Chronic or delayed treatment with an oral dithiocarbamate analog decreases glycation and protects diabetic arteries

In the present study, we examined the efficacy of a dithiocarbamate-based compound, denoted as NOX-700, on diabetes-induced endothelial dysfunction and glycosylation of hemoglobin (Hb). Streptozotocin-induced diabetic rats received 3 mg/ml NOX-700 in drinking water beginning at 72 h or 4 weeks and continued to 8 weeks. Oxidative and glycooxidative stress were examined by electrophoretic mobility shift assay (EMSA) for nuclear factor-κB (NF-κB) in nuclear fractions of aortic homogenates and by glycosylated Hb, respectively. Vascular reactivity was examined in aortic ring segments ex vivo. Treatment with NOX-700 inhibited glycosylated Hb formation when given long-term or after delayed administration. NOX-700 improved endothelium-dependent relaxation to acetylcholine but did not alter reactivity to norepinephrine or nitroglycerin, suggesting selective protection of the endothelium. Nuclear factor-κB (NF-κB) nuclear binding activity was significantly increased in diabetic aortas and abrogated by NOX-700. Thus, vascular protection by NOX-700 is believed to be mediated, in part, by an antioxidant mechanism and decreased protein glycation.