title: Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve.
abstract: 1. To further explore the effect of antioxidants in preventing diabetes-induced vascular and neural dysfunction we treated streptozotocin-induced diabetic rats daily with subcutaneous injections of 10 mg kg(-1) of M40403 (n=11) and compared the results obtained from 17 control rats and 14 untreated diabetic rats. M40403 is a manganese(II) complex with a bis(cyclo-hexylpyridine)-substituted macrocyclic ligand that was designed to be a selective functional mimetic of superoxide dismutase. Thus, M40403 provides a useful tool to evaluate the roles of superoxide in disease states. 2. Treatment with M40403 significantly improved diabetes-induced decrease in endoneurial blood flow, acetylcholine-mediated vascular relaxation in arterioles that provide circulation to the region of the sciatic nerve, and motor nerve conduction velocity (P<0.05). M40403 treatment also reduced the appearance of superoxide in the aorta and epineurial vessels and peroxynitrite in epineurial vessels. Treating diabetic rats with M40403 reduced the diabetes-induced increase in thiobarbituric acid reactive substances in serum but did not prevent the decrease in lens glutathione level. Treating diabetic rats with M40403 did not improve sciatic nerve Na(+)/K(+) ATPase activity or the sorbitol, fructose or myo-inositol content of the sciatic nerve. 3. These studies provide additional evidence that diabetes-induced oxidative stress and the generation of superoxide and perhaps peroxynitrite may be partially responsible for the development of diabetic vascular and neural complications.
authors.affiliation: Veterans Affairs Medical Center, Diabetes Endocrinology Research Center and Department of Internal Medicine, University of Iowa, Iowa City, IA 52246, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Coppey
authors.forename: J S
authors.initials: JS
authors.lastname: Gellett
authors.forename: E P
authors.initials: EP
authors.lastname: Davidson
authors.forename: J A
authors.initials: JA
authors.lastname: Dunlap
authors.forename: D D
authors.initials: DD
authors.lastname: Lund
authors.forename: D
authors.initials: D
authors.lastname: Salvemini
authors.forename: M A
authors.initials: MA
authors.lastname: Yorek
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005632:Fructose / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D008297:Male; D008345:Manganese; D009431:Neural Conduction / Q000187:drug effects*; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D009942:Organometallic Compounds; D017392:Thiobarbituric Acid Reactive Substances; D014280:Triglycerides; D014665:Vasodilator Agents; D013481:Superoxides; C121876:imisopasem manganese; D005632:Fructose; C002744:3-nitrotyrosine; D014443:Tyrosine; D008345:Manganese; D007294:Inositol; D013012:Sorbitol; D000254:Sodium-Potassium-Exchanging ATPase; D000109:Acetylcholine