Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Health, Aarhus University, 8000 Aarhus C, Denmark.
Exp Physiol. 2013 Apr;98(4):957-69. doi: 10.1113/expphysiol.2012.066340. Epub 2012 Dec 13.
Calcium-activated potassium channels of small (K(Ca)2, SK) and intermediate (K(Ca)3.1, IK) conductance are involved in endothelium-dependent relaxation of pulmonary arteries. We hypothesized that the function and expression of K(Ca)2 and K(Ca)3.1 increase as a compensatory mechanism to counteract hypoxia-induced pulmonary hypertension in rats. For functional studies, pulmonary arteries were mounted in microvascular myographs for isometric tension recordings. The K(Ca) channel expression was evaluated by immunoblotting and quantitative PCR. Although ACh induced similar relaxations, the ACh-induced relaxations were abolished by the combined inhibition of nitric oxide synthase (by L-nitro-arginine, L-NOARG), cyclo-oxygenase (by indomethacin) and soluble guanylate cyclase (by ODQ) in pulmonary arteries from hypoxic rats, whereas 20 ± 6% (n = 8) maximal relaxation in response to ACh persisted in arteries from normoxic rats. Inhibiting Na(+),K(+)-ATPase with ouabain or blocking K(Ca)2 and K(Ca)3.1 channels reduced the persisting ACh-induced relaxation. In the presence of L-NOARG and indomethacin, a novel K(Ca)2 and K(Ca)3.1 channel activator, NS4591, induced concentration- and endothelium-dependent relaxations, which were markedly reduced in arteries from chronically hypoxic rats compared with arteries from normoxic rats. The mRNA levels of K(Ca)2.3 and K(Ca)3.1 were unaltered, whereas K(Ca)2.3 protein expression was upregulated and K(Ca)3.1 protein expression downregulated in pulmonary arteries from rats exposed to hypoxia. In conclusion, endothelium-dependent relaxation was conserved in pulmonary arteries from chronically hypoxic rats, while endothelium-derived hyperpolarization (EDH)-type relaxation was impaired in chronically hypoxic pulmonary small arteries despite upregulation of K(Ca)2.3 channels. Since impaired EDH-type relaxation was accompanied by K(Ca)3.1 channel protein downregulation, these findings suggest that K(Ca)3.1 channels are important for the maintenance of EDH-type relaxation.
钙激活钾通道的小（K（Ca）2，SK）和中间（K（Ca）3.1，IK）电导参与肺血管的内皮依赖性松弛。我们假设，功能和表达的 K（Ca）2 和 K（Ca）3.1 增加作为一种代偿机制，以对抗缺氧性肺动脉高压在大鼠。对于功能研究，肺血管安装在微血管肌动描记器等长张力记录。K（Ca）通道的表达进行了评估，通过免疫印迹和定量 PCR。虽然 ACh 诱导相似的松弛，ACh 诱导的松弛被取消的联合抑制一氧化氮合酶（通过 L-硝基-精氨酸，L-NOARG），环氧化酶（通过吲哚美辛）和可溶性鸟苷酸环化酶（通过 ODQ）在肺动脉从缺氧大鼠，而 20 ± 6%（n = 8）最大松弛反应 ACh 持续在动脉从正常氧大鼠。抑制 Na（+），K（+）-ATP 酶与哇巴因或阻断 K（Ca）2 和 K（Ca）3.1 通道减少了持续 ACh 诱导的松弛。在 L-NOARG 和吲哚美辛，一种新型的 K（Ca）2 和 K（Ca）3.1 通道激活剂，NS4591，诱导浓度和内皮依赖性松弛，这是明显减少动脉从慢性缺氧大鼠与动脉从正常氧大鼠。mRNA 水平的 K（Ca）2.3 和 K（Ca）3.1 没有改变，而 K（Ca）2.3 蛋白表达上调和 K（Ca）3.1 蛋白表达下调在肺动脉从大鼠暴露于缺氧。总之，内皮依赖性松弛被保存在慢性缺氧大鼠肺血管，而内皮衍生超极化（EDH）-型松弛受损慢性缺氧性肺小动脉尽管上调 K（Ca）2.3 通道。由于受损的 EDH 型松弛伴随着 K（Ca）3.1 通道蛋白下调，这些发现表明 K（Ca）3.1 通道对 EDH 型松弛的维持是重要的。
