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European Journal of Pharmacology Nov 1999The angiotensin II type 1 (AT(1)) receptor plays a pivotal role in the regulation of blood pressure and electrolyte balance, and is involved in the control of specific... (Comparative Study)
Comparative Study
The angiotensin II type 1 (AT(1)) receptor plays a pivotal role in the regulation of blood pressure and electrolyte balance, and is involved in the control of specific ingestive behaviours. Irbesartan (SR 47436/BMS 186295) is a recently developed angiotensin AT(1) receptor antagonist, chemically described as 2-butyl-3-([2'-¿1H-tetrazol-5-yl¿biphenyl-4-yl]methyl)-1, 3-diazaspiro (4,4)non-1-en-4-one. Irbesartan displays higher affinity for its target receptor than other similar antagonists. In radioligand binding assays performed on membranes from WB-Fischer 344 (WB) rat liver epithelial cells, irbesartan was able to displace [125I]angiotensin II with a K(i) of 4.05 nM as compared to losartan (DuP 753) and tasosartan (WAY 126756), which had K(i) values of 25.2 nM and 46.6 nM, respectively. Similarly, in functional assays, irbesartan exhibited the highest functional potency to block angiotensin II-induced inositol trisphosphate (IP(3)) turnover. The improved affinity of irbesartan for the angiotensin AT(1) receptor does not coincide with a concomitant increase in affinity for the angiotensin AT(2) receptor, as irbesartan and losartan exhibited the same low potency to displace [125I]angiotensin II in radioligand binding assays performed on membranes from PC-12w cells. In binding assays performed on peripheral tissues in rat, irbesartan bound to the angiotensin AT(1) receptor expressed in liver, adrenal, kidney and pituitary with an overall affinity closely approaching that of the high affinity peptidic antagonist [Sar(1), Ile(8)]angiotensin II. Due to the higher affinity of irbesartan over other similar antagonists for the angiotensin AT(1) receptor in many tissues and its greater potency to block receptor activation, irbesartan may be quite useful in the study of the angiotensin AT(1) receptor and its role in controlling ingestive behaviours and, furthermore, shows great potential to improve the treatment of hypertension and other cardiovascular disease states.
Topics: Adrenal Glands; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Binding, Competitive; Biphenyl Compounds; Cells, Cultured; Dose-Response Relationship, Drug; Iodine Radioisotopes; Irbesartan; Kidney; Liver; Losartan; Male; PC12 Cells; Pituitary Gland; Pyrimidines; Radioligand Assay; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Signal Transduction; Tetrazoles
PubMed: 10611423
DOI: 10.1016/s0014-2999(99)00662-7 -
Kidney International Dec 1994Angiotensin II is an eight amino acid peptide which plays a major role in the regulation of cardiovascular homeostasis. The physiologic effects of angiotensin (Ang) II... (Review)
Review
Angiotensin II is an eight amino acid peptide which plays a major role in the regulation of cardiovascular homeostasis. The physiologic effects of angiotensin (Ang) II are mediated by a G-protein coupled receptor, termed AT1, which activates phospholipase C. A major factor regulating angiotensin II receptor function is the rapid desensitization following agonist stimulation. However, despite years of investigation, the mechanism by which the angiotensin receptor is regulated remains unclear. The cloning of the AT-1 receptor and the availability of cell lines which stabily express this receptor has helped elucidate these mechanisms. In this paper, we review the data from our laboratory concerning the post-translational regulation of the angiotensin receptor function.
Topics: Animals; Cell Line; Cloning, Molecular; Humans; Mice; Receptors, Angiotensin; Signal Transduction; Transfection
PubMed: 7699989
DOI: 10.1038/ki.1994.429 -
American Journal of Physiology. Renal... Aug 2004Adult hypertension may be programmed by the prenatal environment in humans and in experimental animals. The potential role of the intrarenal renin-angiotensin system...
Adult hypertension may be programmed by the prenatal environment in humans and in experimental animals. The potential role of the intrarenal renin-angiotensin system (RAS) in prenatally programmed hypertension was investigated. Hypertension in rat offspring was induced by maternal protein restriction during pregnancy. The offspring were studied on day 1 of life and immediately preceding the development of hypertension on day 28. ANG I and II contents were determined by radioimmunoassy. Angiotensin receptor protein and mRNA levels were quantified by immunoblotting and real-time RT-PCR, respectively. Plasma and kidney ANG I and II were unchanged in the offspring from low-protein pregnancies (LP). ANG II type 1 receptor (AT(1)R) protein abundance was low in the newborn LP kidney (P < 0.05) but rose above control values by 28 days of age (P < 0.05); the rise was associated with an increase in AT(1)R subtype A (P < 0.01), but not subtype B, mRNA level. ANG II type 2 receptor protein expression was decreased on day 1 (P < 0.05) and increased on day 28 (P < 0.05) in LP kidneys. The results show that prenatal programming of hypertension is associated with an abnormal pattern of intrarenal RAS ontogeny that may play a pathogenetic role, for instance, by constitutively altering renal hemodynamics or Na reabsorption.
Topics: Aging; Angiotensins; Animals; Animals, Newborn; Diet, Protein-Restricted; Female; Hypertension; Kidney; Pregnancy; Prenatal Exposure Delayed Effects; Protein Isoforms; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin
PubMed: 15100095
DOI: 10.1152/ajprenal.00055.2004 -
PloS One 2014Recent progress in the understanding of seven-transmembrane receptor (7TMR) signalling has promoted the development of a new generation of pathway selective ligands. The...
Recent progress in the understanding of seven-transmembrane receptor (7TMR) signalling has promoted the development of a new generation of pathway selective ligands. The angiotensin II type I receptor (AT1aR) is one of the most studied 7TMRs with respect to selective activation of the β-arrestin dependent signalling. Two complimentary global phosphoproteomics studies have analyzed the complex signalling induced by the AT1aR. Here we integrate the data sets from these studies and perform a joint analysis using a novel method for prediction of differential kinase activity from phosphoproteomics data. The method builds upon NetworKIN, which applies sophisticated linear motif analysis in combination with contextual network modelling to predict kinase-substrate associations with high accuracy and sensitivity. These predictions form the basis for subsequently nonparametric statistical analysis to identify likely activated kinases. This suggested that AT1aR-dependent signalling activates 48 of the 285 kinases detected in HEK293 cells. Of these, Aurora B, CLK3 and PKG1 have not previously been described in the pathway whereas others, such as PKA, PKB and PKC, are well known. In summary, we have developed a new method for kinase-centric analysis of phosphoproteomes to pinpoint differential kinase activity in large-scale data sets.
Topics: Databases, Protein; HEK293 Cells; Humans; Phosphorylation; Protein Structure, Tertiary; Receptors, Angiotensin; Sequence Analysis, Protein; Signal Transduction
PubMed: 24722691
DOI: 10.1371/journal.pone.0094672 -
Asia Pacific Journal of Clinical... 2007Obesity is a major health problem worldwide; it is associated with more than 30 medical conditions and is a leading cause of unnecessary deaths. Adipose tissue not only... (Review)
Review
Obesity is a major health problem worldwide; it is associated with more than 30 medical conditions and is a leading cause of unnecessary deaths. Adipose tissue not only acts as an energy store, but also behaves like an endocrine organ, synthesising and secreting numerous hormones and cytokines. Angiotensin II (ANG II) is the biologically active component of the renin-angiotensin system (RAS). The RAS is present in adipose tissue and evidence suggests that ANG II is intimately linked to obesity. Indeed, ANG II increases fat cell growth and differentiation, increases synthesis, uptake and storage of fatty acids and triglycerides and possibly inhibits lipolysis. Evidence obtained using genetically modified animals has shown that the amount of body fat is directly related to the amount of ANG II, i.e., animals with low levels of ANG II have reduced fat stores while animals with excessive ANG II have increased fat stores. In humans, epidemiological evidence has shown that body fat is correlated with angiotensinogen, a precursor of ANG II, or other components of the RAS. Furthermore, blocking the production and/or actions of ANG II with drugs or natural substances decreases body fat. The decrease in body fat caused by such treatments predominantly occurs in abdominal fat depots and appears to be independent of energy intake and digestibility. Clearly, ANG II has an important role in the accumulation of body fat and the possibility exists that treatment of obesity will be enhanced by the use of natural or synthetic substances that interfere with ANG II.
Topics: Adipose Tissue; Angiotensin II; Angiotensin Receptor Antagonists; Humans; Obesity; Receptors, Angiotensin; Renin-Angiotensin System
PubMed: 17392133
DOI: No ID Found -
Physiological Research 1999The influence of long-lasting blockade of angiotensin AT1 or AT2 receptors by antibody against the particular receptor peptides on blood pressure and relative heart and...
The influence of long-lasting blockade of angiotensin AT1 or AT2 receptors by antibody against the particular receptor peptides on blood pressure and relative heart and kidney weight was studied in spontaneously hypertensive rats (SHR). Young and adult SHR were repeatedly immunized against the sequence 14-23 of angiotensin AT1 receptor from the age of either 1 or 3 months. Other groups of young and adult SHR were immunized against the sequences 37-43 and 106-116 of angiotensin AT2 receptor. Synthetic peptides conjugated to bovine gamma globulin were used as antigens. After 5 months of immunization, blood pressure was measured by the direct method. All immunized animals produced antibodies against the particular peptides. At the end of immunization, the blood pressure was significantly decreased in SHR immunized in youth against angiotensin AT1 receptor peptide, although no difference in heart and kidney hypertrophy was observed compared to sham-immunized SHR. The immunization against angiotensin AT1 receptor peptide in adulthood as well as the immunization against angiotensin AT2 receptor peptides in youth or in adulthood affected neither blood pressure nor heart and kidney weight. No influence of immunization on the studied parameters was observed in normotensive WKY rats. Angiotensin AT1 receptors play a more important role in the pathogenesis of spontaneous hypertension than angiotensin AT2 receptors. The blockade of angiotensin AT1 receptors by active immunization against the receptor peptide attenuated hypertension development in young SHR but did not modify the already established hypertension in adult SHR.
Topics: Aging; Angiotensin Receptor Antagonists; Animals; Hypertension; Hypertrophy; Kidney; Myocardium; Organ Size; Peptide Fragments; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Vaccination
PubMed: 10638677
DOI: No ID Found -
American Journal of Physiology.... Mar 2000Since it was discovered ten years ago, the angiotensin II (ANG II) type 2 (AT(2)) receptor has been an enigma. This receptor binds ANG II with a high affinity but is not... (Review)
Review
Since it was discovered ten years ago, the angiotensin II (ANG II) type 2 (AT(2)) receptor has been an enigma. This receptor binds ANG II with a high affinity but is not responsible for mediating any of the classical physiological actions of this peptide, all of which involve the ANG II type 1 (AT(1)) receptor. Furthermore, the AT(2) receptor exhibits dramatic differences in biochemical and functional properties and in patterns of expression compared with the AT(1) receptor. During the past decade, much information has been gathered about the AT(2) receptor, and the steadily increasing number of publications indicates a growing interest in this new and independent area of research. A number of studies suggest a role of AT(2) receptors in brain, renal, and cardiovascular functions and in the processes of apoptosis and tissue regeneration. Despite these advances, nothing stands out as the major singular function of these receptors. The study of AT(2) receptors has reached a crossroads, and innovative approaches must be considered so that unifying mechanisms as to the function of these unique receptors can be put forward. In this review we will discuss the advances that have been made in understanding the biology of the AT(2) receptor. Furthermore, we will consider how these discoveries, along with newer experimental approaches, may eventually lead to the elusive physiological and pathophysiological functions of these receptors.
Topics: Animals; Apoptosis; Humans; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Regeneration; Signal Transduction
PubMed: 10710489
DOI: 10.1152/ajpendo.2000.278.3.E357 -
PLoS Computational Biology Feb 2022In vertebrates, the octopeptide angiotensin II (AngII) is an important in vivo regulator of the cardiovascular system. It acts mainly through two G protein-coupled...
In vertebrates, the octopeptide angiotensin II (AngII) is an important in vivo regulator of the cardiovascular system. It acts mainly through two G protein-coupled receptors, AT1 and AT2. To better understand distinctive features of these receptors, we carried out a phylogenetic analysis that revealed a mirror evolution of AT1 and AT2, each one split into two clades, separating fish from terrestrial receptors. It also revealed that hallmark mutations occurred at, or near, the sodium binding site in both AT1 and AT2. Electrostatics computations and molecular dynamics simulations support maintained sodium binding to human AT1 with slow ingress from the extracellular side and an electrostatic component of the binding free energy around -3kT, to be compared to around -2kT for human AT2 and the δ opioid receptor. Comparison of the sodium binding modes in wild type and mutated AT1 and AT2 from humans and eels indicates that the allosteric control by sodium in both AT1 and AT2 evolved during the transition from fish to amniota. The unusual S7.46N mutation in AT1 is mirrored by a L3.36M mutation in AT2. In the presence of sodium, the N7.46 pattern in amniota AT1 stabilizes the inward orientation of N3.35 in the apo receptor, which should contribute to efficient N3.35 driven biased signaling. The M3.36 pattern in amniota AT2 favours the outward orientation of N3.35 and the receptor promiscuity. Both mutations have physiological consequences for the regulation of the renin-angiotensin system.
Topics: Angiotensin II; Animals; Phylogeny; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Sodium; Vertebrates
PubMed: 35202400
DOI: 10.1371/journal.pcbi.1009732 -
Kidney International Dec 1994Within the kidney angiotensin II (Ang II) exerts potent effects on renal function. The intrarenal actions of Ang II include modulation of renal blood flow, glomerular... (Review)
Review
Within the kidney angiotensin II (Ang II) exerts potent effects on renal function. The intrarenal actions of Ang II include modulation of renal blood flow, glomerular filtration rate, tubular epithelial transport, renin release and cellular growth. The actions of Ang II on the kidney are mediated by specific intrarenal receptors which, based upon physical characteristics and the selective binding of non-peptide and peptide analogs may be divided into two main subtypes, termed AT1 and AT2. AT1 receptors are present within the kidneys of all species and are located predominantly in the glomerulus, the renal tubules and the renal vasculature, including the afferent and efferent arterioles. Modulation of AT1 receptors within the kidney has been shown to mediate essentially all of the known intrarenal effects of Ang II. AT1 receptors and particularly AT2 receptors are expressed in large numbers in fetal kidney where they may play a role in development and maturation. In some species, intrarenal AT2 receptors disappear shortly after birth. In those species where AT2 receptors are present in the adult kidney their role in the control of renal function has not yet been clearly defined.
Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Humans; Imidazoles; Kidney; Losartan; Oligopeptides; Pyridines; Rats; Receptors, Angiotensin; Species Specificity; Tetrazoles; Tissue Distribution
PubMed: 7699986
DOI: 10.1038/ki.1994.426 -
The Journal of Clinical Investigation Oct 1999Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms - AT1 and AT2. Although blood pressure is increased in AT2 knockout...
Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms - AT1 and AT2. Although blood pressure is increased in AT2 knockout mice, the underlying mechanisms remain undefined because of the low levels of expression of AT2 in the vasculature. Here we overexpressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of Ang II into AT2-TG mice completely abolished the AT1-mediated pressor effect, which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice showed greatly increased cGMP production and diminished Ang II-induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na(+)/H(+) exchanger, promoting intracellular acidosis in VSM cells and activating kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest that AT2 in aortic VSM cells stimulates the production of bradykinin, which stimulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicted to have a beneficial clinical effect in controlling blood pressure.
Topics: Actins; Amiloride; Angiotensin II; Animals; Aorta; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cell Membrane; Cyclic GMP; Endothelium, Vascular; Imidazoles; Kinins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Promoter Regions, Genetic; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Recombinant Fusion Proteins; Tunica Media; Vasoconstriction; Vasodilation
PubMed: 10510333
DOI: 10.1172/JCI7886