Inhibition of lipid peroxidation with the lazaroid U74500A attenuates ischemia-reperfusion injury in a canine orthotopic heart transplantation model

BACKGROUND: The lazaroid U74500A is a 21-aminosteroid that inhibits lipid peroxidation and attenuates ischemia-reperfusion injury. We examined the effect of U74500A on heart preservation with the use of a clinically relevant canine orthotopic heart transplantation model. METHODS AND RESULTS: Six donor dogs (group L) were pretreated intravenously with U74500A (10 mg/kg), and the dogs without pretreatment served as a control (group C, n = 6). The donor heart was preserved in cold University of Wisconsin solution for 24 hours. The heart was then transplanted orthotopically. Myocardial biopsy was performed to measure the adenosine triphosphate level at the end of ischemia. Before reperfusion, recipients in group L received another dose of U74500A (10 mg/kg) intravenously. After 3 hours of reperfusion, left ventricular function was evaluated by left ventricular pressure-volume relations with the use of a Millar catheter and conductance catheter, thereby deriving the slope of the end-systolic pressure-volume relation, the slope of the stroke work-- end-diastolic volume relation, and the slope of the maximum dP/dt--end-diastolic volume relation. At the same time, serum creatine kinase MB isoenzyme and lipid peroxide levels were measured. The slopes of the end-systolic pressure-volume relation, the stroke work--end-diastolic volume relation, and the maximum dP/dt--end-diastolic volume relation for group L were significantly higher than those for group C. The adenosine triphosphate levels for group L were significantly higher than those for group C. Serum creatine kinase MB isoenzyme and lipid peroxide levels for group L were significantly lower than those for group C. CONCLUSIONS: Inhibition of lipid peroxidation by the administration of U74500A was effective for 24-hour canine cardiac preservation. These results indicate that U74500A is a promising agent for heart allograft preservation.