CHRONIC TREATMENT WITH THE 21-AMINOSTEROID U74389F, AN INHIBITOR OF LIPID-PEROXIDATION, DOES NOT PREVENT DIABETIC ENDOTHELIAL DYSFUNCTION

Oxygen-derived free radicals are believed to be involved in diabetes-i nduced vascular complications. The role of oxygen radicals in endothel ial dysfunction in diabetes is not known with certainty. In this study we tested whether inhibition of lipid peroxidation using the patent i nhibitor U74389F, a 21-aminosteroid also known as lazaroid, could prev ent endothelial dysfunction in diabetes. Lewis strain rats were made d iabetic by intravenous injection of streptozotocin. A subgroup of diab etic animals received daily oral doses of 10 mg/kg U74389F at 72 hours post streptozotocin and throughout the 8-week duration of diabetes. T horacic aortas were isolated and suspended in isolated tissue baths an d contracted with norepinephrine. Relaxation due to the endothelium-de pendent vasodilator, acetylcholine, was impaired in diabetic aorta whi le relaxation due to A23187 and nitroglycerin was unaltered. Chronic t reatment of diabetic animals with U74389F normalized the increase in p lasma lipid peroxides as assessed by thiobarbituric acid-reactive subs tances but did not alter serum insulin levels, blood glucose concentra tion, nor total glycosylated hemoglobin. Increases in aortic catalase activity resulting from diabetes was not altered by U74389F. Despite r eductions in lipid peroxides, U74389F did not prevent the diabetes-ind uced impairment in endothelium-dependent relaxation caused by acetylch oline. These data suggest that other pathways that are antecedent to L ipid peroxidation may be responsible for endothelial dysfunction in di abetes.