DEFIBROTIDE IN EXPERIMENTAL MYOCARDIAL ISCHEMIA IN THE CAT: EFFECTS ON HEMODYNAMICS, ENERGY METABOLISM AND INFARCT SIZE

Defibrotide was able to prevent the hemodynamic and biochemical alterations caused by acute myocardial ischemia (AMI) induced by coronary occlusion in the cat when infused 3.5 h before and 5 h after left anterior descending coronary artery (LAD) occlusion. In the platelet perfused heart, Defibrotide was a selective stimulator of coronary vascular PGI^ but not of platelet thromboxane formation. The present study was designed both to investigate the effects of Defibrotide injected 30 min after the induction of acute myocardial ischemia (AMI) in the cat and to evaluate the ability of this drug to reduce infarct size. In the first set of experiments a permanent ligature (5 hours) was placed around LAD. ST segment from ECG, mean aortic pressure (MAP), heart rate (HR) and the pressure-heart rate index (PRI) were considered. Plasma and tissue creatine phosphckinase activity (CFK), tissue lactate and ATP were measured by enzymatic kits from Boehringer Biochemia. 30 min after coronary occlusion a loading dose of Defibrotide (32 ng Kg-1 ) was administered i.v. immediately followed by an infusion (32 ng Kg-1 h 4.5 h-1) MAP, HR and PRI were not modified either by AMI or by the infusion of Defibrotide. AMI-ST segment increases were reduced by Defibrotide from 0.5 h after the beginning of the treatment (—49% vs. AMI control) to the and of experiments (-83% vs. AMI control after 5 h occlusion period). Plasma CFK was reduced from 2.5 h after the beginning of the treatment (-29%) till the end of experiments (-52%). Ischemic tissue CFK, lactate and ATP were normalized by Defibrotide. In the second set of experiments the animals were infused with Defibrotide (50 or 200 mg Kg-1 h-1 , i.v.) starting 2 hours before coronary ligature. The infusion was maintained throughout the 5 h occlusion period. The risk and infarct areas were measured by Evans blu and nitroblue tetrazoliun staining. The 51 ± 3% of risk area was infarcted in AMI control cats. Defibrotide at the two tested doses significantly reduced these infarct areas to 42 ± 4% and 34 ± 2% of risk areas respectively. The beneficial effects of Defibrotide observed in AMI could be attributed both to its ability to enhance PGI2 release from vascular walls and to improved local tissue oxygenation and energy supplies. However it could be taken into account a direct cytoprotective action.