Are AT1 receptor antagonists an alternative to ACE inhibitors in angioedema?

History of angioedema is a contraindication for ACE-inhibitors. Angioedema is caused by: 1. a decreased degradation of bradykinin, 2. a defect in C 1-esterase-inhibitor with the increased generation of bradykinin or 3. other trigger mechanisms as food, pollen and stress. AT1 receptor antagonists do not inhibit the degradation of bradykinin. Thus angioedema is no contraindication for AT1 receptor antagonists. In patients with an anamnestic angioedema or ACE-induced angioedema AT1 receptor antagonists can be given under close monitoring provided that there is strong indication for inhibition of the renin-angiotensin system.     

Neuroprotective effects of AT1 receptor antagonists after experimental ischemic stroke: what is important?

Naunyn-Schmiedeberg's Archives of Pharmacology - The present study conducted in rats defines the requirements for neuroprotective effects of systemically administered AT1 receptor blockers...     

AT1拮抗剂研究进展及安全性

临床上普遍使用的血管紧张素转化酶(ACE)抑制剂具有良好的降压效果,但在应用中,许多患者出现干咳和水肿副反应.一些学者根据血管紧张素Ⅱ(AngⅡ)对心血管的作用是通过AT1受体来介导实现的,研制开发出AT1拮抗剂,它避免了ACE1抑制缓激肽和P物质的降解导致的非剂量相关性干咳和血管神经性水肿.通过对这类药物结构修饰与活性关系的研究,找出此类药物活性结构:能与受体形成氢键的1个或多个N原子中心;能与受体疏水性基团结合的亲脂性侧链或侧环;含有易电离的离子作用基团或羧基、羟甲基及强极性功能团羰基等.临床目前最常用的AT1拮抗剂是氟沙坦和缬沙坦.临床应用证实此类药物不良反应发生率低,如干咳、肾功能障碍、血管性水肿的发生率远低于依那普利,此类药物会成为临床上有前景的抗高血压药物.     

Effect of losartan and captopril on expression of cardiac angiotensin Ⅱ AT1 receptor mRNA in rats following myocardial infarction

目的：探讨氯沙坦（Ｌｏｓ）和卡托普利（Ｃａｐ）对大鼠心肌梗死后血管紧张素Ⅱ（Ａｎｇ）ＡＴ１受体ｍＲＮＡ表达的影响．方法：２４只梗死大鼠随机分为四组并分别用Ｃａｐ（２ｇ·Ｌ－１加水中饮用）、Ｌｏｓ（１０ｍｇ·ｋｇ－１·ｄ－１和３０ｍｇ·ｋｇ－１·ｄ－１，灌胃）及安慰剂治疗６周，假扎鼠作对照，用地高辛标记的ｃＤＮＡ探针，进行点杂交反应，检测ＡｎｇＡＴ１受体ｍＲＮＡ表达．结果：三个药物治疗组的ＡｎｇＡＴ１受体ｍＲＮＡ表达水平分别与安慰剂组比较，均显著降低（Ｐ＜００１）．三个治疗组之间的ＡｎｇＡＴ１受体ｍＲＮＡ表达水平及分别与假扎组比较，均无显著差异（Ｐ＞００５）．结论：Ｃａｐ和Ｌｏｓ均可逆转大鼠心肌梗死后ＡｎｇＡＴ１受体ｍＲＮＡ表达水平的增高．     

AT1受体拮抗剂和ACEI对大鼠心肌肥厚时AT1mRNA表达的影响

目的探讨血管紧张素lI（AngⅡ）及其受体AT。在心肌肥厚中的作用,研究DMP811（AT,受体拈抗剂）、培哚普利（ACEI）对AngⅡ诱导的心肌肥厚大鼠心肌AT,mRNA表达水平的影响。方法24只6周龄的SD雄性大鼠随机分为4组：正常对照组、AngII组、AngⅡ＋DMP811组、AngⅡ＋培哚普利组,每组6只。分别皮下埋藏装有生理盐水或AngⅡ的渗透微泵。1周后观察心脏质量、心脏质量／体质量的变化,采用反转录聚合酶链反应（RT—PCR）检测心肌AT1mRNA表达情况,并进行比较。结果①输注AngII7d不会明显影响大鼠的体质量,但可使大鼠的心脏质量、心脏质量／体质量显著增加。AngⅡ组较正常对照组心脏质量、心脏质量,体质重明显增加（P〈0．05）;与AngⅡ＋DMP811组、AngⅡ＋培哚普利组相比．AngⅡ组心脏质量、心脏质量／体质量也明显增加,差异具有统计学意义（P〈0．05）,而AngⅡ＋DMP811组、AngII＋培哚普利组的心脏质量、心脏质量／体质量差异无统计学意义（P〉0．05）。②AngⅡ组的ATlmRNA水平较对照组上调（84．5＋3．0）％（P〈0．01）,DMP811、培哚普利药物干预,可使AngⅡ诱导的ATlmRNA的转录上调有效阻断。而AngⅡ＋DMP811组、AngU＋培哚普利组的AT,mRNA水平差异无统计学意义（P〉O．05）。结论心肌肥厚时AT1mRNA的表达水平明显增加,且AngⅡ诱导了AT。mRNA的转录上调。而AngII导致的上述改变能被DMP811、培哚普利有效阻断。为以后防治心肌肥厚提供了重要依据。     

血管紧张素受体AT1／AT2均衡拮抗剂的研究现状

简述血管紧张素Ⅱ受体拮抗剂的降压作用机制及AT1／AT2均衡拮抗剂的作用特点,主要介绍了三类AT1／AT2均衡拮抗剂,并对受体结合模型和构效关系进行了探讨。     

Lack of weight gain after angiotensin AT1 receptor blockade in diet-induced obesity is partly mediated by an angiotensin-(1–7)/ Mas-dependent pathway

Background and Purpose

Angiotensin AT₁ receptor antagonists induce weight loss; however, the mechanism underlying this phenomenon is unknown. The Mas receptor agonist angiotensin-(1-7) is a metabolite of angiotensin I and of angiotensin II. As an agonist of Mas receptors, angiotensin-(1-7) has beneficial cardiovascular and metabolic effects.

Experimental Approach

We investigated the anti-obesity effects of transgenically overexpressed angiotensin-(1-7) in rats. We secondly examined whether weight loss due to telmisartan (8 mg·kg⁻¹·d⁻¹) in diet-induced obese Sprague Dawley (SD) rats can be blocked when the animals were co-treated with the Mas receptor antagonist A779 (24 or 72 μg·kg⁻¹·d⁻¹).

Key Results

In contrast to wild-type controls, transgenic rats overexpressing angiotensin-(1-7) had 1.) diminished body weight when they were regularly fed with chow; 2.) were protected from developing obesity although they were fed with cafeteria diet (CD); 3.) showed a reduced energy intake that was mainly related to a lower CD intake; 5.) remained responsive to leptin despite chronic CD feeding; 6.) had a higher, strain-dependent energy expenditure, and 7.) were protected from developing insulin resistance despite CD feeding. Telmisartan-induced weight loss in SD rats was partially antagonized after a high, but not a low dose of A779.

Conclusions and Implications

Angiotensin-(1-7) regulated food intake and body weight and contributed to the weight loss after AT₁ receptor blockade. Angiotensin-(1-7)-like agonists may be drug candidates for treating obesity.     

Recent progress in α1-adrenergic receptor research

Alpha1-Adrenergic receptors (AR) play an important role in the regulation of physiological responses mediated by norepinephrine and epinephrine, particularly in the cardiovascular system. The three cloned alpha1-AR subtypes (alpha1A, alpha1B, and alpha1D) are G protein-coupled receptors that signal through the Gq/11 signaling pathway, each showing distinct pharmacological properties and tissue distributions. However, due to the lack of highly subtype-selective drugs, the functional roles of individual subtypes are still not clear. Development of new subtype-specific drugs will greatly facilitate the identification of the functions of each subtype. Conopeptide rho-TIA has been found to be a new alpha1B-AR selective antagonist with different modes of inhibition at alpha1-AR subtypes. In addition, recent studies using genetically engineered mice have shed some light on alpha1-AR functions in vivo, especially in the cardiovascular system and brain. Several proteins have been shown to interact directly with particular alpha1-AR, and may be important in regulating receptor function. Receptor heterodimerization has been shown to be important for cell surface expression, signaling and internalization. These new observations are likely to help elucidate the functional roles of individual alpha1-AR subtypes.     

Anti-emetic potential of tachykinin NK_1 receptor antagonists

AIM: Evidence has accumulated to indicate the importance ofsubstance P in the emetic reflex. The present investigations weredesigned to charaterize tachykinin NK_1 receptors in the emeticreflex of Suncus murinus. METHODS: Several antagonistswere assessed for a potential to inhibit nicotine (5 mg·kg~(-1),sc)-, copper sulphate pentahydrate (120 mg·kg~(-1) ig)-, andmotion (4 cm lateral displacement at 1 Hz)-induced emesis.RESULTS: CP 122 721, CP-99 994,RP 67 580, and FK 888     

Allosteric interactions within the AT₁ angiotensin receptor homodimer: role of the conserved DRY motif

G protein coupled receptor (GPCR) dimerization has a remarkable impact on the diversity of receptor signaling. Allosteric communication between the protomers of the dimer can alter ligand binding, receptor conformation and interactions with different effector proteins. In this study we investigated the allosteric interactions between wild type and mutant protomers of type 1 angiotensin receptor (AT₁R) dimers transiently expressed in CHO cells. In our experimental setup, one protomer of the dimer was selectively stimulated and the β-arrestin2 binding and conformation alteration of the other protomer was followed. The interaction between β-arrestin2 and the non-stimulated protomer was monitored through a bioluminescence resonance energy transfer (BRET) based method. To measure the conformational alterations in the non-stimulated protomer directly, we also used a BRET based intramolecular receptor biosensor, which was created by inserting yellow fluorescent protein (YFP) into the 3rd intracellular loop of AT₁R and fusing Renilla luciferase (RLuc) to its C terminal region. We have detected β-arrestin2 binding, and altered conformation of the non-stimulated protomer. The cooperative ligand binding of the receptor homodimer was also observed by radioligand dissociation experiments. Mutation of the conserved DRY sequence in the activated protomer, which is also required for G protein activation, abolished all the observed allosteric effects. These data suggest that allosteric interactions in the homodimers of AT₁R significantly affect the function of the non-stimulated protomer, and the conserved DRY motif has a crucial role in these interactions.     

Angiotensin AT2 receptor ligands: do they have potential as future treatments for neurological disease?

In addition to the systemic renin-angiotensin system (RAS), a local RAS has been identified. Recent research has focused on this latter system and has investigated the effects of locally generated angiotensin II, especially in the kidney, heart and CNS. In the mammalian brain, all components of the RAS are present including angiotensin AT(1) and AT(2) receptor subtypes. While the AT(1) receptor is responsible for the classical effects of angiotensin II, it has been found that the AT(2) receptor displays totally different signalling mechanisms and this has revealed hitherto unknown functions of angiotensin II. AT(2) receptors are expressed at low density in many healthy adult tissues, but are up-regulated in pathological circumstances, e.g. stroke or nerve lesion. Evidence has now emerged that the actions of angiotensin II that are exerted via the AT(2) receptor are directly opposed to those mediated by the AT(1 )receptor. For example, the AT(2) receptor has antiproliferative properties and therefore opposes the growth-promoting effect linked to AT(1) receptor stimulation. It has been reported that the AT(2) receptor regulates several functions of nerve cells, e.g. ionic fluxes, cell differentiation and axonal regeneration, but also modulates programmed cell death. It is possible that a more extensive knowledge of the AT(2) receptor could contribute to the understanding of the clinically beneficial effects of AT(1) receptor antagonists, as this treatment may unmask AT(2) receptor activity. This review presents selected aspects of advances in AT(2) receptor pharmacology, molecular biology and signal transduction with particular reference to possible novel therapeutic options for CNS diseases.     

Effects of Apelin-13/putative receptor protein related to AT1 homodimer on behaviors of human umbilical vein endothelial cells北大核心CSCD

Aim To explore the effects of putative receptor protein related to ATI (APJ) homodimer on the behaviors-the proliferation, migration and tube formation of human umbilical vein endothelial cells (HU-VECs). Methods HUVECs at logarithmic growth stage were randomly divided into PBS, Apelin-13 + TM1 (APJ monomer group) and Apelin-13 + PBS group (APJ homodimer group). Western blot and Matrix-Assisted Laser Desorption/Ionization Time of Fligh Mass Spectrometry (MALDI-TOF MS) were used to detect the expression of APJ and APJ homodimer in HUVECs, respectively. Real-Time Cell Analyzers (RT-CA) was used to detect the concentration of the maximum effect of Apelin-13. Cell viability was detected by CCK-8. The cell migration ability was detected by scratch test, and the number of tubes formed on matri-gel that made artificial basement membrane was counted. Results Western blot and MALDI-TOF MS showed that APJ and APJ homodimer were expressed in HUVECs. The EC50 of Apelin-13 was 2.26 x 10 -8 mol • L, and the concentration of the maximum effect was 1.0 X 10 mol • L. The results of CCK-8 experiment, migration experiment and tube formation showed that cells in each group migrated to the scratch bare area gradually with the extension of time, and the tube formation of cells in each group was also observed under the microscope. Data statistics showed that the proliferation, migration and tube forming abilities of HUVECs in Apelin-13 + PBS and Apelin-13 + TM1 groups were significantly higher than those in PBS group, and the abilities of proliferation, migration and tube forming in Apelin-13 + PBS group were significantly better than those in Apelin-13 + TM1 group (P < 0.05). Conclusions APJ homodimer can promote the proliferation, migration and tube formation of HUVECs, and the effects are better than APJ monomer. © 2023 Publication Centre of Anhui Medical University. All rights reserved.     

Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity

Astemizole, a H₁R antagonist shows high affinity to the histamine H₁ receptor but only a moderate affinity to the histamine H₄ receptor. This study aims to modify the astemizole to keep high affinity to the histamine H₁ receptor and to increase affinity to the histamine H₄ receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H₁ and H₄ receptors. The new compounds show affinity to the histamine H₁ receptor in the pK _i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H₄ receptor was surprisingly rather low (pK _i from 4.4 to 5.6). Three representative compounds were docked into the histamine H₁ receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H₄ receptor, a H₁/H₄-pharmacophore hypothesis was developed.     

Effect of the AT₁ receptor antagonist losartan on diurnal variation in pain threshold in spontaneously hypertensive rats

Angiotensin (AT) II plays a key role in the regulation of blood pressure and water-salt balance and modulates nociception. Peptides based on AT influence central functions through the activation of AT?, AT? or AT? receptors. The aim of this study was to elucidate the role of AT? receptors in diurnal variation in nociception in spontaneously hypertensive rats (SHR). Male Wistar rats (16 weeks old) and SHR were caged individually and exposed to light from 08:00 to 20:00 h. The tail cuff method for noninvasive measurement of arterial blood pressure (ABP), paw pressure test for the determination of pain threshold and rotarod test to study motor coordination were used. Chronic treatment was administered to the SHR with the AT? receptor antagonist losartan (10 mg/kg/day, s.c.) for 14 days. Spontaneously hypertensive rats showed lower pain threshold and smaller day-night variations of nociception as compared to Wistar rats. Chronic losartan decreased the ABP and produced an inverted diurnal pattern of nociception in SHR, increasing the pain threshold at 03:00 h. Neither strain differences nor changes in motor coordination after losartan treatment were observed in SHR. Our results suggest that SHR have disturbances in diurnal variation in nociception and that the AT? receptor plays a role in the regulation of the circadian rhythm of mechanical pain threshold in SHR.     

Muscarinic M1receptor agonists and M2 receptor antagonists as therapeutic targets in Alzheimer’s disease

Alzheimer’s disease is the most common form of senile dementia and is of increasing medical and economic importance. One of the earliest findings in the systematic study of Alzheimer’s disease was the progressive loss of acetylcholinergic neurons. This lead to the so-called cholinergic hypothesis of Alzheimer’s disease and provoked a search for cholinergic replacement therapies. This has resulted in compounds capable of inhibiting the catabolism of acetylcholine (acetylcholinesterase inhibitors) being licensed for the treatment of Alzheimer’s disease. However, the search for directly acting, selective, muscarinic M₁ receptor agonists and M₂ receptor antagonists, that are capable of increasing acetylcholine levels in the neocortex, has not yet proved successful. For the muscarinic agonists this failure has been largely due to the difficulty in finding genuinely selective compounds. As a result, there has been a reduction in the number published patents in this area. This review discusses the rationale, progress and the possible future for these two potential approaches to the therapy of Alzheimer’s disease especially in light of some recent patents containing selective compounds.     

AT1R基因与人类疾病的相关性研究

肾素血管紧张素系统(RAS)对机体心血管系统的调节、水盐平衡以及内环境自稳态的维持有重要作用。近十年来,对RAS系统的深入研究使人们逐步认识到,内分泌、旁分泌组织自分泌的RAS在各个组织、器官中发挥着重要的病理生理作用。RAS中自底物血管紧张素原经级联反应,由肾素及血管紧张素工转换酶作用后形成终产物血管紧张素Ⅱ,后者主要通过G蛋白偶联血管紧张素Ⅱ的工型受体(AT1R)发生生物学效应。1 ATIR的理化特性血管紧张素Ⅱ(AngⅡ)是RAS的主要活性肽,作用于An-