大鼠背根神经节神经元上失活 BK 通道特性的研究

大电导的电压和 Ca²⁺ 激活的 K⁺ 通道 (BK 通道 ) 在哺乳动物的组织中广泛表达,起着多种多样的作用 . 目前只有少数组织中 BK 通道的性质被深入地研究,而且鲜见有失活的 BK 通道 (BK_i) 的报道,尤其是在神经元中 . 发现在大鼠小直径的背根神经节 (DRG) 神经元中,普遍存在失活的 BK 通道 . 失活的 BK 电流成分是 Ca²⁺敏感的,可以被大电导的 BK 通道特异阻断剂 ChTX 所阻断,而且木瓜蛋白酶可以从胞外改变通道失活的特性 .     

大鼠海马CA1区锥体细胞上一种Ca2+依赖性KATP通道

K_ATP通道在细胞的新陈代谢与膜兴奋性的耦联中起重要作用.采用膜片钳的内面向外式记录方法,在成年大鼠海马CA1区锥体细胞上记录到一种被胞浆侧ATP和甲糖宁（tolbutamide,一种K_ATP通道阻断剂）抑制的Ca²⁺依赖性钾离子通道.在细胞膜内外的K⁺浓度均为140 mmol/L时,通道的电导为(204±21) pS,翻转电位为(3.57±1.13) mV,通道无整流性.通道开放概率及ATP对通道的抑制作用均呈现电压依赖性.该K_ATP通道与以往报道的“经典”K_ATP通道有显著不同,其活动受膜电位、胞内Ca²⁺和ATP三重调节,表明这是一种新型的K_ATP通道.上述结果表明在海马神经元上至少有两种性质不同的K_ATP通道,提示神经元可能通过不同性质的K_ATP通道感受细胞内的代谢状态,进而调节细胞膜的兴奋性.     

拟南芥根皮层细胞质膜内向K+通道电生理特性分析

利用膜片钳技术对模式植物拟南芥根皮层细胞原生质体的内向跨膜钾电流进行了全细胞记录 ,并对内向K⁺通道的特性进行了分析 .结果表明 ,拟南芥根细胞质膜上的内向K⁺通道由超极化膜电位所激活 ;该通道具有较高的K^+/Na⁺选择性 ,可被TEA⁺和Ba^{2 +}等K+通道阻断剂所抑制 ,而且对胞内自由Ca^{2 +}浓度变化不敏感 .这为进一步利用模式植物拟南芥进行植物K⁺吸收机制以及植物抗盐机制的研究奠定了基础 .     

川楝素对K+、Ca2+通道活动及细胞内Ca2+浓度的调控

川楝素是我国学者从驱蛔中药中分离、鉴定的一个三萜化合物，已证明具选择地影响神经递质释放，有效地对抗肉毒中毒，促进细胞分化、凋亡，抑制肿瘤增殖，抑制昆虫发育和取食，影响K⁺、Ca²⁺通道活动等多种生物效应. 综述了证明川楝素抑制多种K⁺通道，选择地易化L型Ca²⁺通道和进而升高胞内Ca⁺浓度的研究资料，并对川楝素产生这些生物效应的机制进行了讨论.     

ATP敏感钾通道的研究进展

ATP敏感钾通道（K_ATP）是一组将细胞膜电活动与细胞代谢联系在一起的重要通道.该通道是由磺酰脲受体（SUR）和内向整流钾通道（K_IR6.x）亚单位组成的异源四聚体（SUR/K_IR6.x）₄.SUR与K_IR6.x基因在染色体上配对存在.K_IR6.x亚单位形成通道的电流孔道,SUR使通道对磺酰脲类药物、钾通道开放剂和Mg²⁺-NDPs等调节因子敏感.不同亚型K_ATP通道特性由SUR与K_IR6.x亚单位组成决定.K_ATP通道门控受［ATP］_i和［ADP］_i调节,膜磷脂(PIPs)抑制通道对ATP的敏感性,细胞磷酸转移系统也参与ATP/ADP对通道的调节机制;磺酰脲类复合物（SUs）抑制K_ATP通道,钾通道开放剂（KCOs）激活K_ATP通道;G蛋白以及PKA、PKC、PKG等信使物质也参与通道的调节.K_ATP通道对胰岛素的分泌、心肌缺血预适应以及血管的张力起重要调节作用.     

胸腺树突状细胞对胸腺细胞凋亡的促进作用

小鼠胸腺细胞在体外培养一定时间后自发出现凋亡,在与小鼠胸腺树突状细胞(MTSC4)共育后,其凋亡过程可被明显加速;与此相反,小鼠胸腺上皮细胞(MTECI)有抑制凋亡的作用.与MTSC4共育后的胸腺细胞中不仅CD4⁺CD8⁺双阳性细胞明显减小,而且CD4⁺CD8⁺单阳性细胞也减少.提示胸腺基质细胞可通过其对细胞凋亡的促进作用参与胸腺内的阴性选择,并提示阴性选择可能在胸腺髓质区仍在进行.     

多细胞盐腺离子选择性分泌机理及其成因

为揭示多细胞盐腺对阳离子的选择性分泌机理, 在室内水培条件下, 研究了不同盐分胁迫(NaCl, KCl和NaCl+KCl)对多枝柽柳和短穗柽柳Na⁺, K⁺的分泌和累积, 以及不同盐腺抑制剂(orthovanadate, Ba²⁺, ouabain, tetraethylammonium[TEA]和verapami)对Na⁺和K⁺分泌的抑制及其在体内累积的影响. 结果表明, NaCl处理明显增加了盐腺对Na⁺分泌, 而KCl处理则显著促进K⁺分泌; Na⁺和K⁺的分泌量同累积量的比值表明, Na⁺的比值高于K⁺; 单一盐溶液中添加不同离子成分后, Na⁺和K⁺分泌表现不同: KCl处理中添加NaCl后, K⁺分泌速率显著降低, 但在NaCl处理中添加KCl, Na⁺的分泌则不受影响, 这些结果表明, 柽柳对Na⁺的分泌具有较高的选择性. 此外, 添加盐腺抑制剂后, 柽柳对Na⁺分泌分别受orthovanadate, ouabain, tetraethylammonium[TEA]和verapami的显著抑制, 而K⁺的分泌则分别受ouabain, tetraethylammonium[TEA]和verapami的显著抑制. orthovanadate对Na⁺, K⁺分泌抑制效应的差异, 可能是引起多细胞盐腺分泌Na⁺和K⁺能力不同的主要原因.     

短暂脑缺血大鼠海马CA1区锥体细胞大电导Ca2+依赖K+通道活动降低(英)

短暂脑缺血可对随后的损伤性脑缺血表现出明显的耐受.有研究表明大电导Ca²⁺依赖K⁺（BK_Ca）通道活动增强参与了缺血性脑损伤.采用膜片钳的内面向外式,观察了3 min短暂脑缺血后6 h、24 h以及48 h大鼠海马CA1区锥体细胞上BK_Ca通道活动的动态变化.短暂脑缺血后BK_Ca通道的单通道电导和翻转电位均未见明显变化,但通道的开放概率则在缺血预处理后的前24 h内显著降低.通道动力学分析显示通道关闭时间变长是短暂脑缺血后通道活动降低的主要原因,因为通道的开放时间未发生明显变化.结果提示短暂脑缺血所致的BK_Ca通道活动降低可能与缺血耐受的产生有关.     

低渗条件下小肠上皮细胞调节性细胞容积减小的离子通道机制

目的:观察人小肠上皮细胞调节性细胞容积减小(RVD)的过程,探讨参与RVD过程的离子通道机制.方法:将培养的人小肠上皮细胞暴露于低渗溶液, 利用电子细胞体积测量系统测定细胞平均容积变化过程和离子通道的参与过程;采用RT-PCR方法检测人小肠上皮细胞上离子通道的表达.结果:人小肠上皮细胞具有良好的RVD功能; 其RVD过程可被氯通道阻断剂NPPB 和钾通道阻断剂四乙铵所阻断; 进一步的研究发现, 中等电导钙激活性钾通道(IK)的特异性阻断剂Clotrimazole (CLT) (1μmol/L)可以明显抑制细胞的RVD过程,而大电导钙激活性钾通道(BK)和小电导钙激活性钾通道(SK)的特异阻断剂iberiotoxin (100 nmol/L)和apamin (100 nmol/L)对RVD过程无任何抑制作用.RT-PCR的结果也显示, 人小肠上皮细胞只有IK表达, 而无SK和BK的表达.结论:人小肠上皮细胞具有RVD功能,RVD过程的完成有赖于氯通道和钾通道的平行激活, 而其中参与容积调节的钾通道是中等电导钙激活型钾通道IK.     

(Na+/K+)-ATPase研究概况

本文概述(Na⁺/K⁺)-ATPase的一般分子性质。介绍神经元和脂肪细胞中两种不同分子形式(Na⁺/K⁺)-ATPase的分离鉴定和功能性质,以及(Na⁺/K⁺)-ATPase主要功能亚基一级序列和高级结构研究所取得的一些进展。     

Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis

Plasma membrane potassium (K⁺) channels are required for tumor cell proliferation and apoptosis. However, the signal transduction mechanisms underlying K⁺ channel-dependent tumor cell proliferation or apoptosis remains elusive. Using HeLa and A2780 cells as study models, we tested the hypothesis that apoptotic proteins are linked with K⁺ channel-dependent tumor cell cycle and apoptosis. The patch-clamping study using the whole-cell mode revealed two components of voltage-gated outward K⁺ currents: one is sensitive to either tetraethylammonium (TEA) or tetrandrine (Tet), a maxi-conductance Ca²⁺-activated K⁺ (BK) channel blocker, and the other is sensitive to 4-aminopyridine (4-AP), a delayed rectifier K⁺ channel blocker. MTT and flow cytometry assays showed that TEA, Tet, or iberiotoxin (Ibtx), a selective BK channel blocker, inhibited HeLa and A2780 cell proliferation in a dose-dependent manner with G₁ phase arrest. Pretreatment with TEA or Tet also induced apoptosis in HeLa and A2780 cells. However, glibenclamide (Gli), an ATP-sensitive K⁺ channel blocker, did not influence K⁺ currents, proliferation or apoptosis. Western blot analyses showed that while pretreatment of TEA and Tet produced an increase in expressions of p53, p21, and Bax, pretreatment of these two agents led to a decrease in expressions of heat shock protein (hsp)90α, hsp90β, and hsp70. Our results indicate that the blockade of BK channels results in tumor cell apoptosis and cycle arrest at G₁ phase, and the transduction pathway underlying the anti-proliferative effects is linked to the increased expression of apoptotic protein p53 and the decreased expression of its chaperone proteins hsp.     

Characterization of a stretch‐activated potassium channel in chondrocytes

Chondrocytes possess the capacity to transduce load‐induced mechanical stimuli into electrochemical signals. The aim of this study was to functionally characterize an ion channel activated in response to membrane stretch in isolated primary equine chondrocytes. We used patch‐clamp electrophysiology to functionally characterize this channel and immunohistochemistry to examine its distribution in articular cartilage. In cell‐attached patch experiments, the application of negative pressures to the patch pipette (in the range of 20–200 mmHg) activated ion channel currents in six of seven patches. The mean activated current was 45.9 ± 1.1 pA (n = 4) at a membrane potential of 33 mV (cell surface area approximately 240 µm²). The mean slope conductance of the principal single channels resolved within the total stretch‐activated current was 118 ± 19 pS (n = 6), and reversed near the theoretical potassium equilibrium potential, E_K+, suggesting it was a high‐conductance potassium channel. Activation of these high‐conductance potassium channels was inhibited by extracellular TEA (K_d approx. 900 µM) and iberiotoxin (K_d approx. 40 nM). This suggests that the current was largely carried by BK‐like potassium (MaxiK) channels. To further characterize these BK‐like channels, we used inside‐out patches of chondrocyte membrane: we found these channels to be activated by elevation in bath calcium concentration. Immunohistochemical staining of equine cartilage samples with polyclonal antibodies to the α1‐ and β1‐subunits of the BK channel revealed positive immunoreactivity for both subunits in superficial zone chondrocytes. These experiments support the hypothesis that functional BK channels are present in chondrocytes and may be involved in mechanotransduction and chemotransduction. J. Cell. Physiol. 223: 511–518, 2010. © 2010 Wiley‐Liss, Inc.     

Activation of BKCa Channels Mediates Hippocampal Neuronal Death After Reoxygenation and Reperfusion

Excessive K⁺ efflux promotes central neuronal apoptosis; however, the type of potassium channel that mediates K⁺ efflux in response to different apoptosis-inducing stimuli is still unknown. It is hypothesized that the activation of large-conductance Ca²⁺-activated K⁺ channels (BK_Ca) mediates hypoxia/reoxygenation (H/R)- and ischemia/reperfusion (I/R)-induced neuronal apoptosis. Rat hippocampal neuronal cultures underwent apoptosis after reoxygenation, as assessed by morphologic observation, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and caspase-3 activation. Single-channel recordings revealed upregulation of BK_Ca channel activity 6 h after reoxygenation, which might be caused by elevated cytosolic Ca²⁺. The K⁺ ionophore valinomycin and the BK_Ca channel opener NS1619 induced neuronal apoptosis. Transfection of the BK_Ca channel α subunit into Chinese hamster ovary (CHO-K1) cells, which do not express endogenous K⁺ channels, or into neurons will induce cell apoptosis, indicating that the opening of the BK_Ca channel serves as a pivotal event in mediating cell apoptosis. The specific BK_Ca channel blockers charybdotoxin and iberiotoxin and the nonselective K⁺ channel blocker tetraethylammonium at concentrations more specific to the BK_Ca channel were neuroprotective. The A-type potassium channel blocker 4-aminopyridine and apamin, a small-conductance Ca²⁺-activated K⁺ channel blocker, were not protective. This result suggests the involvement of the BK_Ca channel in H/R-induced apoptosis. Similarly, specific BK_Ca channel blockers also showed neuroprotection in neurons subjected to oxygen-glucose deprivation/reoxygenation or animals subjected to forebrain ischemia–reperfusion. These results demonstrate that the over-activity of BK_Ca channels mediates hippocampal neuronal damage induced by H/R in vitro and I/R in vivo.     

Properties and the Cytoskeletal Control of Ca++-independent Large Conductance K+ Channels in Neonatal Rat Hippocampal Neurons

A member of the family of Ca⁺⁺-independent large conductance K⁺ channels (termed BK channels) was identified in patch clamp experiments with cultured neonatal rat hippocampal neurons. Permeation was characterized (at 5 mmol/l external, 140 mmol/l internal K⁺; 135 mmol/l external Na⁺) by a conductance of 107 pS, a ratio P_Na/P_K∼ 0.01, and outward rectification near the reversal potential. Channel activity was not voltage-dependent, could not be reduced by internal TEA or by a shift of internal pH from 7.4 to 6.8, i.e., discriminating features within the Ca⁺⁺-independent BK channel family. Cytosolic proteolysis abolished the functional state of hippocampal Ca⁺⁺-independent BK channels, in contrast to the pronase resistance of hippocampal Ca⁺⁺-activated BK channels which suggests structural dissimilarities between these related channels. Cytoskeletal alterations had an activating influence on Ca⁺⁺-independent BK channels and caused a 3–4-fold rise in P _o , but patch excision and channel isolation from the natural environment provoked the strongest increase in P _o , from 0.07 ± 0.03 to 0.73 ± 0.04. This activation process operated slowly, on a minute time scale and can be most easily explained with the loss of a membrane-associated inhibitory particle. Once activated, Ca⁺⁺-independent BK channels reacted sensitively to a Mg-ATP supplemented brain tissue extract with a P _o decline, from 0.60 ± 0.06 to 0.10 ± 0.05. Heated extracts failed to induce significant channel inhibition, providing evidence for a heat-unstable molecule with reassociates with the internal channel surface to reestablish channel inhibition. A dualistic channel control, by this membrane-associated molecule and by the cytoskeleton seems possible. Received: 16 July 1997/Revised: 3 November 1997     

Apoptosis recruits two-pore domain potassium channels used for homeostatic volume regulation

Cell shrinkage is an incipienthallmark of apoptosis and is accompanied by potassium releasethat decreases the concentration of intracellular potassium andregulates apoptotic progression. The plasma membrane K⁺channel recruited during apoptosis has not been characterized despite its importance as a potential therapeutic target. Here weprovide evidence that two-pore domain K⁺ (K_2P)channels underlie K⁺ efflux during apoptotic volumedecreases (AVD) in mouse embryos. These K_2P channels areinhibited by quinine but are not blocked by an array of pharmacologicalagents that antagonize other K⁺ channels. TheK_2P channels are uniquely suited to participate in theearly phases of apoptosis because they are not modulated bycommon intracellular messengers such as calcium, ATP, and arachidonic acid, transmembrane voltage, or the cytoskeleton. A K⁺channel with similar biophysical properties coordinates regulatory volume decreases (RVD) triggered by changing osmotic conditions. Wepropose that K_2P channels are the pathway by whichK⁺ effluxes during AVD and RVD and that apoptosisco-opts mechanisms more routinely employed for homeostatic cell volume regulation.

     

Ion Channels in Cell Proliferation and Apoptotic Cell Death

Cell proliferation and apoptosis are paralleled by altered regulation of ion channels that play an active part in the signaling of those fundamental cellular mechanisms. Cell proliferation must - at some time point - increase cell volume and apoptosis is typically paralleled by cell shrinkage. Cell volume changes require the participation of ion transport across the cell membrane, including appropriate activity of Cl⁻ and K⁺ channels. Besides regulating cytosolic Cl⁻ activity, osmolyte flux and, thus, cell volume, most Cl⁻ channels allow HCO₃⁻ exit and cytosolic acidification, which inhibits cell proliferation and favors apoptosis. K⁺ exit through K⁺ channels may decrease intracellular K⁺ concentration, which in turn favors apoptotic cell death. K⁺ channel activity further maintains the cell membrane potential, a critical determinant of Ca²⁺ entry through Ca²⁺ channels. Cytosolic Ca²⁺ may trigger mechanisms required for cell proliferation and stimulate enzymes executing apoptosis. The switch between cell proliferation and apoptosis apparently depends on the magnitude and temporal organization of Ca²⁺ entry and on the functional state of the cell. Due to complex interaction with other signaling pathways, a given ion channel may play a dual role in both cell proliferation and apoptosis. Thus, specific ion channel blockers may abrogate both fundamental cellular mechanisms, depending on cell type, regulatory environment and condition of the cell. Clearly, considerable further experimental effort is required to fully understand the complex interplay between ion channels, cell proliferation and apoptosis.     

The potassium ion channel opener NS1619 inhibits proliferation and induces apoptosis in A2780 ovarian cancer cells

Diverse types of voltage-gated potassium (K⁺) channels have been shown to be involved in regulation of cell proliferation. The maxi-conductance Ca²⁺-activated K⁺ channels (BK channels) may play an important role in the progression of human cancer. To explore the role of BK channels in regulation of apoptosis in human ovarian cancer cells, the effects of the specific BK channel activator NS1619 on induction of apoptosis in A2780 cells were observed. Following treatment with NS1619, cell proliferation was measured by MTT assay. Apoptosis of A2780 cells pretreated with NS1619 was detected by agarose gel electrophoresis of cellular DNA and flow cytometry. Our data demonstrate that NS1619 inhibits the proliferation of A2780 cells in a dosage and time dependent manner IC₅₀ = 31.1 μM, for 48 h pretreatment and induces apoptosis. Western blot analyses showed that the anti-proliferation effect of NS1619 was associated with increased expression of p53, p21, and Bax. These results indicate that BK channels play an important role in regulating proliferation of human ovarian cancer cells and may induce apoptosis through induction of p21^Cip1 expression in a p53-dependent manner.     

Role of AQP2 during apoptosis in cortical collecting duct cells

Background information. A major hallmark of apoptosis is cell shrinkage, termed apoptotic volume decrease, due to the cellular outflow of potassium and chloride ions, followed by osmotically obliged water. In many cells, the ionic pathways triggered during the apoptotic volume decrease may be similar to that observed during a regulatory volume decrease response under hypotonic conditions. However, the pathways involved in water loss during apoptosis have been largely ignored. It was recently reported that in some systems this water movement is mediated via specific water channels (aquaporins). Nevertheless, it is important to identify whether this is a ubiquitous aspect of apoptosis as well as to define the mechanisms involved. The aim of the present work was to investigate the role of aquaporin‐2 during apoptosis in renal‐collecting duct cells. We evaluated the putative relationship between aquaporin‐2 expression and the activation of the ionic pathways involved in the regulatory volume response. Results. Apoptosis was induced by incubating cells with a hypertonic solution or with cycloheximide in two cortical collecting duct cell lines: one not expressing aquaporins and the other stably transfected with aquaporin‐2. Typical features of apoptosis were evaluated with different approaches and the water permeability was measured by fluorescence videomicroscopy. Our results show that the rate of apoptosis is significantly increased in aquaporin‐2 cells and it is linked to the rapid activation of volume‐regulatory potassium and chloride channels. Furthermore, the water permeability of cells expressing aquaporin‐2 was strongly reduced during the apoptotic process and it occurs before DNA degradation. Conclusions. These results let us propose that under apoptotic stimulation aquaporin‐2 would act as a sensor leading to a co‐ordinated activation of specific ionic channels for potassium and chloride efflux, resulting in both more rapid cell shrinkage and more rapid achievement of adequate levels of ions necessary to activate the enzymatic apoptotic cascade.     

Staurosporine-induced cell death in salmonid cells: the role of apoptotic volume decrease, ion fluxes and MAP kinase signaling

Apoptotic cell death in mammalian models is frequently associated with cell shrinkage. Inhibition of apoptotic volume decrease (AVD) is cytoprotective, suggesting that cell shrinkage is an important early event in apoptosis. In salmonid hepatoma and gill cells staurosporine induced apoptosis, as assessed by activation of effector caspases, nuclear condensation, and a decrease of mitochondrial membrane potential (MMP), and these changes were accompanied by cell shrinkage. The Cl⁻ transport inhibitor DIDS and the K⁺ channel inhibitor quinidine prevented AVD, but only DIDS inhibited apoptosis. Other Cl⁻ flux inhibitors, as well as a pan-caspase inhibitor, did not prevent cell shrinkage, but still prevented caspase activation. Furthermore, regulatory volume decrease (RVD) under hypotonic conditions was not facilitated, but diminished in apoptotic cells. Since all transport inhibitors used blocked RVD, but only DIDS and quinidine inhibited AVD, the ion transporters involved in both processes are apparently not identical. In addition, our data indicate that inhibition of Cl⁻ fluxes rather than blocking cell shrinkage or K⁺ fluxes is important for preventing apoptosis. In line with this, inhibition of MAP kinases reduced RVD and not AVD, but still diminished caspase activation. Finally, we observed that MAP kinases were activated upon staurosporine treatment and that at least activation of ERK was prevented when AVD was inhibited.     

Overexpression of human KCNA5 increases IK V and enhances apoptosis

Apoptotic cell shrinkage, an early hallmark of apoptosis, is regulated by K⁺ efflux and K⁺ channel activity. Inhibited apoptosis and downregulated K⁺ channels in pulmonary artery smooth muscle cells (PASMC) have been implicated in development of pulmonary vascular medial hypertrophy and pulmonary hypertension. The objective of this study was to test the hypothesis that overexpression of KCNA5, which encodes a delayed-rectifier voltage-gated K⁺ (Kv) channel, increases K⁺ currents and enhances apoptosis. Transient transfection of KCNA5 caused 25- to 34-fold increase in KCNA5 channel protein level and 24- to 29-fold increase in Kv channel current (I_K(V)) at +60 mV in COS-7 and rat PASMC, respectively. In KCNA5-transfected COS-7 cells, staurosporine (ST)-mediated increases in caspase-3 activity and the percentage of cells undergoing apoptosis were both enhanced, whereas basal apoptosis (without ST stimulation) was unchanged compared with cells transfected with an empty vector. In rat PASMC, however, transfection of KCNA5 alone caused marked increase in basal apoptosis, in addition to enhancing ST-mediated apoptosis. Furthermore, ST-induced apoptotic cell shrinkage was significantly accelerated in COS-7 cells and rat PASMC transfected with KCNA5, and blockade of KCNA5 channels with 4-aminopyridine (4-AP) reduced K⁺ currents through KCNA5 channels and inhibited ST-induced apoptosis in KCNA5-transfected COS-7 cells. Overexpression of the human KCNA5 gene increases K⁺ currents (i.e., K⁺ efflux or loss), accelerates apoptotic volume decrease (AVD), increases caspase-3 activity, and induces apoptosis. Induction of apoptosis in PASMC by KCNA5 gene transfer may serve as an important strategy for preventing the progression of pulmonary vascular wall thickening and for treating patients with idiopathic pulmonary arterial hypertension (IPAH). potassium ion channel; pulmonary hypertension