Obrosova IG, Drel VR, Oltman CL, Mashtalir N, Tibrewala J, Groves JT, Yorek MA. Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats. Am J Physiol Endocrinol Metab 293: E1645-E1655, 2007. First published October 2, 2007; doi:10.1152/ajpendo.00479.2007.-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 ⅐ kg Ϫ1 ⅐ day Ϫ1 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 ⅐ kg Ϫ1 ⅐ day Ϫ1 , 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 ⅐ kg Ϫ1 ⅐ day Ϫ1 doses. FP15, 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , 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.OXIDATIVE STRESS resulting from increased production of reactive oxygen species (ROS) and downregulation or insufficient upregulation of antioxidant defense is a well-recognized fundamental mechanism in diabetic complications. Superoxide is a primary free radical produced in diabetic and hyperglycemic conditions. Superoxide is rapidly converted to several other ROS, i.e., hydroxyl radicals (Fenton and Haber-Weiss reactions), peroxynitrite (reaction with nitric oxide), and hydrogen peroxide (reaction catalyzed by intrinsic superoxide dismutase) (22). The rate of superoxide reaction with nitric oxide exceeds by at least one order of magnitude the rates of other aforementioned reactions, which makes peroxynitrite the number one oxidant in biological systems (38,57,71). Peroxynitrite causes the following numerous cytotoxic effects (nitrosative stress): 1) protein nitration and nitrosylation, 2) DNA singl...