Usefulness of defibrotide in protecting ischemic myocardium from early reperfusion damage.
Defibrotide, a partially depolymerized polydeoxyribonucleotide obtained from mammalian lungs, was found to stimulate prostacyclin (PGI2) production and to possess significant antithrombotic and fibrinolytic activities. The present study was designed to evaluate the actions of defibrotide on feline myocardial ischemia, produced by 3 hours of occlusion of the left anterior descending coronary artery (LAD) and followed by 2 hours of reperfusion. Intravenous administration of defibrotide (32 mg/kg/hour subsequent to a 32 mg/kg bolus injection), beginning 30 minutes after LAD occlusion, resulted in a 60% reduction in loss of CK specific activity from ischemic myocardium at 5 hours, while the nonischemic myocardium remained unaffected. Defibrotide largely antagonized the increase in ST segment during LAD occlusion and prevented the appearance of a Q wave during early reperfusion, which was found in all vehicle-treated cats. Although 2 of 8 vehicle-treated cats died from ventricular fibrillation and another had severe ventricular tachyarrhythmia, none of the defibrotide-treated cats had similar severe changes in the electrocardiogram and all 7 cats survived the 5-hour observation period. Defibrotide had no direct action on general hemodynamic functions. In a separate set of experiments, defibrotide (0.1 mg/ml) produced an 8- to 10-fold stimulation of PGI2 release. The data suggest a remarkable protective potential of defibrotide on reperfusion damage of the ischemic myocardium, which may be associated with a PGI2-related mechanism.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002415:Cats; D003327:Coronary Disease / Q000503:physiopathology*; D003402:Creatine Kinase / Q000032:analysis; D004562:Electrocardiography; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D000255:Adenosine Triphosphate; D011464:Epoprostenol; D003402:Creatine Kinase