CN110917195A - 肌松剂阿库氯铵（Alcuronium chloride）可作为抗心律失常药物 - Google Patents
肌松剂阿库氯铵（Alcuronium chloride）可作为抗心律失常药物 Download PDFInfo
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Abstract
本发明公开了阿库氯铵在制备治疗心律失常药物中的应用。本发明首次发现阿库氯铵能够有效的作为IK1特异性激动剂，其具有和zacopride相类似的效果，可以作为制备抗心律失常作用的药物，因而提供了一条有效、安全治疗的新途径。
Description
技术领域
本发明涉及一种心血管疾病药物，具体而言，涉及肌松剂阿库氯铵在制备治疗心律失常药物中的应用。
背景技术
心律失常是指心跳频率和节律的异常，严重心律失常往往是心血管疾病患者的主要死因之一。形成严重心律失常的机制很复杂，往往不是单一的机制，但是究其根本，都有心肌离子通道功能活动的改变，由此引起离子流的变化会影响动作电位的发生和形态。那些能够改变动作电位的药物因而可能具有致心律失常风险或抗心律失常的作用。
目前临床应用的抗心律失常药物几乎全部是各种离子通道阻断剂，其主要靶点作用于Na . Kv , Ca 离子通道上，根据药物对离子通道和受体的作用，将治疗快速型心律失常药物分成四类：
Ⅰ类：钠通道阻滞药
Ⅰa：中等强度（适度阻滞钠通道），奎尼丁、普鲁卡因胺
Ⅰb：轻度阻滞钠通道，利多卡因、苯妥英钠、美西律、妥卡尼
Ⅰc：重度阻滞钠通道，普罗帕酮、氟卡尼
此类药物可使阻断钠通道，改变单向组织区的传导，消除折返。
Ⅱ类：β受体阻断药，如普萘洛尔，此类药物可使4 相去极化电流减小，自律性降低。
Ⅲ类：延长动作电位时程药（钾通道阻滞药），如胺碘酮，抑制Kv 通道，可使复极化3相钾离子外流减少，明显延长动作电位时程，使有效不应期延长，消除折返。
Ⅳ类：钙通道阻滞药，如维拉帕米、地尔硫卓，阻断钙通道，使动作电位4相钙离子内流减少，慢反应细胞自律性降低，可用来治疗室上性心律失常。
——以上四类主要治疗快速型心律失常
目前无论哪种抗心律失常药物均有一定的致心律失常作用。Ⅰ类药物可因阻断钠通道减慢传导而诱发折返；Ⅲ类药物因延长动作电位时程而诱发长QT综合症。这引起了人们的重视，寻找新的更安全的治疗方法迫在眉睫。九十年代中期以后，心导管介入技术治疗各类心律失常取得了很大进展，开辟了心律失常治疗的新方向。但介入治疗有一定的适应症范围，故对于多数心律失常患者而言，药物治疗仍是治疗的主要方法或必需的组成部分。
抗心律失常药物致心律失常作用的原因是多方面的，许多学者认为应开辟新思路，寻找新药物。
内向整流钾通道（Inward rectifier potassium channel，IK1)负载电流是心肌最主要的背景外向电流，参与静息电位（Resting potential，RP)的维持和心肌动作电位（Action potential，AP）3期终末的复极（图1）。调节IK1必将影响心肌静息膜电位的稳定和动作电位复极，从而对心肌的兴奋性和心律失常的发生产生深刻影响。
IK1理应成为抗心律失常药物作用的新靶点。但是目前临床应用的抗心律失常药物没有一种是以IK1作为主要靶点的。其原因来自两个方面：一是迄今没有一种高选择性的IK1阻断剂或激动剂。缺乏必要的药理学工具药，极大限制了IK1与心律失常关系的研究；二是尽管许多实验研究证实阻断IK1可有效抑制折返性心律失常的发生，但阻断IK1带来的风险也是显而易见的。从理论上讲，IK1被抑制将使膜去极化，细胞的兴奋性和自律性增高，易化延迟后除极（DAD）等触发活动的发生；IK1的抑制使膜电阻增大，放大了跨膜电流引起的膜电位波动，造成膜电位的不稳定；抑制IK1还可延长动作电位时程（APD），引发长QT综合征。诸多研究已证实IK1的功能获得或功能缺失参与了心律失常及病理性重构的发生发展。但是既往由于缺乏高选择性IK1阻断剂或激动剂，以及利用转基因或基因敲除方法改变心肌IK1表达，远非生理状态，使得相关研究存在极大限制性。2012年，吴博威教授课题组首次报道了一个IK1选择性激动剂—zacopride，通过激动IK1可使静息电位负值增大（超极化），动作电位时程轻度缩短（Liu QH, Li XL, Xu YW, Lin YY, Cao JM, Wu BW. A Novel Discovery of IK1 Channel Agonist: Zacopride Selectively Enhances IK1 Current and SuppressesTriggered Arrhythmias in the Rat. J Cardiovasc Pharmacol, 2012, 59(1): 37–48.）。 而对其他影响动作电位的主要离子通道或交换体如Ito、ICa-L、INa、INa/Ca、Ipump、IK（豚鼠）等均无显著影响。利用这个工具药，IK1在心律失常中的作用逐渐得到阐释。该课题组在大鼠急性心肌缺血模型和心梗后慢性心律失常模型上首次证实适度激动IK1通道对缺血性心律失常有抑制作用。
缺血性心律失常是临床更常见、危害性更大的心律失常。各种类型的心肌缺血均可诱发心律失常，以室性心律失常为主，是引起心肌梗死患者早期死亡的主要原因；在急性心肌梗死幸存的人群中，50% 以上仍死于致命的室性心律失常。而心肌缺血和心肌梗死时发生的心律失常也被证实与IK1的下降有关。有研究显示大鼠慢性动物心肌梗死模型的心肌IK1减小20%；而慢性心梗的家兔非梗死区心室肌细胞IK1也明显减小；Pinto 等证实，狗心肌缺血区心内膜下普肯野纤维静息电位减小，是由于IK1减小造成的。Kiesecker等在人的心肌细胞证明，内皮素可显著抑制IK1，此作用是内皮素致缺血性心律失常的重要机制。心肌缺血时IK1下调及/或功能减弱使静息钾电导下降，导致静息电位（负值）减小和兴奋传导减慢，易形成折返；钾电导下降还会引发膜电位不稳定和异常自律活动增加，这些都是心肌缺血（包括急性和慢性）时发生心律失常的重要原因。
但目前为止，也只有zacopride这样一个IK1特异性激动剂被公开报道。建立激动心肌IK1与抗心律失常理论关系仍显薄弱，迫切需要找到新的IK1特异性激动剂。
发明内容
目前无论哪种抗心律失常药物均有一定的致心律失常作用，而本药物作为IK1激动剂，可能具有抗心律失常作用，可以成为一条有效、安全治疗的新途径。 对此，本发明人分析认为IK1选择性激动剂—扎考比利（zacopride），通过激动IK1可使静息电位负值增大（超极化），动作电位时程轻度缩短。对此，基于组学大数据的药物重定位平台寻求扎考比利作用相似物，利用人直结肠癌细胞系HCT116，经zacopride孵育24h，行转录组测序（RNA-seq），对两组“Ctl_VS_Za_1(对照组VS zacopride 1 μM)和Ctl_VS_Za_40(对照组VSzacopride 40μM)”的差异表达分析结果进行校验，差异结果一致后，分别得到两组差异基因：Ctl_VS_Za_1组差异基因226个，上调187个，下调39个；Ctl_VS_Za_40组差异基因302个，上调250个，下调52个。将两组差异表达基因导入基于转录组数据的药物重定位平台，最终得到阿库氯铵可能与zacopride具有相似作用，且未见文献报道。
因此，本发明研究发现了阿库氯铵能够有效的作为IK1特异性激动剂，其具有和zacopride相类似的效果。因而能够有望开发一种新的药物。
故本发明提供阿库氯铵在制备治疗心律失常药物中的应用。
其中，所述的药物为胶囊、微囊、脂质体、颗粒体、注射液、片剂，或口服液。
优选地，其阿库氯铵使用剂量为0.06--6mg/kg。
进一步的，将阿库氯铵与钠通道阻滞药、β受体阻断药、钾通道阻滞药、钙通道阻滞药联合使用。
本发明首次发现阿库氯铵能够有效的作为IK1特异性激动剂，其具有和zacopride相类似的效果，可以作为制备抗心律失常作用的药物，因而提供了一条有效、安全治疗的新途径。
附图说明
图1 参与形成心肌动作电位（AP）的离子通道及相应时相。
图2 阿库氯铵可增大静息电位，缩短动作电位时程。
图3 阿库氯铵（Alcuronium chloride）上调大鼠左心室肌细胞IK1蛋白表达(*P<0.05)。
具体实施方式
下面结合具体实施方式进一步阐述本发明。
实验方法：检测阿库氯铵对成年大鼠心肌细胞对左心室肌细胞静息电位和动作电位影响
（1）实验方法：膜片钳全细胞记录，电压钳模式记录膜电流，电流钳模式记录膜电位。
（2）观测指标：药物作用前后大鼠心室肌静息电位（RMP）、动作电位幅度（APA）和时程（APD50，APD90） 的变化。
实施例一、肌松剂阿库氯铵（Alcuronium chloride）对左心室肌细胞静息电位和动作电位影响。
由于IK1是决定静息电位（RMP）水平和动作电位（AP）3期终末复极的主要离子流，我们首先观察肌松剂阿库氯铵对左心室肌细胞静息电位和动作电位影响。
（1）采用胶原酶法急性分离大鼠左室心肌细胞
选用健康成年雄性SD大鼠（体重220~250 g），腹腔注射戊巴比妥钠（40 mg/kg）麻醉，颈动脉放血后开胸迅速取出心脏，将其置于无钙台氏液（4ºC预冷，100%氧气饱和）中，快速修剪后将心脏悬挂在Langendorff灌流装置灌流（灌流液全程充以100%氧气，逆行经主动脉灌至冠状动脉））。先灌流8~10 min（无钙台氏液），后换液（胶原酶液）循环灌流15~20 min。灌流条件：室温和灌流液始终保持37ºC恒温，灌流压80 cmH2O。将配好的KB液分为A、B两部分，观测心脏肌组织变大、变软，冠脉血管边缘不清时迅速剪下左心室，用A液快速冲洗，后将其置于A液中，眼科剪剪至2-3mm3小块，用玻璃吸管（尖端圆润，以免损伤肌细胞）轻轻吹打3~5min。将A液过滤（150 μm孔径的滤网），滤液置于B液中，静置2~3小时（室温）后进行实验。
（2）全细胞膜片钳记录
将静置于高钾KB液中的细胞吹散，梯度复钙（终浓度1.8mmol/L），根据细胞密度吸取2~3滴细胞悬液滴入含台式液约1 ml的细胞池，静置10 min，待细胞充分贴壁后，用流速2 ml/min的台氏液灌流。相应电极内液充灌于玻璃电极，入液后电阻约2~5 MΩ。选取表面光滑、横纹清晰、无自主收缩且与周围细胞无重叠的杆状心肌细胞作为实验细胞。负压抽吸形成高阻（>1 GΩ）封接，进行电极电容补偿，待其稳定2~3 min后给予负压破膜，电流钳模式下，分别观测不同浓度药物对大鼠心室肌细胞RMP和AP的影响。
（3）如图2所示，阿库氯铵可剂量依赖性增大静息电位，并缩短动作电位终末复极时间（APD90）。
实施例二、阿库氯铵（Alcuronium chloride）可上调大鼠左心室肌细胞IK1蛋白表达
在大鼠心室肌细胞，Kir2.1是构成IK1最主要的通道蛋白亚型。将胶原酶法分离的大鼠左心室肌细胞用10 μmol/L阿库氯铵孵育24小时，检测Kir2.1蛋白表达。阿库氯铵可上调大鼠心室肌细胞IK1蛋白表达（P<0.05）（图3），表明阿库氯铵可作为IK1的激动剂。
研究结果显示阿库氯铵（Alcuronium chloride）对动作电位的作用特征符合IK1激动剂的特点，并通过免疫印迹法证实其为IK1激动剂。适度增强IK1，进而增大或恢复静息电位，对抗缺血性心律失常的机制在于：①静息电位负值增大，可反转病理因素导致的膜去极化，降低细胞的兴奋性，②增加钠通道的可利用度，提高缺血区心肌的传导速度，有利于消除折返[19]；③增大膜电导，减小膜电流变化引起的膜电位异常波动，增加膜的电稳定性；④适当缩短动作电位时程（APD），有助于防止早后除极（EAD）和由此引起的触发性心律失常。
因而应用阿库氯铵（Alcuronium chloride）可作为抗新型抗心律失常药物具有抗室性心律失常的作用。
应当理解的是，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，而所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (4)
1.阿库氯铵在制备治疗心律失常药物中的应用。
2.如权利要求1所述的应用，其特征在于：所述的药物为胶囊、微囊、脂质体、颗粒体、注射液、片剂，或口服液。
3.如权利要求1所述的应用，其特征在于：其阿库氯铵使用剂量为0.06--6mg/kg。
4.如权利要求1所述的应用，其特征在于：将阿库氯铵与钠通道阻滞药、β受体阻断药、钾通道阻滞药、钙通道阻滞药联合使用。
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