1,721,032 research outputs found
Certain beta-blockers can decrease beta-adrenergic receptor number: I. Acute reduction in receptor number by tertatolol and bopindolol.
No full textWe have previously reported that a potent new beta-blocker, tertatolol, when given at therapeutic doses to healthy volunteers, rapidly reduced the number of human mononuclear leukocyte beta-receptors. In the present study, the mechanism of receptor regulation by beta-antagonists incubated with target cells in vitro was investigated. Two different cell types (human mononuclear leukocytes and S49 murine lymphoma cells) were used, and beta-adrenergic receptors were measured using either the hydrophilic ligand 3H-CGP 12177 (specific for surface receptors) or lipophilic 125I-pindolol (which measures total receptors). In a comparison between beta-blockers, tertatolol and bopindolol, but not propranolol and pindolol, were found to rapidly (1 hour at 37 degrees C) reduce the number of beta-adrenergic receptors. This was paralleled by a reduction in isoproterenol-stimulated cyclic AMP accumulation. The reduction in receptors was the same whether surface or total receptors were measured; thus, it was not due to receptor sequestration. This effect was not caused by partial agonist activity (bopindolol is a weak partial agonist); in parallel experiments, tertatolol and bopindolol, but not pindolol (potent partial agonist) and isoproterenol (full agonist), reduced beta-adrenergic receptors. Finally, this effect was not due to irreversible binding: the receptor reduction induced by the irreversible blocker bromo-acetyl-alprenolol-methane (BAAM) was stable for several hours, while the effect of tertatolol and bopindolol was slowly reversed over the same time course. We suggest that tertatolol and bopindolol have two effects on beta-adrenergic receptors: they bind competitively, and then they modify the receptors so that they are no longer available for binding by ligands or catecholamines
Low affinity of beta-adrenergic receptors for agonists on intact cells is not due to receptor sequestration.
No full textThe low affinity of beta-adrenergic receptors for agonists described on intact cells at 37 degrees C has usually been interpreted in terms of reduced accessibility of agonists (which are usually hydrophilic) for sequestered receptors. We challenged this hypothesis by eliminating the plasma membrane barrier with low doses of the detergent digitonin. In human mononuclear leukocytes (MNL) permeabilized with digitonin, sequestered receptors became accessible to hydrophilic ligands such as agonists, but the affinity was still low. Then we investigated the relationship between low affinity agonist binding and sequestration using concanavalin A, which blocks sequestration. Even when sequestration was blocked, the affinity of the beta-adrenergic receptors for agonists was low. We conclude that: (a) low affinity agonist binding is independent of receptor sequestration; (b) the receptors which undergo conformational change are those that are sequestered; (c) the low affinity appears before sequestration occurs. This receptor conformational change could be the first step in agonist-induced desensitization
Two subpopulations of alpha 1-adrenergic receptors with high and low affinity for agonists: short-term exposure to agonists reduced the high-affinity sites.
No full textShort-term receptor regulation by agonists is a well-known phenomenon for a number of receptors, including beta-adrenergic receptors, and has been associated with receptor changes revealed by radioligand binding. In the present study, we investigated the rapid changes in alpha 1-adrenergic receptors induced by agonists. alpha 1-receptors were studied on DDT1 MF-2 smooth muscle cells (DDT1-MF-2 cells) by specific [3H]prazosin binding. In competition binding on membranes and on intact cells at 4 degrees C or at 37 degrees C in 1-min assays, agonists competed for a single class of sites with relatively high affinity. By contrast, in equilibrium binding at 37 degrees C on intact cells agonists competed with two receptor forms (high- and low-affinity). We quantified the receptors in the high-affinity form by measuring the [3H]prazosin binding inhibited by 20 microM norepinephrine (this concentration selectively saturated the high-affinity sites). The low-affinity sites were measured by subtracting the binding of [3H]prazosin to the high-affinity sites from the total specific binding. High-affinity receptors were 85% of the total sites in binding experiments at 4 degrees C, but only 30% at 37 degrees C. On DDT1-MF-2 cells preequilibrated with [3H]prazosin at 4 degrees C, and then shifted to 37 degrees C for a few minutes, norepinephrine selectively reduced the high-affinity sites by 30%. We suggest that at 4 degrees C it is the native form of alpha 1-receptors that is measured, with most of the sites in the high-affinity form, while during incubation at 37 degrees C the norepinephrine present in the binding assay converts most of the receptors to an apparent low-affinity form, so that they are no longer recognized by 20 microM norepinephrine. The nature of this low-affinity form was further investigated. On DDT1-MF-2 cells preincubated with the agonist and then extensively washed at 4 degrees C (to maintain the receptor changes induced by the agonist) the number of receptors recognized by [3H]prazosin at 4 degrees C was reduced by 38%. After fragmentation of the cells, the number of receptors measured at 4 degrees C was the same in control and norepinephrine-treated cells, suggesting that the disruption of cellular integrity might expose the receptors which are probably sequestered after agonist treatment. In conclusion, the appearance of the low affinity for agonists at 37 degrees C may be due to the agonist-induced sequestration of alpha 1-adrenergic receptors, resulting in a limited accessibility to hydrophilic ligands
Reduction of beta-adrenergic receptors can explain the lack of rebound effect after tertatolol withdrawal.
No full textTertatolol is a potent beta-blocker with no intrinsic sympathomimetic activity (ISA) or beta 1/beta 2 receptor subtype selectivity. We provide evidence that tertatolol competitively inhibits beta-adrenergic receptors (beta-AR) and induces a marked and persistent reduction of their number. This has been consistently found in vitro and in vivo. The in vitro study showed that the receptor reduction by tertatolol was rapid (about 1 h at 37 degrees C), slowly reversible and independent of ISA. This effect was also observed in vivo. In healthy volunteers, seven days tertatolol treatment lowered the number of beta-AR by 26%. This number gradually rose back to the pretreatment levels, and a significant effect was still present on day 3 after drug withdrawal. The reduction of heart rate by tertatolol was also persistent and was still significant on day 3 to 5 after drug withdrawal. We conclude that the reduction of the receptor numbers may be important in producing a lack of a rebound effect after discontinuation of chronic tertatolol treatment
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The ATRA-21 gene-expression model predicts retinoid sensitivity in CEBPA double mutant, t(8;21) and inv(16) AML patients
No full textAgonist-induced alpha 1-adrenergic receptor changes. Evidence for receptor sequestration.
No full textShort-term receptor regulation by agonists is a well-known phenomenon for a number of receptors but little is known about the regulation of alpha 1-adrenergic receptors. In the present study we provide evidence of alpha 1-adrenergic receptor changes induced by agonists on DDT1 MF-2 smooth muscle cells. The cells were preincubated with the agonist and receptor changes were investigated in the cells washed free of the agonist. On cells pretreated with norepinephrine the number of receptors recognized by [3H]prazosin at 4 degrees C was reduced by 38%. The receptors were not degraded as the number of sites was the same in control and norepinephrine-treated cells when binding was measured at 37 degrees C. When binding was measured on fragmented membranes (at 4 degrees C), the number of receptors was the same in control and norepinephrine-treated cells, suggesting that the disruption of cellular integrity might expose receptors which are probably sequestered after agonist treatment. We conclude that agonists induced rapid sequestration of receptors on intact DDT cells
Agonist-induced beta-adrenoceptor internalization on intact human mononuclear leukocytes : effect of temperature of mononuclear leukocyte separation
No full textAgonist-induced beta-adrenergic receptor internalization on intact human mononuclear leukocytes: effect of temperature of mononuclear leukocyte separation.
No full textThe hydrophilic ligand 3H-CGP 12177 was used to measure beta-adrenergic receptors on intact human mononuclear leukocytes (MNLs). A single homogeneous class of receptor sites was found, with KD value of 0.71 +/- 0.04 nmol/L and Bmax of 3.0 +/- 0.4 fmol/10(6) cells (mean +/- SEM; n = 12). The receptor affinity (KD) and density (Bmax) were similar when measured on MNLs, purified lymphocytes, and a T-lymphocyte-enriched population from the same individual. Preincubation of intact MNLs with 1 mumol/L isoproterenol at 37 degrees C for 20 minutes reduced the number of surface receptors, measured by 3H-CGP 12177 binding at 4 degrees C for 20 hours, by approximately 70% (receptor internalization) without affecting KD. This effect was reversible, and surface receptors completely reappeared when binding was investigated at 37 degrees C for 40 minutes. Receptor internalization was similar when either isolated MNLs or whole blood was incubated with isoproterenol. Agonist-induced receptor internalization was stable during MNL isolation from whole blood at 4 degrees C but was partially or completely lost from MNLs prepared at 20 degrees C
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