title: Protectant activity of defibrotide in cardioplegia followed by ischemia/reperfusion injury in the isolated rat heart.
abstract: BACKGROUND
  Previous studies have shown that defibrotide, a polydeoxyribonucleotide obtained by depolymerization of DNA from porcine tissues, has important protective effects on myocardial ischemia, which may be associated with a prostacyclin-related mechanism. The purpose of this study was to investigate the direct effects of defibrotide (given in cardioplegia or after ischemia) on a model of rat heart recovery after cardioplegia followed by ischemia/reperfusion injury.
  
  
  METHODS
  Isolated rat hearts, undergoing 5 minutes of warm cardioplegic arrest followed by 20 minutes of global ischemia and 30 minutes of reperfusion, were studied using the modified Langendorff model. The cardioplegia consisted of St. Thomas' Hospital solution augmented with defibrotide (50, 100, and 200 microg/mL) or without defibrotide (controls). Left ventricular mechanical function and the levels of creatine kinase, lactate dehydrogenase, and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha; the stable metabolite of prostacyclin) were measured during preischemic and reperfusion periods.
  
  
  RESULTS
  After global ischemia, hearts receiving defibrotide in the cardioplegic solution (n = 8) manifested in a concentration-dependent fashion lower left ventricular end-diastolic pressure (p < 0.001), higher left ventricular developed pressure (p < 0.01), and lower coronary perfusion pressure (p < 0.001) compared to the control group. After reperfusion, hearts receiving defibrotide in the cardioplegic solution also had, in a dose-dependent way, lower levels of creatine-kinase (p < 0.01), lactate dehydrogenase (p < 0.001), and higher levels of 6-keto-PGF1alpha (p < 0.001) compared to the control group. Furthermore, when defibrotide was given alone to the hearts at the beginning of reperfusion (n = 7), the recovery of postischemic left ventricular function was inferior (p < 0.05) to that obtained when defibrotide was given in cardioplegia.
  
  
  CONCLUSIONS
  Defibrotide confers to conventional crystalloid cardioplegia a potent concentration-dependent protective effect on the recovery of isolated rat heart undergoing ischemia/reperfusion injury. The low cost and the absence of contraindications (cardiac toxicity and hemodynamic effects) make defibrotide a promising augmentation to cardioplegia.
authors.affiliation: Department of Pharmacology, Chemotherapy and Medical Toxicology, Institute of Pharmacological Science, University of Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Rossoni
authors.forename: G
authors.initials: G
authors.lastname: Pompilio
authors.forename: P
authors.initials: P
authors.lastname: Biglioli
authors.forename: F
authors.initials: F
authors.lastname: Alamanni
authors.forename: P
authors.initials: P
authors.lastname: Tartara
authors.forename: P
authors.initials: P
authors.lastname: Rona
authors.forename: M
authors.initials: M
authors.lastname: Porqueddu
authors.forename: F
authors.initials: F
authors.lastname: Berti
mesh_terms: D000818:Animals; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006324:Heart Arrest, Induced; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D009926:Organ Preservation; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide