Review: AT1-receptors in the central nervous system (original) (raw)
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Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 1991
Characterization and development of angiotensin II receptor subtypes (AT1 and AT,) in rat brain. Am. J. Physiol. 261 (Regulatory Integrative Comp. Physiol. 30): R209-R216, 1991.-Angiotensin II receptor subtypes (AT1 and AT,) were characterized in rat brain by displacement with the specific angiotensin antagonists Du Pont 753 and CGP 42112A, respectively, and quantitative autoradiography. Young (2-wk-old) rats expressed AT1 receptors in selected limbic system areas, structures involved in cardiovascular and fluid regulation, parts of the hippocampal formation, and the choroid plexus. In young rats, AT, receptors were concentrated in areas involved in control and learning of motor activity, sensory areas, and selected limbic system structures. The cingulate cortex, the molecular layer of the cerebellar cortex, and the superior colliculus contained both ATI and AT, receptors. The number of ATI receptors in most areas of adult (&wk-old) rats was similar to or even higher than that present in young rats. Conversely, AT, receptors were always much lower in number in adult animals, and in some areas they were undetectable in adults. Their differential localization and development suggest different functions for the specific angiotensin II receptor subtypes. angiotensin receptor subtypes; Du Pont 753; CGP 42112A; renin-angiotensin system; receptor development IN ADULT RATS, the brain angiotensin II (ANG II) system, including specific ANG II receptors located in very select areas, is involved in the central regulation of cardiovascular function, drinking and fluid metabolism, salt appetite, vasopressin release, and stress (4, 5, 13, 14, 21, 23, 24). Peripherally formed ANG II, present in the has been proposed on the basis of the response of smooth muscle to ANG II synthetic analogues (19). More recently, terized two subtypes in peripheral of ANG II receptors were charactissues on the basis of their sensitivity to reducing agents (7, 10-12) and their displacement with newly developed specific ANG II antagonists (6, 8, 9, 30). AT, receptors are sensitive to the reducing agent dithiothreitol (DTT) (7,9-12) and to displacement by the selective ANG II antagonist Du Pont 753 (8, 9). ANG II binding to the AT, receptors is resistant to DTT and selectively displaced by the ANG II-receptor antagonist CGP 42112A (30). Q uantitative autoradiography and displacement with the selective ANG II-receptor antagonists revealed that the rat brain contains AT1 receptors lot ular nucleus ated in the s , nucleus of ubfornical organ, pa the solitary tract, raven and tricarea postrema and AT, receptors localized in the inferior olive (27). The characteristics of the brain AT1 and AT2 receptors was similar to those described in peripheral organs (27). We have in the inferior recently shown by autoradiography that, olive, parasolitary and hypoglossal nuclei, and cerebellar cortex, the brain of young rats expresses more ANG II receptors than that of adult animals (28) and that, in the inferior olive of young and adult rats, the binding is insensitive to DTT (29). These observations suggested that young rats may express more AT, receptors than their adult controls. To determine the detailed developmental pattern of the receptor subtypes throughout the brain, we studied all areas containing significant numbers of ANG II receptors and compared their distribution and sensitivity to selected ANG II general circulation, binds to brain ANG II receptors antagonists in young (2-wk-o located in circumventricular organs outside the blood-rats. brain barrier (16, 21, 22) and contributes to the central regulation of cardiovascular function and fluid homeo-MATERIALS AND METHODS
Angiotensin II receptor pharmacology and AT1-receptor blockers
Journal of Human Hypertension, 1999
Angiotensin II (Ang II) has diverse physiological actions leading, for example, to increases in extracellular volume, peripheral vascular resistance and blood pressure, and has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated as AT 1 and AT 2. Most effects of Ang II are mediated by AT 1 receptors. Much less is known about the physiological role of AT 2 receptors. Recent evidence suggests involvement of AT 2 receptors in development, cell differentiation, apoptosis and regeneration in various tissues. AT 1 and AT 2 recep
The Angiotensin II AT2 Receptor Is an AT1Receptor Antagonist
Journal of Biological …
The vasopressor angiotensin II activates AT 1 and AT 2 receptors. Most of the knownin vivo effects of angiotensin II are mediated by AT 1 receptors while the biological functions of AT 2 receptors are less clear. We report here that the AT 2 receptor binds directly to the AT 1 receptor ...
Modulation of the Vascular Smooth Muscle Angiotensin Subtype 2 (AT2) Receptor by Angiotensin II* 1
Biochemical and …, 1998
The angiotensin subtype 2 (AT 2) receptor is scarce in most adult vascular tissues except after injury. Since angiotensin II (AngII) is released upon injury, we examined the possibility that AngII governs AT 2 receptor expression in smooth muscle cells (SMC). A polyclonal antiserum, raised to a peptide corresponding to the AT 2 receptor C-terminus, recognized a ϳ45-kDa protein after transfection of cos-7 cells with AT 2 receptor cDNA. Detection of a ϳ65-kDa band in extracts of SMC indicated that the AT 2 receptor was glycosylated. Treatment of SMCs with AngII increased AT 2 receptor levels fourfold over 24 h. This response was abrogated by losartan, but not by PD123319, indicating AT 1 receptor involvement. AngII-dependent increases in AT 2 receptor levels were also prevented by LY294002, an inhibitor of phosphatidyinositol 3-kinase, but not by rapamycin. These results indicate AngII influences AT 2 receptor expression through the AT 1 receptor via a signaling pathway that includes PI3K.
Mapping tissue angiotensin-converting enzyme and angiotensin AT1, AT2 and AT4 receptors
Journal of Hypertension, 1998
Background The renin-angiotensin system (RAS) functions as both a circulating endocrine system and a tissue paracrine/autocrine system. As a circulating peptide, angiotensin II (Ang II) plays a prominent role in blood-pressure control and body fluid and electrolyte balance by acting on the AT 1 receptor in the brain and peripheral tissues. As a paracrine/autocrine peptide, locally formed Ang II also plays additional roles in tissues involving the regulation of regional haemodynamics, cell growth and remodelling, and neurotransmitter release. Evidence is emerging that Ang II is not the only active peptide of the RAS, and other Ang II fragments may also have important biological activities.
Functional Reconstitution of the Angiotensin II Type 2 Receptor and Gi Activation
Circulation Research, 2000
On the basis of the patterns of conserved amino acid sequence, the angiotensin II type 2 (AT(2)) receptor belongs to the family of serpentine receptors, which relay signals from extracellular stimuli to heterotrimeric G proteins. However, the AT(2) receptor signal transduction mechanisms are poorly understood. We have measured AT(2)-triggered activation of purified heterotrimeric proteins in urea-extracted membranes from cultured COS-7 cells expressing the recombinant receptor. This procedure removes contaminating GTP-binding proteins without inactivating the serpentine receptor. Binding studies using [(125)I] angiotensin (Ang) II revealed a single binding site with a K(d)=0.45 and a capacity of 627 fmol/mg protein in the extracted membranes. The AT(2) receptor caused a rapid activation of alpha(i) and alpha(o) but not of alpha(q) and alpha(s), as measured by radioactive guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding. Activation required the presence of activated receptors, betagamma, and alpha subunits. As a first step aimed at developing an in vitro assay to examine AT(2) receptor pharmacology, we tested a battery of Ang II-related ligands for their ability to promote AT(1) or AT(2) receptor-catalyzed G(i) activation. Two proteolytic fragments of Ang II, Ang III and Ang1-7, also promoted activation of alpha(i) through the AT(2) receptor. Furthermore, we found that [Sar(1),Ala(8)]Ang II is an antagonist for both AT(1) and AT(2) receptors and that CPG42112 behaves as a partial agonist for the AT(2) receptor. In combination with previous observations, these results show that the AT(2) receptor is fully capable of activating G(i) and provides a new tool for exploring AT(2) receptor pharmacology and interactions with G-protein trimers.
Angiotensin II AT2 receptor subtype
Journal of Hypertension, 2003
The renin-angiotensin system (RAS) plays a pivotal role in the regulation of fluid, electrolyte balance and blood pressure, and is a modulator of cellular growth and proliferation. Biological actions of RAS are linked to the binding of the effector molecule, angiotensin II (AngII), to specific membrane receptors, mostly the AT 1 subtype and, to a lesser extent, other subtypes. Following the identification and characterization of the AT 2 subtype receptor, it has been proposed that a complex interaction between AngII and its receptors may play an important role in the effects of RAS. In this paper current information on AngII subtype receptors-their structure, regulation and intracellular signalling-are reviewed, with a particular emphasis on the potential relevance for cardiovascular pathophysiology. In addition, we discuss modulation of expression of the AT 2 receptor and its interaction with the AT 1 receptor subtype, as well as the potential effects of this receptor on blood pressure regulation. A better understanding of the integrated effects of the AngII subtype receptors may help to elucidate the function of the RAS, as well as their participation in the mechanisms of cardiovascular disease and attendant therapeutic implications.
Journal of the renin-angiotensin-aldosterone system : JRAAS, 2002
Angiotensin II (Ang II) causes facilitation of sympathetic neurotransmission via prejunctionallylocated AT 1 -receptors. The pithed rat is a suitable model to study the interactions between endogenously produced Ang II and the sympathetic nervous system at the peripheral level. Previously, we demonstrated that inhibition of the facilitatory actions of Ang II is a class effect of all AT 1 -receptor blockers (ARB). However, all ARBs caused less than maximal inhibition after the highest dose, thus causing a U-shaped dose-response curve with respect to sympatho-inhibition. In the present study, we investigated whether the AT 2 -receptor is involved in this 'upturn' of the dose-response relationship. Accordingly, we studied the effect of the ARB, irbesartan (1-60 mg/kg), on the sequelae of electric stimulation of the thoraco-lumbar sympathetic outflow in the presence and absence of the AT 2blocker, PD 123319 (0.5 mg/kg +50 µg/kg/min). Additionally, the effect of the combined (nonselective) AT 1 /AT 2 -receptor antagonist saralasin (0.001, 0.003, 0.01 or 0.03 mg/kg/min), on stimulation-induced responses was studied. In addition, we measured PRA-levels after administration of irbesartan, in this model.