DIABETIC-INDUCED ENDOTHELIAL DYSFUNCTION IN RAT AORTA - ROLE OF HYDROXYL RADICALS

Previous studies suggest a role of superoxide anion radicals (.O-2(-)) in impaired endothelium-dependent relaxation of diabetic blood vessel s; however, the role of secondary reactive oxygen species remains uncl ear. In the present study, we investigated a role of various potential reactive oxygen species in diabetic endothelial dysfunction. Methods: Thoracic aortic rings from 8-week streptozotocin-induced diabetic and age-matched control rats were mounted in isolated tissue baths. Endot helium-dependent relaxation to acetylcholine (AGH) and endothelium-ind ependent relaxation to nitroglycerin (NTG) were assessed in precontrac ted rings, Results: AGH-induced relaxation was impaired in diabetic co mpared to control rings and was not improved with either indomethacin or daltroban. AGH-induced relaxation in both control and diabetic ring s was completely blocked with the nitric oxide synthase inhibitors, L- nitroarginine methyl ester or L-nitroarginine (L-NA). NTG-induced rela xation was insensitive to L-NA and was unaltered by diabetes, Pretreat ment with superoxide dismutase (SOD) at activities which did not alter contractile tone failed to alter responses to ACH in diabetic rings. Similar results were obtained using either catalase or mannitol, In co ntrast, the combination of SOD plus catalase or DETAPAC, an inhibitor of metal-facilitated hydroxyl radical (.OH) formation, markedly enhanc ed relaxation to ACH in diabetic but not in control rings. Neither the combination of SOD plus catalase nor DETAPAC altered the sensitivity or relaxation to NTG in control rings with or without endothelium. In diabetic rings with endothelium, both DETAPAC or SOD plus catalase inc reased sensitivity but not maximum relaxation to NTG. In diabetic ring s without endothelium, relaxation and sensitivity to NTG were unaltere d by either treatment. In L-NA-treated diabetic rings with endothelium , sensitivity and relaxation to NTG was unaltered by either DETAPAC or SOD plus catalase. Conclusion: Diabetic endothelium produces increase s in both .O-2(-) and H2O2 leading to enhanced intracellular productio n of .OH. Thus, .OH are implicated in diabetes-induced endothelial dys function.