钩藤提取液对自发性高血压大鼠尿液代谢组学的影响
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摘要
目的探讨钩藤的降血压作用及可能作用机制。方法 18只自发性高血压(SHR)大鼠随机分为钩藤组和模型组各9只,9只Wistar大鼠作为正常组。钩藤组大鼠给予钩藤提取液10. 001 g/(kg·d)灌胃,模型组和正常组给予2 ml生理盐水灌胃,每日1次,持续4周。分别于实验0、1、2、3、4周时测定各组大鼠收缩压和舒张压,于实验4周时基于高效液相色谱-飞行时间质谱(HPLC-TOF/MS)技术,分析各组大鼠尿液代谢标志物的变化。结果模型组和钩藤组在0、1、2、3、4周时收缩压和舒张压均明显高于同时间点正常组(P <0. 01)。与模型组同时间点比较,钩藤组收缩压在2、3、4周时降低(P <0. 05);并且钩藤组在4周时收缩压和舒张压均较本组0、1、2、3周时降低(P <0. 05或P <0. 01)。共筛选出12个差异代谢标志物,分析发现钩藤干预后存在雄激素与雌激素代谢、α-亚麻酸和亚油酸代谢、精氨酸与脯氨酸代谢上调,花生四烯酸代谢、部分鞘脂代谢及色氨酸代谢下调。结论钩藤具有良好的降压效果,对一氧化氮的调控是其发挥降压作用的重要环节。
Objective To explore the anti-hypertensive effect and possible mechanism of Guoteng( Uncaria Rhynchophylla). Methods A total of 18 spontaneously hypertensive( SHR) rats were equally divided into a Guoteng group and a model group,and 9 Wistar rats were selected as the normal group. The rats in the Guoteng group were given 10. 001 g/( kg·d) of the extracting solution of Guoteng( Uncaria Rhynchophylla),and the rats in the model group and the normal group were given 2 ml of normal saline,and were intragastrically administered once a day for 4 weeks. Systolic and diastolic blood pressure were measured in each group after treated 0,1,2,3,and 4 weeks.The changes of urine metabolic markers in each group were analyzed by high performance liquid chromatography with time-of-flight mass spectrometry( HPLC-TOF/MS) after 4 weeks. Results The systolic and diastolic blood pressures of the model group and the Guoteng group were significantly higher than those of the normal group in 0,1,2,3,and 4 weeks( P < 0. 01). Compared with the model group,the systolic blood pressure of the Guoteng group was decreased in 2,3,and 4 weeks( P < 0. 05),and the systolic and diastolic blood pressures of the Guoteng group were lower in 4 weeks than those in the 0,1,2 and 3 weeks( P < 0. 05 or P < 0. 01). A total of 12 distinctive biomarkers were screened,and analysis showed that the androgen and estrogen metabolism,α-linolenic acid and linoleic acid metabolism,arginine and proline metabolism up-regulation,arachidonic acid metabolism,sphingolipid metabolism,and tryptophan metabolism were down-regulated. Conclusion Guoteng( Uncaria Rhynchophylla) has a good antihypertensive effect,and an important part of its antihypertensive effect is the regulation of nitric oxide.
Objective To explore the anti-hypertensive effect and possible mechanism of Guoteng( Uncaria Rhynchophylla). Methods A total of 18 spontaneously hypertensive( SHR) rats were equally divided into a Guoteng group and a model group,and 9 Wistar rats were selected as the normal group. The rats in the Guoteng group were given 10. 001 g/( kg·d) of the extracting solution of Guoteng( Uncaria Rhynchophylla),and the rats in the model group and the normal group were given 2 ml of normal saline,and were intragastrically administered once a day for 4 weeks. Systolic and diastolic blood pressure were measured in each group after treated 0,1,2,3,and 4 weeks.The changes of urine metabolic markers in each group were analyzed by high performance liquid chromatography with time-of-flight mass spectrometry( HPLC-TOF/MS) after 4 weeks. Results The systolic and diastolic blood pressures of the model group and the Guoteng group were significantly higher than those of the normal group in 0,1,2,3,and 4 weeks( P < 0. 01). Compared with the model group,the systolic blood pressure of the Guoteng group was decreased in 2,3,and 4 weeks( P < 0. 05),and the systolic and diastolic blood pressures of the Guoteng group were lower in 4 weeks than those in the 0,1,2 and 3 weeks( P < 0. 05 or P < 0. 01). A total of 12 distinctive biomarkers were screened,and analysis showed that the androgen and estrogen metabolism,α-linolenic acid and linoleic acid metabolism,arginine and proline metabolism up-regulation,arachidonic acid metabolism,sphingolipid metabolism,and tryptophan metabolism were down-regulated. Conclusion Guoteng( Uncaria Rhynchophylla) has a good antihypertensive effect,and an important part of its antihypertensive effect is the regulation of nitric oxide.
引文
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[7]焦华琛,李运伦,姜月华,等.钩藤总生物碱和芥子碱硫氰酸盐组分配伍对血管内皮细胞的变化作用和机制[J].中国动脉硬化杂志,2013,21(5):397-403.
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[12]王丽,汪佩,李岩鹏,等. 17β-雌二醇和2-甲氧基雌二醇对慢性低氧性肺动脉高压大鼠体内内皮素-1/一氧化氮体系的影响[J].中国循环杂志,2016,31(5):489-494.
[13]HOX V,DESAI A,BANDARA G,et al. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production[J]. J Allergy Clin Immunol,2015,135(3):729-736.
[14]RESLAN OM,KHALIL RA. Vascular effects of estrogenic menopausal hormone therapy[J]. Rev Recent Clin Trials,2012,7(1):47-70.
[15]AKISHITA M,HASHIMOTO M,OHIKE Y,et al. Low testosterone level is an independent determinant of endothelial dysfunction in men[J]. Hypertens Res,2007,30(11):1029-1034.
[16]WYNNE FL,KHALIL RA. Testosterone and coronary vascular tone:implications in coronary artery disease[J].J Endocrinol Invest,2003,26(2):181-186.
[17]ZHARIKOVA OL,DESHMUKH SV,NANOVSKAYA TN,et al. The effect of methadone and buprenorphine on human placental aromatase[J]. Biochem Pharmacol,2006,71(8):1255-1264.
[18]TAKEUCHI S,MUKAI N,TATEISHI T,et al. Production of sex steroid hormones from DHEA in articular chondrocyte of rats[J]. Am J Physiol Endocrinol Metab,2007,293(1):E410-E415.
[19]CAMPOREZ JP,AKAMINE EH,DAVEL AP,et al. Dehydroepiandrosterone protects against oxidative stressinduced endothelial dysfunction in ovariectomized rats[J]. J Physiol,2011,589(Pt 10):2585-2596.
[20] KERAGE D, BRINDLEY DN, HEMMINGS DG.Review:novel insights into the regulation of vascular tone by sphingosine 1-phosphate[J]. Placenta, 2014,35(Suppl):S86-S92.
[21]ZHANG QJ,HOLLAND WL,WILSON L,et al. Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the e NOS-Akt complex[J]. Diabetes,2012,61(7):1848-1859.
[22]DON AS,ROSEN H. A lipid binding domain in sphingosine kinase 2[J]. Biochem Biophys Res Commun,2009,380(1):87-92.
[2]WEBERA MA,SCHIFFRINB EL,WHITE WB,et al.Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of Hypertension[J]. J Hypertens,2014,32(1):3-15.
[3]GEORGIANOS PI,SARAFIDIS PA,LIAKOPOULOS V.Arterial stiffness:a novel risk factor for kidney injury progression?[J]. Am J Hypertens,2015,28(8):958-965.
[4]LI Y,YANG W,ZHU Q,et al. Protective effects on vascular endothelial cell in N'-nitro-L-arginine(L-NNA)-induced hypertensive rats from the combination of effective components of Uncaria rhynchophylla and Semen Raphani[J]. Biosci Trends,2015,9(4):237-244.
[5]ZHOU J,ZHOU S. Isorhynchophylline:A plant alkaloid with therapeutic potential for cardiovascular and central nervous system diseases[J]. Fitoterapia,2012,83(4):617-626.
[6]NDAGIJIMANA A,WANG X,PAN G,et al. A review on indole alkaloids isolated from Uncaria rhynchophylla and their pharmacological studies[J]. Fitoterapia,2013,86:35-47. doi:10. 1016/j. fitote. 2013. 01. 018.
[7]焦华琛,李运伦,姜月华,等.钩藤总生物碱和芥子碱硫氰酸盐组分配伍对血管内皮细胞的变化作用和机制[J].中国动脉硬化杂志,2013,21(5):397-403.
[8]LI YL,JIANG YH,YANG CH,et al. Enhanced protective effect of the combination of uncaria and semen raphani on vascular endothelium in spontaneously hypertensive rats[J]. Evid Based Complement Alternat Med,2015,2015:358352. doi:10. 1155/2015/358352.
[9]ZHANG C,HEIN T,WANG W,et al. Upregulation of vascular arginase in hypertension decreases nitric oxidemediated dilation of coronary arterioles[J]. Hypertension,2004,44(6):935-943.
[10]DE MEIRELLES LR,MENDES-RIBEIRO AC,MENDES MA,et al. Chronic exercise reduces platelet activation in hypertension:upregulation of the L-arginine-nitric oxide pathway[J]. Scand J Med Sci Sports,2009,19(1):67-74.
[11]ARIAS-LOZA PA,HU K,DIENESCH C,et al. Both estrogen receptor subtypes,alpha and beta,attenuate cardiovascular remodeling in aldosterone salt-treated rats[J]. Hypertension,2007,50(2):432-438.
[12]王丽,汪佩,李岩鹏,等. 17β-雌二醇和2-甲氧基雌二醇对慢性低氧性肺动脉高压大鼠体内内皮素-1/一氧化氮体系的影响[J].中国循环杂志,2016,31(5):489-494.
[13]HOX V,DESAI A,BANDARA G,et al. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production[J]. J Allergy Clin Immunol,2015,135(3):729-736.
[14]RESLAN OM,KHALIL RA. Vascular effects of estrogenic menopausal hormone therapy[J]. Rev Recent Clin Trials,2012,7(1):47-70.
[15]AKISHITA M,HASHIMOTO M,OHIKE Y,et al. Low testosterone level is an independent determinant of endothelial dysfunction in men[J]. Hypertens Res,2007,30(11):1029-1034.
[16]WYNNE FL,KHALIL RA. Testosterone and coronary vascular tone:implications in coronary artery disease[J].J Endocrinol Invest,2003,26(2):181-186.
[17]ZHARIKOVA OL,DESHMUKH SV,NANOVSKAYA TN,et al. The effect of methadone and buprenorphine on human placental aromatase[J]. Biochem Pharmacol,2006,71(8):1255-1264.
[18]TAKEUCHI S,MUKAI N,TATEISHI T,et al. Production of sex steroid hormones from DHEA in articular chondrocyte of rats[J]. Am J Physiol Endocrinol Metab,2007,293(1):E410-E415.
[19]CAMPOREZ JP,AKAMINE EH,DAVEL AP,et al. Dehydroepiandrosterone protects against oxidative stressinduced endothelial dysfunction in ovariectomized rats[J]. J Physiol,2011,589(Pt 10):2585-2596.
[20] KERAGE D, BRINDLEY DN, HEMMINGS DG.Review:novel insights into the regulation of vascular tone by sphingosine 1-phosphate[J]. Placenta, 2014,35(Suppl):S86-S92.
[21]ZHANG QJ,HOLLAND WL,WILSON L,et al. Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the e NOS-Akt complex[J]. Diabetes,2012,61(7):1848-1859.
[22]DON AS,ROSEN H. A lipid binding domain in sphingosine kinase 2[J]. Biochem Biophys Res Commun,2009,380(1):87-92.