ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02814.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1Several residues critically involved in AT1receptor ligand‐binding and activation have now been identified based on mutational and biochemical studies.2Asp281and Lys199of the rat AT1receptor ion‐pair with Arg2and the Phe3α‐COOH of angiotensin II (AngII), respectively, and the Asp281/Arg2interaction is critical for full agonist activity.3Agonist activity of AngII also requires an interaction of the Phe2side chain with His256, which is achieved by docking of the α‐COOH with Lys199. Non‐peptide agonists interact with Lys199and His256in a similar fashion.4The crucial acid pharmacophores of AngII and the non‐peptide antagonist, Iosartan, appear to occupy the same space within the receptor pocket. Binding of the tetrazole anion moiety of losartan involves multiple contacts, such as Lys199and His256. However, this interaction does not involve a conventional salt bridge, but rather an unusual lysine‐aromatic interaction.5Asp1of AngII forms an ion‐pair with His183, which stabilizes the receptor‐bound conformation of AngII but is not critical for receptor activation.6These interactions and the involvement of other residues in stabilizing the wild‐type receptor conformation or in receptor/G‐protein coupling are considered here.7Despite these insights, considerable effort is still needed to elucidate how ligand binding induces receptor activation, what determines the specificity of AT1receptor coupling to multiple G‐proteins and thein vivorole of

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02815.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1The type‐1 angiotensin II (AngII) receptors, designated AT1, mediate most of the biological actions of the peptide hormone AngII. They are the most recent drug target for the treatment of hypertension and cardiac failure and basic research is now focusing on the mechanisms that regulate their expression.2In humans there is a single AT1gene. It encodes a 47 kb pre‐mRNA containing five exons, with the previously described AT1open reading frame (ORF) on exon 5. Alternative splicing results in the production of mature mRNA that are translated at different efficiencies and encode two receptor isoforms. The inclusion of exon 2 markedly inhibits translation of the downstream ORF, bothin vitroandin vivo.Nonetheless, this exon is present in up to one‐half of AT1mRNA in all tissues studied.3Transcripts containing exon 3 spliced to exon 5 encode a receptor with an amino‐terminal extension of 32 amino acids and represent up to one‐third of total AT1mRNA in each tissue examined.In vitro, these latter transcripts are translated to produce a longer receptor and, in transfected cells, they encode a functional AT1receptor with ligand‐binding and signalling properties similar to those of the short isoform.4Exon 4 is of minor significance as it is rarely spliced into AT1mRNA.5These data indicate that, in addition to characterizing factors that modulate AT1promoter activity and RNA stability, it is important to analyse the splicing patterns of this gene when studying the regulation of its

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02816.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1Angiotensin II (AngII) initiates a variety of cellular responses through activation of type 1 (AT1; with subtypes AT1aand AT1b) and type 2 (AT2) cell surface angiotensin receptors. Both AT1and AT2receptors couple to heterotrimeric guanyl nucleotide binding proteins (G‐proteins) and generate intracellular signals following recognition of extracellular AngII, but only AT1is targeted for the rapid ligand‐stimulated endocytosis (internalization) typical of many plasma membrane receptors.2AT1endocytosis proceeds through clathrin‐coated pits and is independent of G‐protein coupling which predicts that the AngII‐AT1receptor complex attains a conformation necessary for interaction with the endocytotic machinery, but separate from receptor signalling activation.3The function of AT1endocytosis and the reason for the disparity between AT1and AT2endocytosis is not fully appreciated, but the latter probably reflects differences in the primary amino acid sequence of these two receptor types.4For many receptors that undergo internalization, it has been established that internalization motifs (2–6 amino acids, often incorporating crucial tyrosine and hydrophobic amino acids) within the cytoplasmic regions of the receptor mediate the selective recruitment of activated receptors into clathrin‐coated pits and vesicles.5Mutagenesis studies on the AT1areceptor, aimed at identifying such motifs, reveal that sites within the third cytoplasmic loop and the cytoplasmic carboxyl terminal region are important for AngII‐stimulated AT1arecep

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02817.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1The development of the transgenic technology for the rat allowed the evaluation of gene functions in the cardiovascular systemin vivo.New insights have been gained particularly in the functions of the renin‐angiotensin system (RAS), as most transgenic rat models established so far carry genes of this system.2TGR(mREN2)27 is a rat harbouring the mouseRen‐2gene and exhibiting fulminant hypertension. The plasma RAS in this animal is down‐regulated; however, the tissue‐specific production of angiotensin II is activated (e.g. in the adrenal gland, the brain and the vessel wall). The physiological consequences of this activation, which finally leads to hypertension, can be studied in TGR(mREN2)27, rendering it a valuable tool in the functional analysis of tissue RAS.3TGR(hREN) and TGR(hAOGEN) carry the human genes for renin and angiotensinogen, respectively. In these animals the species‐specific interaction of the two proteins and the expression pattern of the genes can be studied. Furthermore, these animals can be used to test renin‐inhibitory drugs for use in antihypertensive therapy.4Further refinement of transgenic methodology (e.g. by the development of gene targeting in rats), should enhance our understanding of the functions of the RAS in cardiovascular

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02818.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1This brief review examines the evidence that angiotensin II (AngII) is essential for kidney development.2Several components of the renin‐angiotensin system (RAS) are detected in the foetal kidney early in development.3Angiotensin II is essential for normal foetal and neonatal renal function.4Angiotensin II receptors transduce important signals leading to growth and development.5Angiotensin receptor subtypes show spatial and temporal specificity of localization throughout renal development.6Angiotensin converting enzyme (ACE) inhibition or AngII receptor blockade (specifically AT1subtype blockade) results in functional and structural abnormalities of the developing kidney in both experimental and clinical situations.7While chronic postnatal RAS blockade in rats is associated with structural damage to tubules and blood vessels of the kidney, reports differ on whether treatment also affects glomerular induction and growth.8In metanephric organ culture, glomerular induction proceeds despite AngII receptor blockade.9In summary, the evidence suggests that AngII is not essential for nephron induction and glomerular development in the rat kidney. However, AngII is essential for normal growth and development of renal tubules and vasculatur

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02819.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1In a number of species, high concentrations of angiotensin II (AngII) receptors have been found in the rostral ventrolateral medulla (RVLM) in the hindbrain, which is an important region involved in the modulation of sympathetic vasomotor tone. The present review describes studies in which the contribution of angiotensin receptors in the brainstem to cardiovascular regulation, in particular sympathetic vasomotor reflexes, has been examined in conscious and anaesthetized rabbits.2In conscious rabbits, fourth ventricular infusions of AngII produced dose‐dependent pressor responses as doses 400 times less than equipressor intravenous doses. Chronic baroreceptor denervation increased the sensitivity to AngII by 1000‐fold. Administration of prazosin i.v. blocked the pressor response, suggesting that the mechanism involved sympathetic vasoconstriction.3The pattern of haemodynamic changes in response to AngII injected into the fourth ventricle (4V) involved decreased total peripheral conductance and mesenteric conductance, but a rise in hindlimb conductance. Sinoaortic denervation changed the hindlimb fall in conductance to an increase, suggesting that muscle vasomotor pathways were particularly inhibited by baroreceptor feedback mechanisms.4In anaesthetized rabbits, infusion of AngII into the RVLM increased blood pressure and transiently increased resting renal sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right and the upper plateau of the sympathetic reflex increase was markedly increased.5The pressor actions of 4V AngII were blocked by administration of a peptide antagonist injected into the RVLM or by the angiotensin AT1antagonist losartan injected into the 4V. These results suggest that mainly AT1receptors are involved and that the RVLM is a likely candidate site for the modulation of the renal sympathetic baroreflex.6Losartan administration into the 4V in conscious rabbits increased resting renal sympathetic tone and enhanced renal sympathetic baroreflex and chemoreflexes.7Our studies suggest that there are sympathoexcitatory AT1receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT1receptor pathway normally inhibits the sympathoexcitation produced by baroreceptor unloading or chemoreceptor activation. The effect of losartan suggests that there is greater tonic activity within the sympathoinhibitory pathways. These two actions suggest that angiotensin receptors in the brainstem modulate sympathetic responses to specific afferent inputs, thus forming part of a potentially important mechanism for the integration of characteristic autonomic response patte

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02820.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1Autoradiographic binding studies have shown that the AT1receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT1receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco‐lumbar spinal cord.2While there are differences between species, AT2receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.3Circulating AngII acts on AT1receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.4Centrally administered AngII may act on AT1receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.5Recent evidence shows that centrally administered AT1antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.6Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT1receptors and play a role in the function of sympathetic pathways maintaining arterial pressur

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02821.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action.2The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non‐cardiovascular neurons in this region.3It is known that pressor neurons in the rostral VLM include both catecholamine and non‐catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified.4It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve t

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02822.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1The effects of angiotensin II (AngII) on water and electrolyte transport are biphasic and dose‐dependent, such that low concentrations (10−12to 10−9mol/L) stimulate reabsorption and high concentrations (10−7to 10−6mol/L) inhibit reabsorption. Similar dose‐response relationships have been obtained for luminal and peritubular addition of AngII.2The cellular responses to AngII are mediated via AT1receptors coupled via G‐regulatory proteins to several possible signal transduction pathways. These include the inhibition of adenylyl cyclase, activation of phospholipases A2, C or D and Ca2+release in response to inositol‐1,4,5,‐triphosphate or following Ca2+channel opening induced by the arachidonic acid metabolite 5,6,‐epoxy‐eicosatrienoic acid. In the brush border membrane, transduction of the AngII signal involves phospholipase A2, but does not require second messengers.3Angiotensin II affects transepithelial sodium transport by modulation of Na+/H+exchange at the luminal membrane and Na+/HCO3cotransport, Na+/K+‐ATPase activity and K+conductance at the basolateral membrane.4Atrial natriuretic factor (ANF) does not appear to affect proximal tubular sodium transport directly, but acts via specific receptors on the basolateral and brush border membranes to raise intracellular cGMP levels and inhibit AngII‐stimulated transport.5It is concluded that there is a receptor‐mediated action of ANF on proximal tubule reabsorption acting via elevation of cGMP to inhibit AngII‐stimulated sodium transport. This effect is exerted by peptides delivered at both luminal and peritubular sides of the epithelium and provides a basis for the modulation by ANF of proximal glomerulotubular balance. The evidence reviewed supports the concept that in the proximal tubule, AngII and ANF act antagonistically in their roles as regulators

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb03071.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY