Effect of angiotensin II type 2 receptor on stroke,cognitive impairment and neurodegenerative diseases

Here, we briefly review the role of the renin–angiotensin system (RAS) in cognitive impairment and neurodegenerative disease, mainly discussing our experimental studies on the angiotensin II type 2 (AT₂) receptor. Ischemic brain damage is enhanced in mice with overexpression of angiotensin II, with reduced cerebral blood flow in the penumbra and an increase in oxidative stress in the ischemic area. Angiotensin II binds two types of receptors, type 1 (AT₁) and type 2 (AT₂). Our previous experiments showed that AT₁ receptor signaling has a harmful effect, and AT₂ receptor signaling has a protective effect on the brain after stroke. AT₂ receptor signaling in bone marrow stromal cells or hematopoietic cells was shown to prevent ischemic brain damage after middle cerebral artery occlusion. In contrast, AT₂ receptor signaling also affects cognitive function. We showed that direct stimulation of the AT₂ receptor by a newly generated direct AT₂ receptor agonist, Compound 21 (C21), enhanced cognitive function in wild‐type (C57BL6) mice and an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid β (1–40). Finally, we carried out clinical research by investigating the levels of RAS components in patients with neurodegenerative diseases. We observed a reduction of angiotensin II and angiotensin converting enzyme (ACE) 2 levels, and an increase in ACE level in cerebrospinal fluid from patients with multiple sclerosis. These results suggest that RAS is also involved in neurodegenerative disease. Therefore, regulation of RAS might be a new therapeutic target to protect neurons from neural diseases. Geriatr Gerontol Int 2012; ••: ••–•• .     

In hypertension, the kidney breaks your heart

The renin-angiotensin system (RAS) is a master regulator of blood pressure and fluid homeostasis. Because RAS components are expressed in several tissues that may influence blood pressure, studies using conventional gene targeting to globally interrupt the RAS have not determined the contributions of angiotensin II receptor type 1 (AT₁) receptors in specific tissue pools to blood pressure regulation and tissue injury. Recent experiments using kidney cross-transplantation and mice lacking the dominant murine AT₁ receptor isoform, AT 1A, have demonstrated that 1) AT₁ receptors inside and outside the kidney make equivalent contributions to normal blood pressure homeostasis, 2) activation of renal AT 1 receptors is required for the development of angiotensin II-dependent hypertension, and 3) this blood pressure elevation rather than activation of AT₁ receptors in the heart drives angiotensin II-induced cardiac hypertrophy. These findings, together with previous experiments, confirm the kidney’s critical role in the pathogenesis of hypertension and its complications.     

Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets

Aims/hypothesis A local angiotensin-generating system has been found in the exocrine pancreas. This study aimed, primarily, to investigate the existence of a local angiotensin-generating system in the pancreatic islets and, secondly, to elucidate its role in regulating insulin secretion.Methods Real-time RT-PCR and western blot were used to investigate if angiotensin-generating components are present in the mouse pancreatic islets, which are subject to regulation by islet transplantation. The localisation of AT₁-receptors in islets was investigated by immunohistochemistry. Batch-type incubations of isolated islets were applied for studying the influence of angiotensin II on the glucose-stimulated insulin release, glucose oxidation and (pro)insulin, and total protein biosynthesis.Results Major components, namely angiotensinogen, ACE, AT ₁ - and AT ₂ -receptors, were expressed in endogenous islets. AT₁-receptors were localised to pancreatic beta cells. Exposure of the isolated islets to angiotensin II induced a dose-dependent inhibition of glucose-stimulated insulin release and inhibited (pro)insulin biosynthesis. This inhibitory action was fully preventable by pretreatment of the islets with losartan, an AT₁-receptor antagonist. We also investigated if the expression of these components was changed after islet transplantation. Notably, a markedly increased expression of mRNA for the AT ₁ -receptor was observed in islets retrieved from 4-week-old syngeneic islet transplants, a finding that was confirmed at the protein level.Conclusion/interpretation These data indicate the existence of an islet angiotensin-generating system of potential importance in the physiological regulation of glucose-induced insulin secretion, thus diabetes mellitus. The increased expression of the AT₁-receptor in islet transplants could have relevance to islet-graft function.Abbreviations Ang II Angiotensin II - AT₁ angiotensin II receptor type 1 - AT₂ angiotensin II receptor type 2 - Ao angiotensinogen - RAS Renin-angiotensin system - KRBB Krebs-Ringer bicarbonate buffer     

The renin-angiotensin and adrenergic nervous system in cardiac hypertrophy in fructose-fed rats

BackgroundHyperinsulinemia and insulin resistance are associated with left ventricular hypertrophy (LVH) and cardiovascular complications in hypertensive subjects. The aim of this study was to explore the mechanisms for LVH including activation of the renin-angiotensin system system (RAS) and the sympathetic nervous system and their activation by insulin using a rat model of hyperinsulinemia and insulin resistance.Methods:Male Sprague-Dawley rats were fed a high-fructose or control diet. The fructose-fed rats (FFR) were divided into four subgroups that were administrated either vehicle or the following antihypertensive drugs (n = 6–8) for 4 weeks: 1) olmesartan, an angiotensin II type 1 (AT₁) receptor antagonist; 2) bunazosin, an α₁-receptor blocker; and 3) hydralazine, a direct vasodilator.Results:Fructose feeding induced significant increases in mean systolic blood pressure (BP) levels at 4 weeks (control, 117 v fructose, 131 mm Hg), left ventricular weight, and the sum of the insulin level in response to a glucose tolerance test (2 g/kg). Fructose feeding also increased urinary excretion of epinephrine and norepinephrine, the density of cardiac α₁-adrenergic receptors, and the content of angiotensin II in the left ventricle. All antihypertensive drugs decreased systolic BP, but only the AT₁ receptor antagonist attenuated the development of LVH in FFR. The AT₁ receptor antagonist did not affect glucose-mediated insulin responses, but did suppress urinary catecholamine excretion and cardiac α₁-adrenergic receptor density.ConclusionsLeft ventricular hypertrophy in FFR may be less dependent on systemic elevations of BP and more dependent on the RAS and the sympathetic nervous system. Use of an AT₁ receptor antagonist might be the most beneficial way to prevent progression of LVH through direct effects on tissue RAS and the sympathetic nervous system in FFR. As these changes occur in a rat model with hyperinsulinemia, insulin may have a role in promoting LVH by activating the local RAS and sympathetic nervous system activity.     

Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension

It is well recognized that the renin-angiotensin system (RAS) exists not only as circulating, paracrine (cell to cell), but also intracrine (intracellular) system. In the kidney, however, it is difficult to dissect the respective contributions of circulating RAS versus intrarenal RAS to the physiological regulation of proximal tubular Na⁺ reabsorption and hypertension. Here, we review recent studies to provide an update in this research field with a focus on the proximal tubular RAS in angiotensin II (ANG II)-induced hypertension. Careful analysis of available evidence supports the hypothesis that both local synthesis or formation and AT₁ (AT_1a) receptor- and/or megalin-mediated uptake of angiotensinogen (AGT), ANG I and ANG II contribute to high levels of ANG II in the proximal tubules of the kidney. Under physiological conditions, nearly all major components of the RAS including AGT, prorenin, renin, ANG I, and ANG II would be filtered by the glomerulus and taken up by the proximal tubules. In ANG II-dependent hypertension, the expression of AGT, prorenin, and (pro)renin receptors, and angiotensin-converting enzyme (ACE) is upregulated rather than downregulated in the kidney. Furthermore, hypertension damages the glomerular filtration barrier, which augments the filtration of circulating AGT, prorenin, renin, ANG I, and ANG II and their uptake in the proximal tubules. Together, increased local ANG II formation and augmented uptake of circulating ANG II in the proximal tubules, via activation of AT₁ (AT_1a) receptors and Na⁺/H⁺ exchanger 3, may provide a powerful feedforward mechanism for promoting Na⁺ retention and the development of ANG II-induced hypertension.     

Pathways of hepatic and renal damage through non‐classical activation of the renin‐angiotensin system in chronic liver disease

In liver cirrhosis, renin‐angiotensin system (RAS) activation sustains renal sodium retention and hepatic fibrogenesis. New information has recently enlivened the traditional concept of RAS. For instance, renin and prorenin bind their ubiquitous receptors, resulting in the local production of angiotensin (Ang) II; increased serum calcium and calcimimetic agents, through stimulation of extracellular calcium‐sensing receptors (CaSR), blunt renin production and lead to natriuretic effects in human and experimental cirrhosis. Alongside systemic production, there is Ang II tissue production within various organs through RAS enzymes different from angiotensin‐converting enzyme (ACE), that is chymase, tissue plasminogen activator and several cathepsins. In experimental cirrhosis, inhibition of chymase leads to natriuretic and hepatic antifibrotic effects, without changes in systemic haemodynamics. In the kidney, local RAS coordinates proximal and distal tubular sodium reabsorption. However, renalase, whose plasma and tissue levels are severely altered in experimental cirrhosis, degrades systemic and renal tubule catecholamines, antagonizing the effects of renal RAS. Angiotensinogen‐derived natriuretic and vasodilating peptides (Ang1‐9, Ang1‐7, Ang3‐8) and their receptors have been described. Receptor agonists or antagonists are available to affect portal hypertension and sodium retention in cirrhosis. ACE2‐dependent generation of Ang1‐7 may inhibit experimental liver fibrosis. inhibition of Ang1‐7 clearance by means of neprilysin blockade has portal hypotensive and natriuretic effects. Ang1‐12, whose production renin does not regulate, is converted to several different angiotensin peptides via chymase. Finally, Ang II behaves as either an antinatriuretic or a natriuretic agent, based on the tissue content of AT₁R and AT₂R receptors, their ratio being prone to pharmacological modulation.     

Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders

Angiotensin II (Ang II), acting on the AT₁ and AT₂ receptors in mammalian cells, is the vasoactive component of the renin‐angiotensin system (RAS). Several components of the RAS have been demonstrated in different tissues, including adipose tissue. Although the effects of Ang II on metabolism have not been studied widely, it is intriguing to assume that components of the RAS produced by adipocytes may play an autocrine, a paracrine and/or an endocrine role in the pathophysiology of obesity and provide a potential pathway through which obesity leads to hypertension and type 2 diabetes mellitus. In the first part of this review, we will describe the production of Ang II, the different receptors through which Ang II exerts its effects and summarize the concomitant intracellular signalling cascades. Thereafter, potential Ang II‐induced mechanisms, which may be associated with obesity and obesity‐related disorders, will be considered. Finally, we will focus on the different pharmaceutical agents that interfere with the RAS and highlight the possible implications of these drugs in the treatment of obesity‐related disorders.     

The significance of brain aminopeptidases in the regulation of the actions of angiotensin peptides in the brain

From the outset, the concept of a brain renin-angiotensin system (RAS) has been controversial and this controversy continues to this day. In addition to the unresolved questions as to the means by which, and location(s) where brain Ang II is synthesized, and the uncertainties regarding the functionality of the different subtypes of Ang II receptors in the brain, a new controversy has arisen with respect to the identity of the angiotensin peptide(s) that activate brain AT₁ receptors. While it has been known for some time that Ang III can activate Ang II receptors with equivalent or near-equivalent efficacy to Ang II, it has been proposed that in the brain, only Ang III is active. This proposal, which we have named “The Angiotensin III Hypothesis” states that Ang II must be converted to Ang III in order to activate brain AT₁ receptors. This review examines several aspects of the controversies regarding the brain RAS with a special focus on brain aminopeptidases, studies that either support or refute The Angiotensin III Hypothesis, and the implications of The Angiotensin III Hypothesis for the activity of the brain RAS. It also addresses the need for further research that can test The Angiotensin III Hypothesis and definitively identify the angiotensin peptide(s) that activate brain AT₁ receptor-mediated effects.     

Efeitos cardiovasculares do receptor tipo 2 da angiotensina

The angiotensin type 2 receptor, AT₂R, has been described as having opposite effects to the angiotensin type 1 receptor, AT₁R. Although the quantities of the AT₂R found in the adult are low, its expression rises in pathological situations. The AT₂R has three major signaling pathways: activation of serine/threonine phosphatases (promoting apoptosis and antioxidant effects), activation of the bradykinin/NO/cGMP pathway (promoting vasodilation), and activation of phospholipase A2 (associated with regulation of potassium currents). The AT₂R appears to have effects in vascular remodeling, atherosclerosis prevention and blood pressure lowering (when associated with an AT₁R inhibitor). After myocardial infarction, the AT₂R appears to decrease infarct size, cardiac hypertrophy and fibrosis, and to improve cardiac function. However, its role in the heart is controversial. In the kidney, the AT₂R promotes natriuresis. Until now, treatment directed at the renin‐angiotensin‐aldosterone system has been based on angiotensin‐converting enzyme inhibitors or angiotensin type 1 receptor blockers. The study of the AT₂R has been revolutionized by the discovery of a direct agonist, C21, which promises to become part of the treatment of cardiovascular disease.     

Dimerization of AT<Subscript>2</Subscript> and Mas Receptors in Control of Blood Pressure

Purpose of Review

Angiotensin type 2 receptor (AT₂R) and receptor Mas (MasR) are part of the “protective arm” of the renin angiotensin system. Gene and pharmacological manipulation studies reveal that AT₂R and MasR are involved in natriuretic, vasodilatory, and anti-inflammatory responses and in lowering blood pressure in various animal models under normal and pathological conditions such as salt-sensitive hypertension, obesity, and diabetes. The scope of this review is to discuss co-localization and heterodimerization as potential molecular mechanisms of AT₂R- and MasR-mediated functions including antihypertensive activities.

Recent Findings

Accumulating evidences show that AT₂R and MasR are co-localized, make a heterodimer, and are functionally interdependent in producing their physiological responses. Moreover, ang-(1-7) preferably may be an AT₁R-biased agonist while acting as a MasR agonist.

Summary

The physical interactions of AT₂R and MasR appear to be an important mechanism by which these receptors are involved in blood pressure regulation and antihypertensive activity. Whether heteromers of these receptors influence affinity or efficacy of endogenous or synthetic agonists remains a question to be considered.

     

A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes

Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT₁R) and 2 (AT₂R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFβ)1 or hydrogen peroxide did not. The CF-derived exosomes upregulated the expression of renin, angiotensinogen, AT₁R, and AT₂R, downregulated angiotensin-converting enzyme 2, and enhanced Ang II production in cultured cardiomyocytes. In addition, the CF exosome-induced cardiomyocyte hypertrophy was blocked by both AT₁R and AT₂R antagonists. Exosome inhibitors, GW4869 and dimethyl amiloride (DMA), inhibited CF-induced cardiomyocyte hypertrophy with little effect on Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CF exosomes upregulated RAS in cardiomyocytes via the activation of mitogen-activated protein kinases (MAPKs) and Akt. Finally, Ang II-induced exosome release from cardiac fibroblasts and pathological cardiac hypertrophy were dramatically inhibited by GW4869 and DMA in mice. These findings demonstrate that Ang II stimulates CFs to release exosomes, which in turn increase Ang II production and its receptor expression in cardiomyocytes, thereby intensifying Ang II-induced pathological cardiac hypertrophy. Accordingly, specific targeting of Ang II-induced exosome release from CFs may serve as a novel therapeutic approach to treat cardiac pathological hypertrophy and heart failure.     

Optimal strategies for preventing progression of renal disease: Should angiotensin converting enzyme inhibitors and angiotensin receptor blockers be used together?

Interruption of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT₁ receptor blockers has been shown to delay progression in a variety of renal diseases, suggesting that the RAS, and its major effector molecule, angiotensin II, are important players in renal pathophysiology. Both antagonists combine inhibition of deleterious effects of angiotensin II with activation of potentially beneficial pathways mediated by nitric oxide and prostaglandins. Some concerns have been raised about the completeness of the RAS blockade achieved by these agents. ACE-independent pathways can generate angiotensin II, whereas increases in angiotensin II levels may compete with the AT₁ receptor blocker at the receptor site. It has been suggested that an ACE inhibitor/AT₁ receptor blocker combination offers a better therapeutic effect than treatment with either agent alone. In this review, we focus on mechanisms of actions of ACE inhibitors and AT₁ receptor blockers, implicate them in the rationale for the use of an ACE inhibitor/AT₁ receptor blocker combination, and discuss evidence evaluating the renal effects of the combination as compared to the effects of a single agent. There is a surprising lack of information about the nephroprotective potential of the combination, allowing no consistent conclusions about the superiority of the combination over the single agent. Several experimental and clinical reports suggest that in some conditions, the combination may be beneficial. Rather than providing unequivocal evidence for the use of combination treatment in the renal disease, these studies should be considered as stimuli for more detailed exploration of this issue.     

Prevalence of Metabolic Syndrome and Obesity-Associated Hypertension in the Racial Ethnic Minorities of the United States

It is quite well established that activation of the so-called protective arms of the renin-angiotensin system (RAS), involving both AT₂ and Mas receptors, provides a counter-regulatory role to AT₁ receptor overactivity that may drive pathological changes in the cardiovascular system. In this brief review, we will focus on recent evidence that identifies at least three different pathways that may be effective in the setting of stroke and may be complementary with AT₁ receptor blockade. Such mechanisms include AT₂ receptor stimulation, Mas receptor stimulation and insulin-regulated aminopeptidase blockade. This report highlights recent data demonstrating striking neuroprotective effects in preclinical models of stroke targeting each of these pathways, which may pave the way for translational opportunities in this field.     

Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT4R) in the postmortem brains of individuals without cognitive impairment

The reported primary dementia-protective benefits of angiotensin II type 1 receptor (AT₁R) blockers (ARB) are believed, at least in part, to arise from systemic effects on blood pressure. However, there is a specific and independently regulated brain renin-angiotensin system (RAS). Brain RAS acts mainly through three receptor subtypes; AT₁R, AT₂R, and AT₄R. The AT₁R promotes inflammation and mitochondrial reactive oxygen species generation. AT₂R increases nitric oxide. AT₄R is essential for dopamine and acetylcholine release. It is unknown whether ARB use is associated with changes in the brain RAS. Here, we compared the impact of treatment with ARB on not cognitively impaired individuals and individuals with Alzheimer’s dementia using postmortem frontal-cortex samples of age- and sex-matched participants (70–90 years old, n?=?30 in each group). We show that ARB use is associated with higher brain AT₄R, lower oxidative stress, and amyloid-β burden in NCI participants. In AD, ARB use was associated with lower brain AT₁R but had no impact on inflammation, oxidative stress, or amyloid-β burden. Our results may suggest a potential role for AT₄R in the salutary effects for ARB on the brains of not cognitively impaired older adults.

Graphical abstract

     

Changes in protein and gene expression of angiotensin II receptors (AT1 and AT2) in aorta of diabetic and hypertensive rats

Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT₁ and AT₂ receptors. For that reason, the aim of this work was to study the gene and protein expression of AT₁ and AT₂ receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60?mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT₁ receptors than normotensive rats while the AT₂ expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT₁ and AT₂ receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT₁ and AT₂ receptors. However, the overexpression of AT₂ could be associated with the reduction in the response to Ang II in the early stage of diabetes.     

Mechanism of action of angiotensin-receptor blocking agents

Angiotensin II is the most active hormone of the reninangiotensin system. In humans, two angiotensin receptors have been identified: AT₁ and AT₂. In adults, most of the effects of angiotensin II are mediated by the AT₁ receptor; the function of the AT₂ receptor is not yet well established. Angiotensin II has both systemic and local paracrine effects. Increased activity of angiotensin II and stimulation of the AT₁ receptor have been linked to the development of several cardiovascular and renal diseases, including hypertension, heart failure, left ventricular hypertrophy, and diabetic nephropathy. Over the past two decades, angiotensin-converting enzymes have been used to manage these diseases. However, the side effects and less-thanmaximum therapeutic effects of angiotensin-converting enzyme inhibitors, particularly in the decrease of mortality associated with congestive heart failure, have led to the development of AT₁-receptor blockers.     

Influence of autoantibodies against AT1 receptor and AGTR1 polymorphisms on candesartan-based antihypertensive regimen: Results from the Study of Optimal Treatment in Hypertensive Patients with Anti-AT1-Receptor Autoantibodies trial

The autoantibodies against angiotensin AT₁ receptors (AT₁-AAs) in patients with essential hypertension exhibited an agonistic action like angiotensin II and maintained high blood pressure (BP). Angiotensin II receptor gene (AGTR1) polymorphisms were associated with BP response to RAS inhibition in the hypertensive population. Furthermore, the BP response to AT₁ receptor blockers varied significantly among individuals with hypertension. We hypothesized that the polymorphisms of the AGTR1 and AT₁-AAs might affect antihypertensive response to AT₁ receptor blockers based in patients with primary hypertension. Patients who received a candesartan-based regimen came from the SOT-AT₁ study (Study of Optimal Treatment in Hypertensive Patients with Anti-AT₁-Receptor Autoantibodies). The established enzyme-labeled immunosorbent assay was used to detect AT₁-AAs in the sera of the patients. Genotype 3 single nucleotide polymorphisms in AGTR1 gene was used by DNA sequencing. The correlations among AT₁-AAs, AGTR1 gene polymorphisms or haplotypes, and the antihypertensive effect candesartan-based were analyzed using SPSS. The percentage of systolic BP reduction that was candesartan-based was greater in AT₁-AA positive groups than in AT₁-AA negative ones (21 ± 8 vs. 18 ± 9; P = .001). Meanwhile, systolic BP reduction that was candesartan-based was more significant in the group of rs5186 AC genotypes than AA homozygotes after adjusting for other confounding factors (37.55 ± 13.7 vs. 32.47 ± 17.27 mm Hg; adjusted P = .028). Furthermore, haplotypes (GCC) and (AAC) had impacts on the antihypertensive effect of candesartan therapy. The AT₁-AAs, AGTR1 gene polymorphisms and haplotypes solely or jointly have influences on candesartan-based antihypertensive response in patients with primary hypertension.     

Novel actions of angiotensin II via its renal type-2 (AT2) receptor

The vast majority of the biologic effects of angiotensin II have been considered to be mediated by the subtype-1 (AT₁) receptor. The AT₂ receptor is expressed to a low degree in most adult cells and tissues, and its function has not been understood. Recent studies, however, have identified novel actions of angiotensin II mediated by the AT₂ receptor in the kidney. These AT₂ receptor actions have importance in the control of blood pressure and hypertension. The AT₂ receptor mediates a renal vasodilator cascade, including generation of bradykinin, nitric oxide, and cyclic GMP. This action of angiotensin II occurs when the renin-angiotensin system is activated, as in sodium depletion. The AT₂ receptor also appears to mediate prostaglandin (PG) F_α formation, probably by stimulating conversion of PGE2 to PGF_α. The AT₂ receptor plays a counter-regulatory vasodilator role opposing the vasoconstrictor actions of angiotensin II. The AT₁ and AT₂ receptors engage in inter-receptor “cross-talk.” In the absence of the AT₂ receptor, sustained angiotensin II pressor and antinatriuretic hypersensitivity occurs, mediated by a deficiency of bradykinin, nitric oxide, and cyclic GMP. The AT₂ receptor may play an important role in stimulating pressure natriuresis, but definitive studies are required to resolve this issue. The AT₂ receptor mediates several renal actions of angiotensin II, appears to be important in the physiologic regulation of blood pressure, and may be involved in the pathophysiology of hypertension.     

Assessing the Prognostic Implications of Myocardial Perfusion Studies: Identification of Patients at Risk vs Patients who May Benefit from Intervention?

Angiotensin II (AII), an octapeptide member of the renin-angiotensin system (RAS), is formed by the enzyme angiotensin converting enzyme (ACE) and exerts adverse cellular effects through an interaction with its type 1 receptor (AT₁R). Both ACE inhibitors and angiotensin receptor blockers (ARB) mitigate the vasoconstrictive, proliferative, proinflammatory, proapoptotic, and profibrotic effects of AII and are widely used as effective anti-remodeling agents in clinical practice. Prediction of individual response to these agents, however, remains problematic and is influenced by many factors including race, gender, and genotype. In addition, systemic and tissue RAS activity do not correlate closely. This report summarizes the results of on-going attempts to noninvasively determine tissue ACE activity and AT₁R expression using novel nuclear tracers. It is hoped that the availability of such imaging techniques improve treatment of heart failure through more selective pharmacologic intervention and better dose titration of available drugs.