血管紧张素转换酶抑制剂在心血管疾病中的应用

肾素-血管紧张素系统（RAS）是由肾脏和肝脏分泌的一组相互作用又互相调节的激素或前体,包括肾素,血管紧张素原（Ang）,血管紧张素Ⅰ（Ang Ⅰ）,血管紧张素Ⅱ（AngⅡ）,血管紧张素转化酶（ACE）,血管紧张素受体（AT-1和AT-2受体）等.RAS不仅是存在于血液循环的激素系统,还具有旁分泌和自分泌的作用,且许多组织中（心、脑、肾等）还存在局部的RAS,在器官、组织和细胞的功能调节中具有重要的作用.ACEI抑制生物活性低的AngⅠ转换成生物活性高的AngⅡ,阻止缓激肽灭活而起到对抗AngⅡ和增加缓激肽的作用,在心血管疾病治疗中起到重要作用.     

肾脏局部RAS与糖尿病肾病关系的研究进展

肾素-血管紧张素系统（RAS）主要是由肾素（RA）、血管紧张素Ⅰ（AngⅠ）、血管紧张素Ⅰ转化酶（ACE）、血管紧张素Ⅱ（AngⅡ）、血管紧张素Ⅱ受体以及血管紧张素（1-7）和血管紧张素转化酶相关羧肽酶（ACE2）等组成的具有多元生物活性的系统。Mulrow的研究提示肾脏局部不同于全身RAS它属于具有独立作用的系统,它通过旁分泌和自分泌形式发生作用,通过调节肾脏血流动力学及其它机制参与肾脏多种疾病的病理生理过程。     

血管紧张素Ⅱ受体对血管紧张素-（1-7）作用的影响

目的：探讨血管紧张素-（1-7）[Ang-（1-7）1对血管紧张素Ⅱ（AngⅡ）诱导大鼠系膜细胞（GMC）增殖及血管紧张素Ⅱ受体对血管紧张素-（1-7）作用的影响。方法：选择对数生长期GMC，分为对照组、AngⅡ组、Ang-（1-7）组、[Sar^1,Ile^8]-AngⅡ＋Ang-（1-7）组、、PD123319＋Ang-（1-7）组，通过[^3H]-Thymidine及[^3H]-Leucine掺入分别测定GMC的DNA、蛋白质合成；结晶紫染色检测细胞数日，观察系膜细胞增殖情况，探讨Ang-（1-7）是否通过AngⅡ受体发挥作用。结果：Ang-（1—7）可抑制AngⅡ诱导GMC的DNA、蛋白质合成及细胞数日增加；[Sar^1,Ile^8]-AngⅡ和PD123319不影响Ang-（1—7）的上述作用。结论：Ang-（1—7）能抑制基础和AngⅡ诱导的GMC增殖，其作用的发挥不通过AngⅡ的AT1和AT2受体介导。     

ACE2——新的血管紧张素转换酶

肾素-血管紧张素-醛固酮（RAS）系统是人生理功能的一个重要调节机制,它通过心脏、肾脏和血管等效应器官,维持机体的血压稳定与水盐平衡.它由肾素、血管紧张素原（Ang）、血管紧张素Ⅰ（AngⅠ）、血管紧张素Ⅱ（AngⅡ）及血管紧张素转换酶（ACE）组成.肾素具有蛋白酶活性,能将肝脏产生的Ang转换成10肽的AngⅠ,AngⅠ无组织活性.AngⅠ经ACE作用,去除两个氨基酸后产生8肽的有活性AngⅡ.     

洛沙坦治疗高血压的研究概况

洛沙坦（losartan）是由美国默沙东制药有限公司研制的第一个血管紧张素Ⅱ受体（AT1）拮抗剂。现就该药的作用机制、药代动力学、临床研究介绍如下。1 洛沙坦的作用机制 肾素血管紧张素系统（RAS）在高血压及其他心肾血管疾病的发病机制中起着重要作用,RAS通过血管紧张素Ⅱ（AngⅡ）与相应受体结合产生生物学效应[1]。研究认为在人体心脏及血管中只有约10％的AngⅡ是通过血管紧张素转换酶途径产生的,80％的AngⅡ是由心脏糜酶所产生[2]。AngⅡ是体内最强的血管收缩活性物质之一,经放射性配基结合法测定,Ang     

血管紧张素Ⅱ受体拮抗剂研究进展

随着对肾素-血管紧张素系统(RAS)在心血管病发病学中的作用和重要性的进一步了解[1],血管紧张素转换酶抑制剂(ACEI)不断发展并被广泛应用,血管紧张素Ⅱ(Aug Ⅱ)受体拮抗剂也从多方面确立了其重要地位。目前国外正抓紧开发AngⅡ受体拮抗剂,部分已在临床应用并取得较好的疗效[1-3]。本文从 Ang Ⅱ及Ang Ⅱ受体拮抗剂治沙坦(Losartan)及其与ACEI的区别进行讨论。 血管紧张素Ⅱ 1.Ang Ⅱ的作用 RAS在调节血压、维持机体体液和电解质平衡中起作用,许多心血管病的发生与发展与其密切相关。目前的研究证实,除体循环的RAS外,心脏、血管、…     

血管紧张素Ⅱ/一氧化氮相互作用对心血管疾病发病的影响

肾素-血管紧张素Ⅱ（AngⅡ）系统（RAS）,特别是AngⅡ,在血压和体液电解质调节中起关键作用。如今,血管紧张素转化酶（ACE）抑制剂在心血管疾病治疗中所显示的有益效果越来越受到重视。这些效果是AngⅡ的非血液动力学效果,不是已知的AngⅡ作为血管肽的血液动力学效果。L-精氨酸/一氧化氮     

血管紧张素Ⅱ调控骨代谢的研究进展

骨组织中存在局部肾素-血管紧张素系统(RAS)。RAS组分及其活性肽血管紧张素Ⅱ(AngⅡ)直接参与调控骨代谢的病理生理进程。成骨细胞和破骨细胞都有AngⅡ的受体表达,这些受体介导了AngⅡ调控骨代谢的作用。该文回顾了经典RAS途径,探讨了组织RAS致局部组织病变的作用,并对RAS活性肽AngⅡ调控成骨细胞的靶基因、胞内信号通路、AngⅡ通过成骨细胞间接调控破骨细胞功能、AngⅡ受体在骨代谢调控中的交互作用进行了重点阐述。     

血管紧张素(1-7)心血管保护作用机制的研究进展

<正>肾素–血管紧张素系统(rennin-angiotensin system,RAS)在心血管疾病中起重要作用,血管紧张素Ⅱ(Angio-tensinⅡ,AngⅡ)是RAS的主要效应因子,其作用主要由血管紧张素Ⅱ1型受体(AngⅡtype 1receptor,AT1)介导。长期的AngⅡ高水平会导致血压升高,促进炎症生成、血管壁及心室重构和内皮功能紊乱,使血液高凝和动脉粥样硬化,最终发生卒中、心肌梗死、心力衰竭及肾功能不全等靶     

血管紧张素Ⅱ对血管内皮细胞RAS的影响及药物的干预

目的 探讨血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)在不同浓度和不同作用时间下对血管内皮细胞RAS的影响及地奥心血康的干预作用。方法 采用放射免疫技术测定Ang Ⅱ不同浓度和不同作用时间下血管内皮细胞培养上清液中RAS的浓度变化及地奥心血康对其影响。结果Ang Ⅱ见可明显促进RAS的表达,其作用呈一定的剂量依赖性和时间依赖性;但经地奥心血康处理后的内皮细胞对Ang Ⅱ的反应发生改变,肾素(RA)、Ang Ⅱ表达降低,醛固酮(ALD)虽也有变化,但与对照组相比并无显著差异(P>0.05)。结论 Ang Ⅱ具有明显促进RAS表达的作用,地奥心血康对血管内皮细胞RAS的表达有一定的调节作用。     

Cardiovascular effect of inflammation and nonsteroidal anti-inflammatory drugs on renin–angiotensin system in experimental arthritis

A co-morbidity of inflammatory conditions is increased cardio-renal risks. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs) which are used to treat pain and inflammation are also associated with increase in such risks. We hypothesized that inflammation and NSAIDs impose the cardio-renal risk through the activation of the renin-angiotensin-system (RAS), a regulating pathway of the renal and cardiovascular homeostasis. We investigated the effect of adjuvant arthritis and NSAIDs on the RAS. Western blotting and ELISA were used to measure the RAS components. Inflammation caused significant imbalances in the cardiac and renal angiotensin converting enzymes, their biologically active angiotensin peptides (AngII and Ang1-7) and the target proteins involved in the peptide-receptor binding (AngII type 1 and type 2, and Ang1-7 receptor, Mas) toward cardio-renal toxicity. However, 7 days treatment of arthritic animals with NSAIDs (rofecoxib, meloxicam, celecoxib and flurbiprofen) restored the constitutive balances, perhaps due to their anti-inflammatory properties. Inflammation exerts its cardio-renal effects by causing imbalance in the RAS. NSAIDs through their anti-inflammatory effect restore this imbalance. Thus, mechanisms other than imbalances in the RAS may be involved in the NSAIDs cardiotoxicity.     

ANGIOTENSIN II RECEPTORS AND RENIN IN THE PORCINE UTERUS: MYOMETRIAL AT2 AND ENDOMETRIAL AT1 RECEPTORS ARE DOWN-REGULATED DURING GESTATION

1. The aim of the present study was to characterize the angiotensin II (AngII) receptor subtypes in the porcine uterus and the variation of receptor densities and renin concentrations during gestation. 2. In myometrium from non-pregnant sows, the AngII receptors were almost exclusively AT₂ receptors. During gestation, the AngII receptor density was decreased and the AT₁ receptor became predominant in the last part of gestation as a result of a down-regulation of the AT₂ receptor. 3. In the endometrium, the AT₁ receptor was predominant both in non-pregnant sows and throughout gestation. The AngII receptor density was decreased during gestation as a consequence of down-regulation of the AT₁ receptor. 4. The renin concentrations in the myometrium and endometrium of pregnant sows did not differ from those in non-pregnant animals. 5. The finding of enzymatically active renin and high densities of AngII receptors in the porcine uterus is in accordance with a functional renin-angiotensin system (RAS), which may be important for an increased vascular permeability and stimulated angiogenesis in early pregnancy and for contraction of the myo-metrial smooth muscle cells during parturition. The predominance of ATi receptors in the endometrium of non-pregnant sows differs from an earlier finding in non-pregnant women, where AT2 receptors were predominant in the endometrium. This is in accordance with earlier studies, indicating species differences in the expression and possibly also the physiological roles of the RAS in reproductive tissues.     

不同内径银夹诱导2K1C高血压模型的比较

目的:比较不同内径银夹缩窄大鼠肾动脉诱导的2K1C高血压模型效果.方法:用U型银夹缩窄大鼠右侧肾动脉建立2K1C高血压模型,分为4组:假手术组、2K1C-0.2 mm组、2K1C-0.25 mm组和2K1C-0.3 mm组.0～8周内,用无创尾动脉压测量仪测量大鼠尾动脉压.第8周末,BL-420S生物机能实验系统监测各组动物的心功能,计算大鼠心重量指数(HW/BW)、左和右肾脏重量指数(LKW/BW和RKW/BW),HE染色观察胸主动脉重构情况,比色法测定心肌组织羟脯氨酸含量,放免法测定血清中血管紧张素Ⅱ(Ang Ⅱ)的含量.结果:与假手术组比较,2K1C-0.25 mm组和2K1C-0.3 mm组,成模率高、肾脏固缩少,心功能损伤明显,HW/BW、羟脯氨酸和Ang Ⅱ的含量明显升高,胸主动脉发生明显重构;而2K1C-0.2 mm组,成模率低、肾脏固缩多,心功能损伤不明显.结论:0.25 mm和0.3 mm内径的银夹诱导的2K1C肾性高血压模型,成模率高,模型更稳定.     

Angiotensin receptors and development: the kidney

1. This brief review examines the evidence that angiotensin II (AngII) is essential for kidney development. 2. Several components of the renin-angiotensin system (RAS) are detected in the foetal kidney early in development. 3. Angiotensin II is essential for normal foetal and neonatal renal function. 4. Angiotensin II receptors transduce important signals leading to growth and development. 5. Angiotensin receptor subtypes show spatial and temporal specificity of localization throughout renal development. 6. Angiotensin converting enzyme (ACE) inhibition or AngII receptor blockade (specifically AT(1) subtype blockade) results in functional and structural abnormalities of the developing kidney in both experimental and clinical situations. 7. While chronic postnatal RAS blockade in rats is associated with structural damage to tubules and blood vessels of the kidney, reports differ on whether treatment also affects glomerular induction and growth. 8. In metanephric organ culture, glomerular induction proceeds despite AngII receptor blockade. 9. In summary, the evidence suggests that AngII is not essential for nephron induction and glomerular development in the rat kidney. However, AngII is essential for normal growth and development of renal tubules and vasculature.     

ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis

Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). Most available evidence supports a counter-regulatory role for Ang-(1-7) by opposing many actions of Ang II on AT₁ receptors, especially vasoconstriction and proliferation. Many studies have now shown that Ang-(1-7) by acting via Mas receptor exerts inhibitory effects on inflammation and on vascular and cellular growth mechanisms. Ang-(1-7) has also been shown to reduce key signalling pathways and molecules thought to be relevant for fibrogenesis. Here, we review recent findings related to the function of the ACE2/Ang-(1-7)/Mas axis and focus on the role of this axis in modifying processes associated with acute and chronic inflammation, including leukocyte influx, fibrogenesis and proliferation of certain cell types. More attention will be given to the involvement of the ACE2/Ang-(1-7)/Mas axis in the context of renal disease because of the known relevance of the RAS for the function of this organ and for the regulation of kidney inflammation and fibrosis. Taken together, this knowledge may help in paving the way for the development of novel treatments for chronic inflammatory and renal diseases.     

The correlation between inflammatory injury induced by LPS and RAS in EpH4-Ev cells

Renin–angiotensin system (RAS) plays an important role of regulating inflammatory injury. However, it is not clear about the correlation between renin–angiotensin system (RAS) and inflammation induced by LPS in mammary gland cells. So immunofluorescence was performed to verify the ACE2 expression in mammary gland cells. MTT assay was performed to detect cell viability. ELISA was performed to detect cytokines in cell supernatant. Western Blot was performed to analyze RAS levels and ACE2 level change was observed by immunofluorescence. The TLR4 level and p65 phosphorylation were detected by Western Blot. The ACE2 protein intensively located on the cell membrane. According to the results of MTT assay and TNF-α level, the injury was evidently induced by high concentration LPS after 9 h. The TNF-α, IL-6, IL-8, ACE, AT1R and AngII had an increasing expression with the rise of cell injury. In contrast, the MasR, Ang1-7 and ACE2 had a declining expression with the increase of cell injury degree. The TLR4 level and p65 phosphorylation in high concentration LPS group was significantly higher than that of control group. These results suggest that a valid inflammatory injury was induced after the cells were treated by high concentration of LPS for 9 h. Meanwhile, the ACE/AngII/AT1R axis was activated and the ACE2/Ang1-7/MasR axis was depressed.     

影响血管紧张素Ⅱ作用和合成的新途径及研究进展

肾素-血管紧张素系统(RAS)与多种疾病相关。作为RAS的最终效应途径,血管紧张素II起到了关键作用。本文综述了能够影响其合成及作用的主要途径:血管紧张素II受体拮抗剂(ARB)、糜酶(chymase)抑制剂和晚近发现的ACE2类物质及其相关研究。     

The peripheral renin-angiotensin system is not involved in the hypertension of sheep exposed to prenatal dexamethasone

1. Fetal exposure to an adverse intrauterine environment has been linked with cardiovascular and metabolic disease later in life. We have shown previously, in sheep, that brief exposure (48 h) to maternally administered dexamethasone (0.28 mg/kg per day) at 27 days of gestation (prenatal treatment group (PTG) 1; term approximately 150 days), but not at 64 days of gestation (PTG2), produced hypertensive offspring at 40 months of age. The present study aimed to determine whether the elevated blood pressure in these sheep was associated with an altered peripheral renin-angiotensin system (RAS). 2. Measurements of the basal levels of the RAS components (renin, angiotensinogen, angiotensin (Ang) I, angiotensin- converting enzyme (ACE), AngII and Ang-(1-7)) were made. In addition, we studied the effect of a peripherally administered AngII type 1 (AT1) receptor antagonist (irbesartan at 1.02 mg/kg per h) on mean arterial pressure (MAP) over 4.5 h. 3. There was no significant difference in basal plasma concentrations of the components of the RAS measured between control (n = 7) and PTG1 (n = 5) or PTG2 (n = 6) animals. The MAP in PTG1 was significantly higher than in the control group during both vehicle infusion and AT1 receptor blockade. The effect of 4.5 h irbesartan (1.02 mg/kg per h) infusion on blood pressure was similar between the groups. 4. In conclusion, intrauterine exposure for 48 h to maternally administered dexamethasone at 27 days of gestation caused elevated blood pressure in adult sheep that does not appear to be associated with an alteration in the peripheral RAS.     

Angiotensin II and neurohumoral control of the renal medullary circulation

1. Angiotensin (Ang) II has multiple actions in the renal medullary circulation. It can induce vasodilatation and blunt the response of medullary blood flow (MBF) to renal nerve activation through AT₁ receptor‐mediated release of nitric oxide (NO) and/or vasodilator prostaglandins. These actions require high intravascular and/or intratubular AngII concentrations, so are not apparent under physiological conditions. 2. Nevertheless, these mechanisms blunt the responsiveness of MBF to AT₁ receptor‐mediated vasoconstriction. When these protective mechanisms fail, as when oxidative stress reduces NO bioavailability in the medullary circulation, AngII reduces MBF. If sustained, reduced MBF leads to the development of hypertension. 3. Chronic activation of the renin–angiotensin system (RAS) induces oxidative stress in the kidney. Therefore, MBF may be reduced in models of hypertension associated with RAS activation both because AngII levels per se are increased and because of increased responsiveness of MBF to AngII‐induced vasoconstriction. 4. Endogenous AngII enhances the responsiveness of MBF to renal nerve stimulation, whereas NO blunts it. Chronic RAS activation and/or oxidative stress should therefore be expected to enhance MBF responses to renal nerve stimulation. Consistent with this, reductions in MBF induced by renal nerve stimulation are enhanced in rabbits with AngII‐induced hypertension, renovascular hypertension or after 9 weeks of fat feeding. 5. We conclude that the ability of endogenous AngII to reduce MBF and enhance the response of MBF to activation of the renal nerves could contribute to the development of hypertension under conditions of RAS activation, especially if accompanied by increased renal sympathetic nerve activity.     

Angiotensin-(1-7) and its receptor as a potential targets for new cardiovascular drugs

The identification of novel biochemical components of the renin-angiotensin system (RAS) has added a further layer of complexity to the classical concept of this cardiovascular regulatory system. It is now clear that there is a counter-regulatory arm within the RAS that is mainly formed by the angiotensin-converting enzyme 2-angiotensin (1-7)-receptor Mas axis. The functions of this axis are often opposite to those attributed to the major component of the RAS, angiotensin II. This review will highlight the current knowledge concerning the cardiovascular effects of angiotensin-(1-7) through a direct interaction with its receptor Mas or through an indirect interplay with the kallikrein-kinin system. In addition, there will be a discussion of its role in the beneficial effects of angiotensin-converting enzyme inhibitors and angio-tensin receptor type 1 (AT1) antagonists, and the potential of this peptide and its receptor as a novel targets for new cardiovascular drugs.