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-kappaB (NF-kappaB) 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-kappaB (NF-kappaB) 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.
Pieper
Galen M
GM
Division of Transplant Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. gmpieper@mcw.edu
Siebeneich
Wolfgang
W
Olds
Cara L
CL
Lai
Ching-San
CS
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006442:Glycated Hemoglobin / Q000032:analysis; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
D000975:Antioxidants; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D016328:NF-kappa B; D013859:Thiocarbamates