Blockade of KATP Channels Reduces Endothelial Hyperpolarization and Leukocyte Recruitment upon Reperfusion After Hypoxia
Blockade of KATP Channels Reduces Endothelial Hyperpolarization and Leukocyte Recruitment upon Reperfusion After Hypoxia
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DOI：
10.1111/j.1600-6143.2009.02553.x
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发表时间：
2009-04-01
影响因子：
8.8
通讯作者：
Tibbles, L. A.
中科院分区：
文献类型：
--
作者：
Figura, M.;Chilton, L.;Tibbles, L. A.
肾移植中的缺血/再灌注损伤导致缓慢或最初的无功能，并易于发生急性和慢性排斥反应。事实上，即使使用现代免疫抑制剂，严重的缺血再灌注损伤也会显着降低移植物的存活率。缺血/再灌注引起损伤的机制之一是内皮细胞活化导致炎症。尽管可以使用多种疗法来防止白细胞募集到缺血血管（例如抗粘连分子抗体），但目前还没有报道可以阻止再灌注时初始立即中性粒细胞募集的临床治疗方法。使用活体显微镜，我们描述了 K-ATP 拮抗剂格列本脲 (Glyburide (TM)) 消除了中性粒细胞立即募集到缺血性微血管的情况。此外，我们表明格列本脲可以在生理流动条件下减少体外白细胞的募集。 ATP 调节的钾通道 (K-ATP) 对于细胞膜极化的控制非常重要。在这里，我们描述了缺氧期间内皮细胞的严重超极化，以及使用格列本脲减少这种超极化。这些发现表明，缺血期间控制内皮膜电位可能是避免缺血/再灌注损伤的重要治疗工具，从而增强移植物的长期功能。
Ischemia/reperfusion injury in renal transplantation leads to slow or initial nonfunction, and predisposes to acute and chronic rejection. In fact, severe ischemia reperfusion injury can significantly reduce graft survival, even with modern immunosuppressive agents. One of the mechanisms by which ischemia/reperfusion causes injury is activation of endothelial cells resulting in inflammation. Although several therapies can be used to prevent leukocyte recruitment to ischemic vessels (e.g. antiadhesion molecule antibodies), there have been no clinical treatments reported that can prevent initial immediate neutrophil recruitment upon reperfusion. Using intravital microscopy, we describe abrogation of immediate neutrophil recruitment to ischemic microvessels by the K-ATP antagonist glibenclamide (Glyburide (TM)). Further, we show that glibenclamide can reduce leukocyte recruitment in vitro under physiologic flow conditions. ATP-regulated potassium channels (K-ATP) are important in the control of cell membrane polarization. Here we describe profound hyperpolarization of endothelial cells during hypoxia, and the reduction of this hyperpolarization using glibenclamide. These findings suggest that control of endothelial membrane potential during ischemia may be an important therapeutic tool in avoiding ischemia/reperfusion injury, and therefore, enhancing transplant long-term function.