ischemia; D004187:Disaccharides / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004573:Electrolytes / Q000494:pharmacology / Q000627:therapeutic use; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000494:pharmacology / Q000627:therapeutic use; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006639:Histidine / Q000494:pharmacology / Q000627:therapeutic use; D007035:Hypothermia / Q000503:physiopathology*; D008297:Male; D008353:Mannitol / Q000494:pharmacology / Q000627:therapeutic use; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005996:Nitroglycerin / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D002314:Cardioplegic Solutions; C088453:Celsior; D004187:Disaccharides; D004573:Electrolytes; D005971:Glutamates; D006146:Guanidines; D011720:Pyrazoles; D004921:Erythropoietin; D008353:Mannitol; D006639:Histidine; C424422:zoniporide; D005996:Nitroglycerin; D005978:Glutathione