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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

[125I]EXP985 is the first nonpeptide radioligand with high specific activity for the AT1 angiotensin receptor. The biochemical and pharmacological profiles of this ligand were determined using either ligand-receptor binding techniques in rat adrenal cortical microsomes or cellular Ca2+ mobilization in rat smooth muscle cells. Specific binding with 0.1 nM [125I]EXP985 increased slowly with time reaching an equilibrium at 60 min of incubation (22 degrees C). Scatchard analysis of the inhibition/binding data revealed a single class of binding sites having a Kd of 1.49 +/- 0.06 nM and a Bmax of 3.6 +/- 0.1 pmol/mg protein. These sites were saturable and the ligand-receptor complex dissociated with a t1/2 of 58 min. The binding was inhibited by Ang peptides with the following order of potency and IC50 (nM): Ang II (3.7) > Ang III (69) > Ang I (3650), and by the nonpeptide AT1 receptor antagonist, losartan, with an IC50 of 3.2 nM. PD123177, an AT2 selective antagonist, showed minimal inhibitory effect. Specific binding of [125I]EXP985 was found on rat aortic smooth cells. Ang II-induced Ca2+ mobilization in these cells was blocked by EXP985 in a noncompetitive manner. These data show that [125I]EXP985 (or its unlabeled) is a potent and highly specific radioligand or noncompetitive antagonist which represents a novel tool to further our understanding of the biochemistry of AT1 receptors.
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PMID:[125I]EXP985: a highly potent and specific nonpeptide radioligand antagonist for the AT1 angiotensin receptor. 144 40

This study examines the effects of angiotensin II on hypertrophy and proliferation of aortic smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto rats and the receptor subtypes mediating these effects. In quiescent confluent cells, angiotensin II induced a dose-dependent increase in thymidine and leucine incorporation without stimulating cell proliferation. In nonconfluent cells, angiotensin II stimulated cell proliferation only in combination with a submaximal concentration of fetal calf serum. These effects were enhanced in cells from spontaneously hypertensive rats compared with Wistar-Kyoto rats. The effects of angiotensin II could be blocked by the AT1 receptor antagonist DuP 753 but not by the AT2 receptor ligand PD 123177. In receptor binding studies with cells derived from both rat strains, AT1-typical binding was observed. These data show that the angiotensin II receptors present in vascular smooth muscle cells in culture from both rat strains are of the AT1 receptor subtype. This receptor subtype appears to mediate vascular smooth muscle cell hypertrophy and proliferation as well as vasoconstriction. Although no difference in the receptor profile was detectable between the two rat strains, the affinity for the ligands to the receptor and the receptor density tended to be greater in cells from spontaneously hypertensive rats than in cells from Wistar-Kyoto rats. These results may partly explain the greater hypotensive response to angiotensin II receptor blockade in spontaneously hypertensive rats than in Wistar-Kyoto rats, although both rat strains have the same plasma concentrations of angiotensin II.
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PMID:Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats. 145 90

1. This paper describes the effects of GR117289 (1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzo-furanyl]methyl ]-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid) at angiotensin receptors and binding sites in rabbit aorta, rat liver and bovine cerebellum preparations in vitro. 2. In rabbit isolated aortic strips, GR117289 (0.3, 1 and 3 nM) caused a concentration-related, insurmountable suppression of the concentration-response curve to angiotensin II (AII). When the contact time was increased, a greater degree of antagonism of AII was observed, suggesting that GR117289 is slow to reach equilibrium. A pKB of 9.8 +/- 0.1 was calculated for GR117289 after 3 h incubation. GR117289 (1 microM) did not affect contractile responses to phenylephrine or 5-hydroxytryptamine (5-HT) in the rabbit aorta. 3. GR117289 (1 nM) alone caused a marked suppression and a slight rightward displacement of the AII concentration-response curve. Co-incubation with the competitive, surmountable AT1 receptor antagonist, losartan (10 nM, 100 nM and 1 microM), resulted in a concentration-related upward and rightward displacement of the concentration-response curve to subsequently administered AII. In separate experiments in which preparations were pre-incubated with GR117289 (1 nM), subsequent addition of losartan (1 microM) for 2, 15 or 45 min caused a further, but similar, rightward displacement of the concentration-response curve to subsequently administered AII with a time-dependent increase in the maximum response.4. Suppression of All-induced contractile responses, caused by superfusion with GRI17289 (0.3, 1 or 3 nM) was not reversed by continuously washing the tissues for 3 h; in fact, the potency of GRI 17289 was slightly enhanced after this period.5. In rat liver membranes, GRI17289 was a potent competitor with [3H]-AII for AT, binding sites(pKi = 8.7 +/- 0.1) but in bovine cerebellum membranes, it was a very weak competitor for AT2 binding sites (pKi<6). Pre-incubation of rat liver membranes with GRI17289 had little effect on its affinity(pKi = 9.1 +/- 0.21), but increasing the concentration of bovine serum albumen in the assay buffer from 0.001% to 0.1% w/v decreased affinity (pKi= 7.5 +/- 0.1).6. In saturation binding experiments in rat liver membranes, GRI 17289 (12 nM) increased the Kd of[3H]-AII from 0.28 +/- 0.06 nM to 0.37 +/- 0.02 nM, and decreased Bm. from 10.0 +/- 0.1 to 5.6 +/-0.3 fmol mg' tissue. In other experiments, GR1 17289 (1 jIM) did not alter the rate of dissociation of[3H]-AII from AT1 binding sites, following addition of excess unlabelled All.7. In rabbit aorta vascular smooth muscle membranes, GR1 17289 competed with ['25I]-Sar'1le8 All for binding to AT, binding sites. In the presence of 0.1% w/v bovine serum albumen, a pIC50 of 7.6 +/- 0.1 was calculated. Under the same conditions, but with rat liver membranes, a pIC50 of 7.8 +/- 0.1 was determined.8. Taken together, these results show that GRI17289 is a potent, specific, selective and insurmountable antagonist at angiotensin AT, receptors. Its profile in the rabbit aorta is consistent with the proposalthat GRI17289 is a slowly reversible (pseudo-irreversible) antagonist at these receptors.
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PMID:Pharmacological profile of GR117289 in vitro: a novel, potent and specific non-peptide angiotensin AT1 receptor antagonist. 146 38

This study was designed to characterize the distribution of angiotensin II (AII) binding sites in the hamster brain. Brain sections were incubated with [125I][sar1,ile8]-angiotensin II in the absence and presence of angiotensin II receptor subtype selective compounds, losartan (AT1 subtype) and PD123177 (AT2 subtype). Binding was quantified by densitometric analysis of autoradiograms and localized by comparison with adjacent thionein stained sections. The distribution of AII binding sites was similar to that found in the rat, with some exceptions. [125I][sar1,ile8]-angiotensin II binding was not evident in the subthalamic nucleus and thalamic regions, inferior olive, suprachiasmatic nucleus, and piriform cortex of the hamster, regions of prominent binding in the rat brain. However, intense binding was observed in the interpeduncular nucleus and the medial habenula of the hamster, nuclei void of binding in the rat brain. Competition with receptor subtype selective compounds revealed a similar AII receptor subtype profile in brain regions where binding is evident in both species. One notable exception is the medial geniculate nucleus, predominately AT1 binding sites in the hamster but AT2 in the rat. Generally, the AII binding site distribution in the hamster brain parallels that of the other species studied, particularly in brain regions associated with cardiovascular and dipsogenic functions. Functional correlates for AII binding sites have not been elucidated in the majority of brain regions and species mismatches might provide clues in this regard.
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PMID:Angiotensin II binding sites in the hamster brain: localization and subtype distribution. 146 63

The potent vasoconstrictor peptide, angiotensin II (AII) (200 micrograms/kg, SC), increases tail skin temperature (TST) and tail blood flow when acutely administered either peripherally (SC) or centrally (ICV) to rats. Colonic temperature declines with the increase in TST. These responses are apparently mediated by way of AII subtype receptor AT1 because they are blocked by acute administration of the nonpeptide AT1 receptor antagonist, losartan potassium (DuP 753) (10 mg/kg, SC). The responses were also blocked by the peptide AII receptor antagonist, saralasin, at 100 micrograms/kg SC. Chronic administration of the steroid deoxycorticosterone acetate (DOCA, 250-300 micrograms/day for 45 days) sensitized the response of TST to acute administration of AII. The increase in responsiveness resulting from chronic treatment with DOCA is consistent with the increase in dipsogenic responsiveness to AII under similar conditions. The latter was shown to be correlated with the upregulation of AII receptors in the diencephalon. While the location of the AII receptors mediating the increase in TST is not known with certainty, it is reasonable to suggest that they are also upregulated by chronic treatment with DOCA.
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PMID:Effect of losartan potassium and deoxycorticosterone acetate on tail skin temperature response to acute administration of angiotensin II. 147 62

Radioligand-receptor binding techniques identified two angiotensin II (ANG II) receptor subtypes in rat renal glomerular membranes. This characterization was made possible by employing two highly-specific nonpeptide ANG II antagonists: Losartan (DuP 753), which is specific to the AT1 subtype, and PD 123319, which is specific to the AT2 subtype. The majority of ANG II receptors in glomerular membranes corresponded to the AT1 subtype.
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PMID:Characterization of glomerular angiotensin II receptor subtypes. 147 51

1. Conscious, Long Evans rats (n = 10), chronically instrumented for the measurement of regional haemodynamics, were studied on 3 consecutive experimental days to assess responses to angiotensin II (AII) (125 pmol kg-1, i.v.) and noradrenaline (1 nmol kg-1, i.v.) in the absence and presence of the AT2-receptor antagonist, PD 123319 (10 mg kg-1, i.v.) (day 1), the AT1-receptor antagonist, EXP 3174 (1 mg kg-1, i.v.) (day 2), and PD 123319 (10 mg kg-1, i.v.) given 24 h after EXP 3174 (day 3). 2. In naive rats (day 1), PD 123319 did not antagonize the haemodynamic effects of AII or noradrenaline. EXP 3174 (day 2) caused a marked, prolonged blockade of the haemodynamic effects of AII but not those of noradrenaline. Twenty four h after administration of EXP 3174 (day 3) there was still significant attenuation of the haemodynamic effects of AII. However, administration of PD 123319 at this time caused a further inhibition (lasting 1 h) of the effects of AII but not those of noradrenaline. 3. An identical 3 day protocol was used in a separate group of rats (n = 6) in which the AT2-receptor antagonist, PD 123177, was given instead of PD 123319, and the results were essentially the same, i.e., PD 123177 significantly attenuated the haemodynamic effects of AII but only when given 24 h after EXP 3174.4. In a separate group of rats (n = 4), a low dose of EXP 3174 (60 pg kg-' i.v.) was given to naive rats in order to simulate the degree of inhibition of the effects of All seen after administration of AT2-receptor antagonists in animals pretreated with EXP 3174. This low dose of EXP 3174 did not produce a sustained inhibition of the effects of All and the time course of recovery of All responses was similar to that seen with PD 123319 or PD 123177 given after the high dose of EXP 3174.5. The apparent inhibition of the effects of AII by the AT2-receptor antagonists, PD 123319 and PD 123177, when these were administered 24 h after the AT,-receptor antagonist, EXP 3174, may have been due to the functional activation of AT2-receptors and/or loss of AT2-receptor antagonist selectivity,and/or the displacement of nonspecifically bound EXP 3174 by AT2-receptor antagonists. While the latter explanation seems the most likely, these results raise the possibility that nonpeptide, All-receptor antagonists that act at both AT,- and AT2-receptors may have therapeutic advantages over selective AT,-receptor antagonists.
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PMID:Inhibition of the haemodynamic effects of angiotensin II in conscious rats by AT2-receptor antagonists given after the AT1-receptor antagonist, EXP 3174. 147 80

Angiotensin-II (AII) stimulates smooth muscle contraction by activating angiotensin AT1 receptor which induces intracellular Ca2+ release and Ca2+ influx from extracellular space. In this study, effect of extracellular Ca2+ concentration ([Ca2+]0) on angiotensin AT1 receptor-mediated contractile response to AII has been examined in the absence and presence of [Sar1,Ala8]AII in rabbit aorta. A decrease in agonist potency and an increase in antagonist potency for depression were observed in low [Ca2+]0. Data were interpreted by applying an explanatory model developed previously. The result indicates that [Ca2+]0 is linked to the efficacy expression of AII at angiotensin AT1 receptor and this prompted speculation about the underlying mechanism.
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PMID:Effect of extracellular calcium concentration on angiotensin AT1 receptor-mediated smooth muscle contraction and antagonism in rabbit aorta. 147 69

[3H]L-158,809, a new potent and AT1-selective nonpeptide angiotensin II receptor antagonist, bound saturably and reversibly to rat adrenal membranes. Scatchard and Hill plot analyses indicated a single class of high affinity (Kd = 0.66 nM) binding sites. The relative potencies of various angiotensin II-related peptide and nonpeptide antagonists in displacing [3H]L-158,809 binding correlated with their potencies in displacing the binding of 125I-Sar1,Ile8-angiotensin II to adrenal AT1 receptors. [3H]L-158,809 binding to adrenal membranes was not affected by addition of guanosine-5'-(beta,gamma-imido)triphosphate or various pharmacological agents known to interact with other common peptide and nonpeptide receptor systems. The potencies of angiotensin II receptor agonists, but not antagonists, in inhibiting specific [3H]L-158,809 binding were decreased in the presence of guanosine-5'-(beta,gamma-imido)triphosphate. Specific [3H]L-158,809 binding was also observed in rat liver and kidney. Collectively, the data indicate that [3H]L-158,809 represents a new, potent, nonpeptide, antagonist radioligand suitable for the study of angiotensin II AT1 receptors.
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PMID:Characterization of the binding of [3H]L-158,809: a new potent and selective nonpeptide angiotensin II receptor (AT1) antagonist radioligand. 148 Jan 33

T cell precursors from murine fetal liver enter the fetal thymus where they proliferate, differentiate, and mature. These processes are accompanied by changes in the pattern of transcription factors known to control the expression of specific genes. We have monitored the expression of five different transcription factors during mouse fetal thymus ontogeny: nuclear factor (NF)-kappa B, cAMP-response-element binding protein (CREB), NF-IL-2A, msNF-AT1, and hNF-AT1. NF-kappa B binding activity was not detected in extracts from fetal liver but was present in the thymus at day 14 of embryogenesis. Thereafter, NF-kappa B expression was biphasic, being maximal at 14-16 days gestation and in newborn mice, and decreased during the intermediate gestational stages and in the adult. An inverse correlation was observed between NF-kappa B binding activity in the nuclei and levels of its inactive precursor in the cytoplasm of all samples analyzed. In contrast, CREB activity was uniform throughout thymus development. Similarly, NF-IL-2A activity was detected in fetal liver and thymic extracts from different gestational stages, in approximately equivalent amounts. However, band shift experiments revealed three distinct NF-IL-2A-DNA complexes, whose relative abundance is altered during thymic ontogeny. Likewise, NF-AT1 transcription factor appears to be heterogeneous and includes representatives which are differentially (msNF-AT1) or stably (hNF-AT1) expressed during thymic development. These results are discussed in the context of present knowledge about T cell development within the thymus.
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PMID:Transcription factors in mouse fetal thymus development. 149 84


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