Role of angiotensin in normal blood pressure regulation

Summary Antiangiotensin II plasma induced transitory hypotension in rats when 0.2 ml was injected intravenously in normal males (either awake or anaesthetized), into binephrectomized females or into some males which had been nephrectomized 18–22 or 42–53 hours previously. Antiangiotensin II did not affect the blood pressure of male rats when given between 24 and 26 hours after nephrectomy. Antiangiotensin resulted in a 10–200 fold increase in the dose of angiotensin required to produce a measurable change in blood pressure, and also significantly reduced reactivity to l-noradrenaline.A remaining plasma renin activity was constantly found in binephrectomized females and in most of binephrectomized males. Plasma renin activity was significantly higher in the former than in the latter. It is concluded that angiotensin plays a role in the maintanance of blood pressure, in normal rats, in binephrectomized females and in some binephrectomized males.This work was supported by Grant 67-00-517 from D.G.R.S.T. (Délégation Générale à la Recherche Scientifique et Technique).This study was presented in part at the third Annual Meeting of the European Society for clinical Investigation, Scheveningen, Holland, April 26th 1969, and at the National Meeting of the American Federation for clinical Research, Atlantic City, N.J., U.S.A., May 4th 1969.     

血管紧张素II及其受体在血管平滑肌细胞迁移中的作用

目的:探讨血管紧张素II(AngII)及其受体(ATRs)在局部血管损伤后血管平滑肌细胞(VSMC)迁移中的作用及其机制。方法:以体外培养VSMC为基础,采用细胞化学和改良Boyden'schamber的方法,观察AngⅡ干预VSMC后AngII受体的表达、VSMC迁移能力的变化、肌动蛋白纤维丝的动态组装变化,并探讨AT₁R拮抗剂、AT₂R拮抗剂对上述观测指标的影响。结果:AngII10^-7mol/L可以刺激VSMC发生迁移,该作用是通过影响VSMC内应力纤维动态组装而实现的;AngII干预VSMC后可使AT₁R表达上调,随着作用时间延长AT₁R表达水平下降。AT₁R拮抗剂可下调AT₁R表达。AngII通过AT₁R的介导发挥其影响VSMC迁移能力的生物学效应。AT₂R对此无明显影响。结论:AngII通过AT₁R介导来调节VSMC内肌动蛋白微丝的动态组装,进而改变VSMC的迁移能力,从而发挥其介导VSMC迁移的生物学效应。     

The renin angiotensin system of amphibians

Summary Kidney extracts from several amphibian species were incubated with homologous and non-homologous serum. In a series of experiments the angiotensin formation was studied by enzyme kinetic technics, using acidified, dialysed kidney extracts and dialysed serum. In other experiments incubations were performed in the presence of Dowex 50W-X2 (NH₄ ⁺) resin. The angiotensin was then eluted from the Dowex and its pressor activity tested on the rat. If no Dowex was used in the incubation mixtures the range of the angiotensin formation was from 0 to 210 ng angiotensin formed per ml of serum. If Dowex was added, the values ranged from 0 to 300 ng angiotensin formed per ml of serum. Often angiotensinase was still present in the incubation mixtures, reducing the amount of detectable angiotensin in the incubation mixtures. Dowex protects the formed angiotensin from amphibian angiotensinases. The data suggest, however, that a large amount of angiotensin adsorbed onto the Dowex cannot be recovered. There is at least some species or class specifity of the renin-angiotensin system of the amphibians. Kidney extract of one species incubated with non-homologous serum produced less pressor substance than the same amount of kidney extract when incubated with homologous serum. Amphibian adrenal pressor substances are—at least in part—adsorbed on Dowex and can be eluted from it in a similar fashion as angiotensin.This work was supported by the Deutsche Forschungsgemeinschaft.     

内源性血管紧张素Ⅱ对大鼠血管钙化的作用

目的:在大鼠血管钙化模型上观察内源性血管紧张素II(AngⅡ)对大鼠血管钙化的影响。方法:用VitD₃皮下注射和尼古丁灌胃诱导大鼠血管钙化模型。测定血管组织中钙含量、[⁴⁵Ca²⁺]聚集及碱性磷酸酶活性作为观察钙化的指标。结果:钙化血管组织中钙含量,[⁴⁵Ca²⁺]摄入及碱性磷酸酶活性分别高于对照组。血管组织中的血管紧张素原mRNA、血浆和血管AngⅡ含量均高于对照组水平。血管紧张素转换酶抑制剂卡托普利和AngⅡ受体AT₁阻断剂洛沙坦处理的大鼠血管内钙含量、[⁴⁵Ca²⁺]聚集及碱性磷酸酶活性显著低于单纯钙化组。卡托普利处理的钙化大鼠血浆和动脉中AngⅡ含量、动脉中血管紧张素原mRNA的含量也显著低于钙化组水平。结论:钙化大鼠血浆和血管组织中AngⅡ水平上调,卡托普利和洛沙坦可减轻大鼠血管钙化程度。     

血管紧张素Ⅱ受体在压力超负荷致左室肥大中的作用

目的:探讨血管紧张素Ⅱ受体(ATRs)在压力超负荷致左室肥大中的作用。 方法:采用大鼠腹主动脉缩窄模型,通过放免法测心肌组织血管紧张素Ⅱ(Ang Ⅱ)含量,放射性配基结合分析法检测心肌组织ATRs及其亚型的变化。结果:手术组AngⅡ含量显著增高,与左室重量指数(LVMI)呈正相关(r=0.8066,P<0.01)。ATRs最大结合容量 (Bmax) 显著高于对照组(P＜0.01),但两组之间的平衡解离常数(kd)、血管紧张素Ⅱ1型受体(AT₁R)和血管紧张素Ⅱ2型受体(AT₂R)之间的比例无显著差异。非肽类AT₁R 拮抗剂Irbesartan可显著抑制Ang Ⅱ的升高和左室肥大,非肽类AT₂R 拮抗剂CGP42112A则无此作用。结论: 压力超负荷时心肌组织ATRs上调,Ang Ⅱ致左室肥大的作用主要由AT₁R介导。     

血管紧张素Ⅱ受体拮抗剂对高血压肾小动脉重建的影响

目的:研究血管紧张素II(AngII)受体拮抗剂对高血压肾小动脉重建的影响。方法:18只4周龄雄性大鼠分为:正常血压大鼠(WKY)组、自发性高血压大鼠(SHR)组、SHR口服losartan组,均饲养至16周。在肾组织切片上分别用光镜和电镜配合计算机图像分析法观测肾组织内小动脉的几何形态学指标和小动脉平滑肌及其间隙,离体肾脏灌流法测定最小肾血管阻力。结果:Losartan组的尾动脉收缩压、肾小动脉壁厚、壁面积、壁厚内径比和中层血管平滑肌细胞宽度以及最小肾血管阻力,均显著低于高血压对照组。结论:AngII受体拮抗剂losartan能预防SHR肾小动脉的重建。     

血管紧张素II对巨噬细胞(THP-1细胞)凝集素样氧化低密度脂蛋白受体表达的影响

目的:研究AngII对人单核/巨噬细胞(THP-1细胞)凝集素样氧化低密度脂蛋白受体(LOX-1)蛋白表达和基因转录的影响,从细胞蛋白、分子水平探讨AngII和巨噬细胞LOX-1相互之间的关系,以进一步了解两者在动脉粥样硬化中的地位。方法:将不同浓度AngII(1×10^-9-1×10^-5mol/L)与经0.1μmol/L佛波酯(PMA)诱导分化后的THP-1细胞共孵育24h,以及将1×10^-6mol/L浓度的AngII与诱导分化后的THP-1细胞作用不同时间0、3、6、12、24、48h后,用细胞酶联免疫法和半定量RT-PCR分别检测LOX-1蛋白和mRNA表达的情况。结果:未经诱导的THP-1细胞不表达LOX-1mRNA;而经PMA诱导后,THP-1细胞停止增殖,由单核细胞分化成为巨噬细胞,并表达LOX-1mRNA。不同浓度的AngII作用诱导分化后的THP-1细胞24h,细胞LOX-1蛋白和mRNA的表达呈浓度依赖性显著增加。同一浓度的AngII作用THP-1细胞,可呈时间依赖性诱导LOX-1蛋白和mRNA表达,其趋势是3h左右开始增加,24h左右至最高峰,之后逐渐减低。结论:经PMA诱导分化后的THP-1细胞表达LOX-1;AngII能明显增强分化后的THP-1细胞表达LOX-1蛋白和mRNA,并呈浓度和时间依赖性。AngII这种作用可能是促进动脉粥样硬化发生、发展的机制之一。     

肾内血管紧张素系统在高血压性肾损害中的作用

目的:探讨血管紧张素II(AngII)及血管紧张素II受体(AT₁R)在缺血性肾损害时肾脏局部的作用。方法:采用放射免疫法及逆转录-聚合酶链反应(RT-PCR)技术,检测双肾动脉狭窄时大鼠血浆和肾脏的AngII含量和AT₁RmRNA的表达。结果:缺血性肾损害时大鼠血浆及肾组织AngII水平均高于对照组,P <0.0 5,而肾组织AT₁RmRNA的表达也较对照组高,P <0.0 1。结论:在双肾动脉狭窄缺血性肾损害时存在AngII及其AT₁R的异常,它们可参与肾脏损害作用.     

红花黄色素对糖尿病肾病模型大鼠肾脏细胞血管紧张素Ⅱ1型受体的影响

BACKGROUND: Safflower yellow is known to treat diabetic nephropathy, can protect kidney function, reduce lesions, delay or prevent the development of diabetic nephropathy.     

Impaired drinking to angiotensin II after subdiaphragmatic vagotomy in rats

Rats received total bilateral subdiaphragmatic vagotomy and, one month later, were fitted with chronic intravenous or intracerebroventricular cannulas. The vagotomized rats showed much reduced drinking compared with controls during intravenous infusion of angiotensin II. Their drinking to intracerebroventricularly administered angiotensin II was, however, less affected. The possible role of the vagus nerve in the mediation of angiotensin and other types of drinking is discussed.     

阿托伐他汀对AngⅡ诱导大鼠心肌肥大的抑制作用及对TLR4基因表达的影响

目的： 探讨阿托伐他汀(atorvastatin)对血管紧张素Ⅱ(AngⅡ)诱导的大鼠心肌细胞（CM）肥大的抑制作用及对TLR4基因表达的影响，旨在探索他汀类药物对心肌肥大抑制作用的可能机制。方法: 采用胰酶消化、差速贴壁法培养新生SD大鼠CM，应用考马斯亮蓝法测定CM蛋白含量、RT-PCR分别检测心肌肌球蛋白重链β-MHC、AT₁受体和TLR4 mRNA表达。结果: ① AngⅡ可使CM蛋白含量及β-MHC mRNA表达明显增加，并能够上调AT₁ mRNA和TLR4 mRNA表达。② Ator呈浓度依赖性抑制由AngⅡ诱导的CM蛋白含量及β-MHC mRNA表达的增加。③ Ator呈浓度依赖性下调由AngⅡ诱导的肥大CM AT₁ mRNA和TLR4 mRNA表达。结论: 阿托伐他汀可部分抑制CM肥大的发生，下调AT₁ mRNA和TLR4 mRNA表达是其作用机制之一。     

Metabolism of tritiated angiotensin II in anaesthetized rats

Summary The metabolic fate of small doses of a newly prepared, highly radioactive angiotensin II has been studied in anaesthetized rats. Doses of 25 or 100 ng were administered in a single injection and the following parameters were studied: 1. The variation with time of the concentration of total radioactivity in plasma and urine. 2. The nature of this radioactivity, classifying it as protein-bound, free immunoreactive (angiotensin, 2–8 heptapeptide or 3–8 hexapeptide) or free nonimmunoreactive (smaller tyrosine-containing fragments). 3. The distribution of radioactivity in various tissues, including a detailed study of different regions of the brain.The main results are that: 1. angiotensin II and/or metabolites are rapidly removed from the circulation, mainly by tissue uptake and to a lesser extent by urinary excretion (which reached 12% of the dose injected after 1 hour); 2. remaining angiotensin II circulating in the blood is rapidly degraded, presumably by tissue peptidases; 3. radioactivity concentrates in the adrenal glands, kidney, liver and pituitary and does not readily pass the blood-brain barrier; 4. there is a possible binding of angiotensin and metabolites on to plasma proteins.     

Centrally injected angiotensin II trans-synaptically activates angiotensin II-sensitive neurons in the anterior hypothalamic area of rats

Previously, we have demonstrated that pressure-ejected application of angiotensin II onto some neurons in the anterior hypothalamic area (AHA) of rats increases their firing rate. In contrast, pressure application of the angiotensin AT1 receptor antagonist losartan onto AHA neurons blocked the basal firing of the neurons. To investigate possible participation of these AHA neurons in the brain angiotensin system, we examined whether intracerebroventricular injection of angiotensin II results in an activation of angiotensin II-sensitive neurons in the AHA of rats. Intracerebroventricular injection of angiotensin II increased the firing rate of AHA angiotensin II-sensitive neurons. The angiotensin II-induced increase of unit firing in AHA neurons was abolished by pressure application of losartan onto the same neurons. In addition, the angiotensin II-induced increase of firing in AHA neurons was abolished by pressure application of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W7), a calmodulin inhibitor, onto the same neurons. Pressure application of W7 onto AHA neurons affected neither the basal firing rate nor the increase in unit firing induced by pressure application of angiotensin II onto the same neurons. Intracerebroventricular injection of the cholinergic agonist carbachol did not affect the firing rate of angiotensin II-sensitive neurons in the AHA. These findings suggest that intracerebroventricular injection of angiotensin II activates AHA angiotensin II-sensitive neurons via angiotensinergic inputs to the neurons.     

Chronic intermittent hypoxia augments chemoreflex control of sympathetic activity: Role of the angiotensin II type 1 receptor

Chronic exposure to intermittent hypoxia (CIH) increases carotid sinus nerve activity in normoxia and in response to acute hypoxia. We hypothesized that CIH augments basal and chemoreflex-stimulated sympathetic outflow through an angiotensin receptor-dependent mechanism. Rats were exposed to CIH for 28 days: a subset was treated with losartan. Then, lumbar sympathetic activity was recorded under anesthesia during 20-s apneas, isocapnic hypoxia, and potassium cyanide. We measured carotid body superoxide production and expression of angiotensin II type-1 receptor, neuronal nitric oxide synthase, and NADPH oxidase. Sympathetic activity was higher in CIH vs. control rats at baseline, during apneas and isocapnic hypoxia, but not cyanide. Carotid body superoxide production and expression of angiotensin II type 1 receptor and gp91^phox subunit of NADPH oxidase were elevated in CIH rats, whereas expression of neuronal nitric oxide synthase was reduced. None of these differences were evident in animals treated with losartan. CIH-induced augmentation of chemoreflex sensitivity occurs, at least in part, via the renin–angiotensin system.     

U 50 488H 对高血压大鼠的利尿作用及机制

目的： 观察κ阿片受体激动剂U50 488H对自发性高血压大鼠（SHR）的利尿作用并探讨其作用机制。 方法： 用整体实验观察U50 488H对WKY大鼠和SHR血压和尿量的影响；应用放射免疫分析方法观察WKY大鼠和SHR血浆中体液因子的变化。 结果： U50 488H显著降低WKY大鼠和SHR的血压，对SHR产生的降压效应大于WKY大鼠；U50 488H剂量依赖性地引起WKY大鼠和SHR尿量的增加，而且对SHR的利尿作用强于WKY大鼠；测定血浆因子水平发现，U50 488H不仅能引起WKY大鼠和SHR血浆ADH水平的显著下降，并且对SHR血浆ADH水平的降低效应大于WKY大鼠；另外，U50 488H对WKY大鼠血浆AngⅡ水平无明显影响，但可以引起SHR血浆AngⅡ水平显著下降。U50 488H的以上效应均可被选择性κ阿片受体阻断剂nor-BNI所阻断。 结论： κ阿片受体激动剂U50 488H显著下调血浆中抗利尿激素和血管紧张素Ⅱ的水平可能与其引起SHR强利尿效应有关。     

Pro-inflammatory role of angiotensin II in mercuric chloride-induced nephropathy in rats

Mercuric chloride (HgCl₂), which induces kidney toxicity, constitutes a potential threat to human health. In addition to direct toxic effects, kidney inflammatory events take place during the HgCl₂-induced nephropathy. There is no information currently available about the role of angiotensin II (Ang II) in this inflammatory process. Accordingly, the aim of this study was to determine the expression of Ang II and Ang II-associated inflammatory molecules, i.e. intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS), and mono-cyte/macrophage infiltration (ED-1), in HgCl₂-induced nephropathy. Three groups of Sprague Dawley rats that were to receive HgCl₂ (2.5?mg HgCl₂/kg BW, by gavage) were utilized: one had received Losartan at 30?mg/kg BW; one had received Enalapril at 30?mg/kg BW; and one had received distilled water, in each case daily for 3 days prior to the HgCl₂ exposure. For these studies, an extra set of controls treated with saline solution in place of HgCl₂ and water in place of the test drugs was employed. Renal biopsies were obtained 96?h after HgCl₂ injection and the expressions of Ang II, ICAM-1, iNOS, and ED-1 were analyzed by indirect immunoflourescence while tubular damage was assessed via histopathology. An increased expression of Ang II, ICAM-1, iNOS, and ED-1 as well as increases in tubular necrosis were observed in all HgCl₂-animals. Treatments with Losartan or Enalapril diminished the induced expressions as well as the extent of tubular damage. The data here suggest that Ang II is involved in the pro-inflammatory events during HgCl₂-induced nephropathy, and that this is probably mediated, in part, by Ang II receptors Type 1 (AT-1).     

Pressor effect of angiotensin II in sodium replete and deplete rats

Summary The pressor effect of three doses of angiotensin II (AT) and of single doses of norepinephrine (N) and tyramine (T) was measured in sodium replete and deplete rats before and after ganglionic blockade. In sodium deplete rats, plasma renin concentration (PRC) and hematocrit were significantly higher and plasma sodium was significantly lower than in sodium replete rats. The pressor effect of AT, but not that of N and of T was blunted in sodium deplete rats before and after ganglionic blockade. The relationship between the pressor effect of AT and PRC was significantly negative in the combined material of all groups before ganglionic blockade. The correlation was more pronounced after ganglionic blockade, and it became significant also in the sodium deplete group alone. The pressor effect of AT was not significantly related to plasma sodium concentration and hematocrit, while both exhibited a significant correlation with PRC. Results suggest that the influence of sodium depletion on the pressor action of angiotensin may be mediated by preexisting renin or angiotensin levels and that this relationship is influenced by the autonomous nervous system.Supported by the Deutsche Forschungsgemeinschaft.     

AngⅡ致内皮细胞凋亡中多聚（ADP-核糖）聚合酶活性变化的研究

目的： 探讨体外AngⅡ在引起血管内皮细胞凋亡过程中细胞内多聚（ADP-核糖）聚合酶的活性变化情况。方法: 1 μmol/L的AngⅡ处理原代培养人脐静脉内皮细胞6、12、24和48 h后，用TUNEL法来检测内皮细胞的凋亡，用［³H］掺入法来检测PARP的活性，硝酸还原法检测NO含量。结果: 1 μmol/L的血管紧张素Ⅱ以时间依赖性引起内皮细胞的凋亡，6 h后细胞内的NO含量开始增加(P<0.05)，24 h达到高峰，48 h后下降到对照组水平；6 h后PARP的活性上升(P<0.05)，12 h到达高峰，24 h接近正常，48 h后PARP的活性显著低于对照组(P<0.05)。结论: NO含量增加导致的细胞毒性在血管紧张素Ⅱ引起内皮细胞的凋亡中有着重要的作用，在这一过程中PARP活性的变化是先上升后下降。     

Targeting brain Renin-Angiotensin System for the prevention and treatment of Alzheimer’s disease: Past,present and future

Alzheimer’s disease (AD) is a well-known neurodegenerative disease characterized by the presence of two main hallmarks – Tau hyperphosphorylation and Aβ deposits. Notwithstanding, in the last few years the scientific evidence about the drivers of AD have been changing and nowadays age-related vascular alterations and several cardiovascular risk factors have been shown to trigger the development of AD. In this context, drugs targeting the Renin Angiotensin System (RAS), commonly used for the treatment of hypertension, are evidencing a high potential to delay AD development due to their action on brain RAS. Indeed, the ACE 1/Ang II/AT1R axis is believed to be upregulated in AD and to be responsible for deleterious effects such as increased oxidative stress, neuroinflammation, blood-brain barrier (BBB) hyperpermeability, astrocytes dysfunction and a decrease in cerebral blood flow. In contrast, the alternative axis – ACE 1/Ang II/AT2R; ACE 2/Ang (1−7)/MasR; Ang IV/ AT4R(IRAP) – seems to counterbalance the deleterious effects of the principal axis and to exert beneficial effects on memory and cognition. Accordingly, retrospective studies demonstrate a reduced risk of developing AD among people taking RAS medication as well as several in vitro and in vivo pre-clinical studies as it is herein critically reviewed. In this review, we first revise, at a glance, the pathophysiology of AD focused on its classic hallmarks. Secondly, an overview about the impact of the RAS on the pathophysiology of AD is also provided, focused on their four essential axes ACE 1/Ang II/AT2R; ACE 2/Ang (1−7)/MasR; Ang IV/ AT4R(IRAP) and ACE 1/Ang II/AT1R. Finally, the therapeutic potential of available drugs targeting RAS on AD, namely angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs), is highlighted and data supporting this hope will be presented, from in vitro and in vivo pre-clinical to clinical studies.     

血管紧张素在培养乳鼠心肌细胞肥大发生中的作用

本实验观察到血管紧张素Ⅰ、Ⅱ(AngⅠ、AngⅡ)均可促进培养的乳鼠心肌细胞(MC)DNA、RNA和蛋白质的合成。并发现随着AngⅠ和AngⅡ作用时间的延长,对MC的RNA和蛋白质合成的促进作用也逐渐增强,而对其DNA合成的促进作用则有一定的时间界限。此外,还发现在AngⅠ和AngⅡ长期作用下可使MC体积增大。当AngⅠ和血管紧张素转换酶(ACE)抑制剂同时加入培养基,则无上述结果发生。这提示血管紧张素可能在心肌肥大的发生中起一定作用,而且AngⅠ是通过MC本身的ACE将其转化为AngⅡ后才起作用的。