CN114099679A - 钠-葡萄糖协同转运蛋白2抑制剂的新用途 - Google Patents
钠-葡萄糖协同转运蛋白2抑制剂的新用途 Download PDFInfo
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Abstract
本发明涉及钠‑葡萄糖协同转运蛋白2抑制剂的新用途,钠‑葡萄糖协同转运蛋白2抑制剂可用于制备预防和/或治疗心律失常的药物、预防和/或治疗肺动脉高压的药物。钠‑葡萄糖协同转运蛋白2抑制剂达格列净可以通过改善模型大鼠心室心肌细胞Ca2+运作来抑制室性心律失常的发生,具有治疗心律失常和/或降低肺动脉压等新的药物用途。
Description
技术领域
本发明属于药物技术领域,涉及钠-葡萄糖协同转运蛋白2抑制剂的新用途。
背景技术
心律失常是一种常见的独立疾病或者是心血管疾病合并症,也是导致心衰患者死亡的独立危险因素。尽管近年来对心律失常的发病机制和治疗进行了多种研究,但室性心动过速(VT)或室颤(VF)等致死性心律失常的确切机制尚不清楚,抗心律失常药物治疗效果有限且具有相关副作用,心律植入装置治疗具有一定的局限性。因此,积极寻找新的技术、方法、药物是当前的临床诊疗研究重点。
达格列净,是一种新型钠-葡萄糖共转运蛋白(SGLT-2)抑制剂,可阻断近端小管对葡萄糖和钠的重吸收,导致糖尿和尿钠排泄。与安慰剂相比,达格列净可显著降低糖化血红蛋白及空腹血糖水平,并显著降低体重,还可改善血脂水平;达格列净可以有效改善2型糖尿病患者的血糖状况,其降糖机制与已有的降糖药物完全不同,且不依赖于胰岛素的分泌及作用。然而,现有技术中未见关于达格列净能治疗心律失常的报道。
发明内容
本发明发现达格列净可以通过改善模型大鼠心室心肌细胞Ca2+运作来抑制室性心律失常的发生,证明达格列净具有治疗心律失常和/或降低肺动脉压等新的药物用途。
基于以上发现,本发明提供如下技术方案:
第一方面,提供钠-葡萄糖协同转运蛋白2抑制剂在制备预防和/或治疗心律失常的药物中的应用。
进一步地,心律失常为心肌肥大引起的心律失常。
进一步地,心律失常为肺动脉高压引起的心律失常。
进一步地,预防和/或治疗心律失常的药物为抑制细胞内钙超载的药物。
第二方面,提供钠-葡萄糖协同转运蛋白2抑制剂在制备预防和/或治疗肺动脉高压的药物中的应用。
进一步地,用于预防和/或治疗肺动脉高压的药物为抑制主肺动脉增厚的药物。
进一步地,用于预防和/或治疗肺动脉高压的药物为抑制肺中肺小动脉壁增厚的药物。
进一步地,钠-葡萄糖协同转运蛋白2抑制剂为达格列净或其可药用衍生物。
进一步地,心律失常治疗药物为口服制剂或非口服制剂。
进一步地,口服制剂的剂型为散剂、颗粒剂、口服液、片剂、缓释制剂中的一种或多种。
本发明具有如下有益效果:
本发明提供了钠-葡萄糖协同转运蛋白2抑制剂在制备用于制备预防和/或治疗心律失常和/或肺动脉高压的药物中的新用途,提供了治疗和预防心律失常、降低肺动脉压的新途径。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚,本发明提供如下附图进行说明:
图1为各实验组的血流动力学数据。
图2为各实验组大鼠主肺动脉(MPA)和肺中肺小动脉(PA)的代表性组织切片染色图;其中,图2A为主肺动脉的H&E染色图,图2B为肺中肺小动脉的H&E染色图,图2C为各实验组大鼠MPA壁厚定量数据;图2D为各实验组大鼠PA壁厚定量数据。
图3为各实验组大鼠右心室(RV)的代表性组织切片不同染色图;其中,图3A为H&E染色图,图3B为麦胚凝集素(WGA)染色图,图3C为Masson's Trichrome染色图,图3D展示了图3B中各实验组的心肌细胞截面积,图3E显示图3C中各实验组心肌细胞纤维化程度比例,用胶原容积分数百分比表示(Collagenvolume fraction,CVF%)。
图4A为各实验组的代表性蛋白质印迹图像;图4B为各实验组的蛋白质印迹的定量分析。
图5显示了四组大鼠的代表性ECG(心电图)(图5A至图5D)和特征(图5E至图5M);其中,图5E为心率,图5F为P波时长,图5G为PR间期,图5H为RR间期,图5I为QRS间期,图5J为R波幅值,图5K为T波峰终间期,图5L为QT间期,图5M为QTc间期。
图6为各实验组的光学映射(图6A)及数据分析(图6B、图6C);其中,图6B为四组中BCL 80ms的传导速度(CV)的光学映射,图6C为四组的标准化CV。
图7为各实验组心肌细胞中Ca2+交替,每种条件下细胞Ca2+交替的阈值;其中,图7A显示了来自每组的[Ca2+]i荧光的代表性原始二维快照;图7B:Ca2+火花频率;图7C:Ca2+火花振幅;图7D:Ca2+火花宽度;图7E:Ca2+火花持续时间、图7F:Ca2+火花质量;图7G:Ca2+火花介导的泄漏。
图8为自发性Ca2+瞬变事件;图8A为不同实验组在4秒5Hz刺激下细胞溶质自发性钙瞬变CaT(sCaT)的代表性记录;图8B展示了不同实验组在5到10Hz之间起搏的RV肌细胞CaT记录。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
本发明涉及到钠-葡萄糖协同转运蛋白2抑制剂为达格列净,CAS号:461432-26-8,结构式如下式所示:
实施例1
通过单次腹腔注射野百合碱(MCT)60mg/kg连续5周建立大鼠模型。将60只雄性Sprague-Dawley(SD)大鼠分为4个实验组:CTL组:正常大鼠,仅灌胃赋形剂;MCT组:野百合碱诱导的模型组。MCT+LD组:野百合碱诱导+低剂量达格列净(1mg/kg)干预。MCT+HD组:野百合碱诱导+高剂量达格列净(3mg/kg)干预。
分别通过灌胃将达格列净或等剂量赋形剂喂养大鼠5周。通过超声心动图和血流动力学实验评估动物模型心功能,蛋白质印迹实验测量右心室关键离子通道蛋白,组织化学分析测量右心室纤维化标志物和肥大指数,在离体心脏灌注(Langendorff)下,通过心脏电生理学(EP)研究,光学映射分析(OMP)等评估模型动物心律失常易感性和持续时间,激光共聚焦分析心室肌细胞Ca2+火花及Ca2+交替等相关指标差异。
实验结果:
图1为各实验组的血流动力学数据,图1显示MCT组大鼠的平均PAP(肺动脉压)相对于CTL组显著升高(54mmHg vs 18mmHg,P<0.0001),表明大鼠模型建立成功,而MCT+LD组、MCT+HD组的平均PAP水平显著降低,且随着达格列净剂量的增加,PAP水平降低效果更加明显,表明达格列净具有降低肺动脉压作用。
图2为各实验组大鼠主肺动脉(MPA)和肺中肺小动脉(PA)的代表性组织切片H&E染色图,其中,图2A为主肺动脉,图2B为肺中肺小动脉,通过苏木精和伊红(H&E)检测染色显示。图2C为各实验组大鼠MPA壁厚定量数据,数据显示,与CTL组相比,MCT组大鼠MPA壁厚显著升高(127.44±11.71μm vs 80.23±2.14μm,P<0.0001),而MCT+LD组则较低,MCT+HD组降低效果更明显(118.05±3.87μm vs 93.95±2.98μm,P<0.0001)。图2D为各实验组大鼠PA壁厚定量数据,数据显示,与CTL组相比,MCT组大鼠PA壁厚显著升高(42.86±2.84μm vs27.84±2.19μm,P<0.0001),而MCT+LD组则较低,并且MCT+HD组的减少效果变得更加明显(36.48±1.19μm vs 31.72±1.61μm,P<0.05)。图2C和图2D中,*P<0.05,**P<0.01,***P<0.001,****P<0.0001。
图3为各实验组大鼠右心室(RV)的代表性组织切片不同染色图,其中,图3A通过H&E染色分析RV组织切片,与CTL组相比,MCT组心肌细胞明显肥大,MCT+LD组肥大较少,MCT+HD组与MCT+LD组类似,CTL组未观察到明显肥大。为了进一步支持这一观察,图3B为通过麦胚凝集素(WGA)免疫荧光测量了单个分离的RV肌细胞的几何形状,显示了RV的示例性切片,显示了由荧光凝集素边界划分的肌细胞边界,图3D通过心肌细胞横截面积进行量化。图3C为Masson's Trichrome染色图。图3D所示的麦胎凝集素(WGA)实验结果提示,MCT组右心室心肌细胞截面积显著大于CTL组(39.61±1.85μm2 vs 26.86±2.70μm2,p<0.001),但MCT+LD组、MCT+HD组肌细胞截面积较MCT组减小,MCT+HD组的减轻程度较MCT+LD组更显著(32.37±3.21μm2 vs 26.66±1.13μm2,p<0.01)。图3E显示,与CTL组相比,MCT组大鼠出现大量胶原沉积(6.20±1.91% vs 0.21±0.05%,p<0.001),MCT+LD组和MCT+HD组胶原沉积较MCT组显著减少,MCT+HD组明显更小(1.19±0.71% vs 2.62±1.60%,p<0.01)。图3D和图3E中,*P<0.05,**P<0.01,***P<0.001,****P<0.0001,以上结果提示,达格列净具有改善右心室重塑的作用,从改善心律失常发生机制来起到抑制心律失常发生的作用。
图4A为各实验组的代表性蛋白质印迹图像,图4B展示了蛋白质印迹的定量分析,与CTL组相比,MCT组RyR2、p-RyR2、p-PLB、CaMKⅡ、p-CaMKⅡ的表达显著增加,差异有统计学意义(P<0.05),相比MCT组,这些蛋白表达水平在MCT+HD组、MCT+LD组降低,MCT+HD组降低程度较MCT+LD组更加显著。各实验组PLB、Na-Ca交换剂的表达水平无显著差异(P>0.05)。而MCT组SERCA2A、CaV1.2的表达水平较CTL组降低(P<0.05)。图4B中,*P<0.05,**P<0.01,***P<0.001,****P<0.0001。细胞内钙超载是发生触发性心律失常的重要机制之一。心肌细胞RyR2功能异常主要表现为舒张期异常开放,从而引起钙离子泄漏、钙超载,导致心律失常、心力衰竭等的发生,因此,RyR2可以作为治疗心脏疾病的靶点。RyR2磷酸化水平上调可导致RyR2活性增强,既往大量研究显示RyR2活性持续增强可显著增加心肌细胞舒张期Ca2+泄漏,大量的舒张期Ca2+泄漏一方面导致心肌细胞内Ca2+超载,另一方面还可降低内质网钙容量从而引起收缩期Ca2+释放减。CaMKII是一种在心脏组织广泛分布的多功能蛋白激酶,其活性受细胞内钙浓度的调控,当细胞内钙超载时,CaMKII可通过自动磷酸化而激活。激活后的CaMKII可对RyR2进行磷酸化修饰,从而调节心肌细胞Ca2+运转。CaM/CaMKⅡ/RyR2信号通路通过调节心肌细胞钙离子稳态对室性心律失常的发生起着至关重要的作用。CaMKⅡ是一种丝氨酸/苏氨酸激酶,能够调节多种下游蛋白,是通路中的重要组成部分,其通常先与Ca2+/CaM在M281/282位点结合发生氧化、磷酸化,完成构象变化才能被激活。RyR2是心肌细胞肌浆网(SR)上主要的钙离子释放通道,是CaMKⅡ的下游蛋白。正常情况下,心肌兴奋收缩是由L型钙通道(LTCC)释放少量的钙离子进入细胞膜从而激活SR上的RyR2,促使肌浆网释放大量钙离子进入胞质中,与肌钙蛋白结合,使心肌发生兴奋收缩,即“钙诱导钙释放”。而CaMKⅡ激活可以调节LTCC和RyR2,保持细胞内钙维持在正常水平。VA是由于神经-体液调节失常导致的冲动形成异常。交感神经兴奋、应激和β受体激活时,去甲肾上腺素分泌增多,机体处于氧化应激状态,血液中儿茶酚胺水平升高,氧自由基增多,CaMKⅡ大量激活,促进RyR2磷酸化,从而触发大量Ca2+从肌浆网中释放,增加舒张期钙渗漏,同时CaMKⅡ的过表达还能增加心肌细胞膜LTCC的开放,促进Ca2+内流,从而提高胞质内钙离子浓度,降低钙瞬变幅度,诱发延迟后除极(DAD)和早期后除极(EAD),触发激动室性快速性心律失常。亦有研究证明,CaMKⅡ抑制剂能够明显降低钙火花频率和自发性钙波的发生。
图5显示了四组大鼠的代表性ECG(心电图)(图5A至图5D)和特征(图5E至图5M)。与CTL组比较,MCT组心率较低(图5E),RR间期较长(图5H),R波幅值较短(图5J),T波峰终间期较长(图5K),QT间期较长(图5L),QTc间期较长(图5M)(P<0.05),P波时长(图5F)、PR间期(图5G)、QRS间期有显著性差异(图5I)(P>0.05)。此外,MCT+LD组、MCT+HD组R波幅值、T波峰终间期、QT间期、QTc均有所改善。与MCT组(P<0.05)相比,MCT+HD组更接近CTL组,但与MCT+LD组比较无统计学差异(P>0.05)。*P<0.05,**P<0.01,***P<0.001,****P<0.0001。
图6为各实验组的光学映射及数据分析,其中,图6A为四组分别在BCL80ms处的右心室(RV)光学映射,箭头表示传导方向;右条:代表RV表面的颜色编码激活时间。图6B:四组中BCL 80ms的传导速度(CV)的光学映射,图中显示,CTL组:82.2cm/s,MCT组:41.5cm/s;MCT+LD组:53.2cm/s,MCT+HD组:61.1cm/s,提示达格列净改善大鼠后右心室传导速递,具有抑制心律失常的作用。图6C:四组的标准化CV,分别80-200ms标准化后的传导速度与达格列净干预剂量成正相关关系。*P<0.05,**P<0.01,***P<0.001,****P<0.0001。平均右心室光学标测传导速度在正常组是82.2cm/s,MCT治疗的大鼠中减慢41.5cm/s,经过达格列净干预后,传导速度改善低剂量:53.2cm/s,高剂量61.1cm/s。传导速度减慢,心律异质性增加,有利于触发、折返等心律失常的发生。
图7显示四组大鼠心脏的RV心肌细胞(RVCM)中的自发Ca2+火花(SCaS)特性。图7A显示了来自每组的[Ca2+]i荧光的代表性原始二维快照。与CTL组RVCM相比,MCT组RVCM的Ca2+火花频率、Ca2+火花宽度、Ca2+火花持续时间、Ca2+火花质量、Ca2+火花介导的泄漏显著增加(P<0.05),而MCT+LD组RVCMs较低,并且MCT+HD组RVCMs的降低效果更加明显(P<0.05)。然而,MCT组RVCMs Ca2+火花幅度显著降低(P<0.05),MCT+HD组Ca2+火花幅度比MCT+LD组RVCMs明显改善(P<0.05)。
图8:自发性Ca2+瞬变事件。显示了4秒5Hz刺激下细胞溶质自发性钙瞬变CaT(sCaT)的代表性记录,然后在每组中进行20秒的记录。与CTL组RVCMs相比,MCT组RVCMs细胞刺激停止后sCaT增多,但MCT+LD组sCaT减少,MCT+HD组sCaT更显著(均P<0.0001)。为了研究DAPA是否改善了CaT交替,在5到10Hz之间起搏的RV肌细胞中记录了CaT。与CON组RVCM中稳定的CaT相比,MCT组RVCM中的CaT幅度在较高的起搏频率下急剧下降。MCT+LD组或MCT+HD组RVCMs的CaT在7Hz时显著大于MCT组RVCMs。
钙火花(calcium spark)是指心肌细胞肌浆网上钙释放通道(RyR)自发开放或由单个L型钙通道开放触发引起的局部钙释放事件,是兴奋一收缩耦联的基本单位,也是心肌兴奋一收缩耦联局部控制的理论基础。在静态的心肌细胞上,自发性钙火花的发生频率较低,并呈随机发放。所以钙火花是钙波的基本事件,钙波与电激发的钙瞬变具有相似的时间过程,它们是钙火花在时间和空间上的集合。一个钙瞬变约有几千至一万个钙火花组成。心肌细胞去极化使Ca2+从细胞膜L-型钙通道(LCC)进入后,启动“钙触发钙释放”(Ca2+-in-duced Ca”release,CICR)机制诱发钙火花,这是心肌细胞产生钙火花的主要方式。研究表明,单个LCC开放可引发产生单个钙火花,其峰值为每秒106个。钙火花产生的另一个机制是“超载引发的钙释放”(overload—inducedCa”release,SOICR,肌浆网腔内Ca2+达到一定阈值时,可从内部触发或激活RyR,该机制可能与钙超载情况下自发性钙火花相关。钙火花是肌浆网上一个或几个成簇状分布的ADA所产生的局部钙释放。在静态的心肌细胞上,自发性钙火花的发生频率较低,并呈随机发放。所以钙火花是钙波的基本事件,钙波与电激发的钙瞬变具有相似的时间过程,它们是钙火花在时间和空间上的集合。一个钙瞬变约有几千至一万个钙火花组成。
钙瞬变信号与心律失常病理情况下,心脏舒张期肌浆网释放Ca2+增多,不但使肌浆网中Ca2+减少,还使心律失常的发生率增加。兴奋一收缩耦联及上述舒张期Ca2+经同一通道(RyRs)由肌浆网进入胞浆,但两者效应不同,前者是正常的生理效应,后者却发生心律失常。致心律失常性舒张期RyRs钙释放需肌浆网中Ca2+达一定阈值,适当降低RyRs的开放概率可能会抑制舒张期RyRs钙释放、而不影响收缩期钙瞬变,从而减少心律失常发生。大量研究显示心肌细胞Ca2+稳态异常不仅可引起自发性Ca2+活动,还与心肌细胞CaT交替的发生有关。自发性Ca2+活动是心肌细胞触发活动发生的重要机制,而CaT交替又与折返相关复极电交替的产生有关,两者共同作用最终可增加恶性室性心律失常的易感性。本实验证明了达格列净通过干预修复肺动脉高压相关大鼠右心室Ca2+运作能力,降低的室性心律失常易感性。
本发明通过以上实验证明达格列净可以明显改善大鼠心室结构重构和电重构,肺动脉压随着达格列净剂量的增加降低效果更加明显,肺动脉主干和肺小动脉的壁厚也随药物剂量增加而减少。通过H&E染色分析右心室组织切片,与CTL组相比,MCT组心肌细胞明显肥大,达格列净低剂量组肥大较少,MCT+LD组与CTL组差别不大。
综上所述,本发明通过细胞实验证实:通过激光共聚焦分析心室肌细胞Ca2+火花及Ca2+交替等相关指标差异发现达格列净通过改善模型大鼠心室心肌细胞Ca2+处理来抑制室性心律失常的发生,证明达格列净具有治疗心律失常和/或降低肺动脉压等新的药物用途。通过麦胎凝集素(WGA)免疫荧光测量了单个分离的右心室肌细胞的几何形状,通过心肌细胞横截面积进行量化,MCT组右心室心肌细胞截面积显著大于CTL组(39.61±1.85μm2 vs26.86±2.70μm2,p<0.001),但达格列净治疗组肌细胞截面积较MCT组减小,MCT+HD组的减轻程度较低剂量达格列净干预组更显著(32.37±3.21μm2 vs 26.66±1.13μm2,p<0.01);在马森三色染色中,与CTL组相比,MCT组大鼠发现大量胶原沉积(6.20±1.91% vs 0.21±0.05%,p<0.001),MCT+LD组和MCT+HD组显著胶原沉积较MCT组少,MCT+HD组更明显更小(1.19±0.71% vs 2.62±1.60%,p<0.01)。大鼠离体心脏电生理光学标测图实验(OpticalMapping)结果提示,起搏频率为5Hz时,与CTL组大鼠相比,MCT组大鼠右心室传达时间(CV,Conducting Velocity)减慢(41.5cm/s vs 82.2cm/s,P<0.0001),经达格列净治疗后,CV得到改善,且MCT+HD组较MCT+LD组改善明显(61.1cm/s vs 53.2cm/s,P<0.01)。此外,标准化CV的斜率在四组之间有显著差异。另外,在MCT组大鼠中观察到阻塞线周围的折返和折返转子形成,表明室性心律失常启动与右心室部分传到阻滞后形成相关折返的有关。证明达格列净抑制了大鼠心脏中的心室有效不应期交替和R波电交替(一种恶性心律失常发生的预测指标)。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (10)
1.钠-葡萄糖协同转运蛋白2抑制剂在制备预防和/或治疗心律失常的药物中的应用。
2.根据权利要求1所述的应用,其特征在于:所述心律失常为心肌肥大引起的心律失常。
3.根据权利要求1所述的应用,其特征在于:所述心律失常为肺动脉高压引起的心律失常。
4.根据权利要求1所述的应用,其特征在于:所述预防和/或治疗心律失常的药物为抑制细胞内钙超载的药物。
5.钠-葡萄糖协同转运蛋白2抑制剂在制备预防和/或治疗肺动脉高压的药物中的应用。
6.根据权利要求5所述的应用,其特征在于:所述用于预防和/或治疗肺动脉高压的药物为抑制主肺动脉增厚的药物。
7.根据权利要求5所述的应用,其特征在于:所述用于预防和/或治疗肺动脉高压的药物为抑制肺中肺小动脉壁增厚的药物。
8.根据权利要求1或5所述的应用,其特征在于:所述钠-葡萄糖协同转运蛋白2抑制剂为达格列净或其可药用衍生物。
9.根据权利要求1或5所述的应用,其特征在于:所述心律失常治疗药物为口服制剂或非口服制剂。
10.根据权利要求9所述的应用,其特征在于:所述口服制剂的剂型为散剂、颗粒剂、口服液、片剂、缓释制剂中的一种或多种。
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