KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo
KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo
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DOI：
10.1161/01.cir.0000144304.91010.f0
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发表时间：
2004-10-12
期刊：
影响因子：
37.8
通讯作者：
MacAllister, RJ
中科院分区：
文献类型：
--
作者：
Broadhead, MW;Kharbanda, RK;MacAllister, RJ
背景：内皮功能障碍有助于缺血再灌注损伤（IRI），并可通过缺血预处理（IPC）减少。IPC可能涉及ATP敏感钾通道（K(ATP)）的激活。我们确定了K（ATP）通道的调节是否发生在人类内皮IPC中。方法与结果：健康志愿者将血压袖带充气至200 mm Hg，持续20分钟，诱导前臂iri。K（ATP）的激活是由动脉内格列本脲（阻滞剂）和二氮氧化合物（开启剂）调节的。内皮功能（对动脉内乙酰胆碱的反应）在(1)再灌注15分钟，(2)IRI前IPC（3次5分钟缺血），(3)IRI前IPC与格列本脲，(4)IRI前IPC与格列本脲，(5)IRI前再输注格列本脲，(6)IRI前再输注格列本脲与二氮氧化合物。IRI引起内皮功能障碍（P = 0.002）， IPC阻止了内皮功能障碍（P = 0.40）。格列本脲与IRI同时服用（P = 0.003）或在IRI期间服用（P = 0.0005）可消除IPC。二氮氧化合物可预防IRI后内皮功能障碍（P = 0.68），但与格列苯脲共输注时无此作用。结论：格列本脲能消除和模拟人内皮细胞间质损伤。格列本脲作用的时间过程表明，K（ATP）通道作为体内内皮细胞IPC的效应器参与其中。这些数据可能有助于理解调节K（ATP）通道功能的药物的治疗作用。
Background-Endothelial dysfunction contributes to ischemia-reperfusion injury (IRI) and is reduced by ischemic preconditioning (IPC). IPC may involve activation of ATP-sensitive potassium channels (K(ATP)). We determined whether modulation of K(ATP) channels occurs in endothelial IPC in humans.Methods and Results-IRI of the forearm was induced by inflating a blood pressure cuff to 200 mm Hg for 20 minutes in healthy volunteers. K(ATP) activation was modulated by intra-arterial glibenclamide ( blocker) and diazoxide ( opener). Endothelial function ( response to intra-arterial acetylcholine) was assessed with forearm plethysmography before and after (1) 15-minute reperfusion, ( 2) IRI preceded by IPC ( 3 five-minute periods of ischemia), ( 3) IRI preceded by IPC with glibenclamide, ( 4) IPC followed by glibenclamide before IRI, ( 5) IRI preceded by diazoxide, and ( 6) IRI preceded by coinfusion of glibenclamide with diazoxide. IRI caused endothelial dysfunction (P = 0.002), which IPC prevented (P = 0.40). Glibenclamide abolished IPC when given contemporaneously with (P = 0.003) or during IRI (P = 0.0005). Diazoxide prevented endothelial dysfunction after IRI (P = 0.68) but not when coinfused with glibenclamide.Conclusion-Glibenclamide abolishes and diazoxide mimics endothelial IPC in humans. The time course of the effect of glibenclamide suggests involvement of K(ATP) channels as effectors of endothelial IPC in vivo. These data may have implications for understanding the therapeutic role of agents that modulate K(ATP) channel function.