埃他卡林对K_(ATP)通道亚型选择性作用的研究

目的建立特异性表达以K ir6.x和SUR亚单位组成的不同KATP通道亚型的细胞模型,研究KATP通道开放剂埃他卡林对KATP通道亚型的选择性作用特点。方法利用脂质体转染的方法将编码KATP通道亚单位K ir6.x-pcDNA3、SUR-pcDNA3基因和编码绿色荧光蛋白pEGFP-N1基因共同转染到HEK-293细胞中,免疫组化法鉴定细胞上K ir6.x和SUR蛋白的表达,并采用膜片钳全细胞记录技术,以KATP通道特异性激动剂吡那地尔和二氮嗪为对照,分析埃他卡林对特定刺激条件下对K ir6.x和SUR共同转染的细胞上诱发的钾电流的影响,并观察KATP通道特异性拮抗剂格列苯脲的阻断作用。结果在共同转入KATP通道两亚单位基因的HEK-293细胞上,有K ir6.x和SUR蛋白的表达。在共同表达K ir6.1/SUR2B的细胞上,埃他卡林(100μmol.L-1)、吡那地尔(100μmol.L-1)及二氮嗪(200μmol.L-1)均具有增强诱发电流的效应,给药前后-100 mV时电流值由(-88.0±30.8)pA分别增至(-2042.6±127.3)pA,(-1431.9±142.4)pA及(-1104.7±228.9)pA,三者的作用均能被格列苯脲所阻断。相同条件下,在共同表达K ir6.2/SUR2A的细胞上,埃他卡林和吡那地尔能增强诱发电流,此作用对格列苯脲敏感;而二氮嗪对该电流无影响。相反,在共同表达K ir6.2/SUR1的细胞上,二氮嗪能增强诱发电流,此作用对格列苯脲敏感;而埃他卡林和吡那地尔对该电流无影响。结论不同结构钾通道开放剂对不同亚型KATP通道作用不同,埃他卡林与吡那地尔作用相似,能选择性作用于K ir6.1/SUR2B和K ir6.2/SUR2A型KATP通道,对K ir6.2/SUR1型无影响。     

盐酸埃他卡林对谷氨酸所致PC12细胞损伤的保护作用

目的 研究盐酸埃他卡林(Ipt)对谷氨酸(Gli)所致细胞损伤的保护作用。方法 采用培养PC12细胞,MTT法测细胞存活率。结果 Ipt 1×10~(-10)～1×10~(-4)mol·L~(-1)可拮抗Glu介导的神经毒作用,提高细胞存活率,该保护作用可被10 μmol·L~(-1)格列苯脲(ATP敏感性钾通道拮抗剂)所取消。结论 Ipt可拮抗Glu介导的神经毒作用,该保护作用可能与ATP敏感性钾通道相关。     

盐酸埃他卡林对脑神经元钠、钾、钙通道的影响

目的　研究盐酸埃他卡林 (Ipt)对脑神经元钠、钾、钙通道的影响。方法　在原代培养的大鼠海马神经元上 ,应用膜片钳全细胞记录技术观察Ipt对钠、钾、钙离子通道电流的影响。结果　Ipt对钠、钙电流幅度以及电流 -电压曲线无影响 ,可增强外向钾电流幅度 ,使电流 -电压曲线上移。其中 ,Ipt 1、10、10 0 μmol·L-1分别使钾通道电流峰值增大为给药前的 (12 1 9± 8 1) %、(114 7± 7 1) %和 (10 9 1±10 0 ) % (P <0 0 1～ 0 0 5 )。给予盐酸埃他卡林 1μmol·L-1的同时给予ATP敏感性钾通道拮抗剂格列本脲 30 μmol·L-1时 ,对钾通道电流无影响。结论　盐酸埃他卡林对脑神经元ATP敏感性钾通道具有激活作用 ,它不影响神经元钠通道和钙通道     

盐酸埃他卡林对大鼠海马神经元谷氨酸受体功能及突触活动的影响

目的 :研究盐酸埃他卡林 (Ipt)对脑神经元谷氨酸受体功能及突触活动的影响。方法 :采用原代培养的大鼠海马神经元 ,应用膜片钳全细胞记录技术 ,记录Ipt对培养的海马神经元谷氨酸或天冬氨酸(NMDA)诱发电流及神经元突触后电流的影响。结果 :Ipt(1～ 1 0 0 μmol·L- 1)可浓度依赖性地对抗培养的海马神经元谷氨酸或NMDA诱发电流 ,并为ATP敏感性钾通道拮抗剂格列本脲 30 μmol·L- 1所对抗。Ipt抑制培养的海马神经元之间突触联系形成的自发兴奋性突触后电流 ,降低其发放频率 ,抑制其电流幅度 ;但对微小兴奋性突触后电流无显著性影响。结论 :Ipt可阻断脑神经元谷氨酸受体功能 ,抑制脑神经元谷氨酸的兴奋性突触传递 ,其作用与ATP敏感性钾通道相关     

银杏叶提取物对低氧复氧、H2O2和谷氨酸损伤时谷氨酸引起的大鼠星形胶质细胞［Ca2+］i变化的影响

目的研究银杏叶提取物对低氧复氧、H₂O₂和L-谷氨酸损伤时谷氨酸升高大鼠星形胶质细胞［Ca²⁺］_i的影响。方法钙荧光探针Fluo-3/AM标记胞浆内游离钙离子，激光扫描共聚焦显微镜测定［Ca²⁺］_i的变化。结果 在低氧复氧、H₂O₂以及高浓度的L-谷氨酸损伤后，外源性谷氨酸（27 μmol·L^-1）均不能引起培养乳大鼠星形胶质细胞正常的［Ca²⁺］_i升高，反而使［Ca²⁺］_i分别降低(3.3±1.6)%，(81±11)%和(81±7)%；损伤前预先给予GbE（10 mg·L^-1）不能明显改善星形胶质细胞的谷氨酸反应，但预先给予GbE（100 mg·L^-1）后，27 μmol·L^-1谷氨酸可使损伤的星形胶质细胞［Ca²⁺］_i分别升高(135±98)%，(117±93)%和(89±36)%。结论低氧复氧、H₂O₂以及高浓度的L-谷氨酸均能损伤星形胶质细胞的谷氨酸反应，影响神经细胞与胶质细胞的双向交流。GbE能明显逆转不同损伤后谷氨酸诱导星形胶质细胞［Ca²⁺］_i的异常变化，使星形胶质细胞在不同损伤时能维持正常功能，该作用可能与GbE的脑保护作用有关。     

新型抗高血压药物盐酸埃他卡林对小动脉的选择性扩张作用及其药理学机制

目的 :研究新型抗高血压药物盐酸埃他卡林(Ipt)对小动脉的作用特性及其药理学机制。方法 :采用大鼠尾动脉螺旋状血管条和主动脉离体血管环两种组织 ,对比观察盐酸埃他卡林对大、小动脉扩张作用的药理学特性 ,并且利用膜片钳技术观察盐酸埃他卡林对大鼠尾动脉平滑肌细胞钾电流的影响。结果 :Ipt在 1 0 - 7～ 1 0 - 3 mol·L- 1范围内对KCl预致收缩的大鼠尾动脉血管条产生剂量依赖性舒张反应 ,且具有部分内皮依赖性 ,但对主动脉离体血管环无明显的舒张反应 ,该作用在高血压状态时显著增强 ,能被ATP敏感性钾通道特异性阻断剂格列苯脲阻断 ,并且对大鼠尾动脉平滑肌细胞的钾电流具有显著增强作用。结论 :盐酸埃他卡林具有选择性舒张小动脉作用 ,具有ATP敏感性钾通道开放剂的主要药理学特征     

盐酸埃他卡林对心肌ATP-敏感性钾通道的作用

目的　在急性分离的豚鼠心室肌细胞上观察盐酸埃他卡林 (iptakalimhydrochloride ,Ipt)对钾电流的影响 ;研究Ipt对 [3 H]格列本脲 (glibenclamide ,Gli)与心肌ATP敏感性钾通道 (ATP sensitivepotassiumchannel,KATP)的硫脲受体(Sulfonylureareceptor,SUR2A)结合特征以及 [3 H]Gli与心肌膜KATP结合和解离动力学过程的影响 ,以评价Ipt对心肌KATP的作用。方法　分离豚鼠心室肌细胞 ,用全细胞记录技术记录细胞钾电流 ,通过浴槽内灌流给药 ,观察盐酸埃他卡林对钾电流的影响。KATP拮抗剂 [3 H]Gli与大鼠心肌膜特异性结合与解离的动力学试验。结果　①Ipt在浓度为 1和10 0 μmol·L-1时 ,均可明显引起豚鼠心室肌外向钾电流I U曲线上移 ,Ipt作用后 5min内细胞外向钾电流强度分别增强为初始电流强度的 12 4 9%± 9 5 % (n =5 )和 15 1 6 %±11 2 % (n =7) ,与溶媒对照组 (6 9 8%± 3 5 % ,n =7)比较差异均有统计学意义 (P <0 0 1)。在相同条件下 ,KATP开放剂吡那地尔 (pinacidil,Pin)的作用与之相似 ,也可明显引起豚鼠心室肌外向钾电流I U曲线上移 ,显著增强细胞外向钾电流。②非标记Gli与 [3 H]Gli和大鼠心肌膜标本在 2 5℃孵育 6 0min ,可浓度依赖性地抑制 [3 H]Gli与心肌膜SUR2A的特异性结合 ,其IC50 值为 (     

羟乙基葛根素对脑星形胶质细胞氧化性损伤的保护作用

目的研究羟乙基葛根素对大鼠脑星形胶质细胞氧化性损伤的保护作用。方法取第4代培养的星形胶质细胞，以比色法测定细胞培养液中乳酸脱氢酶(LDH)活性，流式细胞术测定细胞凋亡率，［³H］-谷氨酸摄取法测定细胞摄取功能，比色法测定细胞内超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量。结果羟乙基葛根素可明显降低过氧化氢(H₂O₂)损伤所致的星形胶质细胞LDH的释放、降低细胞凋亡率、增加谷氨酸摄取率、使细胞内MDA含量减少而SOD活性增加。结论羟乙基葛根素可改善星形胶质细胞的神经营养功能、抑制星形胶质细胞凋亡，其机制可能与其抗氧化作用有关。     

吡那地尔对低氧低糖诱导神经细胞凋亡的抑制作用

目的　探讨ATP敏感性钾通道(K_ATP)开放剂吡那地尔(Pin)对低氧低糖再复氧诱导的大鼠皮质神经细胞凋亡的影响。方法　用电镜和流式细胞分析技术,检测原代培养的大鼠皮质神经细胞凋亡。结果　低氧低糖再复氧可诱导大鼠皮质神经细胞凋亡。Pin (10^-5,10^-6,10^-7mol·L^-1 ) 3个剂量组均能降低凋亡细胞百分率,以10^-5mol·L^-1 组效果最好。上述作用可被K_ATP特异性阻断剂格列苯脲(Gli)所拮抗。结论　Pin对低氧低糖再复氧诱导的大鼠皮质神经细胞凋亡有明显的抑制作用,提示KATP通道在调控细胞凋亡的过程中可能起着重要的作用。     

ATP敏感性钾通道开放剂吡那地尔增高Bcl-2表达而抑制PC12细胞缺血性凋亡

目的探讨ATP敏感性钾通道开放剂吡那地尔对缺血缺氧PC12细胞凋亡及对Bcl-2 mRNA和蛋白表达的影响。方法取传代后3d的PC12细胞,分为正常对照组、缺血对照组、吡那地尔处理组、吡那地尔+格列吡嗪处理组共4组。吡那地尔处理组在PC12细胞缺血缺氧前20min加入浓度为100μmol·L-1的吡那地尔;吡那地尔+格列吡嗪处理组则加入浓度100μmol·L-1的吡那地尔和浓度为500μmol·L-1的KATP通道阻断剂格列吡嗪。采用Annexin-V FITC/PI双染流式细胞分析仪检测凋亡率;应用免疫荧光染色和Western blot检测Bcl-2蛋白表达水平;应用RT-PCR检测Bcl-2 mRNA表达水平。结果缺血缺氧后缺血对照组、吡那地尔处理组、吡那地尔+格列吡嗪处理组细胞凋亡率随时间增加而增加,24h达高峰。吡那地尔组与其余组比较差异均有显著性(P<0.01)。缺血对照组、吡那地尔处理组、吡那地尔+格列吡嗪处理组细胞Bcl-2 mRNA及蛋白表达各时间点均增加,12h达高峰。吡那地尔组与其余组比较差异均有显著性(P<0.05,或P<0.01)。缺血对照组和吡那地尔+格列吡嗪处理组比较差异均无显著性(P>0.05)。结论ATP敏感性钾通道开放剂可能通过提高Bcl-2 mRNA及蛋白表达来减轻缺血缺氧后PC12细胞凋亡,发挥保护作用。     

Effects of systemic administration of iptakalim on extracellular neurotransmitter levels in the striatum of unilateral 6-hydroxydopamine-lesioned rats.

The function of ATP-sensitive potassium (KATP) channels in nigrostriatal pathway in Parkinson's disease (PD) was studied by employing a novel KATP channel opener iptakalim (Ipt). Apomorphine-induced rotation behavior test and microdialysis experiment were carried out in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Behavior test showed that systemic administration of Ipt failed to significantly alleviate apomorphine-induced rotation in unilateral 6-OHDA-lesioned PD model rats. However, using in vivo microdialysis in this PD model rats, it was found that Ipt could increase extracellular dopamine levels in the lesioned side of the striatum and decrease dopamine levels in the intact side of the striatum. Meanwhile, Ipt had no influence on glutamate levels in the intact side, but it did decrease glutamate levels in the lesioned side of the striatum of PD rats. Additionally, in primary cultured rat astrocytes, 6-OHDA decreased overall glutamate uptake activity, but this decrease was recovered and glutamate uptake activity was restored by the opening of KATP channels induced by Ipt and pinacidil. The classical KATP channel blocker glibenclamide completely abolished the effects of Ipt and pinacidil. The present study suggests that (i) the function of KATP channels in the lesioned and intact nigrostriatal pathway is different in unilateral 6-OHDA-lesioned PD model rats. (ii) KATP channels regulate extracellular neurotransmitter levels in the striatum of unilateral 6-OHDA-lesioned rats and may play neuroprotective roles due to their effects on glutamate transporters.     

埃他卡林对大鼠尾动脉平滑肌细胞［Ca2+］i， PKA和PKC活性的影响埃他卡林对大鼠尾动脉平滑肌细胞［Ca2+］i， PKA和PKC活性的影响

细胞内钙参与了对几乎所有类型细胞的各种生理活动的调节[1],并通过影响PKA和PKC等大分子蛋白,进一步调控细胞的分裂和增殖。以ATP敏感型钾通道(KATP)为靶点的钾通道开放剂(KCO)是一类新型的抗高血压药物[2,3]。KCO激活血管平滑肌KATP,间接抑制钙通道的开放,从而使[Ca2 ]i降低,     

线粒体KATP开放剂二氮嗪促进星形胶质细胞摄取谷氨酸

目的研究线粒体ATP敏感性钾通道(mitochondrial ATP-sensitive potassium channel, mitoKATP)开放剂二氮嗪(diazoxide)对星形胶质细胞摄取谷氨酸(glutamate)的影响.方法取新生大鼠脑星形胶质细胞作原代培养,用液体闪烁计数仪测定[3H]-D,L-谷氨酸的摄入量判断细胞的谷氨酸摄取功能.结果二氮嗪呈浓度依赖性地促进星形胶质细胞摄取谷氨酸,且能抑制1-甲基-4-苯基吡啶离子(1-methyl-4-phenylpyridinium,MPP+)对星形胶质细胞摄取谷氨酸的损伤作用;浓度在100μmol·L-1以上时,二氮嗪可完全逆转MPP+对星形胶质细胞摄取谷氨酸的抑制作用;二氮嗪的上述作用可被选择性mito KATP 阻断剂5-羟基癸酸 (5-hydroxydecanoate,5-HD)拮抗.结论二氮嗪通过开放mitoKATP增强星形胶质细胞谷氨酸转运体(glutamate transporters, GluTs)的功能.     

Inhibition by glibenclamide of negative chronotropic and inotropic responses to pinacidil, acetylcholine, and adenosine in the isolated dog heart.

The blocking effects of glibenclamide on the chronotropic and inotropic responses to K+ channel openers pinacidil (ATP-sensitive) and acetylcholine (ACh) or adenosine (receptor-operated) were investigated in the isolated, blood-perfused canine atrium or ventricle. Glibenclamide (0.1-3 mumol) induced no significant cardiac effects. Cumulative administration of pinacidil (0.03-3 mumol) dose-dependently decreased sinus rate much less than the contractile force of the atrial and ventricular muscles. Glibenclamide similarly inhibited the negative chronotropic and inotropic responses to pinacidil in a dose-related manner. A high dose of glibenclamide (3 mumol) slightly but significantly attenuated the negative chronotropic and inotropic responses to ACh and adenosine but not to verapamil. These results demonstrate that glibenclamide inhibits the negative chronotropic and inotropic responses to the ATP-sensitive K+ channel opener pinacidil and the receptor-operated K+ channel openers ACh and adenosine but more selectively antagonizes the responses to pinacidil in the dog heart and suggest that in contrast to ACh and adenosine, an ATP-sensitive K+ channel opener has a greater effect on the ventricle than on the sinoatrial node.     

Effect of K+ channel modulators on the antiallodynic effect of gabapentin

The effect of K+ channel inhibitors on the antiallodynic activity induced by spinal gabapentin was assessed in rats. Ligation of L5 and L6 spinal nerves made the rats allodynic, whereas that intrathecal administration of gabapentin (25-200 microg) reduced tactile allodynia in a dose-dependent manner. Spinal pretreatment with glibenclamide (12.5-50 microg, ATP-sensitive K+ channel inhibitor), charybdotoxin (0.01-1 ng) or apamin (0.1-3 ng, large-and small-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (0.01-10 ng, voltage-dependent K+ channel inhibitor), significantly prevented gabapentin-induced antiallodynia. Pinacidil (1-30 microg, K+ channel opener) significantly reduced nerve ligation-induced allodynia. Intrathecal glibenclamide (50 microg), charybdotoxin (1 ng) and apamin (3 ng), but not margatoxin (10 ng), significantly reduced pinacidil-induced antiallodynia. K+ channel inhibitors alone did not modify allodynia produced by spinal nerve ligation. Results suggest that gabapentin and pinacidil may activate Ca2+-activated and ATP-sensitive K+ channels in order to produce part of its spinal antiallodynic effect in the Chung model.     

KATP channel openers facilitate glutamate uptake by GluTs in rat primary cultured astrocytes.

Increasing evidence, including from our laboratory, has revealed that opening of ATP sensitive potassium channels (KATP channels) plays the neuronal protective roles both in vivo and in vitro. Thus KATP channel openers (KCOs) have been proposed as potential neuroprotectants. Our previous studies demonstrated that KATP channels could regulate glutamate uptake activity in PC12 cells as well as in synaptosomes of rats. Since glutamate transporters (GluTs) of astrocytes play crucial roles in glutamate uptake and KATP channels are also expressed in astrocytes, the present study showed whether and how KATP channels regulated the function of GluTs in primary cultured astrocytes. The results showed that nonselective KCO pinacidil, selective mitochondrial KCO diazoxide, novel, and blood-brain barrier permeable KCO iptakalim could enhance glutamate uptake, except for the sarcolemmal KCO P1075. Moreover pinacidil, diazoxide, and iptakalim reversed the inhibition of glutamate uptake induced by 1-methyl-4-phenylpyridinium (MPP+). These potentiated effects were completely abolished by mitochondrial KATP blocker 5-hydroxydecanoate. Furthermore, either diazoxide or iptakalim could inhibit MPP+-induced elevation of reactive oxygen species (ROS) and phosphorylation of protein kinases C (PKC). These findings are the first to demonstrate that activation of KATP channel, especially mitochondrial KATP channel, improves the function of GluTs in astrocytes due to reducing ROS production and downregulating PKC phosphorylation. Therefore, the present study not only reveals a novel pharmacological profile of KCOs as regulators of GluTs, but also provides a new strategy for neuroprotection.     

Inhaled pinacidil,an ATP-sensitive K+ channel opener,and moguisteine have potent antitussive effects in guinea pigs

We investigated whether inhaled pinacidil and moguisteine inhibit capsaicin-induced coughs in guinea pigs. Inhaled pinacidil (15 - 60 microg/ml), an ATP-sensitive K+ channel opener, and moguisteine (15 - 60 microg/ml) each dose-dependently inhibited the number of capsaicin-induced coughs. The antitussive effects of pinacidil and moguisteine were significantly antagonized by pretreatment with glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel blocker. However, pretreatment with naloxone methiodide (10 mg/kg, s.c.) had no significant effect on the antitussive effects of either pinacidil or moguisteine. On the other hand, inhaled dihydrocodeine (15 - 60 microg/ml) also dose-dependently suppressed the number of capsaicin-induced coughs. The antitussive effect of inhaled dihydrocodeine was significantly antagonized by pretreatment with naloxone methiodide (10 mg/kg, s.c.), but not by glibenclamide (10 mg/kg, i.p.). These results indicate that inhaled pinacidil and moguisteine both attenuate capsaicin-induced coughs. Pinacidil and moguisteine may exert their antitussive effects through the activation of ATP-sensitive K+ channels in the tracheobronchial tract. Furthermore, it is possible that ATP-sensitive K+ channels may be involved in the antitussive effects of peripherally acting non-narcotic antitussive drugs.     

吡那地尔,cromakalim和NS1619对电刺激所致大鼠输精管收缩的作用

目的：本文研究新近研制的ＡＴＰ敏感性钾通道开放剂，吡那地尔（Ｐｉｎ）和ｃｒｏｍａｋａｌｉｎ（Ｃｒｏ），以及钙离子激活性钾通道开放剂ＮＳ１６１９对电场刺激所致大鼠输业管收缩的作用，方法：利用电场刺激（０．３Ｈｚ，１ｍｓ，６０Ｖ）反复性引致输精管单相性收缩，结果：Ｐｉｎ和Ｃｒｏ浓度依赖性减低电刺激收缩，格列本脲（Ｇｌｉ）而非ｃｈａｒｙｂｄｏｔｏｘｉｎ拮抗上述两药的舒张的作用，Ｐｉｎ右移去甲肾上腺素的浓     

Involvement of ATP-sensitive K(+) channels in the anti-tussive effect of moguisteine

The effect of glibenclamide, an ATP-sensitive K(+) channel blocker, on the anti-tussive effect of moguisteine and of pinacidil, an ATP-sensitive K(+) channel opener in guinea pigs was studied. Pinacidil (1 and 5 mg/kg, subcutaneous (s.c.)) dose-dependently reduced the number of coughs. The anti-tussive effect of pinacidil was significantly and dose-dependently antagonized by pre-treatment with glibenclamide (3 and 10 mg/kg, i.p.). Moguisteine (1 and 5 mg/kg, s.c.) dose-dependently reduced the number of coughs. The anti-tussive effect of moguisteine was also reduced by pre-treatment with glibenclamide, in a dose-dependent manner. However, pre-treatment with glibenclamide had no effect on the anti-tussive effects of dihydrocodeine and dextromethorphan. Glibenclamide (10 mg/kg, i.p.), by itself, had no significant effect on the number of coughs. These results suggest that pinacidil and moguisteine may exert their anti-tussive effects through the activation of ATP-sensitive K(+) channels. Furthermore, it is possible that ATP-sensitive K(+) channels may be involved in the anti-tussive effect of peripherally acting non-narcotic anti-tussive drugs.     

Iptakalim inhibited endothelin-1-induced proliferation of human pulmonary arterial smooth muscle cells through the activation of K(ATP) channel

To determine whether iptakalim inhibited endothelin-1(ET-1)-induced proliferation of human pulmonary arterial smooth muscle cells (PASMCs) through the activation of ATP-sensitive potassium (K(ATP)) channel, the effect of iptakalim on the ET-1-induced proliferation of human PASMCs was examined by [3H]thymidine incorporation, staining with propidium iodide and flow cytometry analyses, measurement of cytosolic free Ca2+ concentration ([Ca2+]cyt) and Western blot for the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in vitro. The results showed that iptakalim inhibited the ET-1-induced proliferation of human PASMCs, including [3H]thymidine incorporation and the transition of cell cycle phase, and blocked the ET-1-induced transient raise of [Ca2+]cyt, and the ET-1-induced phosphorylation of ERK1/2 in the human PASMCs. Iptakalim exerted a similar role as pinacidil did in human PASMCs and both inhibited the [3H] thymidine incorporation and the transition of cell cycle phase induced by ET-1 in the human PASMCs. Furthermore, we found that the inhibition of iptakalim and pinacidil on the ET-1-induced proliferation of human PASMCs was blocked by glyburide, a selective K(ATP) channel antagonist. These findings provide a strong evidence to support that iptakalim acts as a specific K(ATP) channel opener to antagonize the proliferating effect of ET-1 in the human PASMCs. This study provides further evidence that iptakalim may serve as another candidate drug to treat pulmonary hypertension.