Abstract-Vascular dysfunction in diabetes is attributed to lack of bioavailable nitric oxide (NO) and is postulated as a primary cause of small vessel complications as a result of poor glycemic control. Although it has been proposed that NO is bound by red blood cells (RBCs) and can induce relaxation of blood vessels distal to its site of production in the normal circulation, the effect of RBC glycation on NO binding and relaxation of hypoxic vessels is unknown. We confirm RBC-induced vessel relaxation is inversely related to tissue oxygenation and is proportional to RBC S-nitrosohemoglobin (HbSNO) content (but not nitrosylhemoglobin content Key Words: nitric oxide Ⅲ hemoglobin Ⅲ glycosylation Ⅲ relaxation T he endothelial dysfunction associated with diabetes has been attributed to a lack of bioavailable nitric oxide (NO). [1][2][3] The mechanisms proposed to explain this deficiency include reduced production of NO by NO synthase (NOS) 4,5 and inactivation of NO by reactive oxygen species (ROS) produced either by glycated proteins or directly from vascular endothelium. 6,7 However, these only incompletely explain reduced relaxant responses of microvessels to agonists such as bradykinin in the presence of glycohemoglobin (HbA1c).NO released into the vascular lumen is metabolized (1) by oxyhemoglobin to form methemoglobin and nitrate, (2) by reaction with oxygen (O 2 ) to produce nitrite and nitrate (NOx), (3) through binding to deoxyhemoglobin to produce iron nitrosyl hemoglobin (HbNO), and (4) by reaction with thiol-containing proteins in blood (RSNO) that include glutathione (GSNO) and hemoglobin (S-nitrosohemoglobin, HbSNO). 8 -11 It has been proposed that NO bioavailability in vivo may be governed in part by its reformation from these circulating metabolites as well as by the above local factors. 12,13 This NO "reserve" is likely to be critical in tissue regions where blood supply is limiting and where O 2 demand is increased. The conformational change that occurs during oxygenation of HbNO in the lungs is thought to induce transfer of the NO to an adjacent thiol on the cysteine 93 group of the -chain, producing HbSNO. The levels of HbSNO in human red blood cells (RBCs) are reflected in the physiological O 2 gradient as first shown by Funai et al, 14 and the occurrence of transpulmonary gradients in HbSNO at the expense of HbNO has recently been demonstrated in normal subjects. 15 The HbSNO is thought to pass on its NO to other smaller molecular weight proteins in blood and these can donate NO to cause vasodilatation in the peripheral microvasculature. 16 -19,21 The occurrence and physiological relevance of this NO reserve in the normal circulation has been questioned 21,22 with arguments both for and against. 13,[23][24][25][26] We hypothesized that because protein glycation can produce changes in configuration and ligand binding properties, 27-29 increased HbA1c may directly influence NO metabolism in blood. In a previous study in patients with type 1 diabetes, we demonstrated increased concentrations ...
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