CN101420968B - 血管扩张药 - Google Patents
血管扩张药 Download PDFInfo
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- CN101420968B CN101420968B CN2007800131650A CN200780013165A CN101420968B CN 101420968 B CN101420968 B CN 101420968B CN 2007800131650 A CN2007800131650 A CN 2007800131650A CN 200780013165 A CN200780013165 A CN 200780013165A CN 101420968 B CN101420968 B CN 101420968B
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- vasodilator
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Abstract
本发明提供具有血管内皮依赖性的血管扩张作用的血管扩张药、动脉硬化预防剂和可以日常连续食用、且安全性优异的、具有血管内皮依赖性的血管扩张作用的功能性食品。本发明的血管扩张药和功能性食品的特征在于：包含Val Pro Pro和Ile Pro Pro中的至少一种三肽、或者含有Val Pro Pro和/或Ile Pro Pro的蛋白质分解物作为有效成分。
Description
技术领域
本发明涉及显示血管内皮依赖性的血管扩张作用的血管扩张药和显示上述作用的功能性食品。
背景技术
作为动脉硬化性疾病的最终阶段的心肌梗死或脑梗塞等缺血性疾病与癌症并列显示出占有了日本人疾病死因的最大比例。作为动脉硬化的危险因子可以列举高血脂、高血压、糖尿病、吸烟、肥胖症、高尿酸血症、衰老、应激等，上述危险因子相互关联引起血管病变。因此，尽管单个危险因子的程度是轻度，但由于它们的重叠使危险度相加性、协同性增加，也会提高缺血性疾病的危险率。
另一方面，认为仅降低上述一种危险因子的作用，不能达到预防动脉硬化的发病。例如，非专利文献1和2中记载：血液中胆固醇浓度与动脉硬化的发病并不相关，非专利文献3中记载：即使抑制高血压状态，也未见动脉硬化程度的改变，而且，非专利文献4中记载：即使给予以依那普利为有效成分的血管紧张素转换酶抑制剂，也未见动脉硬化抑制作用。此外，作为以上的结果，根据非专利文献5，在梗塞性的缺血性疾病例如急性心力衰竭发作时，为了谋求血流动力学的稳定化，有必要使用硝普盐、硝酸甘油等血管扩张药或利尿剂、强心药等药剂。
因此，例如，虽然专利文献1和2中记载了三肽Val Pro Pro和Ile Pro Pro具有显示降血压作用的血管紧张素I转换酶的抑制活性、且具有抗应激作用，但这不表明该三肽具有抗动脉硬化作用，且不表明其具有血管扩张作用。
然而，动脉硬化是动脉壁增厚失去弹性的病状，近年来，作为这种症状的因素之一，可以列举血管内皮的损伤或功能低下。
因此，可以期待依赖于血管内皮的血管扩张药具有抑制动脉硬化的作用。
专利文献1：日本特开平6-197786号公报
专利文献2：日本特开平11-100328号公报
非专利文献1：食の科学257(1999)20～25页
非专利文献2：Atherosclerosis151(2000)501～508页
非专利文献3：Circulation104(2001)2391～2394页
非专利文献4：International Journal of Cardiology81(2001)107～115页
非专利文献5：别册·医学のあゆみ循環器疾患，state of arts ver.2(2001)332～334页
发明内容
发明所要解决的课题
本发明的课题在于提供具有血管内皮依赖性的血管扩张作用的血管扩张药。
本发明的另一课题在于提供可以日常连续食用、且安全性优异的、具有血管内皮依赖性的血管扩张作用的功能性食品。
解决课题的手段
根据本发明，提供包含Val Pro Pro和Ile Pro Pro中的至少一种肽作为有效成分的血管扩张药。
根据本发明，还提供包含含有Val Pro Pro和/或Ile Pro Pro的蛋白质分解物作为有效成分的血管扩张药。
根据本发明，进一步提供包含Val Pro Pro和Ile Pro Pro中的至少一种肽作为有效成分的具有血管扩张作用的功能性食品。
并且，根据本发明，提供包含含有Val Pro Pro和/或Ile Pro Pro的蛋白质分解物作为有效成分的具有血管扩张作用的功能性食品。
根据本发明，还提供Val Pro Pro和Ile Pro Pro中的至少一种肽或者含有Val Pro Pro和/或Ile Pro Pro的蛋白质分解物在制备血管扩张药或具有血管扩张作用的功能性食品中的应用。
根据本发明，进一步提供对动物给予有效量的Val Pro Pro和IlePro Pro中的至少一种肽或者含有Val Pro Pro和/或Ile Pro Pro的蛋白质分解物的血管扩张方法。
发明效果
由于本发明的血管扩张药和功能性食品中包含来源于动物乳酪蛋白等的Val Pro Pro和/或Ile Pro Pro，还含有其中至少一种的蛋白质分解物作为有效成分，因而安全性优异，显示血管内皮依赖性的血管扩张作用，特别是作为功能性食品时，可以经常摄取。
因此，本发明的血管扩张药对于确保心肌梗死、脑梗塞等缺血性疾病中的血液循环是有用的，而且，不仅如此，还能舒缓由于衰老、生活方式病等而易于收缩的血管，还可以期待预防动脉硬化、或者预防与血流功能障碍相关的肩膀酸痛、寒体、血栓形成等。而且，本发明的功能性食品作为健康食品或特定保健用食品是有用的，所述健康食品或特定保健用食品标示有用于血管扩张，还标示有用于与血流功能障碍等相关的肩膀酸痛、寒体、血栓形成等各种症状或疾病的效能。
附图简述
[图1]表示实施例1及比较例1中进行的血管扩张试验的结果的图。
[图2]表示实施例1中进行的血管扩张反应的内皮依赖性确认试验的结果的图。
实施发明的最佳方式
以下，更详细地说明本发明。
本发明的血管扩张药及功能性食品包含Val Pro Pro和/或Ile ProPro(以下将这些三肽分别略写为VPP、IPP)、或者含有其中至少一种的蛋白质分解物作为有效成分。
上述三肽可以是加成了药理学上可以接受的盐类的物质，所述盐类例如有盐酸盐、钠盐、磷酸盐等无机盐以及枸橼酸盐、马来酸盐、富马酸盐、酒石酸盐、乳酸盐等有机盐。
作为上述三肽的制备方法，例如，除了可以列举通过利用微生物的发酵，来分解纯化含有VPP和/或IPP的氨基酸序列的肽或蛋白质的方法、酶水解的方法，也可以通过合成法得到。具体可以参考上述的专利文献1和2。因此，作为用于本发明中的有效成分，可以使用利用微生物发酵含有VPP和/或IPP的氨基酸序列的肽或蛋白质而得到的含有VPP和IPP的至少一种肽的发酵产物或其纯化物，或者利用酶分解含有VPP和/或IPP的氨基酸序列的肽或蛋白质而得到的含有VPP和IPP的至少一种肽的水解产物或其纯化物等。
本发明的血管扩张药的有效给予量可通过单次给予获得其作用，在人的情况下，以三肽的量计，通常每天10μg～10g，特别优选每天1mg～1g左右。
可以根据疾病的症状等调整血管扩张药的给予。对于急性症状，单次及持续的非口服给予是适当的。而对于慢性症状及预防性的使用，优选30天以上的常用的口服摄取。
本发明的血管扩张药的给予方法可以列举口服给予、非口服给予等。作为非口服给予可以列举对局部、经皮、静脉内、肌肉内、皮下、皮内、腹腔内、胸腔内、脊髓内等的给予，也可以对患部直接给予。
本发明的血管扩张药的形态，可以根据上述给予方法决定，可以制备成制剂的形态。例如，片剂、丸剂、硬胶囊剂、软胶囊剂、微囊剂、散剂、颗粒剂、液体制剂、混悬剂、乳剂等。
上述的制剂化，例如可以根据适当的需要使用作为药剂可接受的载体、佐剂、赋形剂、辅助赋形剂、防腐剂、稳定剂、结合剂、pH调节剂、缓冲剂、增稠剂、胶凝剂、保护剂、抗氧化剂等，以通常认可的制剂实施中所要求的单位剂量形态进行制备。
本发明的功能性食品可以作为健康食品或特定保健用食品等，所述健康食品或特定保健用食品可以标示或宣传其用于血管扩张、还用于与血液循环障碍相关的各种疾病的效能。
考虑到功能性食品有连续食用和常用的长期摄取的可能，为了得到上述效能，特别是血管扩张作用或与上述作用相关的疾病改善作用的摄取量，以上述三肽的量计，通常为每天10μg～10g，特别优选每天1mg～1g左右。而且，根据每天的摄取次数，以上述三肽的量换算，可以进一步降低功能性食品的单次摄取量。
对本发明的功能性食品的摄取期间没有特别限制，涉及慢性症状的改善或预防的使用则优选长期摄取。为了得到上述效能，常用的摄取通常为30天以上，特别优选3～12个月左右。
本发明的功能性食品可以通过将作为有效成分的上述三肽或含有该三肽的食品素材等混合到各种饮食品中的方法来制造，可以制造为各种饮食品的形态。例如，可以制造为粉片糖、酸乳酪、乳饮料、乳制品、酒类、清凉饮料水、粉状或颗粒状食品、胶囊食品(encapsulated food)、各种营养强化或保健食品等的形态。而且，可以在本发明的功能性食品中混合通常可添加到食品中的各种添加剂。
实施例
以下，通过实施例对本发明进行进一步详细地说明，但本发明并不受限于这些实施例。
合成例
通过如下所示的有机化学合成法合成IPP和VPP。通过固相法使用岛津制作所生产的肽自动合成装置(PSSM-8型)进行合成。
固相载体使用50mg为2-氯三苯甲基型的聚苯乙烯树脂、结合有氨基用芴基甲基氧基羰基(以下简称为Fmoc)保护的脯氨酸的树脂(岛津制作所公司生产，注册商标SynProPep Resin)。按照常规方法，根据上述氨基酸序列，使用以Fmoc基保护氨基的Fmoc-Ile、Fmoc-Pro和Fmoc-Val各100μmol，按照肽序列顺次反应，得到肽结合树脂。
接下来，将该肽结合树脂混悬于1ml反应液A(10％(容量)乙酸、10％(容量)三氟乙醇和80％(容量)二氯甲烷)中，在室温下反应30～60分钟，将肽从树脂上切离后，使用玻璃滤器过滤反应液A。减压除去滤液的溶剂后，直接加入1ml的反应液B(82.5％(容量)三氟乙酸、3％(容量)乙基甲基硫醚、5％(容量)纯水、5％(容量)苯甲硫醚、2.5％(容量)乙二硫醇、2％(容量)苯硫酚)，在室温下反应6小时除去侧链保护基团。向其中加入10ml无水乙醚使肽沉淀，在3000rpm下离心5分钟进行分离。将该沉淀用无水乙醚多次洗涤后，氮气吹干。将如此得到的未纯化的合成肽总量溶解于2ml的0.1N盐酸水溶液中后，通过使用C18的反相柱的HPLC，按照以下条件进行纯化。
泵：型号L6200智能泵(日立制作所)；检测仪器：使用型号L4000UV检测器(日立制作所)检测215nm的紫外部吸收；柱：μBondasphere5μC18(Nihon Waters公司生产)；洗脱液：A液为0.1％(重量)TFA水溶液，B液为含0.1％(重量)TFA的乙腈(B/A+B)×100(％)：0→40％(60分钟)；流速：1ml/分钟。取显示最大吸收的洗脱组分，通过将其冷冻干燥分别得到5.7mg和6.5mg目标合成肽IPP和VPP。使用全自动蛋白质一级结构分析装置(型号PPSQ-10，岛津制作所生产)从肽的N末端开始对纯化肽进行分析，进一步使用氨基酸分析装置(型号800系列，日本分光公司生产)进行分析，其结果确认了上述肽与所设计的相同。
实施例1
(血管扩张试验)
摘出Wistar大鼠的胸主动脉，切取2mm宽，制成主动脉环。将该环置于马格努斯装置(LABO SUPPORT公司生产，产品名为微型组织器官水浴MTB-1Z(micro tissue organ bath MTB-1Z))，加载一定的张力，使其平衡。其后，利用50mM KCl确认主动脉环的收缩反应。接下来，使用1μM去氧肾上腺素使主动脉环收缩，对稳定收缩的标本使用1μM乙酰胆碱，观察血管内皮依赖性的扩张反应，确认了其保持有内皮功能。
接下来，预先使用1μM去氧肾上腺素使主动脉环收缩后，将合成例制备的VPP和IPP从10-9M开始添加，每次增加10倍浓度，根据主动脉环的张力变化观察了扩张反应。此外，还研究了扩张反应的剂量依赖性。
其结果，VPP和IPP引起的血管扩张反应从1mM开始被观察到，在10mM确认了明确的暂时性的血管扩张反应。结果显示在图1中。
(VPP和IPP的血管扩张反应的内皮依赖性确认试验)
为了确认VPP和IPP的血管扩张性与血管内皮的相关，以通过常规方法物理性去除血管内皮的血管为比较对照，对VPP进行了与上述一样的血管扩张试验。其结果，血管扩张反应由于内皮的去除而减弱，因此得知VPP和IPP的血管扩张高度地依赖于血管内皮。结果显示在图2中。
比较例1
使用同浓度的氨基酸：缬氨酸(Val)或脯氨酸(Pro)代替三肽VPP和IPP，与实施例1一样，进行血管扩张试验。
其结果，10mM的Val和Pro均未观察到扩张反应。结果显示在图1中。
综上所述，可以得知，VPP或IPP的血管扩张作用在肽的形态下具有活性。
参考例
日本特开2004-244359号公报报道了将来源于各种乳蛋白的蛋白质水解而得到的肽作为有效成分的血管扩张性药物组合物和血管扩张性健康食品组合物。已知β-酪蛋白和K-酪蛋白中存在含有VPP和IPP的氨基酸序列，所以确认根据该公报记载的制备例得到的肽中是否含有VPP、IPP。
对制备例中作为含有β-酪蛋白和κ-酪蛋白的蛋白质原料的市售脱脂粉乳进行了试验。即，将1kg脱脂粉乳混悬于2升温水中，调整pH为7.5后，加入40g嗜热杆菌蛋白酶(thermoase)(大和化成公司生产)，在50℃下反应16小时。反应后，在100℃下加热10分钟使酶失活，制备水解肽。使用高效液相色谱-质谱联用仪(LC/MS)进行分析，结果是在其中未检测出VPP、IPP。
根据以上结果，得知日本特开2004-244359号公报中报道的血管扩张是由VPP、IPP以外的成分引起的。
Claims (2)
1.Val Pro Pro和Ile Pro Pro中的至少一种三肽在制备血管扩张药中的用途。
2.含有Val Pro Pro和/或Ile Pro Pro的蛋白质分解物在制备血管扩张药中的用途。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0162032A2 (en) * | 1984-05-04 | 1985-11-21 | Washington University | Novel atrial peptide |
| EP1226267B1 (en) * | 1999-11-01 | 2004-05-12 | Valio Ltd. | Process for producing a product containing antihypertensive tripeptides |
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| JP3805804B2 (ja) * | 1994-09-14 | 2006-08-09 | 森永乳業株式会社 | 動脈硬化防止剤 |
| JP3028411B2 (ja) | 1997-09-26 | 2000-04-04 | カルピス株式会社 | トリペプチド高生産性ラクトバチルス・ヘルベチカス乳酸菌 |
| DK1142481T4 (da) | 1999-01-11 | 2009-12-21 | Calpis Co Ltd | Fremgangsmåde til fremstilling af fermenteret mælk indeholdende et peptid, der inhiberer et angiotensinomdannende enzym og fremgangsmåde til fremstilling af mælkeserum |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0162032A2 (en) * | 1984-05-04 | 1985-11-21 | Washington University | Novel atrial peptide |
| EP1226267B1 (en) * | 1999-11-01 | 2004-05-12 | Valio Ltd. | Process for producing a product containing antihypertensive tripeptides |
Non-Patent Citations (1)
| Title |
|---|
| 陈何如、徐杰诚.膦肽类化合物对血管紧张素转化酶的体外抑制活性及构效关系.《药学学报》.1996,第31卷(第9期),671-675. * |
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| EA200870259A1 (ru) | 2009-02-27 |
| JPWO2007094340A1 (ja) | 2009-07-09 |
| EP1992353A4 (en) | 2009-12-23 |
| US20090234097A1 (en) | 2009-09-17 |
| WO2007094340A1 (ja) | 2007-08-23 |
| EP1992353A1 (en) | 2008-11-19 |
| CN101420968A (zh) | 2009-04-29 |
| TW200808338A (en) | 2008-02-16 |
| CA2642537A1 (en) | 2007-08-23 |
| EP1992353B1 (en) | 2014-05-07 |
| BRPI0707827A2 (pt) | 2011-05-10 |
| CA2642537C (en) | 2013-04-09 |
| US20110263516A1 (en) | 2011-10-27 |
| KR20080095898A (ko) | 2008-10-29 |
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