Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation.
Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation.
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DOI：
10.1161/circresaha.115.306642
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发表时间：
2015-09-11
影响因子：
20.1
通讯作者：
Chilian WM
中科院分区：
文献类型：
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作者：
Ohanyan V;Yin L;Bardakjian R;Kolz C;Enrick M;Hakobyan T;Kmetz J;Bratz I;Luli J;Nagane M;Khan N;Hou H;Kuppusamy P;Graham J;Fu FK;Janota D;Oyewumi MO;Logan S;Lindner JR;Chilian WM
在工作心脏中，冠脉血流与代谢产物的产生有关，代谢产物以氧化还原依赖的方式调节平滑肌的张力。电压门控性钾通道在血管平滑肌中起着控制膜电位的作用，它有一些对氧化还原敏感的成员。探讨氧化还原敏感的Kv1.5通道在冠脉代谢流调节中的作用。在小鼠(野生型、Kv1.5缺失[Kv1.5−/−]、Kv1.5−/−和Kv1.5通道可诱导的平滑肌特异性表达的Kv1.5通道)中，我们测量了去甲肾上腺素(NE)诱导心脏应激前后的平均动脉压(MAP)、心肌血流量(MBF)、心肌组织氧分压(PO2)和射血分数(EF)。心脏做功(CW)由平均动脉压(MAP)和心率乘积计算。研究人员对分离的动脉进行了研究，以确定基因改变是否会改善血管的反应性。尽管Kv1.5−/−的CW水平高于WT(与基线和所有剂量NE的WT相比)，但Kv1.5−/−的MBF低于WT。在高CW水平下，组织PO2随EF显著下降。在零背景下，Kv1.5通道在平滑肌中的表达挽救了这一受损的代谢扩张表型。在Kv1.5−/−小鼠的分离血管中，与WT相比，对H_2O_2的松弛受到损害，但对腺苷和乙酰胆碱的反应正常。血管平滑肌上的Kv1.5通道在连接心肌血流和心脏代谢中起重要作用。这些通道的缺失使新陈代谢与血流分离，导致心泵功能障碍和组织缺氧。
In the working heart coronary blood flow is linked to the production of metabolites, which modulate tone of smooth muscle in a redox-dependent manner. Voltage-gated potassium channels, which play a role in controlling membrane potential in vascular smooth muscle, have certain members that are redox sensitive. To determine the role of redox-sensitive Kv1.5 channels in coronary metabolic flow regulation. In mice (wild type [WT], Kv1.5 null [Kv1.5−/−], and Kv1.5−/− and WT with inducible, smooth muscle specific expression of Kv1.5 channels) we measured mean arterial pressure (MAP), myocardial blood flow (MBF), myocardial tissue pO2, and ejection fraction (EF) before and after inducing cardiac stress with norepinephrine (NE). Cardiac work (CW) was estimated as the product of MAP and heart rate. Isolated arteries were studied to establish if genetic alterations modified vascular reactivity. Despite higher levels of CW in the Kv1.5−/− (versus WT at baseline and all doses of NE), MBF was lower in Kv1.5−/− than in WT. At high levels of CW, tissue pO2 dropped significantly along with EF. Expression of Kv1.5 channels in smooth muscle in the null background rescued this phenotype of impaired metabolic dilation. In isolated vessels from Kv1.5−/− mice, relaxation to H2O2 was impaired, but responses to adenosine and acetylcholine were normal compared to WT. Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. Absence of these channels disassociates metabolism from flow resulting in cardiac pump dysfunction and tissue hypoxia.