血管平滑肌的ATP敏感钾通道

ＡＴＰ敏感钾通道（ＫＡＴＰ）是一类较广泛分布的内向整流钾通道。在生理状态及某些病理条件下ＫＡＴＰ参与血管张力的调节。ＫＡＴＰ活性受多种因素的调控,胞内二磷酸核苷酸（ＮＤＰｓ）、钾通道开放剂（ＫＣＯｓ）等可激活通道,而ＡＴＰ和硫脲类药物则特异性抑制通道的开放。分子生物学研究证明ＫＡＴＰ由Ｋｉｒ６０和硫脲类受体（ＳＵＲ）共同组成,Ｋｉｒ６０构成Ｋ＋可穿透的通道核心,ＳＵＲ受体构成通道的调节单位。血管平滑肌中的ＫＡＴＰ是由Ｋｉｒ６１和ＳＵＲ２Ｂ组成的四聚体结构。但两种亚单位如何联结成有功能的多聚体还需进一步的证明。     

ATP敏感钾通道与心肌缺血预适应

198 6年 Murry发现反复短暂缺血可以减轻心肌随后较长时间缺血损伤 [1 ] ,从而首次提出了缺血预适应的概念 ,这一概念的提出为缺血心肌的保护及其机制的探索开辟了一个崭新的领域。十余年来尽管研究人员已提出了缺血预适应可能是通过刺激心脏合成与释放内源性保护物质 ,随后激活细胞内信号转导途径而发挥保护作用 ,但对其信号转导的机制仍不完全清楚。现在人们开始注意对代谢敏感的离子传导性通道—— ATP敏感钾 (KATP)通道。 KATP通道是受细胞内 ATP浓度调控的一种内向整流钾通道 ,它是由 Noma于 1 983年利用膜片钳技术在心肌细胞上…     

心房颤动患者心房组织ATP敏感性钾通道基因转录表达的研究

目的 探讨心房颤动患者心房组织ATP敏感性钾通道(Kir6.2)基因转录的变化。方法 35例风湿性心瓣膜病患者,心外科手术时被取右心耳组织。通过逆转录-聚合酶链反应,以三磷酸甘油醛脱氢酶(GAPDH)为内参照,测量心耳组织Kir6.2通道的mRNA表达量。结果 窦性心律组和阵发性房颤组心房组织Kit6.2的mRNA水平均显著高于慢性房颤组(P<0.05);而阵发性房颤组心房组织Kir6.2的mRNA又显著高于窦性心律组(P<0.05)。结论 Kir6.2通道转录水平的改变可能是相应ATP敏感性钾通道产生的内向整流钾电流(IKATP)重构的分子基础,Kir6.2基因转录改变可能是促进房颤发生和持续的因素之一。     

Kv42钾通道mRNA在大鼠血管平滑肌中的表达

自 8 0年代末Ｌｉｌｙ实验组和Ｐｏｎｇｓ实验组第一次发现ＳｈａｋｅｒＫｖ钾通道以来 ,目前已发现 9大类Ｋｖ钾通道。Ｋｖ4 2亚型可编码瞬间外向钾电流 (Ｉｔｏ) ,此电流是动作电位负极化早期外向电流的主要成分 ,主要调节静息膜兴奋性 ,减慢去极化速度 ,延缓动作电位的产生 ,且该通道亚型广泛存在于心脏和中枢神经系统中 ,Ｋｖ 4 2是否存在于血管平滑肌中目前国内外未见报道 ,因此有必要在血管平滑肌中进行研究。本文应用ＲＮａｓｅ保护实验 (ＲＮａｓｅＰｒｏｔｅｃｔｉｏｎＡｓｓａｙ ,ＲＰＡ)研究大鼠主动脉平滑肌中Ｋｖ 4 2钾通道的…     

神经元ATP敏感钾通道的研究进展

ATP敏感性钾离子通道 (KATP,ATPsensitivepotassi umchannel)广泛存在于包括脑在内的多种组织细胞上。该通道是由磺酰脲受体 (SUR ,sulphonylureareceptor)和内向整流钾通道 (Kir,inwardlyrectifyingpotassiumchannel)亚单位组成的异源四聚体 (SUR/Kir6) 4,其活性可被细胞内ATP调控。脑内的KATP通道在生理状态下可介导中枢糖敏感性及代谢应激过程 ,在脑缺血、帕金森病等急慢性神经疾病中同样发挥重要作用     

心血管系统中的ATP敏感性钾通道

<正> 钾通道几乎存在于每一种细胞,种类繁多,功能复杂。近年来由于膜片钳制技术(patch-clamp)广泛应用,加之发现一些对一定类型钾通道有特异性阻滞作用的毒素、药物以及钾通道开放剂(potassium channel open-er,PCO)等,人们能在单个离子通道水平对复杂多样的钾通道进行分辨和区分,对通道蛋白进行分离、纯化、重组,使钾通道研究取得了长足进展,成为一个非常活跃的研究领     

心血管ATP敏感钾通道及其相关药物研发

综述心肌、血管平滑肌及血管内皮中ATP敏感性钾通道的结构、功能和药理学特性,并展望了ATP敏感性钾通道特异性开放剂和阻断剂的应用前景及该类新药的研究方向。ATP敏感性钾通道是由细胞内ATP调节的一种钾离子通道,不同组织中ATP敏感性钾通道的结构、功能和药理学性质有所不同。     

血管平滑肌ATP敏感性钾通道研究进展

ATP敏感性钾通道 (KATP)广泛存在于各类细胞和组织中 ,是药物作用的重要靶点。KATP是由内向整流钾通道Kir和磺酰脲类受体SUR亚基组成。与血管舒缩特性密切相关的是SUR2B/Kir6 1,电导值小 ,对ATP的抑制作用不敏感 ,需要有NDP才能被开放 ,故这类血管平滑肌KATP又被称为NDP依赖性钾通道。内源性和外源性的很多因子引起的血管舒缩反应与血管平滑肌上的KATP有关 ,此信号途径与PKA、PKC等磷酸化激酶有密切联系。不同血管对钾通道开放剂(potassiumchannelopeners,KCO)的反应有差异 ,KCO对血管的选择性作用机制仍不明确。本文就血管平滑肌KATP的分子结构、电生理、药理学特征、信号转导途径和KCO对血管的选择性作用进行综述     

大脑中动脉栓塞模型大鼠的中枢电压依赖性钾通道mRNA表达的改变

目的观察几种代表性电压依赖性钾通道亚型在脑缺血不同时间大鼠海马和皮层mRNA表达水平的变化。方法采用大脑中动脉栓塞模型致大鼠脑缺血损伤，应用RT-PCR方法检测Kv1.4，Kv1.5，Kv2.1和Kv4.2 mRNA表达水平在海马和皮层中的改变。结果大脑中动脉栓塞模型大鼠出现明显的神经损伤症状。缺血2 h时，海马组织的Kv1.4，Kv2.1和Kv4.2 mRNA表达水平分别增加了50%，67%和90%，在缺血24 h时Kv1.4和Kv4.2 mRNA仍保持高水平表达。大鼠皮层组织在缺血2 h后，Kv1.4，Kv1.5，Kv2.1和Kv4.2 mRNA水平均无明显改变，缺血24 h后，Kv2.1和Kv4.2 mRNA水平分别增加了70%和62%。结论大脑中动脉栓塞模型大鼠的海马和皮层组织中电压依赖性钾通道亚型的mRNA表达发生明显上调。     

线粒体ATP敏感性钾通道不参与异丙酚预处理的心肌保护

目的　观察异丙酚预处理对心肌缺血再灌注损伤的保护机制是否通过开放线粒体ATP敏感性K通道 (KATP)。方法　非循环式Langendorff离体心脏灌注模型 ,灌注 1h ,常温下行全心缺血 2 5min ,恢复再灌注 30min。通过Maclab仪记录左室舒张末压 (LVEDP)、左室发展压 (LVDP)、左室压上升和下降最大速率 (±dp/dtmax)。测恢复再灌注末心肌组织MDA含量。结果　恢复再灌注 30min末 ,对照组(Con)、异丙酚预处理组 (PP)、5 HD +PP和 5 HD组心肌组织的MDA含量分别为 (113 7± 2 0 9)、(89 4± 13 7)、(91 9± 14 4 )和 (114 8± 19 7)nmol·10 0mg-1。PP组和 5 HD+PP组的心肌MDA含量都明显低于Con组和 5 HD组 (P<0 0 5 ) ;PP组和 5 HD +PP组两组间的MDA差异无显著性 (P >0 0 5 )。恢复再灌注 30min末 ,Con组、PP组、5 HD+PP组和 5 HD组的LVEDP值分别为基础值的 5 1、3 2、3 6和 5 3倍。PP组和 5 HD +PP组LVEDP值的上升幅度均明显低于Con组和 5 HD组 (P <0 0 5 ) ,而 5 HD +PP组和PP组之间差异无显著性 (P >0 0 5 )。结论　异丙酚预处理的心肌保护不是通过开放线粒体ATP敏感性K通道 ,其心肌保护作用和线粒体KATP无关     

抗心肌缺血药物的新靶点:线粒体ATP敏感性钾通道

ATP敏感性钾通道 (KATP)是心脏保护作用的调节位点。随着KATP药理学和分子生物学特征的深入研究 ,发现KATP开放剂介导的心脏保护机制并不依赖于动作电位时程(APD)的缩短和负性肌力作用 ,而与线粒体功能有关。细胞内存在线粒体KATP(mitoKATP)。mitoKATP开放的心脏保护作用机制尚不十分清楚 ,可能与K+ 内流 ,线粒体膜去极化 ,降低Ca2 + 超载 ,基质容积增加有关 ,后者可增加ATP合成、促进线粒体呼吸     

Contribution of ATP-sensitive potassium channels to β-adrenoceptor-mediated responses

In isolated hearts the inotropic response to the β-adrenoceptor agonist isoproterenol is known to be abolished after ischaemia and reperfusion. The aim of this study was to investigate whether at decreased glucose levels the β-adrenoceptor-mediated responses in vascular smooth muscle would be depressed, since low glucose conditions mimick the influence of ischaemia. Accordingly, we investigated the influence of low glucose levels in the extracellular space on the vasorelaxation induced by isoproterenol and salbutamol in rat isolated thoracic aortic ring preparations with an intact endothelium and we attempted to further analyze the underlying mechanisms. Therefore, forskolin, dibutyryl-cAMP and glibenclamide (an ATP-sensitive K⁺-channel blocker) were studied as well. In a glucose-free medium the concentration-response curve for isoproterenol was shifted to the left compared to that obtained under normal glucose conditions. The maximal relaxation induced by isoproterenol was not affected by the absence of glucose. In contrast, the maximal relaxation induced by salbutamol in glucose-free medium decreased by 50% compared to that obtained under normal glucose conditions. Glibenclamide caused a concentration-dependent decrease of the maximum relaxation by isoproterenol in a glucose-free medium, but had no effect under normal glucose conditions. Glibenclamide did not influence the concentration-response curves for salbutamol, neither in the presence nor in the absence of glucose in the medium. The relaxation caused by forskolin and dibutyryl-cAMP was not influenced by glibenclamide in a medium devoid of glucose. In endothelium-denuded preparations glibenclamide did not affect isoproterenol-induced responses neither in the presence nor in the absence of glucose. It is concluded that β-adrenoceptor stimulation opens ATP-sensitive potassium channels under conditions of impaired ATP-metabolism by a cAMP-independent pathway, which needs an intact endothelium. Received: 3 January 1995 / Accepted: 31 August 1996     

ATP‐sensitive potassium channels: A promising target for protecting neurovascular unit function in stroke

• 1 Stroke is the second most common cause of death and a major cause of disability worldwide. Despite increasing knowledge of the cellular and molecular mechanisms that occur in stroke, there are still large gaps in our understanding that are impeding therapeutic progress. In addition, there are no drugs yet that can be used effectively in stroke patients.
• 2 In recent years, it has been recognized that stroke is a brain dysfunction that involves multiple cell types and that a purely neurocentric focus or targeting a single point in a single pathway fails to yield sufficient protection. Thus, the concept of the ‘neurovascular unit’ has emerged as a new paradigm for stroke investigation and therapy.
• 3 ATP‐sensitive potassium (K_ATP) channels are unique channel proteins that directly couple the metabolic state of a cell to its electrical activity. These channels are found throughout the brain, being found in neurons, glial cells and in the brain vasculature. It is well documented that K_ATP channels play multifactorial roles in protecting against brain injury induced by hypoxia, ischaemia or metabolic inhibition.
• 4 In the present review, we focus on the function of the neurovascular units in stroke and review current knowledge regarding K_ATP channels, with a focus on their potential role in the remodelling of the neurovascular units.

     

Activation of mitochondrial ATP-sensitive potassium channels delays ischemia-induced cellular uncoupling in rat heart

AIM: To test the hypothesis that cellular uncoupling induced by myocardial ischemia is mediated by activation of cmitochondrial ATP-sensitive potassium channels (mitoKATP). METHODS: Rat hearts were perfused on a Langendorff apparatus and subjected to 40-min ischemia followed by 30-min reperfusion (I/R). Changes in cellular coupling were monitored by measuring whole-tissue resistance. RESULTS: (1) In hearts subjected to I/R, the onset of uncoupling started at (13.3±1.0) mm of ischemia; (2) Ischemic preconditioning (IPC) delayed the onset of uncoupling until (22.7±1.3) min. Blocking mitoKATP channels with 5-     

降钙素基因相关肽对早期糖尿病大鼠血管ATP敏感性钾通道的影响

目的　研究早期糖尿病大鼠血管平滑肌ATP敏感性钾通道 (KATP)的变化 ,进一步探讨糖尿病血管功能的改变机制。方法　大鼠单次注射链佐霉素6 0mg·kg- 1制作糖尿病模型 ;1周或 2周后 ,两步酶消化法进行肠系膜动脉平滑肌细胞 (MASMC)的消化分离 ;全细胞膜片钳制技术记录MASMC的ATP敏感性钾电流 (IKATP)。结果　在保持电位 - 40mV ,指令电位 +5 0mV时 ,对照组 ,糖尿病 1周和 2周组MASMC的IKATP 分别为 (79± 6 ) ,(70± 7)和(4 8± 9)pA·pF- 1,糖尿病 2周组的IKATP明显低于对照组。给予降钙素基因相关肽 0 .0 1～ 10 0nmol·L- 1,3个组的IKATP 均浓度依赖性增加 ,对照组 :Y =118.3+2 .9X ,r =0 .887;糖尿病 1周组 :Y =12 3+4.4X ,r =0 .981;糖尿病 2周组 :Y =10 0 .2 +4.6X ,r =0 .975 ;糖尿病组IKATP对降钙素基因相关肽量效反应斜率高于对照组。结论　早期糖尿病血管平滑肌的基础IKATP减小 ,IKATP对降钙素基因相关肽的量效反应斜率增加。     

Cilostazol protects the heart against ischaemia reperfusion injury in a rabbit model of myocardial infarction: focus on adenosine, nitric oxide and mitochondrial ATP-sensitive potassium channels

1. The present study examined whether or not cilostazol reduces the myocardial infarct size, and investigated its mechanism in a rabbit model of myocardial infarction. 2. Japanese white rabbits underwent 30 min of coronary occlusion, followed by 48 h of reperfusion. Cilostazol (1 and 5 mg/kg) or vehicle was given intravenously 5 min before ischaemia. 8-p-sulfophenyl theophylline (8SPT; an adenosine receptor blocker, 7.5 mg/kg), Nω-nitro-L-arginine methylester (l-NAME; an NOS inhibitor, 10 mg/kg) or 5-hydroxydecanoic acid sodium salt (5-HD; a mitochondrial ATP-sensitive potassium (KATP) channel blocker, 5 mg/kg) was given intravenously 5 min before cilostazol injection. Infarct size was determined as a percentage of the risk area. 3. The myocardial interstitial levels of adenosine and nitrogen oxide (NOx) during ischaemia and reperfusion, and the intensity of myocardial dihydroethidium staining were determined. 4. Infarct size was significantly reduced in the cilostazol 1 mg/kg (38.4% (2.9%)) and cilostazol 5 mg/kg (30.7% (4.7%)) groups compared with that in the control group (46.5% (4.2%)). The infarct size-reducing effect of cilostazol was completely abolished by 8SPT (46.6% (3.5%)), L-NAME (49.0% (5.5%)), or 5HD (48.5% (5.1%)). 8SPT, L-NAME or 5HD alone did not affect the infarct size. Cilostazol treatment significantly increased myocardial levels of adenosine and NOx during ischaemia, and attenuated the intensity of dihydroethidium staining during reperfusion. 5. These findings show that cilostazol reduces the myocardial infarct size by increasing adenosine and NOx levels, attenuating superoxide production and opening the mitochondrial KATP channels. Cilostazol might provide a new strategy for the treatment of coronary heart disease.     

Role of central ATP-sensitive potassium channels in the hyperthermic effect of morphine in mice

Morphine (10 mg/kg, SC) in combination with ICV vehicle induced a significant hyperthermic effect at 120 min (peak time) after injection compared to ICV vehicle plus SC saline (control group). Glibenclamide (50 µg, ICV), a selective adenosine triphosphate-sensitive potassium (K_ATP) channel blocker, in combination with SC saline hardly affected the rectal temperature compared to the control group. ICV glibenclamide antagonized the hyperthermia induced by SC morphine in a dose-dependent manner. From these results, we demonstrated that K_ATP channels play an important role as modulators of the hyperthermic effect of agonists.