CN102379892B - 灵仙新苷的调血脂、抗动脉粥样硬化及抗心肌缺血作用 - Google Patents
灵仙新苷的调血脂、抗动脉粥样硬化及抗心肌缺血作用 Download PDFInfo
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Abstract
本发明涉及天然药物领域，具体涉及一个灵仙新苷的医药用途，即其具有调血脂、抗动脉粥样硬化及抗心肌缺血作用。药理试验证明，灵仙新苷具有治疗心血管疾病的用途，特别是治疗高血脂症、动脉粥样硬化和心肌缺血损伤的功效。
Description
技术领域
本发明涉及天然药物领域，具体涉及一个灵仙新苷的医药用途，即其具有调血脂、抗动脉粥样硬化及抗心肌缺血作用。
背景技术
动脉粥样硬化(atheromsclerosis，AS)是动脉硬化的血管病中常见的最重要的一种，其特点是动脉病变从内膜开始。一般先有脂质和复合糖类积聚、出血及血栓形成，纤维组织增生及钙质沉着，并有动脉中层的逐渐蜕变和钙化，病变常累及弹性及大、中等肌性动脉，一旦发展到足以阻塞动脉腔，则该动脉所供应的组织或器官将缺血或坏死，如心肌缺血等。由于在动脉内膜积聚的脂质外观呈黄色粥样，因此称为动脉粥样硬化。动脉粥样硬化是西方发达国家病人的主要死亡原因。随着我国人民生活水平的提高和饮食习惯改变，该病也已成为我国病人的主要死亡原因。冠心病心绞痛是因心肌缺血造成心肌耗氧量超过供氧量而引起的心肌缺血性损伤，而引起冠心病心绞痛发生的最主要病因即冠状动脉粥样硬化。所以抑制动脉粥样硬化斑块的形成，防治动脉粥样硬化是降低冠心病心绞痛疾病发病风险的重要手段。动脉粥样硬化(AS)的病因是多种发病机制共同作用的结果。在众多发病机制中，AS斑块发生机制主要为炎症与脂代谢紊乱。
高脂血症是目前公认的最重要的致AS的危险因素之一。大量实验室和临床资料提示：总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)水平增高、高密度脂蛋白(HDL)的降低与血管内皮功能紊乱相关。脂质代谢紊乱导致内皮细胞受损是AS发生的始动环节。脂质代谢紊乱促使氧自由基产生，在血管内膜下，LDL被氧化修饰为氧化低密度脂蛋白(ox-LDL)，巨噬细胞在表面受体CD36的介导下内吞氧化型低密度脂蛋白(ox-LDL)形成泡沫细胞，大量泡沫细胞的聚集形成AS的早期病理改变-脂质条纹。脂质代谢紊乱促进粘附分子表达。AS发生早期动脉内皮血管细胞粘附分子(VCAM-1)表达上调，VCAM-1介导单核细胞向内皮细胞黏附，使血中单核细胞更多地粘附于内皮表面，向内皮下游走及促进泡沫细胞形成，同时脂质又可在内皮下沉积，继而启动AS过程。所以通过降低血脂而保护动脉内皮细胞，阻断AS的发生，是抗AS的关键环节
在AS的发生发展过程中，炎症反应始终起着重要作用。Ross等首先提出了AS的“损伤反应”学说，随后，越来越多的研究也表明AS是一个血管受损后的炎性反应过 程。炎症因子作为炎症反应的产物在介导内皮细胞与单核淋巴细胞、巨噬细胞之间的黏附、以及动脉粥样硬化发生发展的各个环节都有重要作用。TNF-α是目前较为明确的参与AS形成、演变和破裂的炎性指标。TNF-α可通过介导内皮细胞损伤、平滑肌细胞增生、抑制内皮细胞合成血栓调节素(TM)，破坏凝血-抗凝血平衡、促进黏附分子、基质金属蛋白酶表达等途径促进AS发生发展，斑块破裂及血栓形成。TNF-α在扩大炎症级联中起核心作用。NOS在体内分布广泛，目前已知有3种形式，即内皮源性NOS(eNOS)，神经源性NOS(nNOS)，诱生性NOS(iNOS)。正常生理情况下，iNOS基因不表达，当细胞受到某些炎症、免疫因子如肿瘤坏死因子等刺激时，经基因转录蛋白而产生。iNOS被某些炎症介质大量后产生的大量NO加重炎症反应对机体造成进一步损害。
综上所述，抗AS的两大手段即干预脂质代谢和干预炎症反应。抑制冠脉动脉硬化斑块的形成，对急性心肌缺血也具有保护作用。
发明人在前期研究中，从我国威灵仙药材主流商品的毛茛科植物威灵仙(Clematis chinensis Osbeck)的干燥根及根茎中提取纯化一种新的单体灵仙新苷，英文名Clematichinenoside，简称AR6，结构式(I)如下：
该单体的制备方法见CN200510040825.7，前期研究表明，AR6具有治疗关节炎、抗肿瘤 等功效。
发明内容
本发明公开了AR6(I)的用于治疗心血管疾病的用途，所述心血管疾病优选高血脂症、动脉粥样硬化和心肌缺血损伤。下面是本发明有关AR6的部分药理试验及结果。
实验动物分组及给药方式：
取SD大鼠70只，随机分为空白组(Control)，高脂饲料和维生素D3组(HFD)，高脂饲料和维生素D3+LPS组(HFD+LPS)，辛伐他汀组(Sim，5mg/kg)，AR6高(H)，中(M)，低(L)剂量(32mg/kg，16mg/kg，8mg/kg)组。除空白组，所有大鼠给予高脂饲料(饲料配方：3％胆固醇，0.5％胆酸钠，10％猪油，0.2％丙基硫氧嘧啶，5％白糖，81.3％基础饲料。浙江省实验动物中心提供。)喂养，自由饮水，室温18～22℃，自然采光。在喂食开始时一次性腹腔注射维生素D360万IU/kg，空白组给予同等体积的生理盐水。饲喂开始后，除空白组及高脂饲料和维生素D3组外，其余五组大鼠每周腹腔注射一次LPS(100μg/kg)[1]。喂食四周后测定血脂浓度，第五周开始，每天灌胃给予受试药和阳性药，连续给药8周，给药容积5ml/kg。空白组、高脂饲料和维生素D3组、高脂饲料和维生素D3+LPS组分别给予等体积的蒸馏水。
血清学指标检测：
分别于造模前，造模后第4周、8周、12周眼眶取血，收集血清，按试剂盒说明书检测血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)，肿瘤坏死因子-α(TNF-α)。结果见图1～5。
第12周眼眶取血，收集血清，检测一氧化氮(NO)、诱导型一氧化氮合酶(iNOS)、氧化型低密度脂蛋白(ox-LDL)水平。结果见图6～8。
组织病理学、免疫组织化学检测：
于12周造模后取大鼠胸主动脉，4％甲醛固定。冰冻切片冷丙酮固定10分钟，自然晾干。用PBS液(0.01mol/L PH7.4)冲洗3次×2min。正常山羊血清封闭，室温孵育10分钟。倾去血清，分别滴加即用型一抗(Santa公司)，37℃孵育1小时。PBS冲洗，2分钟×3次。滴加即用型快速免疫组化MaxVisionTM二抗，37℃或室温孵育10-15分钟。PBS冲洗，2分钟×3次。滴加新鲜配制的显色剂(DAB)3-5分钟，显微镜下观察。自来水冲洗，苏木素复染细胞核，流水冲洗返蓝。梯度酒精脱水、二甲苯透明，中性树胶封片。阴性对照用PBS缓冲液替代一抗进行免疫组织化学法考察AR6对动脉粥样硬化大鼠主动脉壁的血管细胞粘附分子(VCAM-1)和CD36的表达的影响。利用康克新柏图文分析软件进行图像分析。结果见图9～ 12。
于12周造模后取大鼠胸主动脉，置于2.5％戊二醛溶液中4℃初固定24h以上，1％锇酸继续充分固定，梯度酒精逐级脱水，用环氧树脂埋制备超薄切片，在电子显微镜下进行病理学检查，考察AR6对动脉粥样硬化大鼠血管内皮细胞的保护作用。结果见图13。
于12周造模后取大鼠肝脏，经10％福尔马林固定，常规石蜡包埋、切片，切片厚约4-5μm，HE染色。在光镜下观察，考察AR6对动脉粥样硬化大鼠肝脏组织的保护作用。结果见图14。
对垂体后叶素致急性心肌缺血的保护作用：
末次给药后1h，将大鼠用3％水合氯醛腹腔注射麻醉后，仰卧位固定，分离一侧股静脉，记录一段正常II导心电图，观察R-R间期(心率)，J点及T波的高度，然后静脉推注脑垂体后叶素0.7U/kg(1ml/kg)，10秒内推完，于注射前(0s)及注射后5s、10s、30s、1min、2min、5min、10min、20min记录II导联心电图。将注射垂体后叶素后各时间点心电图各指标数值与注射前进行自身前后t检验比较，并进行给药前后差值的组间t检验比较。结果见表1～3。记录末次心电图后，颈动脉插管取血，静置待血液凝固后，3000rpm离心5～10min，得到的上清液即为血清，按试剂盒说明书要求测定血清肌酸激酶(CK)水平，结果见图15。
下面结合附图对试验结果详细分析：
1、AR6对高血脂症大鼠血清胆固醇(TC)水平的影响
见图1，与空白对照组相比，高脂组和高脂+LPS各组大鼠血清TC水平在第4周开始均极显著的升高(P＜0.01)；与高脂组比较，高脂+LPS组大鼠TC水平升高更显著(P＜0.05，P＜0.01)。造模后8周和12周，即给药后4周和8周，辛伐他丁组和AR6高剂量组的TC水平与高脂+LPS组相比显著降低(P＜0.05，P＜0.01)。图中*P＜0.05，**P＜0.01vs.空白组；▲P＜0.05，▲▲P＜0.01vs.HFD组；+P＜0.05，++P＜0.01vs.HFD+LPS组.( 
n＝10)，下同。
2、AR6对高血脂症大鼠血清甘油三酯(TG)水平的影响
见图2，与空白对照组相比，高脂组和高脂+LPS各组大鼠血清TG水平在第4周开始均极显著的升高(P＜0.01)；与高脂组比较，高脂+LPS组大鼠TG水平升高更显著(P＜0.05，P＜0.01)。造模后8周和12周，即给药后4周和8周，辛伐他丁组和AR6高剂量组的TG水平与高脂+LPS组相比显著降低(P＜0.05，P＜0.01)。
3、AR6对高血脂症大鼠高密度脂蛋白(HDL)水平的影响
见图3，造模后各时间点，高脂组和高脂+LPS各组大鼠血清HDL水平都显著的降低(P＜0.01)，高脂+LPS组大鼠HDL水平降低更显著，与高脂组比较有显著差异(P＜0.05， P＜0.01)。造模后8周，即给药后4周，辛伐他丁组和AR6高、中剂量组的HDL水平与高脂+LPS组相比极显著升高(P＜0.01)。造模后12周，即给药后8周，辛伐他丁组和AR6高、中剂量组的HDL水平比高脂+LPS组有较大升高，但没有显著性差异。
4、AR6对高血脂症大鼠血清低密度脂蛋白(LDL)的影响
见图4，造模后各时间点，高脂组和高脂+LPS各组大鼠血清LDL水平都显著的升高(P＜0.01)，高脂+LPS组大鼠LDL水平升高更显著，与高脂组比较有显著差异(P＜0.05，P＜0.01)。造模后8周和12周，即给药后4周和8周，辛伐他丁组和AR6高、中剂量组的LDL水平与高脂+LPS组相比显著降低(P＜0.05，P＜0.01)。
5、AR6对高血脂症大鼠血清TNF-α的影响
见图5，造模后各时间点，高脂组和高脂+LPS各组大鼠血清TNF-α水平都显著的升高(P＜0.01)，高脂+LPS组大鼠TNF-α水平升高更显著，与高脂组比较有显著差异(P＜0.05)。造模后8周和12周，即给药后4周和8周，辛伐他丁组和AR6高、中剂量组的TNF-α水平与高脂+LPS组相比显著降低(P＜0.05，P＜0.01)。
6、AR6对高血脂症大鼠血清NO的影响
见图6，造模后12周，高脂组和高脂+LPS组大鼠血清NO水平都极显著的升高(P＜0.01)，高脂+LPS组大鼠NO水平升高更显著，与高脂组比较有显著差异(P＜0.05)，辛伐他丁组和AR6高、中剂量组的NO水平与高脂+LPS组相比极显著降低(P＜0.01)。
7、AR6对高血脂症大鼠血清iNOS水平的影响
见图7，造模后12周，高脂组和高脂+LPS组大鼠血清诱导型一氧化氮合酶(iNOS)水平都极显著的升高(P＜0.01)，高脂+LPS组大鼠iNOS水平升高更显著，但未呈现显著性差异。辛伐他丁组和AR6高、中剂量组的iNOS水平与高脂+LPS组相比极显著降低(P＜0.05，P＜0.01)。
8、AR6对高血脂症大鼠血清ox-LDL水平的影响
见图8，造模后12周，高脂组和高脂+LPS组大鼠血清ox-LDL水平都显著的升高(P＜0.05，P＜0.01)，高脂+LPS组大鼠ox-LDL水平升高更显著，与高脂组比较有极显著差异(P＜0.01)。辛伐他丁组和AR6高、中剂量组的ox-LDL水平与高脂+LPS组相比极显著降低(P＜0.01)。
9、AR6对高血脂症大鼠主动脉壁VCAM-1的表达的影响
VCAM-1阳性免疫反应产物呈棕黄色，主要分布在主动脉内膜的内皮、内皮下斑块以及外膜微血管内皮处。免疫组织化学染色分析见图9。
利用康克新柏图文分析软件进行图像分析，对平均光密度值进行统计，结果显示，造模后12周，高脂组和高脂+LPS组大鼠主动脉壁VCAM-1表达与空白对照组相比显著增加(P＜0.01)，且高脂+LPS组大鼠更为显著，与高脂组比较有极显著差异(P＜0.01)。辛伐他丁 组和AR6高、中剂量组的VCAM-1表达水平与高脂+LPS组相比极显著降低(P＜0.01)。见图10。10、AR6对高血脂症大鼠主动脉壁CD36的表达的影响
CD36阳性免疫反应产物呈棕黄色，主要分布在主动脉内膜的内皮内皮下斑块处。免疫组织化学染色分析见图11。
利用康克新柏图文分析软件进行图像分析，对平均光密度值进行统计，结果显示，造模后12周，高脂组和高脂+LPS组大鼠主动脉壁CD36表达与空白对照组相比显著增加(P＜0.01)，且高脂+LPS组大鼠更为显著，与高脂组比较有极显著差异(P＜0.01)。辛伐他丁组和AR6高、中剂量组的CD36表达水平与高脂+LPS组相比极显著降低(P＜0.01)。见图12。
11、AR6对高血脂症大鼠胸主动脉血管内皮的保护作用
见图13，空白对照组内皮细胞界限清楚，排列规整，连接紧密，膜表面结构清晰，无细胞肿胀、脱落等，无脂质空泡。高脂组组大鼠血管内皮细胞肿胀，体积增大，细胞器损伤，细胞连接明显扩大，内见多个空泡。高脂+LPS组与高脂组相似，细胞器损伤严重，且现大量脂质空泡。辛伐他丁组与AR6高、中剂量组，内皮细胞形态基本正常，排列稍紊乱，较模型组有显著改善。AR6中、低剂量组血管内皮细胞形态与高脂血症大鼠相似，稍见改善。
12、AR6对高血脂症大鼠肝脏的保护作用
见图14，肉眼观察，正常组大鼠肝脏颜色均匀呈暗红色，质感光滑。高脂组和高脂+LPS组肝脏呈黄褐色，质感油腻。各给药组肝脏形态改变程度较轻。光镜下观察HE染色肝组织切片，正常组肝小叶结构正常，肝索排列整齐呈放射状，胞核结构清晰，无肝细胞脂肪变性和炎症细胞浸润。高脂组和高脂+LPS组大鼠肝脏出现脂肪变性，肝小叶结构破坏，肝索排列紊乱，出现以大泡性脂肪变性为主的混合性脂肪变性，肝细胞明显肿胀，细胞中有大量脂肪积累，核被挤于细胞边缘。辛伐他汀组和AR6给药组肝细胞脂肪变明显减轻，偶见脂滴、空泡样变。
13、AR6对高血脂症大鼠急性心肌缺血后血清CK水平的影响
见图15，垂体后叶素致高脂血症大鼠急性心肌缺血后，高脂组和高脂+LPS各组大鼠血清CK水平与空白对照组相比都极显著的升高(P＜0.01)，高脂+LPS组大鼠CK水平升高更显著，与高脂组比较有极显著差异(P＜0.01)。辛伐他丁组和AR6各剂量组的血清CK水平与高脂+LPS组相比极显著降低(P＜0.01)。
14、AR6对垂体后叶素致高血脂症大鼠心肌缺血的心电图的影响
表1AR6对高血脂症大鼠垂体后叶素所致心肌缺血大鼠J点(mv)的影响
由表1可见，空白对照组大鼠静脉注射垂体后叶素后5秒至20分钟J点显著抬高(P＜0.01)，表明造模成功。注射垂体后叶素后各时间点心电图J点高度减去注射前(0)J点高度的差值与模型对照组比较：高脂+LPS组与空白对照组相比，在造模后5s、10s、10min、20min显著性促进J点抬高(P＜0.05)；与高脂+LPS组相比，辛伐他丁在造模后10s、1min、5min、10min能显著性抑制J点抬高(P＜0.05)，AR6高剂量在造模后10s、5min、10min、20min能显著性抑制J点抬高(P＜0.05，P＜0.01)。注：表中括号中数值表示各组大鼠注射垂体后叶素后各时间点心电图J点高度减去注射前(0s)J点高度的差值；#P＜0.05，##P＜0.01，造模后各时间点与造模前进行自身前后比较；*P＜0.05，**P＜0.01，与空白对照组进行组间比较；+P＜0.05，++P＜0.01，与高脂+LPS组进行组间比较，( n＝10)，下同。
表2AR6对高血脂症大鼠垂体后叶素所致心肌缺血大鼠T波(mv)的影响
由表2可见，空白对照组大鼠静脉注射垂体后叶素后5秒至20分钟T波显著抬高(P＜0.01)，表明造模成功。注射垂体后叶素后各时间点心电图T波高度减去注射前(0s)J点高度的差值与模型对照组比较：与空白对照组相比，高脂组在造模后10min显著性促进T波抬高(P＜0.05)，高脂+LPS组在造模后10s、20min显著性促进T波抬高(P＜0.05，P＜0.01)；与高脂+LPS组相比，辛伐他丁在造模后10s、1min、5min、10min、20min能显著性抑制T波抬高(P＜0.05，P＜0.01)，AR6高剂量在造模后5min、10min、20min能显著性抑制T波抬高(P＜0.05，P＜0.01)。
表3AR6对高血脂症大鼠垂体后叶素所致心肌缺血大鼠R-R间期(s)的影响
由表3可见，空白对照组大鼠静脉注射垂体后叶素后5秒至20分钟R-R间期显著延长(P＜0.05，P＜0.01)，表明造模成功。注射垂体后叶素后各时间点心电图R-R间期减去注射前R-R间期的差值与模型对照组比较：与空白对照组相比，高脂组在造模后2min、5min、10min、20min显著性促进R-R间期延长(P＜0.05，P＜0.01)，高脂+LPS组在造模后5min、10min、20min显著性促进R-R间期延长(P＜0.01)；与高脂+LPS组相比，辛伐他丁组在造模后30s、1min、5min、10min、20min能显著性抑制R-R间期延长(P＜0.05)，AR6高、中剂量在造模后30s、10min、20min能显著性抑制T波抬高(P＜0.05)。
综上所述，结构式(I)的灵仙新苷(AR6)能够有效调节高血脂症大鼠的血脂，抑制动脉粥样硬化斑块的形成，防止肝脏组织脂肪病变。同时，AR6对急性心肌缺血具有缓解保护作用。
附图说明
图1是AR6对高血脂症大鼠血清总胆固醇(TC)水平的影响
图2是AR6对高血脂症大鼠血清甘油三酯(TG)水平的影响
图3是AR6对高血脂症大鼠血清高密度脂蛋白(HDL)水平的影响
图4是AR6对高血脂症大鼠血清低密度脂蛋白(LDL)的影响
图5是AR6对高血脂症大鼠血清TNF-α的影响
图6是AR6对高血脂症大鼠血清NO的影响
图7是AR6对高血脂症大鼠血清iNOS水平的影响
图8是AR6对高血脂症大鼠血清ox-LDL水平的影响
图9是免疫组织化学法测定AR6对高血脂症大鼠主动脉壁VCAM-1表达的影响
图10是定量分析AR6对高血脂症大鼠主动脉壁VCAM-1的表达的影响
图11是免疫组织化学法测定AR6对高血脂症大鼠主动脉壁CD36表达的影响
图12是定量分析AR6对高血脂症大鼠主动脉壁CD36的表达的影响
图13是透射电子显微镜观察血管内皮结构
图14是HE染色后光学显微镜观察肝脏组织结构(×200)
图15是AR6对高血脂症大鼠血清CK水平的影响。
Claims (1)
1.结构式(I)的皂苷用于制备治疗心肌缺血损伤的药物的用途：
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| 灵仙新苷镇痛抗炎作用的实验研究;吕雪等;《中国新药杂》;20091231;第18卷(第16期);1535-1539 * |
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