Protectant activity of defibrotide in cardioplegia followed by ischemia/reperfusion injury in the isolated rat heart

Background: Previous studies have shown that defibrotide, a polydeoxyribonu cleotide obtained by depolymerization of DNA from porcine tissues, has impo rtant protective effects on myocardial ischemia, which may be associated wi th a prostacyclin-related mechanism. The purpose of this study was to inves tigate the direct effects of defibrotide (given in cardioplegia or after is chemia) on a model of rat heart recovery after cardioplegia followed by isc hemia/reperfusion injury. Methods: Isolated rat hearts, undergoing 5 minute s of warm cardioplegic arrest followed by 20 minutes of global ischemia and 30 minutes of reperfusion, were studied using the modified Langendorff mod el. The cardioplegia consisted of St. Thomas' Hospital solution augmented w ith defibrotide (50, 100, and 200 mug/mL) or without defibrotide (controls) . Left ventricular mechanical function and the levels of creatine kinase, l actate dehydrogenase, and 6-keto-prostaglandin F-1 alpha (6-keto-PGF(1 alph a); 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 concentrat ion-dependent fashion lower left ventricular end-diastolic pressure (p < 0. 001), higher left ventricular developed pressure (p < 0.01), and lower coro nary perfusion pressure (p < 0.001) compared to the control group. After re perfusion, hearts receiving defibrotide in the cardioplegic solution also h ad, in a dose-dependent way, lower levels of creatine-kinase (p < 0.01), la ctate dehydrogenase (p < 0.001), and higher levels of 6-keto-PGF(1<alpha>) (p < 0.001) compared to the control group. Furthermore, when defibrotide wa s given alone to the hearts at the beginning of reperfusion (n = 7), the re covery of postischemic left ventricular function was inferior (p < 0.05) to that obtained when defibrotide was given in cardioplegia. Conclusions: Def ibrotide confers to conventional crystalloid cardioplegia a potent concentr ation-dependent protective effect on the recovery of isolated rat heart und ergoing ischemia/reperfusion injury. The low cost and the absence of contra indications (cardiac toxicity and hemodynamic effects) make defibrotide a p romising augmentation to cardioplegia.