Effect of a neutrophil elastase inhibitor (ONO-5046 Na) on ischemia/reperfusion injury using the left-sided heterotopic canine heart transplantation model

Background: Ischemia/reperfusion injury is a major cause of transplanted he art dysfunction. Several reports have demonstrated that polymorphonuclear n eutrophil (PMN) elastase derived from the activated neutrophils might play an important role in this injury. Herein, we investigated the protective ef fects of PMN elastase inhibitor (ONO-5046 Na) on ischemia/reperfusion injur y using a left-sided canine heterotopic heart transplantation model. Methods: We used 10 pairs of adult beagle dogs. The donor heart was transpl anted heterotopically into the left thoracic cavity of the recipient withou t cardiopulmonary bypass. A bolus of ONO-5046 Na (10 mg/kg) was introduced intravenously to 5 recipients (group Il) at 15 minutes before reperfusion a nd was followed by continuous infusion (10 mg/kg per hour) for 180 minutes. Five dogs (group I) did not receive ONO-5046 Na and thus served as a contr ol. After reperfusion, we evaluated transplanted heart function and obtaine d blood samples from the coronary sinus over a 360-minute period. Results: E-max and pre-load recruitable stroke work in group II showed sign ificantly better recovery than group I. Blood levels of PMN elastase, creat ine kinase MB, lactate and inflammatory cytokines (tumor necrosis factor-al pha, interleukin-6, interleukin-8) were significantly lower in group II. De pletion of myocardial concentration of adenosine triphosphate at 120 minute s after reperfusion and myocardial water content was significantly lower in group II. Conclusions: ONO-5046 Na, which inhibits PMN elastase, could reduce ischemi a/reperfusion injury in heart transplantation. These results indicate that clinical application of ONO-5046 Na should be considered.