Endothelium-derived hyperpolarizing factor-mediated renal vasodilatory response is impaired during acute and chronic hyperhomocysteinemia
Endothelium-derived hyperpolarizing factor-mediated renal vasodilatory response is impaired during acute and chronic hyperhomocysteinemia
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DOI：
10.1161/01.cir.0000129138.08493.4d
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发表时间：
2004-05-18
期刊：
影响因子：
37.8
通讯作者：
Lameire, NH
中科院分区：
文献类型：
--
作者：
De Vriese, AS;Blom, HJ;Lameire, NH
背景-内皮功能障碍是高同型半胱氨酸血症血管并发症发展的早期事件。内皮细胞释放许多血管扩张剂，包括一氧化氮和前列环素。一些证据表明存在第三种血管扩张剂途径，由内皮源性超极化因子（EDHF）介导。EDHF是小阻力血管张力的主要决定因素。高同型半胱氨酸血症对EDHF的影响尚不清楚。目前的体内研究评估了EDHF途径在急性和慢性高同型半胱氨酸血症大鼠肾微循环中的完整性。方法与结果- edhf介导的血管舒张作用以肾内乙酰胆碱对全身NO合成酶和环氧化酶抑制时肾血流量（RBF）的反应进行评价。静脉注射高同型半胱氨酸引起的急性高同型半胱氨酸血症不影响edhf介导的血管舒张。相反，静脉注射蛋氨酸伴高同型半胱氨酸血症会损害edhf介导的RBF反应。在输注蛋氨酸之前，为了防止s -腺苷同型半胱氨酸分裂为同型半胱氨酸和腺苷而氧化高碘酸腺苷，EDHF也出现了类似的损伤，但同型半胱氨酸水平正常。与标准饮食的动物相比，高蛋氨酸、低B族维生素饮食8周后引起的慢性高同型半胱氨酸血症的动物edhf介导的血管舒张功能严重下降。急性和慢性高同型半胱氨酸血症不影响内皮非依赖性血管舒张，显示血管平滑肌反应性完整。结论：高同型半胱氨酸血症大鼠肾脏中edhf依赖性反应受损。由于EDHF是小血管血管功能的主要调节因子，这些发现对高同型半胱氨酸血症微血管病变的发展具有重要意义。
Background - Endothelial dysfunction is an early event in the development of vascular complications in hyperhomocysteinemia. Endothelial cells release a number of vasodilators, including NO and prostacyclin. Several lines of evidence have indicated the existence of a third vasodilator pathway, mediated by endothelium-derived hyperpolarizing factor (EDHF). EDHF is a major determinant of vascular tone in small resistance vessels. The influence of hyperhomocysteinemia on EDHF is unknown. The present in vivo study evaluates the integrity of the EDHF pathway in the renal microcirculation of rats with acute and chronic hyperhomocysteinemia.Methods and Results - EDHF-mediated vasodilation was evaluated as the renal blood flow (RBF) response to intrarenal acetylcholine during systemic NO synthase and cyclooxygenase inhibition. Acute hyperhomocysteinemia induced by intravenous homocysteine did not affect EDHF-mediated vasodilation. In contrast, intravenous methionine with subsequent hyperhomocysteinemia impaired the EDHF-mediated RBF response. When the methionine infusion was preceded by adenosine periodate oxidized to prevent the cleavage of S-adenosylhomocysteine to homocysteine and adenosine, a similar impairment of EDHF was observed, but with normal homocysteine levels. Animals with chronic hyperhomocysteinemia induced by a high-methionine, low - B vitamin diet during 8 weeks had a severely depressed EDHF-mediated vasodilation compared with those on a standard diet. Endothelium-independent vasodilation to deta-NONOate and pinacidil was not affected in acute and chronic hyperhomocysteinemia, demonstrating intact vascular smooth muscle reactivity.Conclusions - EDHF-dependent responses are impaired in the kidney of hyperhomocysteinemic rats. Because EDHF is a major regulator of vascular function in small vessels, these findings have important implications for the development of microangiopathy in hyperhomocysteinemia.