Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats.
Evidence for important roles of the highly reactive oxidant peroxynitrite in diabetic complications is emerging. We evaluated the role of peroxynitrite in early peripheral neuropathy and vascular dysfunction in STZ-diabetic rats. In the first dose-finding study, control and STZ-diabetic rats were maintained with or without the potent peroxynitrite decomposition catalyst Fe(III)tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin (FP15) at 3, 5, or 10 mg.kg(-1).day(-1) in the drinking water for 4 wk after an initial 2 wk without treatment for assessment of early neuropathy. In the second study with similar experimental design, control and STZ-diabetic rats were maintained with or without FP15, 5 mg.kg(-1).day(-1), for vascular studies. Rats with 6-wk duration of diabetes developed motor and sensory nerve conduction velocity deficits, mechanical hyperalgesia, and tactile allodynia in the absence of small sensory nerve fiber degeneration. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve and dorsal root ganglia. All these variables were dose-dependently corrected by FP15, with minimal differences between the 5 and 10 mg.kg(-1).day(-1) doses. FP15, 5 mg.kg(-1).day(-1), also corrected endoneurial nutritive blood flow and nitrotyrosine, but not superoxide, fluorescence in aorta and epineurial arterioles. Diabetes-induced decreases in acetylcholine-mediated relaxation by epineurial arterioles and coronary and mesenteric arteries, as well as bradykinin-induced relaxation by coronary and mesenteric arteries, were alleviated by FP15 treatment. The findings reveal the important role of nitrosative stress in early neuropathy and vasculopathy and provide the rationale for further studies of peroxynitrite decomposition catalysts in long-term diabetic models.
Obrosova
Irina G
IG
Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA. obrosoig@pbrc.edu
Drel
Viktor R
VR
Oltman
Christine L
CL
Mashtalir
Nazar
N
Tibrewala
Jyoti
J
Groves
John T
JT
Yorek
Mark A
MA
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D008665:Metalloporphyrins / Q000494:pharmacology / Q000627:therapeutic use; D009431:Neural Conduction / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D001786:Blood Glucose; C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D007004:Hypoglycemic Agents; D008665:Metalloporphyrins; D014665:Vasodilator Agents; D013481:Superoxides; D030421:Peroxynitrous Acid; D011064:Poly Adenosine Diphosphate Ribose; C002744:3-nitrotyrosine; D014443:Tyrosine