| 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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