Novel rhynchophylline analogues as microvascular relaxation agents for the treatment of microvascular dysfunction caused by diabetes
Novel rhynchophylline analogues as microvascular relaxation agents for the treatment of microvascular dysfunction caused by diabetes
复制标题
新型钩藤碱类似物作为微血管舒张剂，用于治疗糖尿病引起的微血管功能障碍
DOI：
10.1016/j.ejmech.2017.08.026
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发表时间：
2017-10-20
影响因子：
6.7
通讯作者：
Gu, Xianfeng
中科院分区：
文献类型：
--
作者：
Guo, Wei;Zhu, Huikun;Gu, Xianfeng
微循环和大循环血管反应性障碍在心血管疾病中是公认的。然而，对于可能改善微血管功能障碍患者血管反应性的方法知之甚少。为了解决这一知识空白，我们合成了一种外消旋类似物（G2）及其立体异构体（G2-a和G2-b）。对大鼠胸主动脉松弛作用的初步药物研究表明，G2及其立体异构体比天然产物蛇尾茶碱更有效（至少30倍），这鼓励我们进一步研究其治疗糖尿病引起的微血管功能障碍的功能和机制。3种化合物中G2-a对大鼠肠系膜动脉微血管的舒张活性最好，G2或G2-a以内皮依赖的方式引起舒张。在离体实验中，G2和G2-a诱导糖尿病大鼠肠系膜动脉微血管松弛的能力弱于正常大鼠，很可能是由于糖尿病引起的微血管内皮损伤。然而，基于动物实验，G2在体内改善了糖尿病诱导的大鼠肠系膜动脉内皮功能障碍。进一步的机制研究表明，G2主要通过上调内皮型一氧化氮合酶（eNOS）表达，并进一步增加血管舒张所需的一氧化氮（NO）浓度，诱导内皮功能恢复。(C) 2017 Elsevier Masson SAS：版权所有
Dysfunction in vascular reactivity in the micro- and macrocirculation is well established in cardiovascular disease. However, little is known about methods that may improve vascular reactivity in patients likely to develop microvascular dysfunction. One of the racemic analogues of rhynchophylline (G2) and its stereoisomers (G2-a and G2-b) were synthesized to address this knowledge gap. The preliminary pharmaceutical studies on the relaxation of the rat thoracic aorta showed that G2 and its stereoisomers are more potent (at least 30-fold) than the natural product rhynchophylline, which encouraged us to further investigate their functions and mechanisms as treatments for microvascular dysfunction caused by diabetes. G2-a displayed the best microvascular relaxation activity on rat mesenteric arteries among the three compounds, and G2 or G2-a caused relaxation in an endothelium-dependent manner. In ex vivo tests, G2 and G2-a exhibited a weaker potency in inducing microvascular relaxation in mesenteric arteries from diabetic rats than from normal rats, most likely, due to microvascular endothelium damage caused by diabetes. However, based on the animal studies, G2 ameliorated diabetes-induced endothelial dysfunction in rat mesenteric arteries in vivo. Further investigations of the mechanism showed that G2 mainly induced the recovery of endothelial function by upregulating endothelial nitric oxide synthase (eNOS) expression and further increasing the concentration of nitric oxide (NO), which is required for vascular relaxation. (C) 2017 Elsevier Masson SAS: All rights reserved.