INHIBITION OF LIPID-PEROXIDATION WITH THE LAZAROID U74500A ATTENUATESISCHEMIA-REPERFUSION INJURY IN A CANINE ORTHOTOPIC HEART-TRANSPLANTATION MODEL

Background: The lazaroid U74500A is a 21-aminosteroid that inhibits li pid peroxidation and attenuates ischemia-reperfusion injury, We examin ed the effect of U74500A on heart preservation with the use of a clini cally relevant canine orthotopic heart transplantation model, Methods and results: Six donor dogs (group L) were pretreated intravenously wi th U74500A (10 mg/kg), and the dogs without pretreatment served as a c ontrol (group C, n = 6). The donor heart was preserved in cold Univers ity of Wisconsin solution for 24 hours, The heart was then transplante d orthotopically. Myocardial biopsy was performed to measure the adeno sine triphosphate level at the end of ischemia, Before reperfusion, re cipients in group L received another dose of U74500A (10 mg/kg) intrav enously, After 3 hours of reperfusion, left ventricular function was e valuated by left ventricular pressure-volume relations with the use of a Millar catheter and conductance catheter, thereby deriving the slop e of the end-systolic pressure-volume relation, the slope of the strok e work-end-diastolic volume relation, and the slope of the maximum dP/ dt-end-diastolic volume relation, At the same time, serum creatine kin ase MB isoenzyme and lipid peroxide levels were measured. The slopes o f the end-systolic pressure-volume relation, the stroke work-end-diast olic volume relation, and the maximum dP/dt-end-diastolic volume relat ion for group L were significantly higher than those for group C. The adenosine triphosphate levels for group L were significantly higher th an those for group C, Serum creatine kinase MB isoenzyme and lipid per oxide levels for group L were significantly lower than those for group C. Conclusions: Inhibition of lipid peroxidation by the administratio n of U74500A was effective for 24-hour canine cardiac preservation, Th ese results indicate that U74500A is a promising agent for heart allog raft preservation.