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Cardiovascular Research 2005 67(2):208-215; doi:10.1016/j.cardiores.2005.04.015
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Copyright © 2005, European Society of Cardiology

Functional evidence that in the cardiovascular system AT1 angiotensin II receptors are AT1B prejunctionally and AT1A postjunctionally

Serafim Guimarãesa,* and Helder Pinheirob

aInstitute of Pharmacology and Therapeutics, Faculty of Medicine, Alameda Hernani Monteiro, 4200-319 Porto, Portugal
bLaboratory of Pharmacology, Faculty of Pharmacy, Rua Anibal Cunha, 136, 4050 Porto, Portugal

* Corresponding author. Tel.: +351 22 5519144; fax: +351 22 5502402. Email address: sguimara{at}med.up.pt

Received 13 January 2005; revised 20 March 2005; accepted 18 April 2005


   Abstract
Top
 Abstract
1. Introduction
 2. Angiotensin II receptors
 3. AT1 receptor subtypes:...
 4. Conclusions
 References
 
Numerous studies have shown that angiotensin II causes vasoconstriction both by a direct action on smooth muscle cells (postjunctional effect) and indirectly through the facilitation of noradrenaline release from postganglionic sympathetic neurons (prejunctional effect). The receptors through which angiotensin II exerts its actions were first divided into AT1 and AT2 subtypes. A further subdivision of AT1 receptors into AT1A and AT1B subtypes was based on cloning and receptor binding studies: AT1A showed a high affinity for losartan, but low affinity for PD123319, while AT1B receptors showed nearly 100-fold lower affinity for losartan and 10,000-fold higher affinity for PD123319 relative to AT1 sites.

The present review deals with functional evidence supporting the existence of AT1A and AT1B subtypes in the cardiovascular system. Taken together, all the functional results obtained in vivo and in vitro–in a wide variety of vascular tissues from different species–allow one to conclude that angiotensin II AT1 receptors are different pre- and postjunctionally and also that prejunctional and postjunctional angiotensin II receptors most probably belong to AT1B and AT1A subtypes, respectively.

KEYWORDS Angiotensin; Arteries; Blood pressure; Receptors; Angiostensin system


   1. Introduction
Top
 Abstract
 1. Introduction
2. Angiotensin II receptors
 3. AT1 receptor subtypes:...
 4. Conclusions
 References
 
This review will deal particularly with the functional evidence showing that there are two subtypes of AT1 angiotensin II receptors, AT1A and AT1B, which are located at the post- and prejunctional level, respectively. Since the most important physiological actions of angiotensin II and also the most important therapeutic uses of angiotensin II antagonists are assigned to the cardiovascular system, this evidence is based on results obtained in heart and vessels.

In 1898, Tigerstedt and Bergman [1] showed for the first time that the extracts of the kidney contained a pressor substance which they termed renin. However, this discovery was not followed by important developments until 1934, when Goldblatt et al. demonstrated that it was possible to produce a hypertensive state in dogs by constricting the renal arteries [2]. Six years later two independent groups reported that renin was an enzyme that acted on a plasma protein substrate to catalyse the formation of the actual pressor substance. This pressor substance, which was named "hypertensin" by one of the groups [3] and "angiotonin" by the other [4], was later isolated and shown to be an octapeptide, (for a review see [5]). The octapeptide took finally the name of angiotensin, which was widely accepted, while the plasma substrate upon which renin acts received the name of angiotensinogen.

It is now known that the renin–angiotensin system plays an important role in the control of arterial blood pressure, body fluid volume and electrolyte balance. Factors that decrease arterial blood pressure through a decrease in blood volume (low-sodium diet, diuretics, liver cirrhosis, nephrotic syndrome, etc) or a reduction in total peripheral resistance (vasodilators) activate renin release from the kidneys. The cascade leading to the formation of angiotensin II, the main effector of the renin–angiotensin system, is now well characterized [6].

Renin acts on angiotensinogen to catalyse the formation of the decapeptide angiotensin I. This decapeptide is then cleaved by angiotensin-converting enzyme (ACE) to yield the octapeptide angiotensin II.

Angiotensin II may be converted by aminopeptidase A to [2–8]-angiotensin II, a heptapeptide commonly known as angiotensin III. Angiotensin III and angiotensin II cause qualitatively similar effects but angiotensin II is more potent [5]. Angiotensin III may be converted by aminopeptidase N into a shorter fragment, [3–8]-angiotensin II, a hexapeptide which is commonly known as angiotensin IV.

It is well known that angiotensin II is able to cause vasoconstriction both by a direct action on smooth muscle cells (postjunctional effect) [7] and indirectly through the facilitation of the exocytic release of noradrenaline from sympathetically innervated tissues (prejunctional effect) [8–11]. Thus, and since the evidence supporting the view that there are AT1A and AT1B subtypes with pharmacological expression rely on differences between pre- and postjunctional AT1 receptors, the comparison of the receptors mediating the prejunctional facilitation of noradrenaline with those mediating the postjunctional effect of angiotensin II will constitute the nuclear message of this review. The facilitation of noradrenaline release caused by angiotensin II–which is apparently mediated by AT1B-receptors–requires an ongoing {alpha}2-autoinhibition (some degree of tonic autoinhibition) since the blockade of {alpha}2-autoreceptors prevents the effect of angiotensin II [12,13].


   2. Angiotensin II receptors
Top
 Abstract
 1. Introduction
 2. Angiotensin II receptors
3. AT1 receptor subtypes:...
 4. Conclusions
 References
 
Angiotensin II binds to two main receptors, AT1 and AT2. Two other receptors (AT3 and AT4) have been proposed, but they have not yet been cloned. Via stimulation of AT1 receptors, angiotensin II causes virtually all of its physiological actions, namely the cardiovascular, neuronal, renal, endocrine and hepatic effects. In rodents, two AT1 receptor subtypes have been found, AT1A and AT1B, which are 95% identical in their amino acid sequence.

Recent reviews gave us comprehensive and updated information on angiotensin II receptors [5,14–16].

Initially, angiotensin II was known to act on at least two pharmacologically distinct receptors: AT1, which are selectively blocked by losartan [17–19], and AT2, which are selectively blocked by the compound PD123319 [17,20]. However, regarding the selectivity of the antagonistic effect of this latter compound, it was shown that it depends on the concentration used. In nM range, PD123319 selectively blocks AT2 receptors, but in µM concentrations it also blocks AT1B receptors (without affecting AT1A receptors).

The angiotensin II binding site blocked by losartan (AT1 receptors) is the predominant receptor found in the vascular smooth muscle, heart, adrenal cortex, liver, kidney and some regions of the brain and is responsible for most of the known functions of the renin–angiotensin system in both physiological and pathophysiological conditions: vascular smooth muscle contraction [20,21], proliferation of vascular smooth muscle cell, aldosterone release [21] and the regulation of fluid electrolyte balance [22]. All these effects are well demonstrated and characterized [5,14]. The AT1 receptor belongs to the G protein-coupled receptor superfamily and is primarily coupled through pertussis-insensitive G proteins to the activation of phospholipase C and calcium signaling [5].

The angiotensin II binding site blocked by PD123319 (AT2 receptors) is predominant in uterine smooth muscle, ovary, adrenal medulla, the developing rat foetus and some brain regions [23]. While the main functions mediated by AT1 receptors are well demonstrated and widely accepted, those mediated by AT2 receptors are less well defined. AT2 receptors are highly and ubiquitously expressed in the fetal stage [24] and involved in kidney and urinary tract development [25,26].

In adults, the expression of AT2 receptors under normal conditions is minimal. However, evidence is accumulating that AT2 receptors have a significant role in the regulation of cardiovascular function [27,28]. From experimental data mainly obtained in vitro, it seems that AT2 receptors mediate vasodilation, antiproliferation, proaptoptosis in the vasculature, cell differentiation and tissue repair. During the past year, the evidence for some AT2-mediated effects was also obtained in vivo such as the protection against neuronal injury caused by ischemia [29] and the counterbalance of the fructose-induced insulin resistance in hypertensive rats [30]. Regarding the vasodilation, some studies strongly suggest that AT2 receptors activate a vasodilatory pathway that counteracts the vasoconstrictor action of angiotensin II exerted through the AT1 receptor [31–33]. First of all, several authors showed that the activation of AT2 receptors caused relaxation of isolated resistance arteries not only in vitro [34–36] but also in vivo [37]. Furthermore, this vasodilatory action is underlined by two important facts: on the one hand, there is upregulation of AT2 receptors in some kinds of hypertension and vascular injury, suggesting that they constitute a compensatory mechanisms to protect the vessels from the mechanical overload resulting from excessive AT1-mediated contractile response [38–42]; on the other hand, experiments carried out in knockout or transgenic mice for the AT2 receptor gene also indicate that AT2 receptors mediate a depressor response to angiotensin II. In fact, disruption of AT2 receptor gene caused hypertension and increased vascular sensitivity to angiotensin II [43] whereas overexpression of AT2 receptors is associated with a decrease in pressor sensitivity to angiotensin II [44].

Another effect presumably mediated by AT2 receptors is that of a cardioprotection. In fact, AT2 are upregulated not only in experimental cardiac hypertrophy, heart failure, and myocardial infarction, as shown in animal models [25,45], but also in several human pathological conditions affecting the heart, such as heart failure, myocardial infarction, ischemia, and diabetes [14].

Biochemical data were also obtained which increase the evidence supporting the role of AT2 receptors at the cardiovascular level. In fact, blockade of AT2 receptors leads to antihypertrophic effects in rat ventricular cardiomyocytes and also to dephosphorylation of the anti-apoptotic protein Bcl-2 and upregulation of the pro-apoptotic protein Bax (for a review, see [46]) on the one hand, and attenuates AT1 receptor-induced phospholipase D activation in vascular smooth muscle, on the other hand [47].

The AT2 angiotensin II receptor is also a typical seven transmembrane domain protein coupled to G proteins that mediate intracellular signaling pathways, including activation of protein phosphatases, phospholipase A2, the NO-cGMP system (stimulation of cGMP production) and inhibition of cGMP production through a negative coupling to guanylate cyclase [5]. In rat and mouse, like in humans, it consists of 363 amino acids and shares 34% homology with the AT1 receptor. Its gene is localized on the X-chromosome [5,48].

Two more angiotensin II receptors have been described: AT3 and AT4. The first of these two was named "AT3" but it was not included in the update of angiotensin receptor nomenclature proposed by the IUPHAR subcommittee on Angiotensin Receptors [49]. Angiotensin II binds with high affinity to this new receptor, which is insensitive to both losartan and PD123319.

The second receptor (AT4) has low affinity for angiotensin II. The AT4 receptor, which was originally defined as the specific, high-affinity binding site for the hexapeptide angiotensin IV, has recently been identified as the transmembrane enzyme insulin-regulated membrane aminopeptidase (IRAP) [50]. The AT4 receptor has a broad distribution and is found in a range of tissues, including the brain, adrenal gland, kidney, lung and heart. The greatest concentration of this receptor subtype appears in structures classically associated with cognitive processes and sensory and motor functions and in the kidney [5]. Several signalling events have been associated with activation of the AT4/IRAP by AT4 ligands, but the underlying pathways are poorly defined. However, some experiments carried out in rat vascular smooth muscle cells have shown a small but sustained increase in intracellular calcium concentration with AT4 ligands, via extracellular influx and an increase in inositol phosphates. By contrast, in the opossum kidney cell line, angiotensin IV stimulated a transient increase in intracellular calcium concentration via voltage-sensitive channels, independent of inositol phosphate. AT4 receptor activation is still associated with an increase in cGMP via stimulation of NO synthase. Signalling systems associated with memory processing include cAMP-responsive element-binding protein and mitogen-activated protein kinase (MAPK) pathways [51]. Until recently it had been difficult to design and synthesize an antagonist for this receptor [5].


   3. AT1 receptor subtypes: AT1A and AT1B
Top
 Abstract
 1. Introduction
 2. Angiotensin II receptors
 3. AT1 receptor subtypes:...
4. Conclusions
 References
 
3.1. Molecular and binding studies
On the basis of data obtained in both cloning and receptor binding studies, further subdivision of AT1 receptors into AT1A and AT1B subtypes was established [52,53]. In some rodents (mice, rats and rabbits) both AT1A and AT1B receptors have been cloned [52,54,55].

AT1A and AT1B receptors are typical seven-transmembrane domain receptors. The rat AT1A receptor protein consists of 359 amino acids; it is coupled to a G-protein and has 95% homology in its amino acid sequence with AT1B subtype [53,56]. In this species, AT1A and AT1B receptor genes are located on chromosomes 17q12 and 2q24, respectively [57]. In humans, AT1 receptor gene is located on chromosome 3. Both in rodents and humans the AT2 receptor gene is located on chromosome X.

On the other hand, in cultured rat mesangial cells, binding studies indicated the existence of two subpopulations of AT1 receptors: one comprising 86% of the total, showed a high affinity for angiotensin II and losartan, but low affinity for PD123319; another which showed nearly 100-fold lower affinity for losartan and 10,000-fold higher affinity for PD123319 relative to AT1 (AT1A) sites . On this basis it was proposed that there are two distinct G-protein-coupled receptor subtypes.

In contrast to the AT1A subtype, the AT1B receptor can be inhibited by high concentrations (greater than 0.5 µM) of PD123319 [23,49,58]. Although the cloned rat AT1A and AT1B receptors expressed in COS-7 and Y-1 cells show the expected coupling to phosphoinositide hydrolysis and other Gq/11-mediated responses, they do not exhibit coupling to Gi-mediated response such as inhibition of adenylate cyclase [59].

3.2. Functional evidence for the existence of two subtypes of angiotensin II receptors (AT1A and AT1B) in the cardiovascular system
3.2.1. Differential potency of agonists
Although it is not acceptable nowadays to classify receptors exclusively on the basis of the relative potency of agonists–other approaches are now available which are recommended by the International Union of Pharmacology (IUPHAR) committee for receptor classification, like the use of selective antagonists, the identification of the involved signal transduction mechanisms or the cloning of receptors–the information given by the relative potency of agonists has been and still is an important step for the characterization of receptors. The differentiation between {alpha} and β adrenoceptors by Ahlquist [60] and the subclassification of β adrenoceptors (into β1 and β2) by Lands et al. [61] were exclusively made on the basis of the relative potency of agonists.

A very recent comparison of the effects of angiotensin II and angiotensin III at pre-and postjunctional level of the rabbit thoracic aorta showed that there are important differences in the potency of each of the two peptides at these two levels: angiotensin II is 11 times more potent postjunctionally than prejunctionally and angiotensin III is 30 times more potent at the postjunctional level. These differences are first indications that pre- and postjunctional angiotensin II receptors may be different [62].

Also recently, an interesting fact was observed which may also indicate a different nature of prejunctional and postjunctional angiotensin II receptors. During the development of the hypertensive state caused by long-term administration of the non-selective adenosine antagonist DPSPX (1,3-dipropyl sulfophenylxanthine) to rats ([63]; for a review, see [64]), it was shown that the sensitivity of postjunctional receptors of the mesenteric vein to angiotensin II was reduced, whereas that of prejunctional receptors remained unchanged [65].

In isolated canine splenic arteries, it was also shown that angiotensin II in concentrations that did not affect postjunctional receptors (no direct vascular effect) enhanced the response to electrical nerve stimulation (which acts on prejunctional receptors). Thus, angiotensin II is more potent at pre- than at postjunctional level, differentiating between pre- and postjunctional receptors [66,67].

3.2.2. Differential effect of antagonists
3.2.2.1. In vivo experiments
The first functional data obtained in vivo suggesting that pre- and postjunctional receptors for angiotensin II might be different were reported by Ohlstein et al. [68] who used several angiotensin II antagonists. In pithed rats, these authors observed that sub-pressor doses of angiotensin II (doses lacking postjunctional effect) shifted to the left the frequency–response curves for increases in blood pressure caused by spinal cord stimulation: this indicates that angiotensin II, in doses that have no postjunctional effect, causes a prejunctional facilitation of noradrenaline release which was not antagonized by losartan, although it was antagonized by eprosartan, another non-peptide antagonist of angiotensin II [68]. In humans, it was also reported that stimulation of the sympathoadrenal response by insulin-evoked hypoglycemia was not antagonized by losartan [69].

In a series of experiments carried out in the pithed rat in which frequency–response curves for increases in blood pressure were determined, it was further observed that the rank order for the potency of several series of different AT1 antagonists was different when their sympathoinhibitory potency (prejunctional effect) was compared with their potency concerning inhibition of direct vasoconstrictor effect of angiotensin II (postjunctional effect) [70–72] (Table 1).


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  		Table 1 Ranking order of potency of antagonists

 
In the pithed rat, Dendorfer et al. [73], who determined the effects of several antagonists against the increase in plasma noradrenaline evoked by intravenous injections of angiotensin II, obtained a rank order of antagonist potency which was very similar to that reported by other authors: high potency of eprosartan and candesartan and low potency of losartan and irbesartan, "typical" of AT1B receptor involvement. However, and since all the antagonists used were able to antagonize the increase in plasma noradrenaline levels–an effect which was taken as a prejunctional effect of angiotensin II, they concluded that the prejunctional and postjunctional AT1 receptors do not differ. In any case, their study has methodological limitations since the authors did not apply the electrical stimulation to the thoracic spinal cord and therefore their results may well be due to a direct angiotensin II-mediated ganglionic stimulation [74]; moreover, no bilateral adrenalectomy was performed and hence the increase in plasma noradrenaline after infusion of angiotensin II might be at least partially due to catecholamine release from the adrenal medulla.

3.2.2.2. In vitro experiments
The first report calling attention to some peculiarities of prejunctional angiotensin II receptors was published by Trachte et al. [75] who suggested that neither AT1 nor AT2 receptors were involved in the enhancement of noradrenergic neurotransmission by angiotensin II. Some years later, in experiments carried out in rat tail artery, it was suggested that the receptors subserving enhancement of noradrenergic transmission by angiotensin II might be regarded as AT1B, while those mediating the vasoconstrictor effect of angiotensin II appeared to be of another, unspecified AT1 subtype [76,77] (Table 2).


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  		Table 2
 
Differences in subtype between pre- and postjunctional AT1 receptors were clearly observed in both the canine mesenteric and pulmonary arteries, on which both saralasin and losartan had different antagonist potencies at the pre- and postjunctional level against angiotensin II. While saralasin was about 40 times more potent post- than prejunctionally, in both vessels, losartan, which at postjunctional level was a potent antagonist of angiotensin II (pA2 of about 8 in both vessels), was ineffective prejunctionally [78,79] (Table 2). On the basis of these differences in potencies at pre- and postjunctional level of these two antagonists, the hypothesis was put forward that the receptors mediating the prejunctional effects of angiotensin II belong to a subtype that differs from that of those receptors involved in the postjunctional effects of this agonist [78]. Confirmatory evidence of this difference was obtained in experiments carried out in the canine pulmonary artery and rat left ventricles: while one "typical" AT1 receptor antagonist (eprosartan), at one and the same low concentration, blocked pre- and postjunctional effects of angiotensin II, another "typical" AT1 antagonist (losartan) blocked postjunctional angiotensin II effects but had no influence on prejunctional ones, unless its concentration was increased by a factor of about 400 [80].

It is somewhat strange that these results had been obtained in the dog since it is known that in contrast to rodents, all other mammals–including the dog–appear to have only one AT1 receptor gene [5]. Thus, the pharmacological characterization of canine angiotensin II AT1 receptors cannot be discussed on the basis of the existence of two distinct genes coding for two functional subtypes.

In spite of the absence of AT1 receptor subtypes in non-rodent mammals, the existence of variants for this receptor is well documented in some cases. For instance, in humans two AT1 isoforms resulting from alternative splicing of the same gene were described [81]. These isoforms showed similar functional properties and equivalent affinities for the same ligands. Also, in human placenta a receptor with 97% identity with the AT1 type, but with some differences in its pharmacological profile, has been described [82].

The existence of AT1 isoforms has been described in other species, including the dog. In fact, in the dog liver, Burns et al. [83] cloned an AT1 receptor which possesses an amino acid sequence highly homologous with that of other mammalian AT1 receptors. However, in spite of this similarity it showed a reduced affinity for losartan. This difference was ascribed to a threonine residue, which instead of alanine–the normal amino acid appearing in the other mammals–occurred in position 163. Some years later, this observation was confirmed in the ferret [84]. These authors showed not only that AT1 receptor in ferrets and dogs were about 99% identical, but also that the substitution of threonine for alanine increased dramatically the affinity for losartan [84].

Some authors contested this hypothesis that pre- and postjunctional AT1 receptors are different [85,86]. In an in vitro study carried out in rat atria preloaded with 3H-noradrenaline, Shetty and Delgrande [85] determined the rank order of potency of several angiotensin II AT1 antagonists at the prejunctional level and found that losartan was the weakest (Table 1). However, these authors have not compared the antagonistic potency of the same antagonists on postjunctional effects of angiotensin II. Thus, it is impossible to draw a conclusion about the relative potency of each of those compounds at pre- and postjunctional angiotensin II receptors. Furthermore, the –log IC50 that they determined for losartan was 6.75, a value which is much lower than those found at the postjunctional level for losartan in several tissues by different authors: 8.48 in the rabbit aorta [87]; 8.52 in the rat tail artery [88]; 8.15 in the canine mesenteric and 7.96 in canine pulmonary artery [78].

In the rat prostate, it was observed that the facilitating effect of angiotensin II on noradrenaline release was mediated by a receptor that is sensitive to both losartan and PD123319. This is an unexpected finding which until now was not confirmed by any other author; a novel functional receptor distinct from the cloned AT1A, AT1B or AT2 was proposed [86].

More recent reports of results obtained in experiments carried out in vitro reinforced the view that pre- and postjunctional AT1 angiotensin receptors are functionally different and most probably correspond to AT1B and AT1A subtypes, respectively. In the rat tail artery it was observed that while eprosartan was equipotent at the pre- and postjunctional level, losartan and candesartan were 101 and 81 times more potent post- than prejunctionally [88], and in the rabbit mesenteric artery, candesartan–but not eprosartan–at concentrations that inhibited postjunctional effects of angiotensin II had no effect at the prejunctional level [89].

In a more recent study, the influence of losartan–a potent AT1 antagonist at the postjunctional level–and PD123319–an effective prejunctional antagonist [52,53] very clearly differentiates between pre- (AT1B) and postjunctional (AT1A) angiotensin AT1 receptors: both the compound PD123319 and losartan showed a clear differential influence on pre- and postjunctional effects of angiotensin II in the rabbit thoracic aorta. However, while PD123319 in µM concentrations antagonized the facilitation of tritium release caused by angiotensin II and angiotensin III (prejunctional effect) and had no influence on the contractions of the aortic rings (postjunctional effect), losartan did the opposite: it concentration-dependently antagonized the contractions of the aortic rings caused by the peptides and had no influence on the facilitation of noradrenaline release elicited by angiotensin II and angiotensin III. For the first time it was shown that in one and the same tissue, two different angiotensin antagonists exert opposite influences on pre- and postjunctional angiotensin receptor-mediated effects [62].


   4. Conclusions
Top
 Abstract
 1. Introduction
 2. Angiotensin II receptors
 3. AT1 receptor subtypes:...
 4. Conclusions
References
 
Taken together, these results–obtained in vivo and in vitro in a wide variety of vascular tissues–show not only that angiotensin II AT1 receptors are different at the pre- and postjunctional level, but also that the prejunctional angiotensin II receptors most probably belong to AT1B subtype and postjunctional angiotensin II receptors to the AT1A subtype.

The relevance of these findings in clinical practice, namely in human hypertension, is not yet clear. Nevertheless, an agent that might be able to block both pre- and postjunctional angiotensin II receptors would be expected to be more effective as an anti-hypertensive agent.


   Acknowledgements
 
This paper was supported by Project POCTI/SAU/14294/2001. We are thankful to Professor Klaus Starke (University of Freiburg, Germany) for valuable suggestions and reviewing the manuscript.


   Notes
 
Time for primary review 20 days


   References
Top
 Abstract
 1. Introduction
 2. Angiotensin II receptors
 3. AT1 receptor subtypes:...
 4. Conclusions
 References
 

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