摘要
背景现代医学研究表明：高血压是一种慢性低级别炎症性疾病，炎症因素在原发性高血压的发生、发展以及转归中扮演着极其重要的角色。p38丝裂原活化蛋白激酶（p38mitogen-activated protein kinase, p38MAPK）存在于多种生物的细胞内，是介导炎症反应重要的信号转导通路，参与心肌及血管平滑肌细胞的增殖、细胞外基质的合成与降解、内皮细胞损伤及心肌肥厚等多种生理病理过程，其活化或抑制对心肌肥厚、血管重构的发展或逆转起着重要作用。肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system, RAAS)既是循环分泌系统，又是局部分泌系统，是血压最重要的调节机制之一，其主要效应由血管紧张素Ⅱ(angiotensin-Ⅱ, AngⅡ)及其特异性1型受体（angiotensin type1receptor，ATlR）介导，当信号分子AngⅡ激活其受体ATlR后可上调p38MAPK表达，从而促进炎症反应的发生、发展，加重高血压的病理进程及靶器官的损害。p38MAPK下游的分子包括多种蛋白激酶、磷脂酶及转录因子，通过磷酸化这些分子使它们活化，继而激活作用于下游的核转录因子-κB（nuclear transcription factor-κB，NF-κB）等，调节相关基因转录。NF-κB是调节黏附因子如血管细胞粘附分子-1（vascular cell adhesion molecule1，VCAM-1）、细胞间粘附因子（intercellular adhesion molecule-1，ICAM-1），化学介质单核细胞趋化蛋白-1（monocyte chemoattractant protein-1，MCP-1），炎症因子如白细胞介素-1（interleukin-1，IL-1）、白细胞介素-6（interleukin-6，IL-6）、肿瘤坏死因子-α（tumor necrosis factor-а，TNF-α）等表达的转录因子，与炎症反应的发生、AngⅡ依赖性内皮损伤、细胞增殖及血管平滑肌细胞的转移有重要的关系。
中医学理论认为：原发性高血压的发生与气血失和、痰湿内蕴、阴阳失调、络脉损伤等病机有关。在慢性低度炎症过程中，损伤的内皮细胞可释放大量活性物质，如炎症因子IL-1、IL-6、C反应蛋白（C-reactive protein，CRP）、ICAM-1、TNF-α、交感神经儿茶酚胺（catecholamine，CA）类递质、缩血管因子AngⅡ、内皮素-1（endothelin-1，ET-1）、血栓素A2（thromboxaneA2，TXA2），扩充血容量物质醛固酮（Aldosterone，ALD），转化生长因子-β1（transforming growth factor-β1，TGF-β1）、血管内皮生长因子（vascular endothelial growth factor，VEGF）等，这与中医所述病理性津液滞留所致“痰”的理论一致。而慢性炎症过程中血小板黏附、聚集及血栓的产生、纤维斑块及结缔组织的形成、单核细胞转变为泡沫细胞在内皮下的沉积、血液粘稠度增高等现象，又符合中医“瘀”的具体表现。“痰”与“瘀”常共同致病，“毒”损心络，加重高血压靶器官心脏的损伤。因此“祛痰化瘀通心络”的中医理论是治疗高血压的新途径。
无患子皂苷(sapindus saponin，Sap)是从无患子科植物无患子树的种子无患子假种皮中提取的有效部位，《本草拾遗》、《本草纲目》记载：性味、苦平，具有清热、祛痰、消积、杀虫之功效，可用于治疗喉痹、肿痛、咳喘、白带、疮癣、肿毒等症。现代医学研究表明，无患子皂苷具有抗菌、消炎、镇痛多种等药理学活性，本课题组前期研究表明无患子皂苷可降低肾性高血压模型大鼠的血压，改善其左心室做功，对脑缺血再灌注损伤模型大鼠炎症反应也有一定的抑制作用。基于以上发现，我们提出“无患子皂苷‘祛痰化瘀通心络’中医理论的细胞分子机制是对AngⅡ上调p38MAPK信号通路所介导的炎症反应起到调控作用”的假说。
目的通过研究无患子皂苷对自发性高血压大鼠（spontaneously hypertensive rats，SHR）的降压效果以及对靶器官的保护作用，观察其药效学的量-效关系及时-效关系；通过观察无患子皂苷对AngⅡ/p38MAPK通路诱导的血管内皮、心肌炎症反应以及对内皮损伤、心肌肥厚的影响，探讨“祛痰化瘀通心络”中医降压理论的细胞分子机制，为传统的中医理论寻找生物学基础。
方法
1.无患子皂苷的药效学研究
取A批SHR40只，随机均分为5组，即SHR模型组、卡托普利（captopril, Cap，27mg· kg-1）组、Sap27mg· kg-1、54mg· kg-1、108mg· kg-1剂量组，另取8只健康WKY大鼠作为正常对照组,按剂量连续给药8周，检测指标如下：①对SHR一般状态的影响；②单次给药对血压值的影响；③连续给药对血压值的影响；③对左心室重量指数（left ventricular weight index，LVMI）的影响；④HE及Masson染色观察对心、脑、肾、主动脉血管的组织形态学的影响。
2.无患子皂苷降压机制研究
A批大鼠内皮功能检查：①对胸主动脉血管对于不同血管收缩剂AngⅡ(10-9mol· L~(-1)～10-5mol· L~(-1))、苯肾上腺素（phenylephrine，PE）(10-8mol· L~(-1)～10-4mol· L~(-1))、KCl(20mmol· L~(-1)～120mmol· L~(-1))收缩反应性的影响；②对乙酰胆碱（acetylcholinechloride，Ach）(10-10mol· L~(-1)～10-5mol· L~(-1))血管内皮依赖性及硝普钠（sodiumnitroprusside dihydrate，SNP）(10-8mol· L~(-1)～10-3mol· L~(-1))非内皮依赖性血管舒张反应的影响；③Elisa法检测对血管活性物质一氧化氮（nitric oxide，NO）、6-酮-前列腺素1α（6-keto–prostacyclin1α，6-KPG1а）、ET-1、TXB2血清含量的影响。
另取B批SHR32只，舍去Sap54mg· kg-1剂量组，其余分组及给药同上，检测指标如下：④Elisa法检测对交感神经递质CA类血浆含量的影响；⑤Elisa法检测对RAAS活性物质血浆肾素活性(plasma renin activity, PRA)、血管紧张素转换酶（angiotensin-converting enzyme，ACE）、AngⅡ及ALD血浆含量的影响；⑥对AngⅡ/p38MAPK通路诱导的血管内皮炎症反应的影响：Elisa法检测主动脉血管组织匀浆AngⅡ的含量，RT-PCR法检测AT1RmRNA的基因表达，Western-blot法检测主动脉p-p38MAPK的蛋白表达，免疫组化法检测血管细胞炎症因子ICAM-1、TGF-β1及VEGF的蛋白表达，放免法检测血清炎症因子IL~(-1)，IL-6及TNF-α含量；⑦对AngⅡ/p38MAPK通路诱导的心肌炎症反应的影响：Elisa法检测心肌匀浆AngⅡ的含量，免疫组化法检测心肌组织AT1R的蛋白表达情况，免疫组化法检测心肌组织NF-κB的蛋白表达，western-blot法检测心肌组织p-p38MAPK的蛋白表达情况，Elisa法检测心肌匀浆hs-CRP含量，免疫组化法检测心肌组织TGF-β1及VEGF的蛋白表达情况。
结果
1.药效学研究结果
1.1模型大鼠病理变化
SHR进食量减少、体重减轻，血压随着鼠龄增长，心、脑、肾、血管出现明显的病理损伤，上述指标与正常对照组或实验前比较均有显著性差异（P<0.05或P<0.01）。1.2无患子皂苷降压效果及对及靶器官的保护作用
无患子皂苷具有以下作用：①Sap27、54、108mg· kg-1剂量组可增加SHR进食量及体重，改善其行为学一般状态；②单次药后30min即表现出降压效果，药效可持续至药后240min；③连续给药8周期间，血压值持续降低，Sap27mg· kg-1降压作用有一定的波动，但Sap54、108mg· kg-1降压效果较为平稳；④可改善高血压靶器官的病理损伤状态：逆转心肌肥厚及心室重构，改善脑皮质区及海马区血管及神经元病变，抑制肾小球的肥大或萎缩，保护主动脉血管内皮、抑制中膜平滑肌的增殖等，上述指标与SHR模型组或用药前比较均有显著性差异（P<0.05或P<0.01）。
2.降压机制研究结果
2.1模型大鼠病变机制
研究发现，自发性高血压大鼠表现为：①内皮损伤、功能失衡，表现为主动脉环对AngⅡ(10-9mol· L~(-1)～10-5mol· L~(-1))、PE(10-8mol· L~(-1)～10-4mol· L~(-1))、KCl(20mmol· L~(-1)～120mmol· L~(-1))诱发的血管收缩反应性增强；②对Ach(10-10mol· L~(-1)～10-5mol· L~(-1))诱发的内皮依赖性舒张反应减弱，而对SNP(10-8mol· L~(-1)～10-3mol· L~(-1))诱发的非内皮依赖性舒张反应未见明显变化；③血清TXB2，ET-1含量增加，而NO，6-k-PGF1a含量减少；④交感神经及RAAS活性物质增强： CA，PRA，ACE,AngⅡ及ALD的血浆含量升高；⑤AngⅡ/p38MAPK通路诱导的血管内皮炎症反应增强：使血管组织AngⅡ含量增加， AT1R基因表达增加，促进血管细胞内p-p38MAPK蛋白表达,使炎症因子ICAM-1、TGF-β1，VEGF在血管的蛋白表达增加，hs-CRP,IL~(-1)，IL-6及TNF-α的释放增加；⑥AngⅡ/p38MAPK通路诱导的心肌炎症反应增强：心肌AngⅡ含量增加，心肌细胞内AT1R蛋白表达增加，使p-p38MAPK蛋白表达增加,进而促进核转录因子NF-κB的蛋白表达，使炎症因子CRP在心肌组织含量增加，TGF-β1，VEGF在心肌的蛋白表达水平升高，上述指标与正常对照组比较有显著性差异（P<0.05或P<0.01）。
2.2无患子皂苷对SHR内皮损伤及心肌肥厚的保护机制
无患子皂苷可逆转SHR上述病理变化，表现为：①Sap可抑制主动脉对PE、AngⅡ、KCl的收缩反应；②增强对Ach的内皮依赖性舒张效应，对SNP非内皮依赖性舒张效应未见明显影响；③降低血清TXB2，ET-1含量，增加NO，6-k-PGF1a含量；④抑制交感神经及RAAS活性：降低血浆CA，PRA、ACE、AngⅡ及ALD含量；⑤抑制AngⅡ/p38MAPK通路诱导的血管内皮炎症反应：降低血管组织AngⅡ含量，抑制AT1R的基因表达，抑制p-p38MAPK的蛋白表达，使其表达产物ICAM-1，TGF-β1，VEGF，hs-CRP,IL~(-1)，IL-6及TNF-α的释放减少；⑥抑制AngⅡ/p38MAPK通路诱导的心肌炎症反应：抑制信号分子AngⅡ在心肌组织的含量，抑制其特异性受体AT1R的蛋白表达，抑制心肌p-p38MAPK的蛋白表达，使其表达产物hs-CRP，TGF-β1及VEGF释放减少，上述指标与SHR对照组有显著性差异（P<0.05或P<0.01）。
结论
1.无患子皂苷对SHR有显著的降压作用，对高血压靶器官具有一定的保护作用，降压作用可从30min持续至240min，并在27、54、108mg· kg-1范围内存在一定的剂量依赖性关系；
2.无患子皂苷通过保护血管内皮、逆转心肌肥厚产生抗高血压作用；
3.无患子皂苷“祛痰化瘀通心络”中医降压理论的细胞分子机制与调控AngⅡ/p38MAPK信号通路所介导炎症反应有关。
Background It has been reported that hypertension is a chronic inflammatory diseaseof low-level. Inflammation response has been verified as a very important role in theoccurrence and development of hypertension. p38MAPK exists in a variety of biological cells,which is a very important signal transduction pathway leading to inflammatory response,involved in lots of physiological and pathological processes, such as the proliferation ofcardiac and vascular smooth muscle cells, the synthesis or degradation of extracellularmatrix, the damage of endothelial cells and so on. RAAS is both one of a cyclic but alsoa local secretion system, which is the most important regulatory pathway in the bloodpressure. The principal effects of RAAS are mediated by Ang II and its specific ATlR. Itcan induce the expression of p38MAPK. When signaling molecule Ang II is integratedwith its receptor ATlR, inflammatory response will be activated. NF-κB is an importantnuclear transcription factor. It can regulate the transcription of cytokines, which isclosely related to the inflammatory response.
In traditional Chinese medicine theory, it has been considered that the essentialhypertension is caused by the pathogenesis such as the disharmony of “Qi”and “Blood”,the imbalance of “Yin” and “Yang”. In chronic inflammation process, endothelial cellswill release much active substances, such as inflammatory factors IL~(-1), IL-6, CRP, ICAM-1, TNF-α, sympathetic neurotransmitter CA, vasoconstrictor Ang II, ET andTXA2, blood volume expansion material ALD, transforming growth factor TGF-β1,vascular endothelial growth factor VEGF and so on, which are consistent with "Tan"theory defined as products of pathological body fluid in Chinese medicine. And theadhesion of platelets, aggregation and thrombosis, fibrous plaque and connective tissue,subcutaneous deposition of the monocytes into foam cells, and the increasing of bloodviscosity are also consistent with the “Yu” theory." Tan " and "Yu" often cause diseasesynergistically, and its “Toxicity” will destroy heart. Therefore, we propose the Chinesemedicine theory “removing ‘Tan’ and ‘Yu’ to dredge heart network” as a new way totreat hypertension.
Sapindus saponins was the effective parts and extracted from the skin of Sapindus.In “Herbal Supplements” and “Compendium of Materia Medica”, it was recordedthat sapindus is mild, bitter with the effects of detoxification, expectorant, circulationand insecticidal. In modern medical research, it has been shown that there wereantibacterial, anti-inflammatory and analgesic multiple pharmacological activities insapindus saponin. Our preliminary studies indicated that Sapindus saponins couldreduce the blood pressure of renal hypertensive model rats, improve their leftventricular acting, and inhibit inflammatory response of cerebral ischemia andreperfusion injury model rats. According to these findings, we proposed the hypothesisthat the cellular and molecular mechanism of the Chinese medicine theory “removing‘Tan’ and ‘Yu’ to dredge heart network” is the regulation of inflammatory responsemediated by p38MAPK signal pathway based on activated Ang Ⅱ.
Objective To investigate the dose-effect and time-effect relationship of sapindussaponins by studying the effects of antihypertension and protection on target organs inSHR. And also to explore the cellular and molecular mechanism of the Chinesemedicine theory “removing ‘Tan’ and ‘Yu’ to dredge heart network” by observing theeffects on vascular inflammation, endothelial damage and cardiac hypertrophy mediated by Ang Ⅱ/p38MAPK signal pathway.
Methods (1) The study on pharmacodynamic of sapindus saponins: Forty16-week-oldspontaneously hypertensive rats were randomly divided into five groups, one with placebo asmodel group, one with captopril tablets(27mg·kg-1) as positive control, one withlow-dose (27mg· kg-1), one with medium-dose (54mg· kg-1), one with high-dose (108mg·kg-1) sapindus saponins. And another eight healthy Wistar-Kyoto strain(WKY) ratswere used as the normal group. The animals were treated for eight weeks, and theindicators to be detected were as follows:①the general state of SHR;②the bloodpressure after single treatment;③the blood pressure after continuous treatment;④themorphology of the target organs (heart, brain, kidney and aortic) were observed by HEand Masson staining.
(2) The mechanism on antihypertension of Sapindus saponins: The indicators to bedetected were as follows:①the response of thoracic aorta on different vasoconstrictorsAngⅡ(10-9mol· L~(-1)～10-5mol· L~(-1)), PE(10-8mol·L~(-1)～10-4mol·L~(-1)), KCl(20mmol·L~(-1)～120mmol·L~(-1));②the endothelium-dependent ornon-endothelium-dependent vasodilation on Ach(10-10mol· L~(-1)～10-5mol· L~(-1)) orSNP(10-8mol· L~(-1)～10-3mol· L~(-1));③the content of NO,6-KPG, ET-1and TXB2inserum was determined by Elisa;④the content of CA in plasma was determined byElisa;⑤the content of PRA, ACE, AngⅡand ALD in plasma was determined byElisa;⑥the effects on inflammatory response induced by AngⅡin aortic endothelialcells: the content of AngⅡ in plasma was determined by Elisa, the gene expression ofAT1RmRNA was determin by RT-PCR, the protein expression of p-p38MAPK wasdetermin by Western-blot, the protein expression of ICAM-1, TGF-β1and VEGF wasdetermin by immunohistochemical method, the content of hs-CRP，IL~(-1)，IL-6andTNF-α in serum was determined by radioimmunoassay;⑦the effects on cardiachypertrophy induced by AngⅡin myocardial cells: the content of AngⅡ in myocardialhomogenate was determined by Elisa, the protein expression of AT1R was determin by immunohistochemical method, the protein expression of p-p38MAPK in myocardialcells was determin by Western-blot, the protein expression of NF-κB，TGF-β1andVEGF in myocardial cells was determin by immunohistochemical method.
Results (1) The results on pharmacodynamics: In the SHR model group, food intakewas reduced, body weight was lost, the blood pressure was increased as the age growth,the target organs (heart, brain, kidney and aortic) were damaged badly, Vs the normalcontrol group and before treatment, there were significant differences (P<0.05or P<0.01); in the Sapindus saponins treatment groups, food intake and body weight wereincreased, the blood pressure was reduced after single treatment30min and continuoustreatment8weeks, the damages of target organs (heart, brain, kidney and aortic) werereversed, Vs the SHR model group and before treatment, there were significantdifferences (P<0.05or P<0.01).
(2) The results on mechanism of antihypertension: In SHR model group, theresponse of thoracic aorta on different vasoconstrictors AngⅡ, PE and KCl wasimproved, the endothelium-dependent vasodilation on Ach was reduced, but the effectson SNP were not obvious, the content of ET-1and TXB2was increased, the content ofNO and6-KPG1awas reduced, the content of CA, PRA, ACE, AngⅡand ALD inplasma, the gene expression of AT1RmRNA, the protein expression of p-p38MAPK,ICAM-1, TGF-β1and VEGF, the content of hs-CRP, IL~(-1)，IL-6and TNF-α in serum,the content of AngⅡ in aorta and myocardial homogenate, the protein expression ofAT1R, p-p38MAPK, NF-κB, TGF-β1and VEGF in myocardial cells were increased, Vsthe normal control group, there were significant differences (P <0.05or P <0.01); in theSapindus saponins treatment groups, all the above indicators were all reduced, Vs theSHR model group, there were significant differences (P <0.05or P <0.01).
Conclusions Our findings suggested that (1) Sapindus saponins reduced bloodpressure and protected the target organs. The antihypertensive effects of sapindussaponins could be sustained from30min to240min after treatment, and there wasdose-dependent relationship amount27,54and108mg· kg-1dose;(2) The antihypertensive effects of sapindus saponins were carried out by protecting the vascularendothelium and cardiac;(3) Sapindus saponins inhibited the vascular inflammatoryresponse, endothelial injury and cardiac hypertrophy, its cellular and molecularmechanisms of the Chinese medicine theory “removing ‘Tan’ and ‘Yu’ to dredge heartnetwork” were relevant to the regulation of inflammatory responses mediated by AngⅡ/p38MAPK signal pathway.
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