Enhanced, unaltered and impaired nitric oxide-mediated endothelium-dependent relaxation in experimental diabetes mellitus: importance of disease duration

Long-term diabetes mellitus is characterized by impaired endothelium-dependent relaxation. In contrast, there is limited information on endothelial function in the early stages of the disease. In this study, we evaluated endothelial function ex vivo at early, intermediate and later stages of streptozotocin (STZ)-induced diabetes mellitus. We also evaluated the contribution of various endothelium-derived vasoactive factors at these stages of disease. In aortic rings contracted with norepinephrine, endothelium-dependent relaxation to acetycholine was increased at 24 h following injection with streptozotocin compared with controls, normal after 1 and 2 weeks of disease or impaired at 8 weeks of disease. Endothelium-independent relaxation to nitroglycerin was unaltered at all stages. The enhanced relaxation at 24 h was mimicked in rings from alloxan-induced diabetic rats. Acute exposure of normal rings to streptozotocin in vitro caused no perturbation in acetylcholine-stimulated relaxation. Enhanced relaxation in diabetic rings at 24 h persisted in the presence of either indomethacin or tetraethylammonium. Acetylcholine-induced relaxation was blocked in both control and diabetic rings using L-nitroarginine but not by aminoguanidine. This suggests that the increased response was mediated by enhanced constitutive nitric oxide (NO). These studies show a triphasic response of increased, unaltered and impaired endothelium-dependent relaxation within the same model but dependent on the duration of disease. These studies could reconcile previous conflicting data in the literature and account for the observations of increases in tissue blood now seen in early stages of experimental and human diabetes mellitus.