Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

1 Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana; 2 Department of Medicine, University of Iowa, and Veterans Affairs Medical Center, Iowa City, Iowa; and 3 Department of Chemistry, Princeton University, Princeton, New Jersey Submitted 24 July 2007 ; accepted in final form 27 September 2007 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. Address for reprint requests and other correspondence: I. G. Obrosova, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808 (e-mail: obrosoig{at}pbrc.edu )