Antioxidative treatment reverses imbalances of nitric oxide synthase isoform expression and attenuates tissue-cGMP activation in diabetic rats

Oxidative stress and impaired bioactivity of vascular nitric oxide (NO) play an important role in the pathogenesis of macro- as well as microangiopathic complications in diabetes mellitus. To determine the cause of this impaired bioactivity, we tested the effect of long-term hyperglycemia and antioxidative treatment on tissue-specific endothelial (e)NOS- and inducible (i)NOS-expression and the main target of NO action, cGMP, in diabetic rats. After 4 weeks of hyperglycemia, eNOS-mRNA expression was significantly down-regulated in all tissues tested. In contrast, iNOS-mRNA was significantly up-regulated and tissue generation of cGMP significantly increased. Treatment with alpha-lipoicacid reversed changes of NOS-isoform expression as well as cGMP-concentration without changing blood glucose levels. In addition, oxidative stress significantly decreased in diabetic rats treated with alpha-lipoicacid. Together, diabetes regulates NOS-isoforms differentially by down-regulating eNOS and up-regulating iNOS. In addition, our data suggest that the cause of impaired endothelial vasodilatation in experimental diabetes is not degradation or inactivation of NO. On the contrary, these results support the concept of decreased reactivity of the vascular smooth muscle to NO or increased NO activity as a possible vascular damaging agent, e.g., by inducing apoptosis in vascular cells. Furthermore, our data show that antioxidative treatment is capable of reversing changes in the NO-cGMP system and may therefore be an important therapeutic option for preventing vascular damage in diabetes mellitus.