糖尿病大鼠内源性ADMA升高与代谢控制的关系

Relationship between the elevation of endogenous inhibitor of nitric oxide and metabolic control in streptozotocin-induced diabetic rats

目的 以链脲佐菌素诱导的糖尿病大鼠为实验模型 ,研究内源性一氧化氮合酶 (NOS)抑制物非对称性二甲基精氨酸 (ADMA)升高与糖尿病代谢控制的关系。方法 用高效液相色谱测定大鼠血清ADMA浓度 ;用离体胸主动脉环检测乙酰胆碱诱导的内皮依赖性舒张反应 ;并检测血糖、糖基化血清蛋白和血清脂质过氧化产物丙二醛 (MDA)浓度以反映代谢控制。结果 糖尿病大鼠血清ADMA浓度比正常组大鼠明显升高 ,并伴有离体血管内皮依赖性舒张反应的显著抑制 ;经胰岛素治疗 8wk后 ,不仅阻止内源性ADMA的升高 ,也明显改善血管的内皮依赖性舒张功能。此外 ,糖尿病大鼠血糖、糖基化血清蛋白和血清MDA水平也比正常组明显升高。用胰岛素改善代谢控制后 ,血糖、糖基化血清蛋白和血清MDA水平均恢复正常 ,血中ADMA浓度也显著降低。结论 糖尿病大鼠血中内源性NOS抑制物ADMA浓度升高与代谢控制密切相关 ;

AIM To determine the relationship between the elevation of endogenous inhibitor of nitric oxide synthase (NOS)N G,N G-asymmetric dimethylarginine (ADMA) and metabolic control in diabetic rats. METHODS Diabetes was induced in Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. At 72 h after injection, half of diabetic rats received insulin treatment for 8 weeks (20 U·kg -1·d -1,ih, bid). Serum levels of ADMA were measured by high-performance liquid chromatography. Thoracic aortic rings from non-diabetic age-matched control, untreated diabetic, and insulin-treated diabetic rats were tethered in isolated organ baths,contracted with 1 μmol·L -1 phenylephrine, and challenged with either the endothelium-dependent vasodilator acetylcholine or the endothelium-independent vasodilator sodium nitroprusside. Serum concentrations of glucose, glycosylated serum protein, and malondialdehyde, derived from lipid peroxidation were also examined to estimate metabolic control.RESULTS Serum levels of ADMA significantly elevated in untreated diabetic rats compared with control rats. This elevation of ADMA was accompanied by impairment of relaxation response to acetylcholine but not sodium nitroprusside in aortic rings. Chronic insulin treatment not only prevented the elevation of serum ADMA, but also improved the impaired endothelium-dependent relaxation in diabetic rats. Serum levels of glucose, glycosylated serum protein, and malondialdehyde were significantly increased in parallel with the elevation of ADMA in untreated diabetic rats compared with control rats. These parameters were normalized after diabetic rats received insulin treatment. CONCLUSION These results provide the first evidence that the elevation of endogenous inhibitor of NOS in streptozotocin-induced diabetic rats is close related to metabolic control of the disease.