Goodwill Adam G, Fu Lijuan, Noblet Jillian N, Casalini Eli D, Sassoon Daniel, Berwick Zachary C, Kassab Ghassan S, Tune Johnathan D, Dick Gregory M
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and.
California Medical Innovations Institute, San Diego, California.
Am J Physiol Heart Circ Physiol. 2016 Mar 15;310(6):H693-704. doi: 10.1152/ajpheart.00688.2015. Epub 2016 Jan 29.
Hydrogen peroxide (H2O2) and voltage-dependent K(+) (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli.
过氧化氢（H2O2）和电压依赖性钾离子（KV）通道在响应代谢、缺血和旁分泌刺激来调节冠状动脉血流中起关键作用。相关的KV通道尚未明确，但KV7通道可能是候选通道。关于冠状动脉循环中KV7通道功能的现有数据（仅限于离体评估）并不一致。因此，我们检验了这样一个假设，即KV7通道存在于猪冠状动脉血管壁细胞中并调节血管舒张。我们进行了各种分子、生化和功能（体内和离体）研究。冠状动脉表达KCNQ基因（定量PCR）和KV7.4蛋白（蛋白质免疫印迹法）。免疫染色显示KV7.4在传导血管和阻力血管中表达，可能在内皮和外膜层最为明显。氟吡汀是一种KV7开放剂，可使冠状动脉环舒张，而这一作用被KV7阻滞剂利诺吡啶减弱。内皮剥脱抑制了氟吡汀诱导的和利诺吡啶敏感的冠状动脉环舒张。此外，利诺吡啶减弱了缓激肽诱导的冠状动脉环内皮依赖性舒张。在体内静息心率下，冠状动脉内注射氟吡汀或利诺吡啶对冠状动脉血流没有影响。利诺吡啶对体内由缺血、H2O2或心动过速引起的冠状动脉舒张没有影响。然而，缓激肽可增加体内冠状动脉血流，而这一作用被利诺吡啶减弱。这些数据表明KV7通道在某些冠状动脉细胞类型中表达并影响内皮功能。冠状动脉血管KV7通道的其他生理功能仍不清楚，但它们似乎确实有助于对旁分泌刺激的内皮依赖性反应。
