硫酸多糖DPS对肾血管性高血压大鼠的降压作用及其相关机制(英文)

目的:观察硫酸多糖(DPS)对肾血管性高血压大鼠的降压作用并对其机制进行初步探讨。方法:(1)急性降压实验:DPS单次舌下静脉注射给药,给药前后以颈总动脉插管法测定大鼠动脉血压和心率。(2)口服预防给药实验:在肾血管性高血压大鼠造模第二天起口服预防给药五周,每日一次。于给药前、后第三周和第六周分别以大鼠尾动脉测压法测定动脉血压和心率。实验结束前,将大鼠断头取血,测定血清中一氧化氮(NO)的含量;用放射免疫法测定血浆中血管紧张素Ⅱ(Ang Ⅱ)和内皮素-1(ET-1)的含量。血管紧张素转化酶抑制剂卡托普利作为口服预防给药实验阳性对照药。结果:在急性降压实验中,DPS能够显著降低肾血管性高血压大鼠的收缩压和舒张压且其降压强度呈剂量依赖性,降压的同时伴有心率减慢。DPS口服预防给药五周,剂量依赖性抑制大鼠的收缩压和舒张压升高,DPS 50 mg/kg的降压效果与卡托普利14 mg/kg相当。DPS给药五周,可显著增加血清中NO的含量和降低血浆中ET-1的含量;亦降低血浆中Ang Ⅱ的含量。结论:硫酸多糖DPS对肾血管性高血压大鼠具有良好的降压作用。其降压机制可能与其促进体内NO生成或释放、降低ET-1和Ang Ⅱ的含量有关。     

鲜铁皮石斛对自发性高血压大鼠的降压作用及机制研究

目的 观察鲜铁皮石斛对自发性高血压（spontaneously hypertensive,SH）大鼠的降压作用及可能机制。方法 将24只SH大鼠随机分为3组,鲜铁皮石斛组（生药量0.8 g·kg^-1）、络活喜组（0.5 mg·kg^-1）和模型组,另设正常对照组。经口每日等容量给药,给药前测量3次血压,给药后每周测量1次2 h血压。治疗8周后测量血浆中血管紧张素Ⅰ（angiotensinⅠ,AngⅠ）、血管紧张素Ⅱ（angiotensin Ⅱ,AngⅡ）、肾素活性（renin activity,RA）、醛固酮（aldosterone,ALD）,并用RT-qPCR法检测肾组织中血管紧张素Ⅱ1型受体（angiotensin Ⅱ receptor type 1,AT1R）、内皮素-1 mRNA表达水平。结果 与模型组相比,鲜铁皮石斛和络活喜2组在每个给药时点后收缩压和舒张压均显著降低（P<0.05）;鲜铁皮石斛组和络活喜组相比,仅在给药1周收缩压和舒张压有显著性差异（P<0.05）,其余时点血压无显著差异。与模型组相比,鲜铁皮石斛组和络活喜组AT1R mRNA水平显著降低,差异具有显著性（P<0.05）;两治疗组相比,无显著差异。鲜铁皮石斛组和络活喜组对AngⅠ、AngⅡ、RA及ALD激素水平没有显著改变。结论 鲜铁皮石斛能够显著降低SH大鼠血压水平,降压效果与西药络活喜接近,可能通过降低AT1R mRNA水平起作用。     

性别及雌激素水平对肾血管性高血压大鼠血管组织ACE_1-AngⅡ-ATR轴的影响

目的探讨性别及雌激素水平对肾血管性高血压(RVH)大鼠血管组织中血管紧张素转换酶1(ACE1)-血管紧张素Ⅱ(AngⅡ)-血管紧张素受体(ATR)轴的影响。方法45只SPF级SD大鼠制备两肾一夹(2K1C) RVH动物模型,分为雌性手术组(2K1C-F)、雄性手术组(2K1C-M)、雌性去势组(2K1C-OVX)。常规喂养32周,测量血压;取血,检测血清中雌二醇的浓度,血浆中AngⅡ的浓度;检测血管组织中ACE1、血管紧张素1型受体(AT_1R)和2型受体(AT_2R)的mRNA及蛋白表达。结果 2K1C-F组的收缩压明显高于2K1C-M组和2K1C-OVX组(P <0. 05)。2K1C-F组的AngⅡ的含量明显低于2K1C-M组和2K1C-OVX组(P<0. 01)。与2K1C-F组相比,2K1C-M组ACE1、AT_1R、AT_2R的mRNA及蛋白表达明显上调(P <0. 05),2K1C-OVX组ACE1、AT_1bR的mRNA表达明显上调(P <0. 05),AT_2R的mRNA表达明显下调(P <0. 05);与2K1C-M组比较,2K1COVX组ACE1、AT_1bR、AT_2R mRNA的表达,以及ACE1、AT_2R的蛋白表达明显下调(P <0. 05)。结论血管组织中ACE1、AngⅡ、AT_1aR、AT_1bR的mRNA及蛋白表达存在性别及雌激素差异性,雌激素可降低ACE1-AngⅡ-AT_1R轴的活性。     

益心脑滴丸对肾性高血压大鼠的降压作用及其机制研究

目的探讨益心脑滴丸对肾性高血压大鼠(RHR)的降压作用及机制。方法构建两肾一夹(2K1C)经典肾性高血压大鼠模型,选取造模成功的大鼠并按收缩压水平分为模型组,益心脑高、中、低剂量组(2,1,0.5 g·kg^(-1)·d^(-1))及卡托普利组(25 mg·kg^(-1)·d^(-1)),同时设立假手术组,每组8只。灌胃给药每日1次,每周末测量血压,6周后处死并检测血浆内皮素(ET)和一氧化氮(NO),总抗氧化能力(T-AOC)、丙二醛(MDA)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和肾组织活性氧(ROS)、谷胱甘肽过氧化物酶(GSH-Px)的变化;用酶联免疫法(ELISA)检测血浆肾素活性(RA)及血管紧张素Ⅰ(AngⅠ),AngⅡ的含量。结果益心脑滴丸能明显降低高血压大鼠收缩压(SBP)(P<0.05);增加血浆NO,降低ET含量(P<0.05);降低ROS和MDA的含量,提高抗氧化酶SOD,CAT和GSH-Px活性(P<0.05),使T-AOC增强;升高血浆AngⅠ含量,降低血浆AngⅡ含量(P<0.05)。结论益心脑滴丸有一定的降压作用,其机制可能与抗氧化,影响肾素-血管紧张素系统有关。     

抗血管生成药物致高血压的降压治疗的合理用药

高血压是抗血管生成药物常见不良反应之一,多为轻、中度。一般通过标准降压治疗即可控制,而严重者可影响患者的抗肿瘤疗效果甚至中断靶向药物治疗。因此,合理选择降压药物对于患者的抗肿瘤治疗具有重要意义。笔者主要探讨抗血管生成药物致高血压的降压药物选择,以期为临床用药提供参考。     

室旁核血管紧张素Ⅱ在慢性间歇性低氧诱发大鼠高血压中的作用及机制

目的研究下丘脑室旁核(paraventricular nucleus,PVN)中血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)在慢性间歇性低氧(chronic intermittent hypoxia,CIH)诱发高血压大鼠中的作用及机制。方法将♂SD大鼠随机分为对照(Sham)组和慢性间歇性低氧(CIH)组(每日8 h,连续15d)。用无创套尾法测大鼠尾动脉收缩压(SBP)和动脉插管法记录平均动脉压(MAP)、心率(HR),用立体定位仪进行PVN核团定位并微量注射药物,用Western blot测定PVN中AngⅡ水平及AngⅡ1型受体(AT1R)蛋白表达。结果与Sham组相比,CIH组大鼠PVN内AngⅡ水平及AT1R表达明显增加。双侧PVN内微量注射AngⅡ(0.03、0.3、3 nmol),均可剂量依赖性地升高Sham组和CIH组大鼠MAP,且CIH大鼠MAP升高更明显;双侧PVN内微量注射AT1R阻断剂氯沙坦(50 nmol),对Sham大鼠血压没有影响,但可使CIH大鼠血压降低,并抑制AngⅡ升压作用。结论室旁核中AngⅡ及AT1R功能上调在慢性间歇性低氧诱发大鼠高血压中起重要作用。     

替米沙坦对肾性高血压大鼠外周血单核细胞趋化因子1的影响

目的 探讨替米沙坦对肾性高血压大鼠外周血单核细胞趋化因子1(MCP-1)、血管紧张素Ⅱ(AngⅡ)的作用.方法 24只SD大鼠随机分为假手术组(A组,6只)、两肾一夹组(B组,9只)和替米沙坦10 mg·kg-1·d-1组(C组,9只).采用两肾一夹方法制备高血压模型,分别于手术前后经动脉插管测血压,术后4周收集腹主动脉血,用放射免疫法及ELISA分别检测血清AngⅡ和MCP-1水平.结果 术后B组血压、MCP-1水平较A、C组明显升高(P＜0.01);与A组比较,B组及C组AngⅡ水平均增加(P＜0.01).结论 替米沙坦可降低肾性高血压大鼠外周血MCP-1水平,这可能是其另一降压机制.     

AT1R基因A1166C多态性与缬沙坦降压疗效无关

目的探讨AT1R基因A／C多态性与血管紧张素II受体拮抗剂缬沙坦降压疗效的关系。方法55例高血压患者,每日晨服缬沙坦80mg,连续8周,每2周随访一次。观察结束后应用聚合酶链反应一限制性片段长度多态性方法测定所有患者AT．R基因的A／C多态性基因型。将高血压患者分为AC＋CC组和AA组。观察二组治疗前及治疗后2、4、6、8周的血压水平。结果治疗前AC＋CC组和AA组收缩压与舒张压均无差别。治疗后二组的血压逐步下降,在2、4、6、8周时收缩压及舒张压水平无差别。结论AT1R基因A／C多态性与缬沙坦的降压效果无关。     

依那普利对2型糖尿病大鼠血浆AngII水平及血管、肾脏AT_1受体表达的影响

目的　研究依那普利对2型糖尿病大鼠血浆AngII和AT1受体表达的影响。方法用放射免疫法测定 血浆AngII水平,免疫组化法观察血管和肾脏AT1受体表达。结果　糖尿病大鼠血浆AngII明显高于对照组,应用依那普利后大鼠血浆AngII明显降低。免疫组化染色发现糖尿病大鼠血管内皮细胞、平滑肌细胞和肾脏AT1受体表达明显增加,依那普利治疗组大鼠血管内皮细胞、平滑肌细胞和肾脏AT1受体表达与正常组接近。结论　糖尿病大 鼠血浆AngII升高,血管和肾脏AT1受体表达增加,依那普利可降低糖尿病大鼠血浆AngII水平,下调血管和肾脏 AT受体表达。     

消旋TJ0711长期给药对肾性高血压大鼠的药效学研究

观察消旋TJ0711长期给药对肾性高血压大鼠的血压、心率的影响及对心血管的保护作用。制备两肾一夹型肾性高血压大鼠模型(renal hypertensive rats,RHR),将血压升高4 kPa的大鼠随机分为消旋TJ071110、20及40 mg.kg 1剂量组、卡维地洛阳性对照组和模型组以及假手术组(n=10)。每日1次灌胃给药。每周测量给药前后的血压和心率。于6～8周尾部取血,测定血浆丙二醛(MDA)、肾素、血管紧张素II(Ang II)和内皮素-1(ET-1)含量;9周后取左心室测左心室重量指数(LVWI)和羟脯氨酸含量。给药4周后,TJ0711 40 mg.kg 1剂量组的血压较第1周给药前显著降低,该作用一直延续至实验结束。TJ0711 10、20及40 mg.kg 1剂量组血浆中MDA、肾素、Ang II和ET-1含量均显著低于模型组(P<0.05,P<0.01),LVWI和心肌羟脯氨酸含量有降低趋势。结果显示,TJ0711连续给药后使给药前的血压值持续下降,除了直接阻断肾上腺素α和β受体产生降压外,其持续降压作用与减少血浆中缩血管物质和氧化产物MDA有关,这有利于对心血管发挥保护作用。     

A complicated role for the renin–angiotensin system during pregnancy: highlighting the importance of drug discovery

Introduction: Blood pressure management is recommended to avoid maternal cerebrovascular or cardiovascular compromise during pregnancy. Current antihypertensive treatment during pregnancy with positive safety profiles includes labetalol, hydralazine, methyldopa and nifedipine.

Areas covered: Many earlier animal and human studies indicate that angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are associated with fetopathy; therefore, these drugs are contraindicated during pregnancy, especially if these medications were taken during the second and third trimesters. The role of the RAS is quite complex, with fetal development heavily dependent on its appropriate expression and function. New findings indicate that the placental unit expresses its own RAS in order to regulate angiogenesis. Multiple studies have shown that women with abnormal uterine doppler sonography produce an agonistic autoantibody to the angiotensin I receptor, implicating a role for RAS function and regulation in abnormal pregnancies. Importantly, interruption of a normal RAS compromises fetal development.

Expert opinion: Traditional medications that inhibit components of RAS for long-term hypertension control are not appropriate for use before or during pregnancy. Further study and drug discovery are needed to find alternative pathways for treatment of hypertensive disorders when pregnancy is present or a possibility.     

甘草次酸抑制K562细胞增殖的机制的实验研究

目的:探讨甘草次酸(GA)抑制K562细胞增殖的机制.方法:对体外培养的K562细胞体系,采用MTT,放免,免疫组织化学的测定方法.结果:K562细胞抑制率与GA浓度及用药后培养时间呈正相关性.GA作用48 h后细胞上清液中血管紧张素Ⅱ(AngⅡ)含量明显上升.K562细胞中检测到AngⅡ 1型受体(AT1R)及2型受体(AT2R)蛋白的表达,但GA对其表达的影响无统计学意义.结论:GA可能通过抑制AngⅡ与AT1R的结合而抑制肿瘤细胞的增殖.     

Irbesartan treatment up-regulates hepatic expression of PPAR�� and its target genes in obese Koletsky (fak/fak) rats: a link to amelioration of hypertriglyceridaemia

BACKGROUND AND PURPOSE

Hypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well-established angiotensin II type 1 receptor (AT₁) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear.

EXPERIMENTAL APPROACH

Male obese Koletsky (fa^k/fa^k) rats, which exhibit spontaneous hypertension and metabolic abnormalities, received irbesartan (40 mg·kg⁻¹·day⁻¹) or vehicle by oral gavage over 7 weeks. Adipocyte-derived hormones in plasma were measured by ELISA. Gene expression in liver and other tissues was assessed by real-time PCR and Western immunoblotting.

KEY RESULTS

In Koletsky (fa^k/fa^k) rats irbesartan lowered plasma concentrations of triglycerides and non-esterified fatty acids, and decreased plasma insulin concentrations and the homeostasis model assessment of insulin resistance index. However, this treatment did not affect food intake, body weight, epididymal white adipose tissue weight, adipocyte size and plasma leptin concentrations, although plasma adiponectin was decreased. Irbesartan up-regulated hepatic expression of mRNAs corresponding to peroxisome proliferator-activated receptor (PPAR)α and its target genes (carnitine palmitoyltransferase-1a, acyl-CoA oxidase and fatty acid translocase/CD36) that mediate hepatic fatty acid uptake and oxidation; the increase in hepatic PPARα expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARγ and its downstream genes or hepatic genes that mediate fatty acid synthesis.

CONCLUSIONS AND IMPLICATIONS

These findings demonstrate that irbesartan treatment up-regulates PPARα and several target genes in liver of obese spontaneously hypertensive Koletsky (fa^k/fa^k) rats and offers a novel insight into the lipid-lowering mechanism of irbesartan.     

抗高血压新药选择性AT1亚型血管紧张素II受体拮抗剂——阿齐沙坦酯

阿齐沙坦酯为新一代选择性AT1血管紧张素II亚型1受体拮抗剂,临床前和临床研究证实其具有平稳持久的抗高血压作用。2011年2月25日,FDA批准阿齐沙坦酯(商品名为Edarbi)用于治疗成人高血压。本综述主要介绍其药物作用机制,药物代谢动力学、疗效、安全性及临床研究进展。     

Functional coupling of angiotensin II type 1 receptor with insulin resistance of energy substrate uptakes in immortalized cardiomyocytes (HL-1 cells)

BACKGROUND AND PURPOSE: Increased angiotensin II levels and insulin resistance coexist at the early stages of cardiomyopathies. To determine whether angiotensin II increases insulin resistance in cardiomyocytes, we studied the effect of angiotensin II on basal and insulin-stimulated transport rate of energy substrates in immortalized cardiomyocytes (HL-1 cells). EXPERIMENTAL APPROACH: Glucose and palmitic acid uptakes were measured using [(3)H]2-deoxy-D-glucose and [(14)C]palmitic acid, respectively, in cells exposed or not exposed to angiotensin II (100 nM), angiotensin II plus irbesartan or PD123319, type 1 and 2 receptor antagonists, or PD98059, an inhibitor of ERK1/2 activation. Cell viability, DNA, protein synthesis and surface area were evaluated by the MTT test, [(3)H]thymydine, [(3)H]leucine and morphometric analysis, respectively. Type 1 receptor levels were measured by western blot analysis. KEY RESULTS: Basal uptakes of glucose and palmitic acid by HL-1 cells (0.37+/-0.07 and 7.31+/-0.22 pmol per 10(4)cells per min, respectively) were both stimulated by 100 nM insulin (+91 and +64%, respectively). Cells exposed to angiotensin II remained viable and did not show signs of hypertrophy. In these conditions, the basal palmitic acid uptake of the cells increased (11.41+/-0.46 pmol per 10(4) cells per min) and insulin failed to stimulate the uptake of glucose and fatty acids. Changes in the rate of uptake of energy substrates were prevented or significantly reduced by irbesartan or PD98059. CONCLUSIONS AND IMPLICATIONS: Angiotensin II is a candidate for increasing insulin resistance in cardiomyocytes. Our results suggest a further mechanism for the cardiovascular protection offered by the angiotensin II type 1 receptor blockers.     

Farnesoid X receptor regulates vasoreactivity via Angiotensin II type 2 receptor and the kallikrein‐kinin system in vascular endothelial cells

Vascular farnesoid X receptor (FXR) ligands have been shown previously to regulate vascular tension. This study investigated whether FXR activation regulates vasoreactivity via the angiotensin II (Ang II) type 2 receptor (AT₂R) and the kallikrein‐kinin system in rat aortic vascular endothelial cells (RAECs). Protein abundances of Ang II type 1 receptor (AT₁R), AT₂R, bradykinin type 1/2 receptor (B₁R, B₂R), small heterodimer partner‐1 (SHP‐1) and the endothelial and inducible NO synthases (eNOS/iNOS) were analysed by Western blotting. Real‐time quantitative polymerase chain reaction was performed to analyse expression of eNOS and iNOS mRNA. Kallikrein activity and bradykinin content were assayed using spectrophotometry and a bradykinin assay kit, respectively. Aortic vasoconstriction and vasodilation were also investigated following FXR activation in the presence or absence of AT₂R and B₂R blockade. It was found that the FXR agonists GW4064 and INT‐747, in a dose‐dependent manner, increased the protein abundance of AT₂R, B₂R and SHP‐1 and decreased that of AT₁R. AT₂R blockade with PD123319 reversed effects of FXR agonists on kallikrein activity and levels of SHP‐1, B₂R and bradykinin. Moreover, it was found that GW4064 and INT‐747 upregulated expression of eNOS and enhanced NOS activity, which attenuated vasoconstriction and induced vasodilation, respectively. These effects were partially reversed by PD123319 and by B₂R blockade with HOE140. The current work suggests that FXR regulates vascular tension by controlling the eNOS‐NO system via activation of a pathway mediated by AT₂R‐B₂R pathway in RAECs.     

THE A1166C MUTATION IN THE ANGIOTENSIN II TYPE I RECEPTOR AND HYPERTENSION IN THE ELDERLY

1. Using a nested case-control study of 661 non-institutionalized elderly (> or = 60 years) residents of Dubbo, New South Wales, Australia, the aim of this study is to determine whether the A1166C polymorphism of the angiotensin II type I (AT1) receptor gene is associated with hypertension in the elderly. 2. Individuals were classified as isolated systolic hypertension (ISH, n = 146), systolic diastolic hypertension (SDH, n = 188), or normotensive, age- and sex-matched controls (n = 327). AA, CC and AC genotypes were determined using restriction fragment length polymorphism analysis of DNA generated by nested polymerase chain reaction. 3. A univariate analysis (chi 2) was complemented by a logistic regression analysis, facilitating adjustment for potential confounders. The unadjusted genotype and allele frequencies in ISH or SDH subjects did not differ significantly from the control subjects (chi 2 = 3.0, P = 0.55, 4 d.f.; chi 2 = 3.0, P = 0.23, 2 d.f., respectively). After adjustment for potential confounders neither genotype nor allele predicted ISH or SDH in this cohort. 4. From this study we conclude that the A1166C polymorphism of the AT1 receptor gene is not a marker for ISH nor for SDH in this large, elderly community sample.