Ang II Receptor Blockers

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Good discussion of angiotensin II receptor blockers, basic and insightful. Good information for scientists and med students.

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Clinical Science (2001) 100, 481–492 (Printed in Great Britain)

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Angiotensin receptors: distribution, signalling and function
Diem T. DINH*, Albert G. FRAUMAN†, Colin I. JOHNSTON* and Maurice E. FABIANI *
*Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Austin Campus, Studley Road, Heidelberg, VIC 3084, Australia, and †Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Austin and Repatriation Medical Centre, Austin Campus, Studley Road, Heidelberg, VIC 3084, Australia

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Angiotensin II (Ang II) is a multi-functional hormone that plays a major role in regulating blood pressure and cardiovascular homoeostasis. The actions of Ang II are mediated by at least two receptor subtypes, designated AT1 and AT2. In addition, other angiotensin receptors have been identified which may recognize other angiotensin peptide fragments ; however, until now only the AT1 and AT2 receptor have been cloned in animals or humans. Most of the well-described actions of Ang II, such as vasoconstriction, facilitation of sympathetic transmission, stimulation of aldosterone release and promotion of cellular growth are all mediated by the AT1 receptor. Much less is known about the function of the AT2 receptor, but recent studies suggest that it may play a role in mediating anti-proliferation, cellular differentiation, apoptosis and vasodilatation. In this review, we discuss recent advances in our understanding of Ang II receptors, in particular, their distribution, signalling and function.

INTRODUCTION
The renin–angiotensin system (RAS) is a bioenzymic cascade that plays an integral role in cardiovascular homoeostasis by influencing vascular tone, fluid and electrolyte balance and the sympathetic nervous system (Figure 1). The biological actions of the RAS are mediated primarily by the highly active octapeptide angiotensin II (Ang II). Traditionally, the RAS was viewed as a circulating endocrine system, whereby renin released from the juxtaglomerular cells of the kidney cleaves the liver-derived macroglobulin precursor angiotensinogen, to produce the inactive decapeptide angiotensin I, which is then converted to the active octapeptide Ang II by angiotensin-converting enzyme (ACE) within the pulmonary circulation [1,2].

In addition to the systemic (circulating) RAS, there is evidence to indicate that many tissues, including the vasculature, heart, kidney and brain, are capable of producing Ang II, which may thereby mediate autocrine, paracrine and intracrine effects [1,2]. Numerous studies have also shown that the requisite components of the RAS, such as angiotensinogen, renin and ACE are present in such tissues [3,4]. Furthermore, Ang II can be formed via non-ACE and non-renin enzymes (Figure 1) including chymase, cathepsin G, chymostatin-sensitive Ang II-generating enzyme (‘ CAGE ’), tissue plasminogen activator and tonin [5,6]. In addition to the RAS playing an important role in normal cardiovascular homoeostasis, overactivity of the RAS has been implicated in the development of various cardiovascular diseases, such as hypertension, congestive

Key words: angiotensin, angiotensin receptors, renin–angiotensin system. Abbreviations: Ang II, angiotensin II; RAS, renin–angiotensin system; ACE, angiotensin-converting enzyme; MAP, mitogenactivated protein; VSMC, vascular smooth muscle cells; MKP-1, MAP kinase phosphatase 1; SHP-1, SH2-domain-containing phosphatase 1. Correspondence: Dr Maurice E. Fabiani (e-mail m.fabiani!austin.unimelb.edu.au).

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AT1

AT2

Figure 1

Bioenzymic cascade of the renin–angiotensin system

heart failure, coronary ischaemia and renal insufficiency [7]. Therefore drugs which interfere with the RAS, such as ACE inhibitors and AT receptor antagonists, have " been shown to be of great therapeutic benefit in the treatment of such cardiovascular disorders [8,9]. Regardless of how it is formed, the effects of Ang II are mediated via specific membrane-bound receptors (see below). This review will discuss our current understanding of Ang II receptors, with particular emphasis on their distribution, signalling pathways and functional role.

AT receptors in mediating anti-proliferation, apoptosis, # differentiation and possibly vasodilatation [13,14]. The general properties of Ang II receptor subtypes are summarized in Table 1 and elaborated below.

AT1 RECEPTORS
Properties
AT receptors selectively bind biphenylimidazoles, in" cluding losartan, candesartan and irbesartan, with high affinity and are rather insensitive to tetrahydroimidazolpyridines, such as PD123319 and PD123177 [11]. Moreover, the affinity of Ang II for the AT receptor is " dramatically decreased in the presence of the reducing agent dithiothreitol and GTP analogues [15]. The gene for the AT receptor was first cloned from rat " vascular smooth muscle cells [16] and bovine adrenal gland [17]. The AT receptor gene product consists of 359 " amino acids and has a molecular mass of 41 kDa. The human genome contains a unique gene coding for the AT receptor, which is localized on chromosome 3 [18]. " In contrast, there are two isoforms of the AT receptor in " rodents, termed AT A and AT B, which share 94 % " " similarity [19,20]. In the rat, the AT A gene is localized to " chromosome 17 and the AT B gene to chromosome 2 " [21]. AT A receptors are found predominantly in kidney,

ANGIOTENSIN RECEPTORS
The actions of Ang II are mediated by specific heterogenous populations of Ang II receptors. Ang II is known to interact with at least two distinct Ang II receptor subtypes, designated AT and AT [10]. The charac" # terization of Ang II receptor subtypes was made possible by the discovery and development of selective nonpeptide Ang II receptor antagonists, namely losartan (AT -selective) and PD123319 (AT -selective) [11]. " # Virtually all the known biological actions of Ang II, including vasoconstriction, release of aldosterone, stimulation of sympathetic transmission and cellular growth, are exclusively mediated by the AT receptor [11,12]. The " functional role of the AT receptor is not fully under# stood, but recent studies have ascribed a possible role of
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Table 1

Classification and general properties of AT1 and AT2 receptors

Properties Selective ligands Isoforms Effect of dithiothreitol Effect of GTP Coupling mechanism Signal transduction

AT1 Receptor Losartan, irbesartan, candesartan Single isoform (humans) AT1A, AT1B (rodents) Binding Affinity G-protein : Gi, Gq Phospholipase C Phospholipase A2 Phospholipase D Adenylate cyclase Ca2+ influx (L-type channel) MAP/JAK/STAT pathway AT1 : 3 (human) AT1A : 17 (rat) AT1B : 2 (rat) 359 Amino acids 7-Transmembrane 41 kDa Yes

AT2 Receptor PD123319, PD123177, CGP42112 ? Binding No effect G-protein : Gi ? Guanylate cyclase PP2A, MKP-1, SHP-1 K+ channel activity Ca2+ influx (T-type channel) NO/cGMP Phospholipase A2 X (mouse, rat, human)

Chromosomal localization

Structure Molecular mass Internalization

363 Amino acids 7-Transmembrane 41 kDa No

lung, liver and vascular smooth muscle, whereas AT B " receptors are expressed mainly in the adrenal and anterior pituitary glands. The AT receptor belongs to the seven transmembrane " class of G-protein-coupled receptors [22]. Four cysteine residues are located in the extracellular domain, which represent sites of disulphide bridge formation and are critical tertiary structure determinants. The transmembrane domain and the extracellular loop play an important role in Ang II binding [23]. The binding site for Ang II is different from the binding site for AT " receptor antagonists, which interacts only with the transmembrane domain of the receptor [24]. Like most G-protein-coupled receptors, the AT receptor is also " subject to internalization when stimulated by Ang II, a process dependent on specific residues on the cytoplasmic tail [25].

Signal transduction
There are five classical signal transduction mechanisms for the AT receptor ; activation of phospholipase A , " # phospholipase C, phospholipase D and L-type Ca#+ channels and inhibition of adenylate cyclase (Figure 2). Stimulation of phospholipase C-β which is coupled to Gq/ protein, is the most well described intracellular "" signalling pathway, in which two secondary messengers, Ins(1,4,5)P and diacylglycerol, are formed by hydrolysis $ of PtdIns(4,5)P . Ins(1,4,5)P stimulates the release of # $ Ca#+ from intracellular stores, and diacylglycerol induces protein kinase C activity, both of which lead to vasoconstriction [26,27]. Activation of phospholipases A and

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D stimulates the release of arachidonic acid, the precursor molecule for the generation of prostaglandins [26,27]. Ang II-mediated stimulation of the AT receptor coupled " to Gi/o protein can also inhibit adenylate cyclase in several target tissues, including liver, kidney and adrenal glomerulosa, thereby attenuating the production of the second messenger cAMP [28,29]. cAMP is a vasodilator and when its production is decreased due to AT receptor " activation, vasoconstriction ensues. Moreover, the AT " receptor is also involved in the opening of Ca#+ channels and influx of extracellular Ca#+ into cells. This mechanism has been linked to Ang II-mediated stimulation of aldosterone production and secretion, as well as vasoconstriction [30]. It has also been reported that activation of L-channels in rat portal vein myocytes, is mediated by AT receptors coupled to G / proteins [31]. " "# "$ It has been reported that activation of the AT receptor " stimulates growth factor pathways, such as tyrosine phosphorylation and phospholipase C-γ, leading to activation of downstream proteins, including mitogenactivated protein (MAP) kinases, Janus kinases (‘ JAK ’), and the signal transducers and activators of transcription (‘ STAT ’) proteins [32,33]. Ang II stimulating cellular proliferation and growth has been defined in adrenal medulla and vascular smooth muscle cells (VSMC). These growth-like effects are associated with increased tyrosine phosphorylation and activation of MAP kinase and related pathways, which results in increased expression of early response genes, such as c-fos, c-jun and c-myc, which control thymidine incorporation, cellular proliferation and growth [34]. Such actions have been linked
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Figure 2

Signal transduction mechanisms and physiological effects mediated by the AT1 receptor

Abbreviations : PLA, phospholipase A ; PLC, phospholipase C ; JAK, Janus kinase ; STAT, signal transducers and activators of transcription ; IP3, Ins(1,4,5)P3 ; DAG, diacylglycerol ; PKC, protein kinase C. to cardiovascular diseases, including hypertension, cardiac failure and atherosclerosis. cular organ of the lamina terminalis, anterior pituitary and the area of postrema in the hindbrain [35,39]. Furthermore, other regions of the hypothalamus, nucleus of the solitary tract and ventrolateral medulla in the hindbrain also contain a high density of AT receptors " [35]. AT receptors have also been identified in the adrenal " gland of rodents, primates and humans [40,41]. AT " receptors are localized mainly in the zona glomerulosa of the adrenal cortex and chromaffin cells of the adrenal medulla. In the heart, the highest density of AT receptors " is found in the conducting system [42,43]. Punctate AT " receptor binding is found in the epicardium surrounding the atria, with low binding seen throughout the atrial and ventricular myocardium [42,44]. Moreover, AT " receptors in the vasculature, including the aorta, pulmonary and mesenteric arteries, are present in high levels

Distribution and localization
The tissue distribution of AT receptors has been studied " extensively in humans and animals. AT receptors are " primarily found in the brain, adrenals, heart, vasculature and kidney, and serve to regulate blood pressure and fluid and electrolyte balance. AT receptors have been " demonstrated in the central nervous system of the rat [35], rabbit [36] and human [37,38], using in vitro autoradiography and more recently with in situ hybridization histochemistry [39]. AT receptors are " localized to areas of the brain that are exposed to bloodborne Ang II, such as the circumventricular organs, including the subfornical organ, median eminence, vas# 2001 The Biochemical Society and the Medical Research Society

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on smooth muscle cells and low levels in the adventitia [45]. The anatomical distribution of the AT receptor in the " kidney has been mapped in various species [45,46]. High levels of AT receptor binding occur in glomerular " mesangial cells and renal interstitial cells located between the tubules and vasa recta bundles within the inner stripe of the outer medulla [47]. Moreover, moderate binding is located in proximal convoluted tubular epithelia. More recently, the presence of AT receptors has been " shown in the human prostate, being concentrated around the peri-urethral region and localized to stromal smooth muscle [48]. This finding suggests that Ang II may play a role in this region by modulating cellular growth and sympathetic activity in the prostate, in relation to urinary flow.

AT1-receptor ‘ knockout ’ mice
Targetted gene manipulation has provided significant insights into the functional role of the RAS in regulating blood pressure, cardiovascular homoeostasis and development. Deletion of the gene encoding the AT A " receptor subtype in mice significantly reduces blood pressure and pressor responses to infused Ang II [64,65]. Conversely, in AT B-receptor ‘ knockout ’ mice, systemic " blood pressure is normal, suggesting that the AT A " receptor is the major receptor involved in blood pressure regulation [66]. However, exogenous Ang II infusion can still elicit pressor effects in AT A-deficient mice, which " can be blocked by AT receptor antagonists [67]. " Although these pressor responses were smaller than those seen in wild-type mice, it still suggests a role for the AT B receptor in blood pressure regulation, particularly " in the absence of functional AT A receptors. " In contrast with ACE [68,69] and angiotensinogen [70,71] ‘ knockout ’ mice, deletion of either the AT A or " AT B receptor in mice is not associated with impaired " development or survival, or major tissue abnormalities in the kidney, heart and vasculature [64,65,72]. However, follow-up studies have revealed that ‘ double knockout ’ of AT A and AT B receptors in mice results in a greater " " lowering of blood pressure, impaired growth and marked renal abnormalities compared with mice lacking only the AT A receptor [73,74]. Indeed, the double AT A and " " AT B receptor ‘ knockout ’ mice display a similar ab" normal phenotype to that observed with angiotensinogen or ACE ‘ knockout ’ mice [73,74]. These observations indicate that, although the AT B receptor plays a lesser " role in blood pressure regulation, growth and renal development in normal mice, it may compensate for many of the effects normally mediated by the AT A " receptor in AT A receptor ‘ knockout ’ mice. " It is curious that whilst the RAS has been implicated in cardiac hypertrophy, AT A-receptor ‘ knockout ’ mice " still develop cardiac hypertrophy on pressure overload [75,76]. This suggests that AT A-mediated Ang II sig" nalling is not critical for the development of pressureoverload-induced cardiac hypertrophy. It is possible that signalling pathways other than those elicited by Ang II can evoke hypertrophic responses during haemodynamic overload in the absence of the AT A receptor. Alterna" tively, it remains to be determined whether the AT B " receptor may contribute to pressure-overload-induced cardiac hypertrophy in AT A-receptor ‘ knockout ’ mice, " and so may compensate for the loss in AT A receptor " function in a similar fashion to that described above.

Function
Ang II stimulation of AT receptors in blood vessels " causes vasoconstriction leading to an increase in peripheral vascular tone and systemic blood pressure [49,50]. AT receptors in the heart are known to mediate the " positive ionotropic and chronotropic effects of Ang II on cardiomyocytes [51]. Ang II is also known to mediate cell growth and proliferation in cardiac myocytes and fibroblasts, as well as in vascular smooth muscle cells, and can induce the expression and release of various endogenous growth factors, including fibroblast growth factor, transforming growth factor-β and platelet-derived growth " factor [7,52,53]. It is now clear that these long-term trophic effects of Ang II are implicated in the development of cardiac hypertrophy and remodelling, and in the pathophysiology of hypertension [54,55]. Recently, it was shown that transgenic mice over-expressing the AT receptor in cardiac myocytes developed cardiac " hypertrophy and remodelling, with no change in blood pressure, and died prematurely of heart failure [56]. This suggests that Ang II, via activation of AT receptors, is " directly involved in the development of cardiac hypertrophy and heart failure, independently of blood pressure. It is well documented that Ang II facilitates sympathetic transmission by enhancing the release of noradrenaline from peripheral sympathetic nerve terminals, as well as from the central nervous system [57,58]. Moreover, Ang II stimulates the release of catecholamines from the adrenal medulla and aldosterone from the adrenal cortex [59]. Ang II also exerts diverse actions on the brain by modulating drinking behaviour and salt appetite, central control of blood pressure, stimulation of pituitary hormone release and has effects on learning and memory [60–62]. Renal Ang II is involved in regulating sodium and water reabsorption from the proximal tubules and inhibition of renin secretion from the macula densa cells [63], the latter action preventing further activation of the RAS.

AT2 RECEPTORS
Properties
The AT receptor is characterized by its high affinity for # PD123319, PD123177 and CGP42112, and very low
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Figure 3

Signal transduction mechanisms and physiological effects mediated by the AT2 receptor

Abbreviations : PLA2, phospholipase A2 ; PTP protein tyrosine phosphatase ; PP2A, serine/threonine phosphatase 2A ; ERK, extracellular signal-regulated kinase. affinity for losartan and candesartan [11]. Ang II binds to the AT receptor with similar affinity as to the AT # " receptor [10]. In contrast to the AT receptor, the " AT receptor is not inhibited by dithiothreitol or GTP # analogues [15]. The AT receptor has been cloned in a variety of # species, including human [77,78], rat [79] and mouse [80,81]. The AT receptor is also a seven transmembrane # domain receptor, encoded by a 363-amino-acid protein with a molecular mass of 41 kDa, and shares only 34 % sequence identity with the AT receptor [82]. The AT " # receptor gene has been mapped in humans to chromosome X, containing an intronless coding region [77]. The AT receptor protein consists of five potential N# glycosylation sites in the extracellular N-terminal domain and 14 cysteine residues. The second intracellular loop consists of a potential protein kinase C phosphorylation site, and the cytoplasmic tail contains three consensus sequences for phosphorylation by protein kinase C and one phosphorylation site for cAMP-dependent protein kinase [26]. The third intracellular loop has been shown to be essential for AT -receptor signal transduction by the inactivation of MAP kinase, and the ability to induce apoptosis (programmed cell death) [83].

Signal transduction
Previously, various second messengers coupled to the AT receptor have been described and include indirect # negative coupling to guanylate cyclase (inhibition of cGMP production) [84] and activation of potassium channels [85,86]. Recently, there have been new insights into AT receptor signalling pathways, including # activation of protein phosphatases and protein dephosphorylation, the NO–cGMP system, and phospholipase A (release of arachidonic acid) (Figure 3). # In particular, stimulation of AT receptors leads to # activation of various phosphatases, such as protein tyrosine phosphatase, MAP kinase phosphatase 1 (MKP-1) [87,88], SH2-domain-containing phosphatase 1 (SHP-1) [89,90] and serine\threonine phosphatase 2A [91,92], resulting in the inactivation of extracellular signalregulated kinase (‘ ERK ’), opening of potassium channels and inhibition of T-type Ca#+ channels [93,94]. Importantly, MAP kinase plays a major role in cellular

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proliferation, and the AT receptor has been reported to # block MAP kinase activation in rat neurons in culture by dephosphorylation of tyrosine phosphate by MKP-1 or serine\threonine phosphate by serine\threonine phosphatase 2A [91]. Moreover, two mechanisms have been shown in PC12W cells (rat phaeochromocytoma cell line) to mediate pro-apoptotic effects of the AT receptor, # namely bcl-2 dephosphorylation via MKP-1 [87] and SHP-1 activation [90]. It is still unclear whether the AT # receptor is coupled to a G-protein, but it has been reported that an inhibitory G-protein (Gi) is linked to the AT receptor signalling mechanism [95]. Although vari# ous signalling pathways have been assigned to the AT # receptor, it is still not clear which of these is the most important.

interferon regulatory factors 1 and 2, and interleukin-1β [95,111–113].

Function
Since the AT receptor is highly abundant in foetal # tissues, it is believed to play an important role in foetal development. However, AT -receptor knockout # mice appear to develop and grow normally (see below), suggesting that the AT receptor may not be crucial for # foetal development [114,115]. In mice lacking the AT # receptor, drinking response is impaired and locomotion reduced. In addition, the animals exhibit an increase in vasopressor response to Ang II. Recent studies have demonstrated that the AT re# ceptor is involved in the production of cGMP [116], NO [117] and prostaglandin F α [118] in the kidney, # suggesting an important role in renal function, including vasodilatation and blood pressure regulation. Moreover, the AT receptor predominates in normal rat carotid " arteries but, after balloon injury, there is an up-regulation of AT receptors [119]. Treatment of these rats, after # balloon injury, with the AT -receptor ligand CGP42112 # leads to a decrease in neointimal formation [120], suggesting a role for AT receptors in vascular repair. # The AT receptor has been shown to promote nerve # generation and neuronal differentiation in cells of neuronal origin, NG108–15 [121] and PC12W cells [122], through an increase in NO production [123]. Furthermore, it has been reported that the AT receptor mediates # anti-proliferative effects in cultured coronary endothelial cells [124], VSMC [108] and PC12W cells [125]. This is in contrast to the growth promoting effects mediated by the AT receptor. Moreover, the AT receptor has been " # shown to mediate apoptosis in R3T3 (mouse fibroblast cell line) and PC12W cells [126], and VSMC [127]. AT # receptor-mediated apoptosis appears to be linked to activation of MKP-1 [87] and SHP-1 [90], and the subsequent inactivation of the pro-apoptotic protein Bcl-2.

Distribution and localization
The AT receptor is highly expressed during foetal # development but rapidly declines at birth [96,97]. In the adult, AT receptors are present in brain, heart, adrenal # medulla, kidney and reproductive tissues [45]. The distribution of the AT receptor in the brain varies # markedly between species [35–39]. In rat brain, AT # receptors are found in areas with sensory functions, including the thalamic nuclei, medial geniculate nucleus and inferior colliculus [35]. In contrast, only the molecular layer of the cerebellum in the human brain contains AT receptors [37,38]. # Using molecular, immunohistochemical and in vitro autoradiographic techniques, low density AT receptors # have been demonstrated in the myocardium and coronary vessels throughout the atrium and ventricle in the rat heart [44,98,99]. However, in the human heart, the AT # receptor is localized mainly to fibroblasts in interstitial regions, whereas a lower degree of binding is seen in the surrounding myocardium, using emulsion autoradiography [100,101]. Moreover, AT receptors are highly # expressed in the adrenal medulla of most species but expression is much lower in humans [41]. In the adult rat kidney, the AT receptor is localized mainly in glomeruli # but it is also found at low levels in cortical tubules and interstitial cells, using immunohistochemistry and Western-blot analysis [102]. In humans, the AT receptor # is localized to glomeruli, tubules and renal blood vessels [102]. In the human uterine myometrium, the AT # receptor is highly abundant but is down-regulated during pregnancy, possibly due to sex hormones [103]. In the ovary, AT receptors are localized in follicular granulosa # cells [104]. Importantly, the expression of the AT receptor is up# regulated in pathological conditions, such as heart failure, renal failure, myocardial infarction, brain lesions, vascular injury and wound healing [105–110]. Several agents responsible for the stimulation of AT -receptor # expression have been identified, and include Ang II, insulin, insulin-like growth factor, nerve growth factor,

AT2-receptor ‘ knockout ’ mice
In contrast to AT receptor gene deletion, targetted " deletion of the AT receptor gene in mice results in raised # blood pressure and enhanced sensitivity to the pressor effects of Ang II [114,115]. This suggests that the AT # receptor mediates a vasodepressor effect and may functionally oppose the effects mediated by the AT " receptor, possibly via bradykinin and NO [128]. Given that AT receptors are highly abundant in foetal # tissues, such as the heart, kidney and brain, and disappear soon after birth, they were believed to play an important role in foetal development. However, AT -receptor # ‘ knockout ’ mice apparently develop and grow normally and do not show observable morphological defects, suggesting that the AT receptor may not be essential for # foetal development [114,115].
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AT -receptor knockout mice have impaired drinking # responses to water deprivation and reduced exploratory behaviour [114,115]. More recently, it has been reported that mice lacking the AT receptor exhibit anxiety-like # behaviour [129] and have increased sensitivity to pain [130]. Thus the AT receptor may also play a role in # modulating behavioural effects, mood and the pain threshold.

ATYPICAL ANGIOTENSIN RECEPTORS
There is now mounting evidence for the existence of additional angiotensin receptors, which are pharmacologically distinct from AT and AT receptors. The " # recently designated angiotensin AT receptor is a novel % binding site that displays high specificity and affinity for the hexapeptide fragment angiotensin (3–8), referred to as angiotensin IV (‘ Ang IV ’), but with low affinity for Ang II [131]. The binding of angiotensin IV to the AT % receptor is insensitive to both losartan and PD123319, but is selectively blocked by the peptide antagonist divalinal-angiotensin IV [132]. Although the AT re% ceptor is distributed in many tissues, the most extensive mapping has been conducted in the brain and kidney. The functional role of the AT receptor remains to be % elucidated but studies suggest that it may play a role in mediating cerebral and renal blood flow, memory retention and neuronal development [131]. Recent studies have also demonstrated a unique binding site for the peptide fragment angiotensin (1–7), which is also unaffected by losartan and PD123319 [133]. Angiotensin (1–7) has been reported to mediate some physiological effects that are identical to those of Ang II, such as the stimulation of vasopressin and prostanoid release, via its own receptor. However, increasing evidence suggests that angiotensin (1–7) may oppose the actions of Ang II by stimulating the release of vasodilator prostaglandins and NO [134,135]. Another atypical angiotensin binding site, loosely termed the AT receptor, has also been identified in $ cultured mouse neuroblastoma (Neuro-2A) cells, which binds Ang II with high affinity, but which has low affinity for Ang III and no affinity for losartan or PD123319 [136].

congestive heart failure. However, because of their lack of specificity, ACE inhibitors are frequently associated with cough and the rare but serious condition of angiooedema. These side effects attributed to ACE inhibitors are due to the accumulation of bradykinin and other peptides, since ACE inhibitors interfere with their metabolism. Furthermore, Ang II can be formed by alternative non-ACE pathways ; hence, ACE inhibitors may not provide total inhibition of Ang II generation. Ang II AT -receptor antagonists were developed to exert " more specific and complete blockade of the RAS in an effort to overcome some of the shortcomings of ACE inhibitors. ACE inhibitors interfere with the formation of Ang II, whereas Ang II-receptor antagonists inhibit the actions of Ang II at the AT -receptor site. Losartan " was the first AT -receptor antagonist developed clinically " for the treatment of hypertension and others followed, including irbesartan, valsartan and candesartan cilexetil. Since all the well-known cardiovascular actions of Ang II are mediated by AT receptors, blockade of AT " " receptors should provide more complete inhibition of the RAS. AT -receptor antagonists have been shown to " decrease blood pressure and to block the effects of Ang II on vasoconstriction, sodium reabsorption, thirst, release of aldosterone, renin, catecholamine and vasopressin [137,138]. Ang II-receptor antagonists increase circulating levels of Ang II, which is due to interruption of negative feedback of renin release, leading to a rise in plasma renin activity. As such, raised levels of Ang II by AT -receptor antagonists may cause hyper-stimulation " of the AT -receptor subtype. Since AT receptors may # # counteract the effects of AT receptors, it is therefore " possible that stimulation of exposed AT receptors, as # well as blockade of AT receptors, may contribute to the " anti-hypertensive action and beneficial effects of AT " receptor antagonists.

Conclusion
Ang II is a multi-functional hormone that exerts diverse physiological effects. The actions of Ang II are mediated by at least two receptor subtypes, namely AT and AT . " # All the well-described cardiovascular actions of Ang II are mediated by the AT receptor. Very little is known " about the role of the AT receptor, but recent studies # have suggested that it may mediate anti-proliferation, cellular differentiation, apoptosis and possibly vasodilatation. Additional angiotensin receptor subtypes have been postulated but only the AT and AT receptor " # subtypes have been completely cloned and pharmacologically characterized. Further insight into the structure and functional relationship of these and other angiotensin receptor subtypes should improve our understanding of the important cardiovascular and non-cardiovascular effects of the RAS.

BLOCKADE BY ANG II AT1-RECEPTOR ANTAGONISTS
There are two major classes of anti-hypertensive agents, ACE inhibitors and AT -receptor antagonists, which " interfere with the RAS. ACE inhibitors were the first class of drugs to be developed clinically and achieved great success in the treatment of hypertension and
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ACKNOWLEDGMENTS
We acknowledge the financial support of the National Health and Medical Research Council of Australia, the Commonwealth Department of Veteran’s Affairs, the Sir Edward Dunlop Medical Research Foundation and the Ramaciotti Medical Research Foundation.

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# 2001 The Biochemical Society and the Medical Research Society

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