血管紧张素Ⅱ受体与高血压性心肌重塑

血管紧张素Ⅱ（angiotensinⅡ,AngⅡ）是肾素-血管紧张素系统（RAS）的效应因子,通过其受体介导生物学效应。放射配基结合分析证实哺乳动物存在AT_1、AT_2受体,大鼠和小鼠AT_1受体存在AT_(1A)、AT_(1B)、和AT(1C)受体亚型。近年来还发现了AT_3和AT_4受体亚型,但结构和功能不清。AT_1受体具有G蛋白耦联受体超家族的特性,有7个螺旋的跨膜段,与其他G蛋白受体有20％～30％同源性,主要分布于成年动物血管、心、肾上腺等;AT_2受体仅有32％氨基酸序列与AT_1受体同源,主要分布于胚胎组织和间质组织。最新研究显示AngⅡ绝大多数生物学效应都是AT_1受体介导的。AngⅡ刺激AT_1受体诱导c-fos、c-jun和c-myc等原癌基因的表达,引起心肌细胞肥大,成纤维细胞增殖和间质胶原沉积,AT_1受体拮抗剂能逆转高血压所致的心肌肥厚,减少胶原积累,AT_2受体拮抗剂无此作用。AT_2受体的生物学效应知之甚少,可能在抑制生长因子引起的细胞增殖、对抗AT_1受体的促细胞有丝分裂作用和诱导细胞凋亡中起作用。心肌组织AT_1和AT_2受体可能共同调节了高血压心肌重塑的发生发展。     

Effects of angiotensin II and its metabolites in the rat coronary vascular bed: is angiotensin III the preferred ligand of the angiotensin AT2 receptor?

Aminopeptidases metabolize angiotensin II to angiotensin-(2-8) (=angiotensin III) and angiotensin-(3-8) (=angiotensin IV), and carboxypeptidases generate angiotensin-(1-7) from angiotensin I and II. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1 (AT1) receptor blockers affect the concentrations of these metabolites, and they may thus contribute to the beneficial effects of these drugs, possibly through stimulation of non-classical angiotensin AT receptors. Here, we investigated the effects of angiotensin II, angiotensin III, angiotensin IV and angiotensin-(1-7) in the rat coronary vascular bed, with or without angiotensin AT1 - or angiotensin II type 2 (AT2) receptor blockade. Results were compared to those in rat iliac arteries and abdominal aortas. Angiotensin II, angiotensin III and angiotensin IV constricted coronary arteries via angiotensin AT1 receptor stimulation, angiotensin III and angiotensin IV being approximately 20- and approximately 8000-fold less potent than angiotensin II. The angiotensin AT2 receptor antagonist PD123319 greatly enhanced the constrictor effects of angiotensin III, starting at angiotensin III concentrations in the low nanomolar range. PD123319 enhanced the angiotensin II-induced constriction at submicromolar angiotensin II concentrations only. Angiotensin-(1-7) exerted no effects in the coronary circulation, although, at micromolar concentrations, it blocked angiotensin AT1 receptor-induced constriction. Angiotensin AT2 receptor-mediated relaxation did not occur in iliac arteries and abdominal aortas, and the constrictor effects of the angiotensin metabolites in these vessels were identical to those in the coronary vascular bed. In conclusion, angiotensin AT2 receptor activation in the rat coronary vascular bed results in vasodilation, and angiotensin III rather than angiotensin II is the preferred endogenous agonist of these receptors. Angiotensin II, angiotensin III, angiotensin IV and angiotensin-(1-7) do not exert effects through non-classical angiotensin AT receptors in the rat coronary vascular bed, iliac artery or aorta.     

Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and cardiac remodelling

1. Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor. Angiotensin AT1 receptor antagonism has been considered as a specific approach to block the renin-angiotensin system and been demonstrated to be able to prevent or regress LVH by interfering with the remodelling process of the heart. 2. Angiotensin AT1 receptor blockade induces a marked increase in angiotensin (Ang) II, which may stimulate the AT2 receptors. Gene expression of AT1 and AT2 receptors increases in a time-dependent manner in cardiac remodelling following myocardial infarction. 3. Considerable efforts have been made to clarify the role of AT2 receptors in cardiac hypertrophy and remodelling since the mid-1990s, resulting in controversial reports: the AT2 receptor mediates actions either opposite to or in coordination with those of the AT1 receptor. Moreover, there are many reports of no significant effects mediated by AT2 receptors. 4. Based on the studies reviewed in the present article, we assume that the predominant effect of AngII in cardiac hypertrophy and cardiac remodelling is growth promoting and that this effect is mediated mainly via AT1 receptors. The AT2 receptors may affect the hypertrophic process by interacting with other cardiac membrane proteins, enzymes and autacoids. Before coming to a conclusion as to whether AT2 receptor stimulation or antagonism is beneficial to the heart, more studies should be performed in different LVH models, especially long-term treatment protocols in vivo.     

Prejunctional and postjunctional inhibitory actions of eprosartan and candesartan in the isolated rabbit mesenteric artery

Effects of angiotensin II type 1 (AT1) receptor antagonists eprosartan and candesartan and AT2 receptor antagonist PD123319 on Ang II-induced facilitation of noradrenergic neurotransmission were investigated in isolated rabbit mesenteric artery under isometric conditions. Sympathoinhibitory potency of AT1 blockers was compared with their potency concerning inhibition of direct vasoconstrictor effect of Ang II. To investigate blockade of presynaptic AT1 and AT2 receptors, effects of Ang II on electrical field stimulation (EFS)-induced contractions in presence or absence of eprosartan, candesartan, or PD123319 were studied. To investigate blockade of postsynaptic AT1 receptors, effects of either eprosartan or candesartan on concentration-response curves of Ang II were studied. In addition, effect of Ang II on postsynaptic alpha-adrenoceptor-mediated responses was studied using noradrenaline. EFS (1, 2, and 4 Hz) caused an increase of contractile force. At stimulation frequencies of 1, 2, and 4 Hz, a subpressor concentration of Ang II (0.5 nM) increased stimulation-induced vasoconstrictor responses by 2.8 +/- 0.5, 2.4 +/- 0.4, and 1.6 +/- 0.1 of control values, respectively (p < 0.05 compared with control for all frequencies). The enhancement could be antagonized by eprosartan (1 nM-0.1 microM) and candesartan (1 nM-0.1 microM). The AT2 antagonist PD123319 (10 nM) did not influence Ang II-induced facilitation of stimulation-induced contractions. Contractile responses to exogenous noradrenaline were unaltered in presence of Ang II 0.5 nM. Ang II (1 nM-0.3 microM) caused a concentration-dependent increase in contractile force, which could be antagonized by eprosartan (pD2; 8.8 +/- 0.19) and candesartan (pD2; 11.3 +/- 0.23). Thus, the facilitating effect of Ang II on noradrenergic neurotransmission is mediated by presynaptically located AT1 receptors and not by AT2 receptors. For eprosartan, sympathoinhibition was achieved at concentrations that also block AT1 receptors on vascular smooth muscle. In contrast, for candesartan, presynaptic inhibitory concentrations were considerably higher than those required for postsynaptic inhibition.     

Clinical experience with the use of angiotensin receptor blockers in patients with cardiovascular, cerebrovascular and renal diseases

The Angiotensin II receptor blockers (ARBs) have been efficacious and safe drugs for the treatment of hypertension, heart failure, diabetic nephropathy and stroke from several short and long term clinical trials. The ARBs exert their effects through selective blockade of the angiotensin II (Ang-II) subtype 1 (AT1) receptor and quite possibly through stimulation by Ang-II of the unoccupied subtype 2 (AT2) receptor. The ARBs are equipotent to other antihypertensive drugs with respect to their effect on blood pressure, heart failure or diabetic nephropathy. They appear to be superior to the other drugs with respect to their stroke protective effect. They exert their stroke protective effect by a dual action, selectively blocking the action of Ang-II on the AT1 receptors, while allowing Ang-II to stimulate the unoccupied AT2 receptors. This dual action is unique to ARBs and results in vasodilation and increase in blood flow to the ischemic zone of the brain leading to improvement and prevention of its extension. All these actions of the ARBs will be discussed in this comprehensive review.     

Angiotensin II type 1 receptor expression in polymorphonuclear leukocytes from high-risk subjects: changes after treatment with simvastatin

Statins may directly interfere with the effects of angiotensin (Ang) II, which is a key player in the pathogenesis of atherosclerosis (ATH). Ang II promotes a wide array of detrimental processes including a prominent proinflammatory effect, increasingly regarded as a target for therapeutic intervention. Because the proinflammatory effects of Ang II are exerted mainly through the activation of Ang II type 1 receptors (AT1Rs) the present study was devised to investigate by means of real-time polymerase chain reaction (PCR) and flow cytometry techniques the expression of such receptors on circulating polymorphonuclear leukocytes (PMNs) from subjects at high risk for vascular events before and during treatment with simvastatin and in sex- and age-matched healthy controls. In vitro experiments were also performed to assess the ability of simvastatin to interfere with Ang II signaling in human PMNs. In comparison to controls, high-risk subjects had similar AT1R expression on the cell membranes but significantly higher AT1R messenger ribonucleic acid (mRNA) levels. Treatment of high-risk subjects with simvastatin for 30 days resulted in a reduction of AT1R mRNA down to the levels of cells from healthy subjects. In vitro, Ang II-induced activation of the guanosine triphosphate (GTP)-binding protein Rac 1 in human PMNs was inhibited by simvastatin. In conclusion, simvastatin induces downregulation of AT1R expression, interferes with Ang II activity in PMNs, and contributes to the antiinflammatory profile of statins that can explain the therapeutic effects of these drugs.     

Angiotensin II type 2 receptor-dependent increase in nitric oxide synthase activity in the endothelium of db/db mice is mediated via a MEK pathway

Angiotensin II type 2 receptor (AT(2)R) stimulation may cause vasodilation. It could thereby contribute to the antihypertensive effects of angiotensin II type 1 receptor (AT(1)R) antagonists since AT(1)R blockade reportedly increases endogenous levels of Ang II, and this may then bind to the unblocked AT(2)R. Because this is potentially an important consideration in diabetes, we examined whether or not AT(2)R mediates vasorelaxation in db/db diabetic mice. We also examined if AT(2)R-mediated vasorelaxation is preserved after long-term treatment with the AT(1)R antagonist losartan. The effects of AT(2)R stimulation, with either Ang II or the selective agonist CGP-42112A, were studied in aortas from db/db mice (a type 2 diabetic model). CGP-42112A induced a concentration-dependent relaxation in db/db aortas (not in Lean aortas), and this was significantly weakened by the MEK-inhibitor PD98059. CGP-42112A-induced relaxations were increased by Ang II-stimulation (by the organ-culture method) or by AT(1)R blockade (by long-term losartan treatment) only in Lean aortas. Basal AT(2)R expression, and Ang II-stimulated MEK and eNOS phosphorylations were all increased in aortas from db/db (vs. Lean) mice. Long-term losartan treatment increased Ang II-stimulated MEK and eNOS phosphorylations in aortas from Lean, but not db/db, mice. Therefore, this study has provided evidence that AT(2)R-mediated NO production and vasorelaxation through a MEK pathway are enhanced (under basal conditions) in aortas from db/db (vs. Lean) mice. The preservation of such AT(2)R function during AT(1)R blockade needs to be considered in the search for a physiological role for AT(2)R.     

Angiotensin II type 2 (AT2) receptor signal and cardiovascular action

Due to the discovery of nonpeptic ligands, the receptors for angiotensin (Ang) II are classified into two subtypes (AT1-R and AT2-R). AT1-R mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetus. Its expression is very low in the cardiovascular system of the adult. The expression of AT2-R can be modulated by pathological states associated with tissue remodeling or inflammation. In failing hearts or neointima formation after vascular injury, AT2-R is reexpressed in cells proliferating in interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular matrix proteins, resulting in attenuation of the tissue remodeling. An extreme form of cell growth inhibition ends in programmed cell death, and this process, which is initiated by the withdrawal of growth factors, is also enhanced by AT2-R. Cardiac myocyte- or vascular smooth muscle-specific mice that overexpress AT2-R display an inhibition of Ang II-induced chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells and the maintenance of vascular resistance. AT2-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal systems, resulting in AT2-R-mediated cardioprotection, vasodilation and pressure natriuresis. These effects, transmitted by AT2-R, are mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in a Gi-protein-dependent manner. The expression level of AT2-R is much higher in human hearts than in rodent hearts, and the AT2-R-mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists. Thus, in this review, the regulation of AT2-R expression, its cellular localization, its pathological role in cardiovascular and kidney diseases, and pharmacotherapeutic effects of AT2-R stimulation are discussed.     

A newly found angiotensin II receptor subtype mediates cyclic GMP formation in differentiated Neuro-2A cells.

In search of the functional role of the newly found angiotensin II (Ang II) binding site which is expressed in differentiated Neuro-2A cells, we found that Ang II causes a marked stimulation of cGMP formation dose-dependently. The stimulation was blocked by the nonselective Ang II receptor antagonist [Sar1,Ile8]Ang II but not by the AT1 antagonist DuP 753 or the AT2 antagonist PD 123319. These results suggest that Ang II increased cGMP level via a new Ang II receptor subtype in differentiated Neuro-2A cells.     

Angiotensin type 2 receptor-dependent vasodilation

Angiotensin II (Ang II) signaling is mediated by two receptor subtypes, type 1 (AT(1)) and type 2 (AT(2)). The activation of AT(1) receptors is responsible for the development of Ang II-dependent hypertension, whereas the activation of AT(2) receptor is thought to play a counter-regulatory protective role in the regulation of blood pressure that opposes the AT(1) receptor-mediated vasoconstriction. However, the precise mechanisms by which increased numbers of AT(2) receptors counterbalance the AT(1)-mediated actions of Ang II are unknown. We have demonstrated that the abdominal aortic banding in mice and rats and the 2-kidney, 1-clip Goldblatt model of hypertension in mice induces up-regulation of AT(2) receptors in the pressure-overloaded thoracic aorta. In these hypertensive animals, the AT(1)-receptor antagonists but not calcium antagonist abolish up-regulation of the aortic AT(2) receptor as well as blood pressure elevation, suggesting that the pressure-overload up-regulates the aortic AT(2) receptor by Ang II via the activation of AT(1) receptor. Ang II binding to up-regulated AT(2) receptors induces vasodilation in these aortas through bradykinin B(2)-receptor-mediated phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser(633) and Ser(1177) via a protein kinase A-dependent signaling pathway, resulting in sustained production of nitric oxide. These studies provide evidence that the vascular AT(2) receptor is up-regulated in the course of hypertension through the activation of AT(1) receptor, thereby activating a vasodilatory pathway in vessels through the AT(2) receptor via the bradykinin/nitric oxide/cGMP. This issue is important because the antihypertensive effect of AT(1)-receptor blockers is, at least in part, dependent on AT(2)-receptor activation.     

The coronary endothelium behaves as a functional diffusion barrier for intravascular Angiotensin II

Diverse intracoronary hormones cause their cardiac effects solely via activation of their coronary endothelial luminal membrane (CELM) receptors. To test this hypothesis for Ang II, we synthesized: a) two large polymers of Ang II (Ang II-POL) and Losartan (Los-POL) which act only in the CELM's AT1R because they cannot cross the endothelial barrier and b) biotin-labeled Ang II (Ang II-Biotin) and Ang II-POL-Biotin to be identified by microscopy in tissues. Sustained coronary perfusion of Ang II (potentially diffusible) or Ang II-POL caused a positive inotropic effect (PIE) and an increase in coronary perfusion pressure (CPP) of equal magnitude that were blocked by Losartan and Los-POL. However, Ang II effects, in contrast to Ang II-POL effects, were transient due to desensitization and resulted in tachyphylaxis to a second administration of Ang II or Ang II-POL. Furthermore, if Ang II and Ang II-POL acted differently on the same receptor; a competition of effects would be expected. This was demonstrated by infusing simultaneously a molar ratio of Ang II:Ang II-POL. As this molar ratio decreased, Ang II-induced desensitization and tachyphylaxis decreased. Intravascularly‐administered Ang II-Biotin and Ang II-POL-Biotin remained bound and confined to the endothelium. Our results support the hypothesis and indicate intravascular Ang II, not by mass exchange with the interstitium, but by an action restricted to the CELM's AT1R, causes release of endothelial chemical messengers that exert physiological effects and modulate the effects and metabolism of paracrine Ang II. Endocrine Ang II controls and communicates with its paracrine counterparts solely through endothelial receptors.     

Role of angiotensin type 2 receptors in human forearm vascular responses of normal volunteers

1. It has been hypothesized that the expression of angiotensin (Ang) II type 2 (AT(2)) receptors may become important in vascular disease; however, the functional existence of AT(2) receptors in normal adult humans remains to be established. 2. Vascular responses to AngII after the administration of the specific AT(2) receptor antagonist PD 123319 were determined in the forearm circulation of normal volunteers. 3. PD 123319 (8 microg/min) did not alter basal forearm blood flow, or forearm blood flow or forearm vascular resistance responses to AngII. 4. These results suggest that AT(2) receptors do not play a significant role in the regulation of forearm blood flow or forearm vascular resistance of normal volunteers, but do not preclude a role for AT(2) receptors in other vascular beds or in patients with cardiovascular disease.     

Captopril avoids hypertension,the increase in plasma angiotensin II but increases angiotensin 1–7 and angiotensin II‐induced perfusion pressure in isolated kidney in SHR

相似文献   

Differential regulation by AT(1) and AT(2) receptors of angiotensin II-stimulated cyclic GMP production in rat uterine artery and aorta

1. In the present study we determined whether angiotensin II (Ang II) could increase cyclic GMP levels in two blood vessels that exhibit markedly different angiotensin II receptor subtype expression: rat uterine artery (UA; AT(2) receptor-predominant) and aorta (AT(1) receptor-predominant), and investigated the receptor subtype(s) and intracellular pathways involved. 2. UA and aorta were treated with Ang II in the absence and presence of losartan (AT(1) antagonist; 0.1 microm), PD 123319 (AT(2) antagonist; 1 microm), NOLA (NOS inhibitor; 30 microm), and HOE 140 (B(2) antagonist; 0.1 microm), or in combination. 3. Ang II (10 nm) induced a 60% increase in UA cyclic GMP content; an effect that was augmented with PD 123319 and HOE 140 pretreatment, and abolished by cotreatment with losartan, as well as by NOLA. 4. In aorta, Ang II produced concentration-dependent increases in cyclic GMP levels. Unlike effects in UA, these responses were abolished by PD 123319 and by NOLA, whereas losartan and HOE 140 caused partial inhibition. 5. Thus, in rat UA, Ang II stimulates cyclic GMP production through AT(1) and, to a less extent, AT(2) receptors. In rat aorta, the Ang II-mediated increase in cyclic GMP production is predominantly AT(2) receptor-mediated. In both preparations, NO plays a critical role in mediating the effect of Ang II, whereas bradykinin has differential roles in the two vessels. In UA, B(2) receptor blockade may result in a compensatory increase in cyclic GMP production, whilst in aorta, bradykinin accounts for approximately half of the cyclic GMP produced in response to Ang II.     

Aldosterone synthesis and cytokine production in human peripheral blood mononuclear cells

Previously, we reported that spironolactone reduced cytokine production in cultured human peripheral blood mononuclear cells (PBMCs) with angiotensin (Ang) II stimulation. To address the mechanisms underlying this effect, we examined the contribution of aldosterone to cytokine production in cultured human PBMCs with Ang II stimulation. PBMCs expressed the messenger RNA (mRNA) of Ang II type 1 receptor (AT1R) and mineralocorticoid receptor (MR) both spontaneously and after Ang II stimulation, but expressed Ang II type 2 receptor (AT2R) under neither condition. After 24 h of incubation, exogenous Ang II induced the expression of CYP11B2 (a key enzyme of aldosterone synthesis) mRNA and caused aldosterone synthesis. CV-11974 (an AT1R antagonist) reduced Ang II-induced aldosterone synthesis, whereas PD-123319 (an AT2R antagonist) had no effect. The concentration of aldosterone peaked earlier than those of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha). After 48 h of incubation (under the influence of synthesized aldosterone), CV-11974 and spironolactone significantly reduced the Ang II-enhanced production of MCP-1 and TNF-alpha, whereas PD-123319 also had no effect. In conclusion, Ang II induces aldosterone synthesis through AT1R and enhances cytokine production through an AT1R-dependent mechanism and, at least partly, through a MR-dependent mechanism in human PBMCs.     

Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells.

Angiotensin II (Ang II) has powerful sodium-retaining, growth-promoting and pro- inflammatory properties in addition to its physiological role in maintaining body salt and fluid balance and blood pressure homeostasis. Increased circulating and local tissue Ang II is one of the most important factors contributing to the development of sodium and fluid retention, hypertension and target organ damage. The importance of Ang II in the pathogenesis of hypertension and target organ injury is best demonstrated by the effectiveness of angiotensin- converting enzyme (ACE) inhibitors and AT1-receptor antagonists in treating hypertension and progressive renal disease including diabetic nephropathy. The detrimental effects of Ang II are mediated primarily by the AT1-receptor, while the AT2-receptor may oppose the AT1-receptor. The classical view of the AT1-receptor-mediated effects of Ang II is that the agonist binds its receptors at the cell surface, and following receptor phosphorylation, activates downstream signal transduction pathways and intracellular responses. However, evidence is emerging that binding of Ang II to its cell surface AT1-receptors also activates endocytotic (or internalisation) processes that promote trafficking of both the effector and the receptor into intracellular compartments. Whether internalised Ang II has important intracrine and signalling actions is not well understood. The purpose of this article is to review recent advances in Ang II research with focus on the mechanisms underlying high levels of intracellular Ang II in proximal tubule cells and the contribution of receptor-mediated endocytosis of extracellular Ang II. Further attention is devoted to the question whether intracellular and/or internalised Ang II plays a physiological role by activating cytoplasmic or nuclear receptors in proximal tubule cells. This information may aid future development of drugs to prevent and treat Ang II-induced target organ injury in cardiovascular and renal diseases by blocking intracellular and/or nuclear actions of Ang II.     

氯沙坦对自发性高血压大鼠脑组织肾素血管紧张素系统的影响

目的　探讨氯沙坦对自发性高血压大鼠 (SHR)脑组织血管紧张素Ⅰ型受体 (AT1 R)mRNA的表达及脑组织局部肾素 血管紧张素系统 (RAS)活性的影响。方法　 6wk龄♂WKY和SHR各 1 6只分别随机分为氯沙坦用药组和生理盐水对照组 ,喂养 1 8wk后运用RT PCR法检测脑组织AT1 RmRNA的表达 ;放免法测定肾素活性 (RA)和血管紧张素Ⅱ(AngⅡ )的水平 ;紫外分光光度法测定血管紧张素转换酶活性 (ACEA)。结果　SHR组各部位脑组织AT1 RmRNA和血浆、下丘脑RA、AngⅡ、血清ACEA表达均高于WKY组(P <0 0 5) ;氯沙坦可降低各部位脑组织AT1 RmRNA的表达但升高血浆RA、AngⅡ ,对下丘脑RA、AngⅡ、ACEA则无明显影响。结论　SHR脑组织AT1 RmRNA的表达及循环和组织RAS活性增加可能与高血压的发生有关 ,氯沙坦可能通过降低脑组织AT1 RmRNA表达发挥脑保护作用     

Angiotensin AT1 receptor signalling pathways in neurons

1. The aim of the present article is to review the intracellular signal transduction pathways that are influenced by the peptide angiotensin (Ang) II, acting via its type 1 (AT1) receptor, in neurons. 2. The AT1 receptors couple to a wide variety of signalling pathways in peripheral tissues, such as kidney, heart and vascular smooth muscle. A similar diversity of signalling mechanisms exists for AT1 receptors in neurons. 3. We outline the known neuronal AT1 receptor signalling pathways as they relate to function. Pathways that couple activation of AT1 receptors to short-term changes in neuronal membrane ionic currents and firing rate will be reviewed. These are different from the pathways that elicit longer-term changes in enzyme activity and gene expression and, ultimately, increases in noradrenaline synthesis. 4. Novel AT1 receptor signalling pathways discovered through gene expression profiling and their potential functional significance have been discussed.     

The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition

Background and Purpose

The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease.

Experimental Approach

The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of β-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays.

Key Results

Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP₁) and β-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin.

Conclusions and Implications

Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology.

Linked Article

This article is commented on by Goupil et al., pp. 1101–1103 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12040