Previous studies have indicated that
cardiovascular abnormalities such as depressed blood pressure and heart rate occur in
streptozotocin (STZ) diabetic rats. Chronic diabetes, which is associated with increased expression of
inducible nitric oxide synthase (iNOS) and oxidative stress, may produce
peroxynitrite/
nitrotyrosine and cause nitrosative stress. We hypothesized that nitrosative stress causes cardiovascular depression in STZ diabetic rats and therefore can be corrected by reducing its formation. Control and STZ diabetic rats were treated orally for 9 weeks with
N-acetylcysteine (NAC), an
antioxidant and inhibitor of iNOS. At termination, the mean arterial blood pressure (MABP) and heart rate (HR) were measured in conscious rats.
Nitrotyrosine and
endothelial nitric oxide synthase (eNOS) and iNOS expression were assessed in the heart and mesenteric arteries by immunohistochemistry and Western blot experiments. Untreated diabetic rats showed depressed MABP and HR that was prevented by treatment with NAC. In untreated diabetic rats, levels of
15-F(2t)-isoprostane, an
indicator of lipid peroxidation increased, whereas plasma
nitric oxide and
antioxidant concentrations decreased. Furthermore, decreased eNOS and increased iNOS expression were associated with elevated nitrosative stress in blood vessel and heart tissue of untreated diabetic rats.
N-acetylcysteine treatment of diabetic rats not only restored the
antioxidant capacity but also reduced the expression of iNOS and
nitrotyrosine and normalized the expression of eNOS to that of control rats in heart and superior mesenteric arteries. The results suggest that nitrosative stress depress MABP and HR following diabetes. Further studies are required to elucidate the mechanisms involved in nitrosative stress mediated depression of blood pressure and heart rate.