肾素血管紧张素系统与糖尿病肾病

肾素血管紧张素系统是生理功能颇为复杂的内分泌系统，广泛存在于机体各个组织。该系统的关键基因决定着个体的糖尿病肾病易感性。血管紧张素Ⅱ通过细胞外基质成分合成增多、降解减少而促使肾小球硬化。血管紧张素转化酶抑制剂及血管紧张素受体拮抗刑具有独立于血压的治疗糖尿病肾病的作用。     

Characterization of angiotensin II formation in human isolated bladder by selective inhibitors of ACE and human chymase: a functional and biochemical study

1. Functional recordings of smooth muscle tension and biochemical experiments on membrane fractions were performed to characterize angiotensin II (AII) formation in human isolated bladder smooth muscle.
2. A novel human chymase inhibitor CH 5450 (Z-Ile-Glu-Pro-Phe-CO₂Me) and a recently developed human chymase substrate Pro¹¹-,D-Ala¹²)-angiotensin I, claimed to be resistant to angiotensin converting enzyme (ACE) and carboxypeptidase, were used.
3. Angiotensin I (AI) (0.3 μM) induced a contractile response amounting to 58±5% (n=12) of the initial K⁺ (124 mM)-induced contractions. This response was reduced to 36±3% (n=8) by the ACE-inhibitor enalaprilat (10 μM), while pretreatment with soybean trypsin inhibitor (STI 200 μg ml⁻¹) or CH 5450 (10 μM) had no effect. However, the combination of enalaprilat and STI reduced the AI-induced contractions to 19±5% (n=6), and the combination of enalaprilat and CH 5450 caused an almost complete inhibition of the AI-induced contractions to 1±1% (n=6).
4. The substrate (Pro¹¹-,D-Ala¹²)-AI (3 μM) produced contractions which amounted to 57±4% (n=13) of the initial K⁺ (124 mM) contractions. These contractions were not affected by enalaprilat (10 μM). On the other hand, STI (200 μg ml⁻¹) and CH 5450 (10 μM) added separately, depressed the (Pro¹¹-,D-Ala¹²)-AI-induced contractions to 34±5% (n=6) and 24±4% (n=6), respectively. The combination of enalaprilat and STI or enalaprilat and CH 5450 did not produce any further inhibition.
5. Experiments with detrusor membrane fractions incubated with AI (50 μM) were performed. In the presence of enalaprilat (100 μM), carboxypeptidase inhibitor CPI (10 μg ml⁻¹) and aprotinin (15 μM), CH 5450 (10 nM–1 μM) caused a concentration-dependent inhibition of AII formation.
6. The results confirm that AII is a potent contractile agent in the human isolated detrusor muscle. They also indicate that the serine protease responsible for AII formation in the human bladder in vitro is human chymase or an enzyme similar to human chymase.

     

血管紧张素受体及其拮抗剂与肾脏病关系

肾素血管紧张素系统（RAS）在肾脏病变及其慢性进展中起着非常重要的作用，体内血管紧张素水平升高，可引进血液动力学变化及肾脏分泌众多细胞因子，促进并加重肾脏损害。如何阻断RAS一直是肾脏病学界关注的焦点。近年来随着血管紧张素受体拮抗剂的出现，其与肾脏疾病的关系也日益受到人们的重视。     

EFFECT OF CONVERTING ENZYME INHIBITION WITH CAPTOPRIL ON IN VITRO ANGIOTENSIN PRODUCTION IN SHEEP

1. The effect of captopril on in vitro production of angiotensin I (ANG I), [Val5]-angiotensin II ([Val5]-ANG II) and [Val4]-angiotensin III ([Val5]-ANG-(2-8)) in central venous blood taken from sodium-deficient sheep was studied. 2. Captopril enhances in vitro production of ANG I but blocks the in vitro production of [Val5]-ANG II and [Val5]-ANG-(2-8). 3. The production of ANG I in blood is faster than that of [Val5]-ANG II and [Val5]-ANG-(2-8). 4. The half-life of [Val5]-ANG II and [Val5]-ANG-(2-8) in vitro in blood in the presence of captopril was 10 and 14 min, respectively. 5. This in vitro study suggests that the production of [Val5]-ANG II and [Val5]-ANG-(2-8) in blood forms a small part of the total body production of each peptide.     

血管紧张素Ⅱ及其受体在肿瘤中作用的研究进展

血管紧张素Ⅱ作为肾素-血管紧张素系统中的主要效应分子,除了收缩血管,调节血压功能外,还参与肿瘤的发生发展、炎症反应以及血管形成转移,并且发挥重要作用。该文就血管紧张素Ⅱ及其受体在肿瘤中的表达及信号传通路研究进展做一综述。     

Brain and retinal microglia in health and disease: An unrecognized target of the renin–angiotensin system

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心肌顿抑与血管紧张素受体表达的研究进展

心肌顿抑是心脏直视手术和介入治疗后心功能障碍的主要病理基础,其确切的发病机制至今尚未阐明。近年来的研究表明,心肌缺血再灌注后肾素一血管紧张素系统被激活,局部心肌中血管紧张素受体表达增高,引起Ca^2＋超负荷,促进缺血再灌注损伤的病理生理改变,很可能是造成心肌顿抑的关键机制。这些研究进展为进一步揭示心肌顿抑机制提供了新的理论和实验依据。     

Antihypertensive efficacy of olmesartan medoxomil alone and in combination with hydrochlorothiazide

Angiotensin receptor blockers (ARBs) are highly effective antihypertensive agents with excellent safety profiles. ARBs have been shown to improve cardiovascular morbidity and mortality in hypertensive patients with heart failure or diabetic nephropathy. For this later class of patients, the American Diabetes Association recommends ARBs as the primary treatment option. The ARBs function by blocking the binding of angiotensin-II (A-II) to its receptor, thereby inhibiting the action of A-II. Unlike the angiotensin-converting enzyme (ACE) inhibitors, which block the production of A-II through the ACE pathway, the ARBs effectively inhibit A-II regardless of whether it is produced through ACE or some alternate enzyme pathway. This difference in action offers a distinct advantage of ARBs over ACE inhibitors. Olmesartan medoxomil, the latest addition to the ARB class, is a long-acting, safe and well-tolerated antihypertensive drug. The combination of olmesartan medoxomil with a low-dose diuretic, potentiates the blood pressure lowering effect of either agent alone and is highly effective in achieving the recommended blood pressure goals in the majority of patients treated.     

A novel sequence in kangaroo angiotensin I

SUMMARY 1. The incubation of kangaroo renin-substrate with renin from kangaroo, hog or sheep yields angiotensin having pressor activity in the rat.
2. Kangaroo angiotensin I is not reactive in radioimmunoassay which is sensitive to other forms of angiotensin I.
3. Kangaroo angiotensin I is converted by passage through the rat pulmonary circulation or by equine converting enzyme to a reactive product in radioimmunoassay for angiotensin II.
4. The findings suggest that the amino acid sequence of kangaroo angiotensin I differs from that of other known angiotensins.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ENDOGENOUS ANGIOTENSIN II LEVELS AND THE MECHANISM OF ACTION OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR TYPE 1 ANTAGONISTS

• 1 Modification of endogenous angiotensin II (AngII)-mediated processes by inhibitors of the angiotensin-converting enzyme (ACE) and antagonists of the angiotensin type 1 (AT₁) receptor is dependent upon both the levels of each agent in the plasma and tissues and on the concomitant changes in plasma and tissue AngII levels.
• 2 Both ACE inhibitors and AT₁ receptor antagonists increase renin secretion and angiotensin peptide formation in plasma and extrarenal tissues. Clinical doses of ACE inhibitors produce incomplete inhibition of ACE and the increased AngI levels act to restore AngII towards basal levels. Clinical doses of AT₁ receptor antagonists produce incomplete blockade of AT₁ receptors and the increased AngII levels in plasma and extrarenal tissues counteract (to an unknown degree) the effects of the antagonist.
• 3 The effects of ACE inhibitors and AT₁ receptor antagonists on AngII levels show tissue specificity. Angiotensin II-mediated processes in the kidney are most sensitive to inhibition by these agents. ACE inhibitors reduce renal AngII levels at doses much less than those required to reduce AngII levels in plasma and other tissues. Moreover, in contrast to increased AngII levels in plasma and extrarenal tissues, renal AngII levels do not increase in response to AT₁ receptor antagonists. The inhibition of AngII-mediated processes in the kidney may, therefore, play a primary role in mediating the effects of ACE inhibitors and AT₁ receptor antagonists on blood pressure and other aspects of cardiovascular function and structure.
• 4 Combination of an ACE inhibitor with an AT₁ receptor antagonist prevents the rise in plasma AngII levels that occurs with AT₁ receptor antagonism alone. This combination would, therefore, be predicted to produce more effective inhibition of endogenous AngII-mediated processes than either agent alone. We must await further studies to determine whether the combination of ACE inhibition and AT₁ receptor antagonism results in superior clinical outcomes.

     

IN VIVO GENERATION AND ELIMINATION OF ANGIOTENSIN IN THE RAT

1. Combined high performance liquid chromatography (HPLC) and radio-immunoassays were used to study the in vivo kinetics of the renin-angiotensin system in the rat. The HPLC-verified plasma concentrations of angiotensin I (AI) were 1.0 nmol/L (0.52-1.6) in anaesthetized normal and 4.2 nmol/L (2.5-7.0) in salt-depleted rats. The plasma concentrations of angiotensin II (AII) were 0.07 nmol/L (0.04-0.13) in anaesthetized normal and 1.0 (0.60-1.6) nmol/L in salt-depleted rats. 2. The fate of injected AI and AII passing through the vascular bed of the lungs was determined. Two-thirds of the injected AI was converted to AII and one-third was unchanged after a single passage through the lungs. Only trace amounts of angiotensin III (AIII), the only other metabolite, were demonstrated. 3. This verifies that the majority of AI is metabolized through AII. Injected AII disappeared from the circulation with formation of only trace amounts of AIII, the half-life being about 10 s. This corresponds to a calculated in vivo generation rate of AII of about 12 nmol/L per h in normal rats. It is in agreement with the AI generation rate (plasma renin activity) measured as 9.5 nmol/L per h in vitro.     

肾素-血管紧张素系统抑制药和糖尿病

血管紧张素转换酶抑制药(ACEI)和血管紧张素Ⅱ受体1拮抗药(ARB)是目前抑制肾素-血管紧张素系统的主要药物大量研究结果表明ACEI和ARB不仅可降低糖尿病的发生率、延迟糖尿病的进展,而且可降低糖尿病患者心血管事件的发生率和心血管死亡率。本文对其作用及机制进行探讨     

福辛普利对大鼠血管球囊损伤后血管紧张肽Ⅱ1型受体表达的影响

目的 :研究血管紧张肽转换酶 (ACE)抑制剂福辛普利 (fosinopril)对血管球囊损伤后血管紧张肽Ⅱ 1型受体 (AT1R)表达的影响。方法 :采用免疫组织化学技术SP法检测在大鼠髂动脉球囊损伤模型 (Clowes法[1] )中福辛普利干预后局部AT1R表达的变化。结果 :球囊损伤后d 1 4,血管中层AT1R表达 (0 .1 2 0±0 .0 1 0 )比假手术组 (0 .1 0 2± 0 .0 2 1 )显著增多 (P <0 .0 5 ) ,而此时内膜层AT1R(0 .2 82±0 .0 1 6)为中层的 2倍以上 ,福辛普利使球囊损伤后d 1 4血管AT1R(中层 0 .0 86± 0 .0 2 2 ,内膜层 0 .1 74±0 .0 1 8)表达显著减少 (P <0 .0 1 )。结论 :福辛普利能降低血管球囊损伤后AT1R表达     

Structural requirements for angiotensin analogues to accumulate cyclic AMP and release vasopressin from the incubated rat neurohypophysis

1. Angiotensin I, a decapeptide, stimulated the accumulation of cyclic 3',5'-AMP (cyclic AMP) and the release of vasopressin from incubated rat neurohypophyses. 2. Various octapeptides related to angiotensin II were capable of producing similar neurohypophyseal effects. 3. Longer incubation periods were needed with peptides having alterations or omission (e.g. heptapeptide 2–8) at position 1 of the parent molecule to evoke similar effects to those of angiotensin II. 4. Our results suggest strongly that physiological doses of angiotensin-related molecules stimulate the secretion of vasopressin through cyclic AMP, and that the neurohypophyseal receptor responsible for these effects is similar to that involved in their peripheral actions.     

Therapeutic potential of angiotensin II receptor antagonists

The circulating renin-angiotensin system plays an important role in cardiovascular homeostasis. More importantly, the local tissue renin angiotensin plays a pivotal role in cell growth and remodelling of cardiomyocytes and on the peripheral arterial vasculature. In addition, the renin angiotensin system is related to apoptosis, control of baroreflex and autonomic responses, vascular remodelling and regulation of coagulation, inflammation and oxidation. The cardioprotective and vascular protective effects of the angiotensin receptive blockade appears to be related to selective blockade of the angiotensin II (A-II) Type I (AT₁) receptors. However, there is now growing evidence showing that some of the effects of AT-II receptor blockers (ARBs) are related to the activation of the kinin pathways. This paper will review some of the recent mechanisms related to the cardiovascular effects of angiotensin and more specifically of ARBs. This paper will present the novel data on the role of ARB in the development of atherosclerosis, vascular remodelling, coagulation balance and autonomic regulation. Finally, the role of ARBs, used alone or in combination with ACE inhibitor in patients with heart failure, will be discussed.     

ACE抑制剂和血管紧张肽Ⅱ受体阻滞剂门诊处方调查

目的:通过对医院门诊血管紧张素转换酶(ACE)抑制剂和血管紧张肽(AⅡ)受体阻滞剂的处方调查,以了解医生处方习惯和这两类药物的门诊应用情况。方法:回顾性调查华东医院2001-11～2002-01共3个月的门诊处方,包括ACE抑制剂和AⅡ受体阻滞剂的处方频度、药物类别、剂量、合并处方、患者的性别和年龄分布等情况。结果:3个月门诊处方量分别为18381、22186和20866张,其中ACE抑制剂的处方频度分列为4.2％、5.1％和4.7％,以福辛普利和苯那普利的处方频度最高,依那普利和赖诺普利的处方频度最低。患者平均年龄65.3±10.9岁,男性多于女性,89.9％的患者合并1种或以卜处方药物。AⅡ受体阻滞剂氯沙坦的处方频度分别为0.70％、0.84％和0.88％,患者平均年龄65.1±11.7岁。处方剂量多数在治疗指南和建议推荐的剂量范围的低限。22张处方在用ACE抑制剂的同时合并处方AⅡ受体阻滞剂。结论:门诊ACE抑制剂和AⅡ受体阻滞剂的处方应根据患者的耐受性和经济情况等加以选择,并按治疗指南或建议进行给药方案调整。     

缬沙坦联合贝那普利对慢性肾小球肾炎蛋白尿降低和肾功能保护作用的临床研究

目的:观察血管紧张素转化酶抑制剂(ACEI)联合血管紧张素受体拮抗剂(ARB)治疗慢性肾小球肾炎的疗效。方法:将65例慢性肾小球肾炎患者随机分为三组:ACEI组、ARB组和联合组。ACEI组应用贝那普利,ARB组应用缬沙坦,联合组联合应用贝那普利及缬沙坦。观察治疗后3,6,9个月的相关指标变化。结果:经过9个月治疗后,三组患者24 h尿蛋白及血压显著下降(P<0.05);肾功能及血钾无明显变化(P>0.05);不良反应小。三组中联合组有最强的减少尿蛋白和降低舒张压作用(P<0.05),而在改善肾功能、血钾波动及不良反应方面,三组间差异无统计学意义(P>0.05)。结论:联合药物治疗慢性肾小球肾炎有更强的降低蛋白尿和舒张压的作用。     

The role of the renin-angiotensin system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS

Atrial fibrillation (AF) is the most common rhythm disturbance in medical practice and represents a very expensive health problem. AF can be managed with the prevention of thromboembolism and either a rate control of rhythm strategy. As both strategies have important limitations, probably a preventative strategy in patients at risk of developing arrhythmia can be a more attractive option. The renin-angiotensin system (RAS) seems to be involved in the genesis of arrhythmia by the following two mechanisms: 1. the induction of atrial fibrosis and structural remodelling by mitogen-activated protein kinase (MAPK) expression and reduction of collagenase activity; 2. the induction of electrical remodelling by shortening of the atrial effective refractory period (AERP) and of the action potential duration. For these reasons it has been hypothesized that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin-II receptor blockers (ARBs) may play a role in preventing AF recurrence. The aim of the present review was to analyse evidence supporting the usefulness of RAS inhibition in patients with AF in order to focus on which specific subset of patients it would most favour. After reviewing the literature, we conclude that, although many studies and meta-analysis have supported the advantage of RAS block in preventing AF recurrence, it is premature to recommend the use of ACE-Is and ARBs specifically for the prevention of AF. However we believe that as these drugs are safe and manageable, they should be considered the drugs of choice in patients with AF and coexisting clinical conditions such as hypertension, coronary disease, heart failure and diabetes mellitus.     

TCV-116和Delapril逆转左心室肥厚机制的探讨

目的：观察用血管紧张素Ⅱ（ＡｎｇⅡ）受体阻断剂ＴＣＶ－１１６和血管紧张素转化酶抑制剂Ｄｅｌａｐｒｉｌ阻断肾素－血管紧张素系统（ＲＡＳ）后，对左心室肥厚和血清、左心室组织血管紧张素转化酶（ＡＣＥ）活性及ＡｎｇⅡ含量的影响。方法：采用大剂量（显著降低血压）和小剂量（血压无明显改变）２种剂量口服给药，治疗ＳＨＲ２ｗｋ。结果：大小剂量组ＴＣＶ－１１６和Ｄｅｌａｐｒｉｌ均能显著降低左心室重量／体重指数，而大小剂量的肼苯哒嗪对此无影响；Ｄｅｌａｐｒｉｌ可降低左心室ＡＣＥ的活性和ＡｎｇⅡ的含量，但对血清ＡＣＥ活性和ＡｎｇⅡ浓度无影响；ＴＣＶ－１１６显著升高血清ＡｎｇⅡ的水平，对ＡＣＥ活性和左室ＡｎｇⅡ水平无影响。结论：ＴＣＶ－１１６和Ｄｅｌａｐｒｉｌ逆转ＳＨＲ之ＬＶＨ的机制并不在于降低血压本身，而是通过抑制左心室局部的ＲＡＳ，减低或阻断ＡｎｇⅡ对心肌细胞和成纤维细胞的作用。