De Vriese A S, Van de Voorde J, Blom H J, Vanhoutte P M, Verbeke M, Lameire N H
The Renal Unit, Ghent University, Belgium.
Diabetologia. 2000 Sep;43(9):1116-25. doi: 10.1007/s001250051502.
AIMS/HYPOTHESIS: Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease.
Endothelium-dependent and endothelium-independent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor L-NG-nitroarginine methylester HCI (L-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses.
The L-NAME- and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-i um-1,2-diolate (DETA-NONOate) and to the K+-channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. CONCLUSION-INTERPRETATION: Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes.
目的/假设：内皮功能障碍促进糖尿病血管并发症的发生。更好地了解糖尿病内皮功能障碍的病理生理学可能会带来预防微血管疾病的新方法。
在链脲佐菌素诱导的糖尿病大鼠的肾微循环中研究内皮依赖性和非内皮依赖性血管舒张反应。我们用电磁流量探头测量肾血流变化。此外，使用肾积水肾技术通过视频显微镜评估肾微循环不同节段的反应。由于内皮细胞释放不同的舒张因子（一氧化氮、前列环素和一种未确定的内皮衍生超极化因子），在用一氧化氮合酶抑制剂盐酸L-NG-硝基精氨酸甲酯（L-NAME）和环氧化酶抑制剂吲哚美辛治疗前后测量对乙酰胆碱的反应。我们评估了叶酸的活性形式5-甲基四氢叶酸对这些反应的影响。
与对照大鼠相比，糖尿病大鼠对肾内乙酰胆碱的L-NAME和吲哚美辛抵抗性血管舒张显著降低，提示内皮衍生超极化因子介导的血管舒张受损。糖尿病大鼠和对照大鼠对一氧化氮供体（Z）-1-[-2-（氨基乙基）-N-（2-氨乙基）氨基]重氮-1-鎓-1,2-二醇盐（DETA-NO）和钾通道开放剂吡那地尔的反应相似，表明非内皮依赖性血管舒张机制完整。内皮衍生超极化因子对乙酰胆碱诱导的血管舒张的贡献在最小的小动脉中最大。在糖尿病大鼠中，随着血管尺寸减小，对乙酰胆碱的反应越来越受损。糖尿病肾中受损的血管舒张通过5-甲基四氢叶酸迅速恢复正常。结论解读：糖尿病大鼠肾微循环中内皮衍生超极化因子介导的血管舒张受损，尤其是在最小的动脉中。叶酸治疗可恢复糖尿病中受损的内皮功能。
