降压药物个体敏感性与中医证型的代谢组学桥接研究
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摘要
目的：①研究和分析高血压肝火亢盛证及痰湿壅盛证患者血浆内源性小分子代谢物的差异,鉴定与证型相关的生物标志物群；②研究和分析高血压人群与正常组的血浆代谢谱,分析高血压人群体内的代谢组学异常；③探讨个体对降压药敏感程度与高血压中医证型的相关性,构筑个体对降压药敏感性——代谢组——中医证型的桥梁。
方法：高血压组119例,正常对照组(K组)25例。高血压组分为氨氯地平组(A组)59例,厄贝沙坦组(B组)60例。氨氯地平组分为药物敏感组(E+M)29例,不敏感组(F+N)30例；按中医辨证分型氨氯地平敏感组分为肝火亢盛证组(M组)14例,痰湿壅盛证组(E组)15例；氨氯地平不敏感组分为肝火亢盛证组(N组)15例,痰湿壅盛证组(F组)15例。厄贝沙坦组分为药物敏感组(G+L)30例,不敏感组(H+P)30例；按中医辨证分型厄贝沙坦敏感组分为肝火亢盛证组(L组)13例,痰湿壅盛证组(G组)17例；厄贝沙坦不敏感组分为肝火亢盛证组(P组)16例,痰湿壅盛证组(H组)14例。采用基于气相色谱-飞行时间质谱(GC-TOF/MS)代谢组学方法测定各组人群血浆代谢谱,应用偏最小二乘-判别分析(PLS-DA)比较氨氯地平组内肝火亢盛组与痰湿壅盛组、厄贝沙坦组内肝火亢盛组与痰湿壅盛组、氨氯地平组与对照组、厄贝沙坦组与对照组、氨氯地平药物敏感组与不敏感组、厄贝沙坦药物敏感组与不敏感组,得到各样本的主成分得分图(scores plot),分析和鉴定组间异同内源性化合物。
结果：①在氨氯地平组和厄贝沙坦组中,采用GC/MS的代谢组学方法均能区分肝火亢盛证型和痰湿壅盛证型的代谢谱,与肝火亢盛证相关的生物标志物群可能是葡萄糖、木糖、乳酸、缬氨酸、甘氨酸的升高以及α-亚麻酸、甘油酸的降低;与痰湿壅盛证相关的生物标志物群可能是α-亚麻酸、甘油酸的降低以及缬氨酸、甘氨酸、羟脯氨酸、S-甲基-L-半胱氨酸的升高；②氨氯地平药物敏感组与不敏感组表现为不同的代谢特征,在氨氯地平敏感组有10种化合物均低于不敏感组(P<0.05),氨氯地平敏感组内代谢谱表现为糖代谢及部分氨基酸的水平较低；③厄贝沙坦药物敏感组与不敏感组表现为不同的代谢特征,在厄贝沙坦敏感组与不敏感组中有显著差异的化合物有8种(P<0.05),厄贝沙坦敏感组代谢谱表现为氨基酸水平较高,而脂类物质较低；④氨氯地平敏感组与痰湿壅盛证组表现为相似的代谢谱——糖类(葡萄糖)及部分氨基酸(缬氨酸、羟脯氨酸)的水平较低,厄贝沙坦敏感组和肝火亢盛证表现为相似的代谢谱——部分氨基酸(缬氨酸、甘氨酸)及脂类的水平较低。
结论：①高血压肝火亢盛证和痰湿壅盛证的血浆代谢谱变化为中医辨证分型提供了部分客观化的科学依据；②高血压人群存在糖、脂、氨基酸代谢异常,代谢组学方法具有研究高血压病理的优势；③降压药物的敏感性与中医证型在代谢学上的联系,对临床使用个体化的思路来选择降压药物提供帮助,并为中西医结合治疗高血压构筑桥梁。
Objectives:①Research and analyze the difference of endogenous plasma small molecule metabolites between overabundant liver-fire syndrome and phlegm-dampness accumulation syndrome, and identify syndrome-related biomarker cluster.②Research and analyze plasma metabolomic profiling between hypertension group and normal group, analyze abnormality of metabolomics in people with hypertension③Explore the correlation between individual sensitivity to antihypertensive drugs and TCM syndrome types to establish a bridge between these two and metabolome.
Methods:119 patients with hypertension, in addition to normal control group (K group) with 25 cases. Hypertension group is divided into amlodipine group (A group) with 59 cases, irbesartan group (B group) with 60 cases. Amlodipine group is divided into drug-sensitive group (E+M) with 29 cases, and non-sensitive group (F+N) with 30 cases. According to TCM syndrome differentiation, amlodipine sensitive group is then divided into abundant liver-fire syndrome group (M group) with 14 cases and phlegm-dampness accumulation syndrome group (E group) with 15 cases, while amlodipine non-sensitive group is divided into abundant liver-fire syndrome group (N group) with 15 cases and phlegm-dampness accumulation syndrome group (F group) with 15 cases. Irbesartan group is separated into drug-sensitive group (G+L) with 30 cases as well as non-sensitive group (H+P) with 30 cases. The former group is then sub-divided into abundant liver-fire syndrome group (L group) with 13 cases and phlegm dampness accumulation syndrome group (G group) with 17 cases, while the later group is divided into hyperactive liver-fire syndrome group (P group) with 16 cases and phlegm dampness accumulation syndrome group (H group) with 14 cases according to TCM syndrome differentiation. The next step is to apply gas chromatography - time of flight mass spectrometry (GC-TOF/MS) to test plasma metabolomic profiling in all groups, and then to compare hyperactive liver-fire syndrome group to phlegm dampness accumulation syndrome group in amlodipine and irbesartan group, amlodipine group to control group, irbesartan group to control group, amlodipine sensitive group to non-sensitive group, irbesartan sensitive group to non-sensitive group, by way of Partial Least Squares-Discriminative Analysis (PLS-DA), so as to obtain each sample's score plot of principal components as well as to analyze and identify similarities and differences of endogenous compounds between groups.
Results:①In amlodipine group and irbesartan group, the metabolomic profiling of abundant liver-fire syndrome and phlegm dampness accumulation syndrome can be distinguished by gas chromatography - time of flight mass spectrometry (GC-TOF/MS) metabolomic method, Biomarker cluster associated with abundant liver-fire syndrome group may be higher glucose, xylose associated with glucose metabolism, lactic acid, valine and glycine belonging to amino acid but lower a-linolenic acid and glycerol acid; while biomarker cluster of phlegm dampness accumulation syndrome group may be lower a-linolenic acid and glycerol belonging to lipid but higher valine, glycine、hydroxyproline and S-methyl-L-cysteine.②Amlodipine sensitive group and non-sensitive group have different metabolomic characteristic,10 compounds in amlodipine sensitive group are lower than non-sensitive group (P<0.05). and metabolomic profiling in amlodipine sensitive group exhibits a lower level of glucose metabolism and part of the amino acids.③Irbesartan sensitive group and non-sensitive group also showing different metabolomic characteristic, there are 8 significant different compounds in irbesartan sensitive group and non-sensitive group (P<0.05), the metabolomic profiling of irbesartan sensitive group shows higher amino acids but lower lipide.④Amlodipine sensitive group and phlegm dampness accumulation syndrome group show similar metabolomic profiling——lower level of sugar (glucose) and some amino acids (valine, hydroxyproline), and the same goes with irbesartan sensitive group and abundant liver-fire syndrome group——lower level of amino acids (valine, glycine) and level of lipids.
Conclusions:①Plasma metabolomic profiling of abundant liver-fire syndrome and phlegm-dampness accumulation syndrome of hypertension can supply some objective evidence for syndrome differentiation.(2)Hypertension patients have abnormal metabolism of sugar, fat, amino acid during metabolism, so metabolomics takes advantages in researching the pathology of hypertention.③The connection between the sensitivity of anti-hypertensive drug and TCM syndrome types in metabolomics, which can help us use individual thinking to choose antihypertension drugs, and established a bridge between integrative treatment of hypertension.
方法：高血压组119例,正常对照组(K组)25例。高血压组分为氨氯地平组(A组)59例,厄贝沙坦组(B组)60例。氨氯地平组分为药物敏感组(E+M)29例,不敏感组(F+N)30例；按中医辨证分型氨氯地平敏感组分为肝火亢盛证组(M组)14例,痰湿壅盛证组(E组)15例；氨氯地平不敏感组分为肝火亢盛证组(N组)15例,痰湿壅盛证组(F组)15例。厄贝沙坦组分为药物敏感组(G+L)30例,不敏感组(H+P)30例；按中医辨证分型厄贝沙坦敏感组分为肝火亢盛证组(L组)13例,痰湿壅盛证组(G组)17例；厄贝沙坦不敏感组分为肝火亢盛证组(P组)16例,痰湿壅盛证组(H组)14例。采用基于气相色谱-飞行时间质谱(GC-TOF/MS)代谢组学方法测定各组人群血浆代谢谱,应用偏最小二乘-判别分析(PLS-DA)比较氨氯地平组内肝火亢盛组与痰湿壅盛组、厄贝沙坦组内肝火亢盛组与痰湿壅盛组、氨氯地平组与对照组、厄贝沙坦组与对照组、氨氯地平药物敏感组与不敏感组、厄贝沙坦药物敏感组与不敏感组,得到各样本的主成分得分图(scores plot),分析和鉴定组间异同内源性化合物。
结果：①在氨氯地平组和厄贝沙坦组中,采用GC/MS的代谢组学方法均能区分肝火亢盛证型和痰湿壅盛证型的代谢谱,与肝火亢盛证相关的生物标志物群可能是葡萄糖、木糖、乳酸、缬氨酸、甘氨酸的升高以及α-亚麻酸、甘油酸的降低;与痰湿壅盛证相关的生物标志物群可能是α-亚麻酸、甘油酸的降低以及缬氨酸、甘氨酸、羟脯氨酸、S-甲基-L-半胱氨酸的升高；②氨氯地平药物敏感组与不敏感组表现为不同的代谢特征,在氨氯地平敏感组有10种化合物均低于不敏感组(P<0.05),氨氯地平敏感组内代谢谱表现为糖代谢及部分氨基酸的水平较低；③厄贝沙坦药物敏感组与不敏感组表现为不同的代谢特征,在厄贝沙坦敏感组与不敏感组中有显著差异的化合物有8种(P<0.05),厄贝沙坦敏感组代谢谱表现为氨基酸水平较高,而脂类物质较低；④氨氯地平敏感组与痰湿壅盛证组表现为相似的代谢谱——糖类(葡萄糖)及部分氨基酸(缬氨酸、羟脯氨酸)的水平较低,厄贝沙坦敏感组和肝火亢盛证表现为相似的代谢谱——部分氨基酸(缬氨酸、甘氨酸)及脂类的水平较低。
结论：①高血压肝火亢盛证和痰湿壅盛证的血浆代谢谱变化为中医辨证分型提供了部分客观化的科学依据；②高血压人群存在糖、脂、氨基酸代谢异常,代谢组学方法具有研究高血压病理的优势；③降压药物的敏感性与中医证型在代谢学上的联系,对临床使用个体化的思路来选择降压药物提供帮助,并为中西医结合治疗高血压构筑桥梁。
Objectives:①Research and analyze the difference of endogenous plasma small molecule metabolites between overabundant liver-fire syndrome and phlegm-dampness accumulation syndrome, and identify syndrome-related biomarker cluster.②Research and analyze plasma metabolomic profiling between hypertension group and normal group, analyze abnormality of metabolomics in people with hypertension③Explore the correlation between individual sensitivity to antihypertensive drugs and TCM syndrome types to establish a bridge between these two and metabolome.
Methods:119 patients with hypertension, in addition to normal control group (K group) with 25 cases. Hypertension group is divided into amlodipine group (A group) with 59 cases, irbesartan group (B group) with 60 cases. Amlodipine group is divided into drug-sensitive group (E+M) with 29 cases, and non-sensitive group (F+N) with 30 cases. According to TCM syndrome differentiation, amlodipine sensitive group is then divided into abundant liver-fire syndrome group (M group) with 14 cases and phlegm-dampness accumulation syndrome group (E group) with 15 cases, while amlodipine non-sensitive group is divided into abundant liver-fire syndrome group (N group) with 15 cases and phlegm-dampness accumulation syndrome group (F group) with 15 cases. Irbesartan group is separated into drug-sensitive group (G+L) with 30 cases as well as non-sensitive group (H+P) with 30 cases. The former group is then sub-divided into abundant liver-fire syndrome group (L group) with 13 cases and phlegm dampness accumulation syndrome group (G group) with 17 cases, while the later group is divided into hyperactive liver-fire syndrome group (P group) with 16 cases and phlegm dampness accumulation syndrome group (H group) with 14 cases according to TCM syndrome differentiation. The next step is to apply gas chromatography - time of flight mass spectrometry (GC-TOF/MS) to test plasma metabolomic profiling in all groups, and then to compare hyperactive liver-fire syndrome group to phlegm dampness accumulation syndrome group in amlodipine and irbesartan group, amlodipine group to control group, irbesartan group to control group, amlodipine sensitive group to non-sensitive group, irbesartan sensitive group to non-sensitive group, by way of Partial Least Squares-Discriminative Analysis (PLS-DA), so as to obtain each sample's score plot of principal components as well as to analyze and identify similarities and differences of endogenous compounds between groups.
Results:①In amlodipine group and irbesartan group, the metabolomic profiling of abundant liver-fire syndrome and phlegm dampness accumulation syndrome can be distinguished by gas chromatography - time of flight mass spectrometry (GC-TOF/MS) metabolomic method, Biomarker cluster associated with abundant liver-fire syndrome group may be higher glucose, xylose associated with glucose metabolism, lactic acid, valine and glycine belonging to amino acid but lower a-linolenic acid and glycerol acid; while biomarker cluster of phlegm dampness accumulation syndrome group may be lower a-linolenic acid and glycerol belonging to lipid but higher valine, glycine、hydroxyproline and S-methyl-L-cysteine.②Amlodipine sensitive group and non-sensitive group have different metabolomic characteristic,10 compounds in amlodipine sensitive group are lower than non-sensitive group (P<0.05). and metabolomic profiling in amlodipine sensitive group exhibits a lower level of glucose metabolism and part of the amino acids.③Irbesartan sensitive group and non-sensitive group also showing different metabolomic characteristic, there are 8 significant different compounds in irbesartan sensitive group and non-sensitive group (P<0.05), the metabolomic profiling of irbesartan sensitive group shows higher amino acids but lower lipide.④Amlodipine sensitive group and phlegm dampness accumulation syndrome group show similar metabolomic profiling——lower level of sugar (glucose) and some amino acids (valine, hydroxyproline), and the same goes with irbesartan sensitive group and abundant liver-fire syndrome group——lower level of amino acids (valine, glycine) and level of lipids.
Conclusions:①Plasma metabolomic profiling of abundant liver-fire syndrome and phlegm-dampness accumulation syndrome of hypertension can supply some objective evidence for syndrome differentiation.(2)Hypertension patients have abnormal metabolism of sugar, fat, amino acid during metabolism, so metabolomics takes advantages in researching the pathology of hypertention.③The connection between the sensitivity of anti-hypertensive drug and TCM syndrome types in metabolomics, which can help us use individual thinking to choose antihypertension drugs, and established a bridge between integrative treatment of hypertension.
引文
[1]中华人民共和国卫生部,卫生部心血管病防治研究中心,高血压联盟(中国),中国高血压防治指南[M].2005.
[2]Katovich MJ, Gelband CH, Reaves P, et al. Reversal of hypertension by angiotensin II type 1 receptor antisense gene therapy in the adult SHR[J]. Am Physiol 1999;277(3 Pt 2):H1260-H1264.
[3]Aenet DK, Class SA, Glasser SP. Pharmacogenetics of antihypertensive treatment [J]. Vascular Pharmacology,2006,44(2):107-118.
[4]Johnson JA, Turner ST. Hypertension pharmacogenomics:current status and future directions [J]. Current Opinion In Molecular Therapeutics,2005,7(3):218-225.
[5]Mellen PB, Herrington DM. Pharmacogenetics of blood pressure response to antihypertensive treatment [J]. Journal of Hypertension,2005 23(7):1311-1325.
[6]Burns MA, He W, Wu CL, Cheng LL. Quantitative pathology in tissue MR spectroscopy based human prostate metabolomics[J]. Technol Cancer Res Treat.2004,3(6):591-598.
[7]Verhoeckx KC, Bijlsma S, Jespersen S, et al. Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis[J]. Int Immunopharmcol.2004,4(12):1499-514.
[8]胡晓抒,郭志荣,喻荣彬.高血压与多代谢异常的对照研究[J].中国公共卫生,2003,19(11)：1315-1317.
[9]Brindle JT, Antti H, Holmes E, Tranter G, Nicholson JK, Bethell HW, Clarke S, Schofield PM, McKilligin E, Mosedale DE, Grainger DJ. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics[J]. Nat Med.2002 Dec;8(12):1439-44.
[10]刘爱萍,李立明,曹卫华.脂蛋白酯酶S447X及Hind多态性与原发性高血压代谢代谢综合征血脂异常的关系[J].中华医学遗传杂志.2005,22(2)：151-157.
[11]Akira, Imachi M, Hashimoto T. Investigations into biochemical changes of genetic hypertensive rats using 1H Nuclear magnetic resonance-based metabonomics[J]. Hypertens Res.2005,28(5):525-530.
[12]Bridle JT, Nicholson JK, Schofield PM, et al. Application of chemometrics to NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertens ion [J]. Analyst.2003,128(1): 32-36.
[13]LU Yi-hong, HAO Hai-ping, WANG Guang-ji, et al. Matabolomics approach to the biochemical differentiation of traditional Chinese medicine syndrome types of hypertension[J].Chin J Clin Pharmacol Ther. 2007,10:1144-1150.
[14]孙广仁.中医基础理论[M].北京：中国中医药出版社,2002：215-216.
[15]Chobanian AV,Bakris GL,Black HR,et al.The Seventh Report of the Joint National Committee on Prevention,Detection,Evaluation,and Treatment of High Blood Pressure.The JNC-7 Report[J]. JAMA,2003, 289(19):2560-2571.
[16]Hajjar I, Kotchen TA.Trends in Prevalence, Awareness, Treatment, and Control of Hypertension in the United States,1988-2000[J].JAMA.2003,290(2):199-206.
[17]Muntner P, He J, Cutler JA, et al. Trends in blood pressure among children and adolescents [J]. JAMA, 2004,291(17):2107-2113.
[18]卫生部心血管病防治研究中心.中国心血管病报告2007[M].北京：中国大百科全书出版社,2007：2-3.
[19]科技部、卫生部、国家统计局.中国居民营养与健康现状.中国心血管病研究杂志,2004,12：919-922.
[20]毛焕元,杨心田主编.心脏病学[M].人民卫生出版社出版.2001年3月第2版：793-794.
[21]中华人民共和国卫生部,高血压联盟(中国),中国高血压防治指南(基层版),中华高血压杂志,2010,18(1)：11-29.
[22]李立明,胡永华.心血管疾病研究进展[M].北京：北京医科大学出版社,2001.
[23]刘力生.高血压[M].北京：人民卫生出版社,2001：289-319.
[24]Bakris GL,Hart P,Ritz E. Beta blockers in the management of chronic kidney disease[J].Kidney Int 2006, 70:1905-1913.
[25]张仁蓉,王一尘.交感神经与高血压关系的研究现状[J].中国心血管杂志1999,4(3)：181-183.
[26]Sarzani R, Salvi F, DessiFulgheri P, et al. Renin-angiotensin system, natriuretic peptides, obesity,metabolic syndrome, and hyperension:an integrated view in humans. J Hypertens,2008,26 (5):831-843.
[27]Defronzo R A,Kashyap S R.The insulin resistance syndrome:physiological considerations[J].Diab Vasc Dis Res,2007,4(1):13-19.
[28]GinerV,CocaA, de la SierraA. Increased insulin resistance in salt sensitive essential hypertension[J]. Hum Hypertens,2001,15 (7):481-485.
[29]PotenzaMA,MarasciuloFL,ChieppaDM, et al.Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production.Am J Physiol Heart Circ Physiol 2005,289(2):813-823.
[30]葛金文,梅志刚,朱惠斌.一种新的2型糖尿病血管并发症细胞研究模型：葡萄糖、胰岛素、低密度脂蛋白联合诱导血管内皮细胞损伤的研究[J].血栓与止血学,2005,11(6)：245-249.
[31]Wallace SM,Yasmin L,McEniery CM, et al. Isolate systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction[J]. Hypertension,2007,50:228-233.
[32]Murray Esler, Nora Straznicky, Nina Eikelis, et al。Mechanisms of Sympathetic Activation in Obesity -Related Hypertension[J]. Hypertension,2006,48:787-796.
[33]傅仁杰.老年高血压病的辨证论治[J].中医杂志.1993,34(8)：495.
[34]屈松柏,李家庚主编.实用中医心血管病学[M].北京科学技术文献出版社.1993年第1版：347-354.
[35]郑筱萸.中药新药临床研究指导原则[M].北京：中国医药科技出版社,2002：73-76.
[36]黎秋明.中医辨证分型治疗高血.压病103例[J].广西中医学院学报,2003,6(3)：48-49.
[37]高宇,李英华.高血压病的中医辨证论治[J].内蒙古中医药,2008,(6)：28-29.
[38]周春刚,张志斌,夏成霞,等.ACE I/D基因多态性与高血压中医证型的相关性[J].辽宁中医药大学学报,2010,]2(6)：68-71.
[39]孟云辉.PPAR γC161T基因多态性与原发性高血压证型的相关性研究[J].中国中医急症,2009,18(11)：1815-]816.
[40]高树彪,戴雁彦,王硕仁,等.高血压病不同中医证型左室舒张功能评价指标E/e比值的变化[J].北京中医药大学学报(中医临床版),2010,17(5)：7-9.
[41]刘福明,陈晓虎,杜午奇,等.高血压病中医证型与大动脉功能参数的相关研究[J].中国临床医学.2009,16(6)：972-974.
[42]张文,王剑,吕全胜.高血压病中医证型与同型半胱氨酸的相关性研究[J].新疆中医药,2010,28(4)：11-13.
[43]罗芳.高血压病中医证型与血脂关系的研究[J].现代中西医结合杂志,2010,19(28)：3588-3589.
[44]K jekdsen SE,Fansang C,Sleign P,et al 1999WHO/ISH hypertension guidelines-highlights and ESH update[J],Hypertension,2001,19(12):2285.
[45]Patowary S. Pharmacogenomics-Therapeutic and ethical issues [J].Kathmandu Univ Med J (KUMJ),2005,3:428-430. Shastry BS. Role of SNP/haplotype map in gene discovery and drug development: an overview[J].Drug Dev Res,2004,62:143-150.
[46]Stavroulakis GA,Makris TK,Krrapi PG,et al.Predicting response to chronic antihypertensive treatment with fosinoprit:the role of angiotensin-converting enayme gene polymorphism [J],Cardiovasc Drugs Ther.2000.14:427-432.
[47]Arnett DK, Davis BR, Ford CE, et al. Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment:the Genetics of hypertension associated treatment (GenHAT) study[J]. Circulation,2005, 111:3374-3383.
[48]Schelleman H, Klungel OH, van Duijn CM, et al. Drug-gene interaction between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and antihypertensive therapy [J]. Ann Pharmacother,2006,40:212-218.
[49]Cusi D, Barlassina C, Azzani T,et al. Polymorphisms of a-adducin and salt sensitivity in patients with essential hypertension[J]. Lancet,1997;349:1353-1357.
[50]Glorioso N, Manunta P, Filigheddu F,et al. The role of alpha-adducin polymorphism in blood pressure and sodium handing regulation may not be excluded by a negative association study[J]. Hypertension, 1999;34:649-654.
[51]侯嵘,刘治全,薛明战,等.α-内收蛋白Gly460Trp变异与中国汉族人原发性高血压的相关性研究[J].中华医学遗传学杂志,2000,17：413-416.
[52]许国旺等著.代谢组学——方法与应用[M].科学出版社,2008年8月：2.
[53]Nicholson, J. K., Lindon, J. C.,Holmes, E. " Metabonomics" under-standing themetabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectro-scopic data[J].Xenobiotica,1999,29(11):1181.
[54]Fiehn O.Metabolomics-the link between genotypes and phenotypes[J].Plant Mol Biol,2002,48:155.
[55]Taylor J, King RD, Altmann T et al. Application of metabonomics to plant genotype discrimination using statistics and machine learning[J]. Bioinformatics,2002,18:241.
[56]DAYKIN, C A., CORCORAN, O., HANSEN, S H et al.Application of directly coupled HPLC NMR to separation and characterization of lipoproteins from human serum[J].Analytical Chemistry,2001,73(6):1084.
[57]Nicholson JK, Holmes E, Lindon JC, et al. The challenges of mo-deling mammalian biocomplexity[J].Nat Biotechol,2004,22(10):1268.
[58]Clayton TA, Lindon JC, Cloarec O,etal.Pharmaco-metabonomic phenotyping and personalized drug treatment [J].Nature,2006,440(7087):1073-1077.
[59]Watkins S M, German J B.Toward the imp lementation of metabolomic assessments of human health and nutrition [J].CurrOp in Biotechnol,2002,13(5):512-516.
[60]邓铁涛.辨证论治[J].中国中医药信息杂志,2000,7(9)：1.
[61]简维雄.中医“证候”与代谢组学研究[J].中华中医药学刊,2009,27(2)：351.
[62]罗和古,陈家旭.代谢组学技术与中医证候的研究[J].中医药信息杂志,2007,14(5)：3.
[63]林景超,李后开,周明眉,等。代谢组学、药物代谢组学与中医药现代化[J],中国医学科学院学报,2007,29(6)：818-822.
[64]朱萱萱,王广基,阿基业,等.冠心病中医辨证分型的代谢组学研究[J].中华中医药学刊,2009,27(6)：1267.
[65]王广基,阿基业,严蓓,等.代谢组学研究冠心病中医分型的体内物质基础[J].世界科学技术--中医药现代化,2009,11(1)：127.
[66]冯雯,孙永宁.中医证候标准化现代化研究与代谢组学方法的应用[J].山东中医药大学学报,2009,33(2)：100.
[67]徐进秀,焦安饮.中医证候规范化研究的思路与设想[J].中国中医基础医学杂志,2005,11(4)：263.
[68]王桐生,谢鸣.代谢组学与中医药现代研究[J].中医杂志,2006,10(10)：724.
[69]罗和古,丁杰,岳广欣,等.大鼠肝郁脾虚证的代谢组学研究[J].中西医结合学报,2007,5(3)：307.
[70]徐舒,陈合兵,李洪,等.“肝郁证”大鼠模型的建立及代谢组学的初步研究[J].中华中医药杂志,2009,24(6)：787.
[71]刘树民,卢芳,王喜军,等.基于代谢组学的热病证候模型评价方法研究[J].中国药理学通报,2009,25(4)：549.
[72]吴斌,沈自尹,王丽丽,等.应用核磁共振代谢组技术研究生理性肾虚证[J].中医杂志,2009, 50(4)：338.
[73]简维雄,黄献平,陈清华,等.基于气相色谱-质谱的大鼠心血瘀阻证血浆代谢组学研究[J].中华中医药学刊2009,27(4)：796.
[74]刘国仗,胡大一,陶萍,等.心血管药物临床试验评价方法的建议[J].中华心血管病杂志,1998,26(1)：5-11.
[75]Nicholson JK, Holmes E, Lindon JC, et al. The challenges of mo-deling mammalian biocomplexity[J].Nat Biotechol,2004,22 (10):1268.
[76]董海琪.高血压病痰湿壅盛证现代科学内涵的代谢组学研究[D].南京中医药大学,2009.
[77]蒋海强,马斌,聂磊,等.高血压病肝阳上亢证患者血清样品的核磁共振谱代谢组学研究[J].药学实践杂志,20]0,28(4)：258-261.
[78]Kazuki AK, Misako IM.Investigations into biochemical changes of genetic hypertensive rats using 1H nuclear magnetic resonance-based metabonomics[J].Hypertens Res,2005,28:425-430.
[79]Lu Y,A J,Wang G,et al.Gas chromatography/time-of-flight mass spectrometry based metabonomic approach to differentiating hypertension-and age-related metabolic variation in spontaneously hypertensive rats[J].Rapid Commun Mass Spectrom,2008,22(18):2882-8.
[80]Keith NF.Non-esterified fatty acid metabolism and postprandial lipemia[J] Atherosclerosis,1998,141 (Suppl 1):S41-S46.
[81]Kraemer FB,Takeda D,Natu V,et al.Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin-and rapamycin sensitive pathways[J]. Metabolism,1998,47(5):555-559.
[82]Grekin RJ,Vollmer AP,Sider RS.Pressor effects of portalvenous oleate infusion:A proposed mechanism for obesity hypertension[J]. Hypertension,1995,26(1):193-198.
[83]Steinberg HO,Tarshoby M,Monestel R,et al.Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.J Clin Invest,1997,100(5):1230-1239.
[84]Lopes HF,Martin KL,Nashar K,et al.DASH diet lowers blood pressure and lipid-induced oxidative stress in obesity[J]. Hypertension,2003,41(3):422-430.
[85]Fagot-Campagna A,Balkau B,Simon D.et al.High free fatty acid concentration:an independent risk factor for hypertension in the Paris Prospective Study[J].Int J Epidemiol,1998,27(5):808-813.
[86]王顺,马爱群,宋少武,等.中青年高血压病患者动脉弹性功能与血浆脂肪酸[J].中华高血压杂志,2007,12(15)：992-996.
[87]王顺,脂肪酸代谢异常在高血压发病机制中的作用[J].国外医学·心血管疾病分册,2005,32(2)：80-82.
[88]Olivieri O, Lombardi S, Russo C, et al. Olivieri O, Lombardi S, Russo C, et al. Neutrophil arachidonic acid level and adhesive capability are increased in essential hypertension.J Hypertens,1998; 16(5):585-592.
[89]Steinberg HO,Tarshoby M,Monestel R,et al.Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.J Clin Invest,1997,100(5):1230-1239.
[90]Egan BM, StepniakowskiKT. Evidence linking fatty acids, the risk factor cluster, and vascular pathophysiology. Implicationsfor the diabetic hypertensive patient[M]. In:Sowers JR(ed). Contemporary Endocrinology:Endocrinology of the vasculature. TotowaMJ:Humana Press Inc,1996:157-172.
[91]Steinberg HO,Paradisi G,Hook Get al.Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production[J].Diabetes,2000,49(7):1231-1238.
[92]De Jongh RT, Serne EH, Ijzerman RG, et al.Free fatty acid level modulate microvascular function: relevance for obesity associated insulin resistance, hypertension, and microangiopathy[J].Diabetes,2004, 53:2873-2882.
[93]刘春兰,刘勇,曲卫,等.血浆游离氨基酸的水平变化与高血压病的相关性[J].实用医学杂志,2002,19(12)：926-928.
[94]高新星.高血压病的代谢组学研究[D].沈阳药科大学硕士学位论文,2008.
[95]安芳,张洪飞,林丽娜,等.高血压患者血浆中游离氨基酸的柱前衍生HPLC法测定[J].分析测试学报,2009,28(1)：72-75.
[96]高连如,刘国仗,赵云涛,等.内皮衍生舒张因子和成前体降压机制的研究[J].中华心血管病杂志,1996,6：117-124.
[97]Hishikawa K,Nakaki T,Suauki H,et al. Role of L-argininenitric oxide pathway in hypertension[J]. Hypetension,1993,11(6):639-645.
[98]Yamori y. et al. The hypotensive effect of centrally ad-ministrated tyrosine[J]. Tur J Phamacol 1980; 68:201-204.
[99]Sari E. et al. Cadiovascular effects of L-tyrosine innormotensive and hypertensive rats[J]. Eur J Pharmacol 1987; 143:27-34.
[100]Conlay LA. et al.Tyrosine increase blood pressure inhypotensive rats[J]. Science 1981,212:559-560.
[101]顾天华,赵光胜,陈庄.苯丙氨酸阻止幼年自发性高血压大鼠血压升高机理的初步探讨[J].中华心血管病杂志,1994,22(4)：297-299.
[102]贾晓波,庞会从.L-羟脯氨酸用于减肥的实验研究[J].氨基酸和生物资源,2003,25(3)：60-62.
[103]张能,方海立,张徽,等.牛磺酸对链尿佐菌素糖尿病鼠胰岛β细胞功能的保护作用[J].中国糖尿病杂志,1998,6(1)：30.
[104]任晓丽,杨波,黄陈平,等.高蛋氨酸饮食对大鼠血管内皮细胞分泌功能的影响[J].氨基酸和生物资源,2010,32(4)：50-54.
[105]汪昌树,顾统元,黎明.高血压并心、脑、肾损害患者血浆5—轻色胺和去肾上腺素的变化[J].心血管康复医学杂志,2000,2(9)：297-299.
[106]Ji-ye AA, Guang-ji WANG, Hai-ping HAO, et al.Differential regulations of blood pressure and perturbed metabolism by total ginsenosides and conventional antihypertensive agents in spontaneously hypertensive rats[J].Acta Pharmacologica Sinica (2010) 31:930-937.
[107]Paker M, Nieod P, Khanderla BR, et al. Randomized multicenter double blind Placebo controlled evaluation of amlodipine in Patients with mild to moderate heart failure[J].J Am Coll Cardiol,1991; 15:77.
[108]Ueshiba H, Tsuboi K, Miyachi Y. Effects of amlodipine on serum levels of adrenal androgens and insulin in hypertensive men with obesity[J].Horm Metab Res.2001 Mar;33(3):167-169.
[109]KAPLAN N M. Effects of antihypertensive therapy on insulin resistence[J]. Hypertension,1992,19(suppl 1):116-118.
[2]Katovich MJ, Gelband CH, Reaves P, et al. Reversal of hypertension by angiotensin II type 1 receptor antisense gene therapy in the adult SHR[J]. Am Physiol 1999;277(3 Pt 2):H1260-H1264.
[3]Aenet DK, Class SA, Glasser SP. Pharmacogenetics of antihypertensive treatment [J]. Vascular Pharmacology,2006,44(2):107-118.
[4]Johnson JA, Turner ST. Hypertension pharmacogenomics:current status and future directions [J]. Current Opinion In Molecular Therapeutics,2005,7(3):218-225.
[5]Mellen PB, Herrington DM. Pharmacogenetics of blood pressure response to antihypertensive treatment [J]. Journal of Hypertension,2005 23(7):1311-1325.
[6]Burns MA, He W, Wu CL, Cheng LL. Quantitative pathology in tissue MR spectroscopy based human prostate metabolomics[J]. Technol Cancer Res Treat.2004,3(6):591-598.
[7]Verhoeckx KC, Bijlsma S, Jespersen S, et al. Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis[J]. Int Immunopharmcol.2004,4(12):1499-514.
[8]胡晓抒,郭志荣,喻荣彬.高血压与多代谢异常的对照研究[J].中国公共卫生,2003,19(11)：1315-1317.
[9]Brindle JT, Antti H, Holmes E, Tranter G, Nicholson JK, Bethell HW, Clarke S, Schofield PM, McKilligin E, Mosedale DE, Grainger DJ. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics[J]. Nat Med.2002 Dec;8(12):1439-44.
[10]刘爱萍,李立明,曹卫华.脂蛋白酯酶S447X及Hind多态性与原发性高血压代谢代谢综合征血脂异常的关系[J].中华医学遗传杂志.2005,22(2)：151-157.
[11]Akira, Imachi M, Hashimoto T. Investigations into biochemical changes of genetic hypertensive rats using 1H Nuclear magnetic resonance-based metabonomics[J]. Hypertens Res.2005,28(5):525-530.
[12]Bridle JT, Nicholson JK, Schofield PM, et al. Application of chemometrics to NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertens ion [J]. Analyst.2003,128(1): 32-36.
[13]LU Yi-hong, HAO Hai-ping, WANG Guang-ji, et al. Matabolomics approach to the biochemical differentiation of traditional Chinese medicine syndrome types of hypertension[J].Chin J Clin Pharmacol Ther. 2007,10:1144-1150.
[14]孙广仁.中医基础理论[M].北京：中国中医药出版社,2002：215-216.
[15]Chobanian AV,Bakris GL,Black HR,et al.The Seventh Report of the Joint National Committee on Prevention,Detection,Evaluation,and Treatment of High Blood Pressure.The JNC-7 Report[J]. JAMA,2003, 289(19):2560-2571.
[16]Hajjar I, Kotchen TA.Trends in Prevalence, Awareness, Treatment, and Control of Hypertension in the United States,1988-2000[J].JAMA.2003,290(2):199-206.
[17]Muntner P, He J, Cutler JA, et al. Trends in blood pressure among children and adolescents [J]. JAMA, 2004,291(17):2107-2113.
[18]卫生部心血管病防治研究中心.中国心血管病报告2007[M].北京：中国大百科全书出版社,2007：2-3.
[19]科技部、卫生部、国家统计局.中国居民营养与健康现状.中国心血管病研究杂志,2004,12：919-922.
[20]毛焕元,杨心田主编.心脏病学[M].人民卫生出版社出版.2001年3月第2版：793-794.
[21]中华人民共和国卫生部,高血压联盟(中国),中国高血压防治指南(基层版),中华高血压杂志,2010,18(1)：11-29.
[22]李立明,胡永华.心血管疾病研究进展[M].北京：北京医科大学出版社,2001.
[23]刘力生.高血压[M].北京：人民卫生出版社,2001：289-319.
[24]Bakris GL,Hart P,Ritz E. Beta blockers in the management of chronic kidney disease[J].Kidney Int 2006, 70:1905-1913.
[25]张仁蓉,王一尘.交感神经与高血压关系的研究现状[J].中国心血管杂志1999,4(3)：181-183.
[26]Sarzani R, Salvi F, DessiFulgheri P, et al. Renin-angiotensin system, natriuretic peptides, obesity,metabolic syndrome, and hyperension:an integrated view in humans. J Hypertens,2008,26 (5):831-843.
[27]Defronzo R A,Kashyap S R.The insulin resistance syndrome:physiological considerations[J].Diab Vasc Dis Res,2007,4(1):13-19.
[28]GinerV,CocaA, de la SierraA. Increased insulin resistance in salt sensitive essential hypertension[J]. Hum Hypertens,2001,15 (7):481-485.
[29]PotenzaMA,MarasciuloFL,ChieppaDM, et al.Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production.Am J Physiol Heart Circ Physiol 2005,289(2):813-823.
[30]葛金文,梅志刚,朱惠斌.一种新的2型糖尿病血管并发症细胞研究模型：葡萄糖、胰岛素、低密度脂蛋白联合诱导血管内皮细胞损伤的研究[J].血栓与止血学,2005,11(6)：245-249.
[31]Wallace SM,Yasmin L,McEniery CM, et al. Isolate systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction[J]. Hypertension,2007,50:228-233.
[32]Murray Esler, Nora Straznicky, Nina Eikelis, et al。Mechanisms of Sympathetic Activation in Obesity -Related Hypertension[J]. Hypertension,2006,48:787-796.
[33]傅仁杰.老年高血压病的辨证论治[J].中医杂志.1993,34(8)：495.
[34]屈松柏,李家庚主编.实用中医心血管病学[M].北京科学技术文献出版社.1993年第1版：347-354.
[35]郑筱萸.中药新药临床研究指导原则[M].北京：中国医药科技出版社,2002：73-76.
[36]黎秋明.中医辨证分型治疗高血.压病103例[J].广西中医学院学报,2003,6(3)：48-49.
[37]高宇,李英华.高血压病的中医辨证论治[J].内蒙古中医药,2008,(6)：28-29.
[38]周春刚,张志斌,夏成霞,等.ACE I/D基因多态性与高血压中医证型的相关性[J].辽宁中医药大学学报,2010,]2(6)：68-71.
[39]孟云辉.PPAR γC161T基因多态性与原发性高血压证型的相关性研究[J].中国中医急症,2009,18(11)：1815-]816.
[40]高树彪,戴雁彦,王硕仁,等.高血压病不同中医证型左室舒张功能评价指标E/e比值的变化[J].北京中医药大学学报(中医临床版),2010,17(5)：7-9.
[41]刘福明,陈晓虎,杜午奇,等.高血压病中医证型与大动脉功能参数的相关研究[J].中国临床医学.2009,16(6)：972-974.
[42]张文,王剑,吕全胜.高血压病中医证型与同型半胱氨酸的相关性研究[J].新疆中医药,2010,28(4)：11-13.
[43]罗芳.高血压病中医证型与血脂关系的研究[J].现代中西医结合杂志,2010,19(28)：3588-3589.
[44]K jekdsen SE,Fansang C,Sleign P,et al 1999WHO/ISH hypertension guidelines-highlights and ESH update[J],Hypertension,2001,19(12):2285.
[45]Patowary S. Pharmacogenomics-Therapeutic and ethical issues [J].Kathmandu Univ Med J (KUMJ),2005,3:428-430. Shastry BS. Role of SNP/haplotype map in gene discovery and drug development: an overview[J].Drug Dev Res,2004,62:143-150.
[46]Stavroulakis GA,Makris TK,Krrapi PG,et al.Predicting response to chronic antihypertensive treatment with fosinoprit:the role of angiotensin-converting enayme gene polymorphism [J],Cardiovasc Drugs Ther.2000.14:427-432.
[47]Arnett DK, Davis BR, Ford CE, et al. Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment:the Genetics of hypertension associated treatment (GenHAT) study[J]. Circulation,2005, 111:3374-3383.
[48]Schelleman H, Klungel OH, van Duijn CM, et al. Drug-gene interaction between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and antihypertensive therapy [J]. Ann Pharmacother,2006,40:212-218.
[49]Cusi D, Barlassina C, Azzani T,et al. Polymorphisms of a-adducin and salt sensitivity in patients with essential hypertension[J]. Lancet,1997;349:1353-1357.
[50]Glorioso N, Manunta P, Filigheddu F,et al. The role of alpha-adducin polymorphism in blood pressure and sodium handing regulation may not be excluded by a negative association study[J]. Hypertension, 1999;34:649-654.
[51]侯嵘,刘治全,薛明战,等.α-内收蛋白Gly460Trp变异与中国汉族人原发性高血压的相关性研究[J].中华医学遗传学杂志,2000,17：413-416.
[52]许国旺等著.代谢组学——方法与应用[M].科学出版社,2008年8月：2.
[53]Nicholson, J. K., Lindon, J. C.,Holmes, E. " Metabonomics" under-standing themetabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectro-scopic data[J].Xenobiotica,1999,29(11):1181.
[54]Fiehn O.Metabolomics-the link between genotypes and phenotypes[J].Plant Mol Biol,2002,48:155.
[55]Taylor J, King RD, Altmann T et al. Application of metabonomics to plant genotype discrimination using statistics and machine learning[J]. Bioinformatics,2002,18:241.
[56]DAYKIN, C A., CORCORAN, O., HANSEN, S H et al.Application of directly coupled HPLC NMR to separation and characterization of lipoproteins from human serum[J].Analytical Chemistry,2001,73(6):1084.
[57]Nicholson JK, Holmes E, Lindon JC, et al. The challenges of mo-deling mammalian biocomplexity[J].Nat Biotechol,2004,22(10):1268.
[58]Clayton TA, Lindon JC, Cloarec O,etal.Pharmaco-metabonomic phenotyping and personalized drug treatment [J].Nature,2006,440(7087):1073-1077.
[59]Watkins S M, German J B.Toward the imp lementation of metabolomic assessments of human health and nutrition [J].CurrOp in Biotechnol,2002,13(5):512-516.
[60]邓铁涛.辨证论治[J].中国中医药信息杂志,2000,7(9)：1.
[61]简维雄.中医“证候”与代谢组学研究[J].中华中医药学刊,2009,27(2)：351.
[62]罗和古,陈家旭.代谢组学技术与中医证候的研究[J].中医药信息杂志,2007,14(5)：3.
[63]林景超,李后开,周明眉,等。代谢组学、药物代谢组学与中医药现代化[J],中国医学科学院学报,2007,29(6)：818-822.
[64]朱萱萱,王广基,阿基业,等.冠心病中医辨证分型的代谢组学研究[J].中华中医药学刊,2009,27(6)：1267.
[65]王广基,阿基业,严蓓,等.代谢组学研究冠心病中医分型的体内物质基础[J].世界科学技术--中医药现代化,2009,11(1)：127.
[66]冯雯,孙永宁.中医证候标准化现代化研究与代谢组学方法的应用[J].山东中医药大学学报,2009,33(2)：100.
[67]徐进秀,焦安饮.中医证候规范化研究的思路与设想[J].中国中医基础医学杂志,2005,11(4)：263.
[68]王桐生,谢鸣.代谢组学与中医药现代研究[J].中医杂志,2006,10(10)：724.
[69]罗和古,丁杰,岳广欣,等.大鼠肝郁脾虚证的代谢组学研究[J].中西医结合学报,2007,5(3)：307.
[70]徐舒,陈合兵,李洪,等.“肝郁证”大鼠模型的建立及代谢组学的初步研究[J].中华中医药杂志,2009,24(6)：787.
[71]刘树民,卢芳,王喜军,等.基于代谢组学的热病证候模型评价方法研究[J].中国药理学通报,2009,25(4)：549.
[72]吴斌,沈自尹,王丽丽,等.应用核磁共振代谢组技术研究生理性肾虚证[J].中医杂志,2009, 50(4)：338.
[73]简维雄,黄献平,陈清华,等.基于气相色谱-质谱的大鼠心血瘀阻证血浆代谢组学研究[J].中华中医药学刊2009,27(4)：796.
[74]刘国仗,胡大一,陶萍,等.心血管药物临床试验评价方法的建议[J].中华心血管病杂志,1998,26(1)：5-11.
[75]Nicholson JK, Holmes E, Lindon JC, et al. The challenges of mo-deling mammalian biocomplexity[J].Nat Biotechol,2004,22 (10):1268.
[76]董海琪.高血压病痰湿壅盛证现代科学内涵的代谢组学研究[D].南京中医药大学,2009.
[77]蒋海强,马斌,聂磊,等.高血压病肝阳上亢证患者血清样品的核磁共振谱代谢组学研究[J].药学实践杂志,20]0,28(4)：258-261.
[78]Kazuki AK, Misako IM.Investigations into biochemical changes of genetic hypertensive rats using 1H nuclear magnetic resonance-based metabonomics[J].Hypertens Res,2005,28:425-430.
[79]Lu Y,A J,Wang G,et al.Gas chromatography/time-of-flight mass spectrometry based metabonomic approach to differentiating hypertension-and age-related metabolic variation in spontaneously hypertensive rats[J].Rapid Commun Mass Spectrom,2008,22(18):2882-8.
[80]Keith NF.Non-esterified fatty acid metabolism and postprandial lipemia[J] Atherosclerosis,1998,141 (Suppl 1):S41-S46.
[81]Kraemer FB,Takeda D,Natu V,et al.Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin-and rapamycin sensitive pathways[J]. Metabolism,1998,47(5):555-559.
[82]Grekin RJ,Vollmer AP,Sider RS.Pressor effects of portalvenous oleate infusion:A proposed mechanism for obesity hypertension[J]. Hypertension,1995,26(1):193-198.
[83]Steinberg HO,Tarshoby M,Monestel R,et al.Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.J Clin Invest,1997,100(5):1230-1239.
[84]Lopes HF,Martin KL,Nashar K,et al.DASH diet lowers blood pressure and lipid-induced oxidative stress in obesity[J]. Hypertension,2003,41(3):422-430.
[85]Fagot-Campagna A,Balkau B,Simon D.et al.High free fatty acid concentration:an independent risk factor for hypertension in the Paris Prospective Study[J].Int J Epidemiol,1998,27(5):808-813.
[86]王顺,马爱群,宋少武,等.中青年高血压病患者动脉弹性功能与血浆脂肪酸[J].中华高血压杂志,2007,12(15)：992-996.
[87]王顺,脂肪酸代谢异常在高血压发病机制中的作用[J].国外医学·心血管疾病分册,2005,32(2)：80-82.
[88]Olivieri O, Lombardi S, Russo C, et al. Olivieri O, Lombardi S, Russo C, et al. Neutrophil arachidonic acid level and adhesive capability are increased in essential hypertension.J Hypertens,1998; 16(5):585-592.
[89]Steinberg HO,Tarshoby M,Monestel R,et al.Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.J Clin Invest,1997,100(5):1230-1239.
[90]Egan BM, StepniakowskiKT. Evidence linking fatty acids, the risk factor cluster, and vascular pathophysiology. Implicationsfor the diabetic hypertensive patient[M]. In:Sowers JR(ed). Contemporary Endocrinology:Endocrinology of the vasculature. TotowaMJ:Humana Press Inc,1996:157-172.
[91]Steinberg HO,Paradisi G,Hook Get al.Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production[J].Diabetes,2000,49(7):1231-1238.
[92]De Jongh RT, Serne EH, Ijzerman RG, et al.Free fatty acid level modulate microvascular function: relevance for obesity associated insulin resistance, hypertension, and microangiopathy[J].Diabetes,2004, 53:2873-2882.
[93]刘春兰,刘勇,曲卫,等.血浆游离氨基酸的水平变化与高血压病的相关性[J].实用医学杂志,2002,19(12)：926-928.
[94]高新星.高血压病的代谢组学研究[D].沈阳药科大学硕士学位论文,2008.
[95]安芳,张洪飞,林丽娜,等.高血压患者血浆中游离氨基酸的柱前衍生HPLC法测定[J].分析测试学报,2009,28(1)：72-75.
[96]高连如,刘国仗,赵云涛,等.内皮衍生舒张因子和成前体降压机制的研究[J].中华心血管病杂志,1996,6：117-124.
[97]Hishikawa K,Nakaki T,Suauki H,et al. Role of L-argininenitric oxide pathway in hypertension[J]. Hypetension,1993,11(6):639-645.
[98]Yamori y. et al. The hypotensive effect of centrally ad-ministrated tyrosine[J]. Tur J Phamacol 1980; 68:201-204.
[99]Sari E. et al. Cadiovascular effects of L-tyrosine innormotensive and hypertensive rats[J]. Eur J Pharmacol 1987; 143:27-34.
[100]Conlay LA. et al.Tyrosine increase blood pressure inhypotensive rats[J]. Science 1981,212:559-560.
[101]顾天华,赵光胜,陈庄.苯丙氨酸阻止幼年自发性高血压大鼠血压升高机理的初步探讨[J].中华心血管病杂志,1994,22(4)：297-299.
[102]贾晓波,庞会从.L-羟脯氨酸用于减肥的实验研究[J].氨基酸和生物资源,2003,25(3)：60-62.
[103]张能,方海立,张徽,等.牛磺酸对链尿佐菌素糖尿病鼠胰岛β细胞功能的保护作用[J].中国糖尿病杂志,1998,6(1)：30.
[104]任晓丽,杨波,黄陈平,等.高蛋氨酸饮食对大鼠血管内皮细胞分泌功能的影响[J].氨基酸和生物资源,2010,32(4)：50-54.
[105]汪昌树,顾统元,黎明.高血压并心、脑、肾损害患者血浆5—轻色胺和去肾上腺素的变化[J].心血管康复医学杂志,2000,2(9)：297-299.
[106]Ji-ye AA, Guang-ji WANG, Hai-ping HAO, et al.Differential regulations of blood pressure and perturbed metabolism by total ginsenosides and conventional antihypertensive agents in spontaneously hypertensive rats[J].Acta Pharmacologica Sinica (2010) 31:930-937.
[107]Paker M, Nieod P, Khanderla BR, et al. Randomized multicenter double blind Placebo controlled evaluation of amlodipine in Patients with mild to moderate heart failure[J].J Am Coll Cardiol,1991; 15:77.
[108]Ueshiba H, Tsuboi K, Miyachi Y. Effects of amlodipine on serum levels of adrenal androgens and insulin in hypertensive men with obesity[J].Horm Metab Res.2001 Mar;33(3):167-169.
[109]KAPLAN N M. Effects of antihypertensive therapy on insulin resistence[J]. Hypertension,1992,19(suppl 1):116-118.