The Role Of Endogenous Inhibitor Of Nitric Oxide Synthase In Macroangiopathy Of Diabetes Mellitus And Its Mechanisms

Backgrounds and Objectives It has been demonstrated thatendogenous inhibitor of nitric oxide synthase N , N -asymmetric dimethylarginine (ADMA) was significantly increased in the plasma of atherosclerosis animals and hypercholesterolemic individuals and the increased endogenous ADMA was associated with impairment of endothelium-dependent vasodilatation. Epidemiological studies found that patients with type 2 diabetes have an accelerated atherosclerosis and an increased prevalence of cardiovascular diseases. Therefore, we designed the present study to determine whether endogenous inhibitor of nitric oxide synthase ADMA elevates in serum of diabetic rats and type 2 diabetic patients and whether elevated endogenous ADMA is associated with endothelial dysfunction and macroangiopathy in diabetes. Methods Experimental diabetic animal model was induced by a single intraperitoneal injection of streptozotocin (60 mg/kg dissolved in 0.1 mol/L citrate buffer) to Male Sprague-Dawley rats (weighing 210 + 18 g). An equal volume of citrate buffer was administrated to age-matchecontrol rats. Type 2 diabetic patients were recruited from Xiangya Hospital (20 male and 18 female, aged 38 to 76, 58 + 10.3) including 19 with macroangiopathy and 19 without macroangiopathy. Healthy control subjects were selected among Xiangya Medical College staffs (22 male and 16 female, aged 38 to 66, 50 + 7.5). The concentrations of plasma glucose and serum ADMA were measured in both strptozotocin-induced diabetic rats and type 2 diabetic patients. Furthermore, serum malondialdehyde (MDA) levels and endothelium-dependent vasorelaxation to acetylcholine of aortic rings were detected in diabetic rats. Plasma levels of total cholesterol, triglyceride and creatinine were determined in type 2 diabetic patients. Results The concentrations of plasma glucose and serum ADMA were significantly elevated not only in strptozotocin-induced diabetic rats (ADMA level is 5.4 + 1.0 vs 0.7 + 0.3 umol/L in diabetic vs control group, n=10, P<0.01) but also in type 2 diabetic patients (ADMA level is 5.22 + 2.83 vs 1.08 + 0.88mol/L in diabetic vs control group, n=38, P<0.01). This elevation of endogenous ADMA was accompanied by the impairment of endothelium-dependent vasorelaxation and the increase of serum MDA contents in diabetic rats (2.5 + 0.3 vs 1.5 + 0.1 umol/L in diabetic vs control group, n=10, P<0.01). The levels of endogenous ADMA in type 2 diabetic patients with macroangiopathy were higher than those of patients without macroangiopathy (6.61 + 2.63 vs 3.84 + 2.33mol/L in group withmacroangiopathy vs without macroangiopathy, n=19, P<0.01). But no difference was observed in serum ADMA concentrations between groups of patients with different diabetic duration. Conclusions The present study demonstrated for the first time that serum concentrations of endogenous inhibitor of nitric oxide synthase ADMA were significantly elevated in streptozotocin-induced diabetic rats and type 2 diabetic patients, and this elevation of endogenous ADMA induced by hyperglycemia may be a contributor to endothelial dysfunction and macroangiopathy in diabetes mellitus. This study provides a new insight into the mechanisms for endothelial dysfunction and macroangiopathy associated with diabetes.