Vasodilation and increased blood flow are characteristic early vascular responses to acute hyperglycemia and tissue hypoxia. In hypoxic tissues these vascular changes are linked to metabolic imbalances associated with impaired oxidation of NADH to NAD+ and the resulting increased ratio of NADH/NAD+. In hyperglycemic tissues these vascular changes also are linked to an increased ratio of NADH/NAD+, in this case because of an increased rate of reduction of NAD+ to NADH. Several lines of evidence support the likelihood that the increased cytosolic ratio of free NADH/NAD+ caused by hyperglycemia, referred to as pseudohypoxia because tissue partial pressure oxygen is normal, is a characteristic feature of poorly controlled diabetes that mimics the effects of true hypoxia on vascular and neural function and plays an important role in the pathogenesis of diabetic complications. These effects of hypoxia and hyperglycemia-induced pseudohypoxia on vascular and neural function are mediated by a branching cascade of imbalances in lipid metabolism, increased production of superoxide anion, and possibly increased nitric oxide formation.
C-peptide, a cleavage product from the processing of proinsulin to insulin, has been considered to possess little if any biological activity other than its participation in insulin synthesis. Injection of human C-peptide prevented or attenuated vascular and neural (electrophysiological) dysfunction and impaired Na+- and K+-dependent adenosine triphosphate activity in tissues of diabetic rats. Nonpolar amino acids in the midportion of the peptide were required for these biological effects. Synthetic reverse sequence (retro) and all-D-amino acid (enantio) C-peptides were equipotent to native C-peptide, which indicates that the effects of C-peptide on diabetic vascular and neural dysfunction were mediated by nonchiral interactions instead of stereospecific receptors or binding sites.
Increased blood flow and vascular leakage of proteins preferentially affect tissues that are sites of diabetic complications in humans and animals. These vascular changes in diabetic rats are largely prevented by aminoguanidine. Glucose-induced vascular changes in nondiabetic rats are also prevented by aminoguanidine and by A^-monomethyl-L-arginine (NMMA), an established inhibitor of nitric oxide (NO) formation from L-arginine. Aminoguanidine and NMMA are equipotent inhibitors of interleukin-1 p-induced 1) nitrite formation (an oxidation product of NO) and cGMP accumulation by the rat p-cell insulinoma cell line RINm5F, and 2) inhibition of glucose-stimulated insulin secretion and formation of iron-nitrosyl complexes by islets of Langerhans. In contrast, NMMA is ~40 times more potent than aminoguanidine in elevating blood pressure in nondiabetic rats. These results demonstrate that aminoguanidine inhibits NO production and suggest a role for NO in the pathogenesis of diabetic vascular complications. Diabetes 41:552-56, 1992 N itric oxide synthase catalyzes the mixed functional oxidation of a guanidino nitrogen atom of L-arginine to yield L-citrulline and NO-(1,2). The constitutive isoform of NO-synthase is Ca 2+ dependent and produces small amounts of NO-that activate guanylate cyclase, resulting in the formation of cGMP, which mediates endothelium-dependent relaxation (2) and neural transmission (3). NO-is produced in much larger amounts by the cytokine-and endotoxininducible isoform of NO-synthase, which is Ca 2+ inde-
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