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

Irina G Obrosova; Viktor R Drel; Christine L Oltman; Nazar Mashtalir; Jyoti Tibrewala; John T Groves; Mark A Yorek

doi:10.1152/ajpendo.00479.2007

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

Journal article

Peer reviewed

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

Irina G Obrosova, Viktor R Drel, Christine L Oltman, Nazar Mashtalir, Jyoti Tibrewala, John T Groves and Mark A Yorek

American journal of physiology: endocrinology and metabolism, Vol.293(6), pp.E1645-1655

12/2007

DOI: 10.1152/ajpendo.00479.2007

PMID: 17911342

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Abstract

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.

Mesenteric Arteries - physiopathology

Rats, Wistar

Coronary Vessels - physiopathology

Body Weight - drug effects

Male

Mesenteric Arteries - drug effects

Sciatic Nerve - physiopathology

Aorta - metabolism

Metalloporphyrins - pharmacology

Tyrosine - analogs & derivatives

Diabetic Angiopathies - physiopathology

Metalloporphyrins - therapeutic use

Sciatic Nerve - metabolism

Regional Blood Flow - drug effects

Arterioles - physiopathology

Superoxides - metabolism

Neural Conduction - drug effects

Peroxynitrous Acid - antagonists & inhibitors

Sciatic Nerve - drug effects

Diabetes Mellitus, Experimental - metabolism

Diabetes Mellitus, Experimental - physiopathology

Diabetic Neuropathies - physiopathology

Hypoglycemic Agents - therapeutic use

Diabetic Angiopathies - metabolism

Coronary Vessels - drug effects

Vasodilator Agents - pharmacology

Hyperalgesia - metabolism

Rats

Diabetic Neuropathies - drug therapy

Diabetic Angiopathies - drug therapy

Hyperalgesia - physiopathology

Hypoglycemic Agents - pharmacology

Blood Glucose - drug effects

Poly Adenosine Diphosphate Ribose - metabolism

Tyrosine - metabolism

Animals

Arterioles - metabolism

Peroxynitrous Acid - metabolism

Diabetic Neuropathies - metabolism

Ganglia, Spinal - metabolism

Details

Title: Subtitle: Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats
Creators: Irina G Obrosova - Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA. obrosoig@pbrc.edu
Viktor R Drel
Christine L Oltman
Nazar Mashtalir
Jyoti Tibrewala
John T Groves
Mark A Yorek
Resource Type: Journal article
Publication Details: American journal of physiology: endocrinology and metabolism, Vol.293(6), pp.E1645-1655
DOI: 10.1152/ajpendo.00479.2007
PMID: 17911342
ISSN: 0193-1849
eISSN: 1522-1555
Grant note: DK-07156601 / NIDDK NIH HHS P30 DK072476 / NIDDK NIH HHS DK-073990 / NIDDK NIH HHS R56 DK073990 / NIDDK NIH HHS GM-36298 / NIGMS NIH HHS
Language: English
Date published: 12/2007
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094591702771

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