Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest.
Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest.
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DOI：
10.1161/circulationaha.107.755827
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发表时间：
2008-09-30
期刊：
影响因子：
37.8
通讯作者：
Sellke FW
中科院分区：
文献类型：
--
作者：
Feng J;Liu Y;Clements RT;Sodha NR;Khabbaz KR;Senthilnathan V;Nishimura KK;Alper SL;Sellke FW
体外循环后心脏骤停再灌注引起冠状动脉微血管功能障碍。我们研究了钙活化钾（KCa）通道在人类冠状动脉微血管功能障碍中的作用。在CP前从非缺血段采集人心房组织，在CP后从暴露于高钾低温CP的心房段采集人心房组织（平均CP时间58分钟），然后再灌注10分钟。在KCa通道激活剂/阻滞剂和其他几种血管扩张剂的存在下，研究了加压无流状态下预收缩小动脉（直径80 ~ 180 μm）的体外松弛反应。我们还使用逆转录聚合酶链反应、免疫印迹和免疫荧光显微技术检测了冠状动脉微血管中KCa通道基因产物的表达和定位。与cp前相比，cp后对中、小电导KCa通道激活剂（IKCa/SKCa） NS309 （10-5 M）和内皮依赖性血管扩张剂P物质（10-8 M）和5 '二磷酸腺苷（10-5 M）的再灌注弛缓反应显著降低（P<0.05, n=8/组）。相比之下，大电导KCa通道激活剂（BKCa） NS1619 （10-5 M）和内皮非依赖性血管扩张剂硝普钠（10-4 M）的舒张反应在cp再灌注前和后没有变化（n=8/组）。内皮剥脱可显著降低ns309诱导的血管舒张，消除P-物质或5 '二磷酸腺苷诱导的舒张（P<0.05），但对NS1619和硝普钠诱导的舒张无影响。cp再灌注后，BKCa、IKCa、SKCa总多肽水平及IKCa mRNA表达均无明显变化。体外循环后心脏骤停再灌注导致微血管功能障碍，这与冠状动脉微循环中SKCa和IKCa通道功能受损有关，部分原因可能是这些通道功能受损。这些结果提示心脏手术后内皮和平滑肌微血管功能障碍的新机制。
Cardioplegic arrest (CP) followed by reperfusion after cardiopulmonary bypass induces coronary microvascular dysfunction. We investigated the role of calcium-activated potassium (KCa) channels in this dysfunction in the human coronary microvasculature. Human atrial tissue was harvested before CP from a nonischemic segment and after CP from an atrial segment exposed to hyperkalemic cold blood CP (mean CP time, 58 minutes) followed by 10-minute reperfusion. In vitro relaxation responses of precontracted arterioles (80 to 180 μm in diameter) in a pressurized no-flow state were examined in the presence of KCa channel activators/blockers and several other vasodilators. We also examined expression and localization of KCa channel gene products in the coronary microvasculature using reverse transcriptase-polymerase chain reaction, immunoblot, and immunofluorescence photomicroscopy. Post-CP reperfusion relaxation responses to the activator of intermediate and small conductance KCa channels (IKCa/SKCa), NS309 (10-5 M), and to the endothelium-dependent vasodilators, substance P (10-8 M) and adenosine 5′diphosphate (10-5 M), were significantly reduced compared with pre-CP responses (P<0.05, n=8/group). In contrast, relaxation responses to the activator of large conductance KCa channels (BKCa), NS1619 (10-5 M), and to the endothelium-independent vasodilator, sodium nitroprusside (10-4 M), were unchanged pre- and post-CP reperfusion (n=8/group). Endothelial denudation significantly diminished NS309-induced vasodilatation and abolished substance P- or adenosine 5′ diphosphate-induced relaxation (P<0.05), but had no effect on relaxation induced by either NS1619 or sodium nitroprusside. The total polypeptide levels of BKCa, IKCa, and SKCa and the expression of IKCa mRNA were not altered post-CP reperfusion. Cardioplegic arrest followed by reperfusion after cardiopulmonary bypass causes microvascular dysfunction associated with and likely in part due to impaired function of SKCa and IKCa channels in the coronary microcirculation. These results suggest novel mechanisms of endothelial and smooth muscle microvascular dysfunction after cardiac surgery.