1,721,905 research outputs found
Suitability of CGP-12177 and CGP-26505 for quantitative imaging of β-adrenoceptors
No full text[H-3]GP-12177, a non-selective beta-adrenoceptor antagonist, and [H-3]CGP-26505, a beta-1-selective beta-adrenoceptor antagonist, were intravenously administered to rats. 94-97% of the injected radioactivity disappeared from plasma with t1/2 0.2 and 0.5 min. Total/non-specific binding ratios of 5.4 and 6.9 (CGP-12177) or 2.0 and 2.8 (CGP-26505) were maintained in heart and lung from 10 to 40 min post-injection. Labelled plasma metabolites appeared after > 20 min (CGP-12177) or within 2 min (CGP-26505). No metabolites were found in the heart. CGP-12177 binds to blood cells, but CGP-26505 does not. CGP-12177 can be used for PET imaging of total (beta-1 and beta-2) adrenoceptors in the heart and lung of experimental animals, but CGP-26505 is less suitable for in vivo analysis of the beta-1-subpopulation
Inhibition of cimaterol-induced <sup>3</sup>H-cAMP accumulation responses by CGP 12177.
No full text<p><sup>3</sup>H-cAMP accumulation in response to cimaterol in <b>A</b> wildtype cells, <b>B</b> Gly49/Gly389 cells and <b>C</b> Ser49/Arg389 cells in the absence and presence of CGP 12177. Bars represent basal <sup>3</sup>H-cAMP accumulation, that in response to 10 µM isoprenaline and that in response to 1 nM and 10 nM CGP 12177. Data points are mean ± s.e.mean of triplicate determinations and these single experiments are representative of 4 separate experiments in each case. Here, CGP 12177 inhibits the catecholamine conformation response with high affinity in all three receptor variants.</p
Putative beta(4)-adrenoceptors in rat ventricle mediate increases in contractile force and cell Ca2+: comparison with atrial receptors and relationship to (-)-[H-3]-CGP 12177 binding
No full text1 We identified putative beta(4)-adrenoceptors by radioligand binding, measured increases in ventricular contractile force by (-)-CGP 12177 and (+/-)-cyanopindolol and demonstrated increased Ca2+ transients by (-)-CGP 12177 in rat cardiomyocytes. 2 (-)-[H-3]-CGP 12177 labelled 13-22 fmol mg(-1) protein ventricular beta(1), beta(2)-adrenoceptors (pK(D) similar to 9.0) and 50-90 fmol mg(-1) protein putative beta(4)-adrenoceptors (pK(D) similar to 7.3). The affinity values (PKi) for (beta(1),beta(2)-) and putative beta(4)-adrenoceptors, estimated from binding inhibition, were (-)-propranolol 8.4, 5.7; (-)-bupranolol 9.7, 5.8; (+/-)-cyanopindolol 10.0,7.4. 3 In left ventricular papillary muscle, in the presence of 30 mu M 3-isobutyl-1-methylxanthine, (-)CGP 12177 and (+/-)-cyanopindolol caused positive inotropic effects, (pEC(50) (-)-CGP 12177, 7.6; (+/-)-cyanopindolol, 7.0) which were antagonized by (-)-bupranolol (pK(B) 6.7-7.0) and (-)-CGP 20712A (pK(B) 6.3-6.6). The cardiostimulant effects of(-)-CGP 12177 in papillary muscle, left and right atrium were antagonized by (+/-)-cyanopindolol (pK(i), 7.0-7.4). 4 (-)-CGP 12177 (1 mu M) in the presence of 200 nM (-)-propranolol increased Ca2+ transient amplitude by 56% in atrial myocytes, but only caused a marginal increase in ventricular myocytes. In the presence of 1 mu M 3-isobutyl-1-methylxanthine and 200 nM (-)-propranolol, 1 mu M (-)-CGP 12177 caused a 73% increase in Ca2+ transient amplitude in ventricular myocytes. (-)-CGP 12177 elicited arrhythmic transients in some atrial and ventricular myocytes. 5 Probably by preventing cyclic AMP hydrolysis, 3-isobutyl-1-methylxanthine facilitates the inotropic function of ventricular putative beta(4)-adrenoceptors. suggesting coupling to G(s) protein-adenylyl cyclase. The receptor-mediated increases in contractile force are related to increases of Ca2+ in atrial and ventricular myocytes. The agreement of binding affinities of agonists with cardiostimulant potencies is consistent with mediation through putative beta(4)-adrenoceptors labelled with (-)-[H-3]-CGP 12177
In vivo quantification of pulmonary beta-adrenoceptor density in humans with (S)-[11C]CGP-12177 and PET
No full text The in vivo regional distribution of pulmonary beta-adrenoceptors was imaged and quantified in humans with the hydrophilic beta-adrenoceptor antagonist (S)-CGP-12177 labeled with carbon-11 [(S)-[11C]CGP-12177] and positron emission tomography (PET). Six normal male volunteers and eight patients with hypertrophic cardiomyopathy were studied. PET scanning consisted of transmission (tissue density), C15O (blood volume), and (S)-[11C]CGP-12177 (beta-adrenoceptor) emission scans. High-specific-activity (S)-[11C]-CGP-12177 (7.1 +/- 2.0 micrograms, 6.5 +/- 2.1 GBq/mumol) was given intravenously followed by a low-specific-activity (S)-[11C]CGP-12177 injection (34.0 +/- 4.8 micrograms, 2.3 +/- 0.8 GBq/mumol). Binding capacity (Bmax) was calculated in each region of interest as picomoles per gram by normalizing it to the local extravascular tissue density. In normal subjects, average Bmax for all regions of interest was 14.8 +/- 1.6 (SD) pmol/g, which is similar to previously reported in vitro values. In both groups there were no differences in beta-adrenoceptor density between peripheral and central regions nor between right and left lungs. In patients with hypertrophic cardiomyopathy, extravascular tissue density was 24% higher than in normal subjects; Bmax per milliliter thoracic volume was correspondingly higher but was not different from that in normal subjects when expressed per gram tissue (15.8 +/- 2.6 pmol/g). These data suggest that in vivo beta-adrenoceptor density may be quantifiable in humans with the use of PET. This should offer a means to study physiological regulation through repeat measurements. </jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Radioligand binding studies of the atypical β3-adrenergic receptor in rat brown adipose tissue using [3H]CGP 12177
No full textAbstractTwo populations of [3H]CGP 12177 binding sites exist in rat interscapular brown adipose tissue (IBAT) plasma membrane. The majority of binding sites are of low affinity with a Kd of 31 nM, a value in close agreement with that for the Kd or [3H]CGP 12177 binding to a cloned rat β3-adrenergic receptor (AR) expressed in CHO cells (44 nM). Competition binding studies demonstrate that the Ki values of the cloned rat β3-AR and of the low affinity sites in IBAT are 45 and 29 nM, respectively, for BRL 37344 and 1.4 and 1.0 μM, for (−)-propranolol. These findings strongly suggest that the low affinity [3H]CGP 12177 binding site measured in IBAT plasma membranes represents the atypical β3-AR in this tissue
Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta(1)/beta(2)-adrenoceptor knockout mice. Obligatory role of beta(1)-adrenoceptors for putative beta 4-adrenoceptor pharmacology
No full textSome beta (1)- and beta (2)-adrenoceptor-blocking agents, such as (-)-CGP 12177, cause cardiostimulant effects at concentrations considerably higher than those that antagonise the effects of catecholamines. The cardiostimulant effects of these non-conventional partial agonists are relatively resistant to blockade by (-)-propranolol and have been proposed to be mediated through putative beta (4)-adrenoceptors or through atypical states of either beta (1)- or beta (2)-adrenoceptors. We investigated the effects of (-)-CGP 12177 on sinoatrial rate and left atrial contractile force as well as the ventricular binding of (-)-[H-3]CGP 12177 in tissues from wild-type, beta (2)-adrenoceptor knockout and beta (1)/beta (2)-adrenoceptor double knockout mice. The cardiostimulant effects of (-)-CGP 12177 were present in wildtype and beta (2)-adrenoceptor knockout mice but were absent in beta (1)/beta (2)-adrenoceptor double knockout mice. Thus, the presence of beta (1)-adrenoceptors is obligatory for the cardiostimulant effects of (-)-CGP 12177. It appears therefore that an atypical state of the beta (1)-adrenoceptor contributes to the mediation of the cardiostimulant effects induced by non-conventional partial agonists. Ventricular beta (1)- and beta (2)-adrenoceptors, labelled in wild-type with a K(D)similar to0.5 nmol/l (similar to 16 fmol/mg protein), were absent in beta (1)/beta (2)-adrenoceptor double knockout mice. However, a high density binding site (similar to 154-391 fmol/mg protein) that did not saturate completely (K(D)similar to 80-200 nM) was labelled by (-)-[H-3]CGP 12177 in the three groups of mice, being distinct from beta (1)- and beta (2)-adrenoceptors, as well as from the site mediating the agonist effects of(-)-CGP 12177
Negative cooperativity across 1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 1-adrenoceptor binding conformation
Get PDFAt the β1-adrenoceptor, CGP 12177 potently antagonizes agonist responses at the primary high-affinity catecholamine conformation while also exerting agonist effects of its own through a secondary low-affinity conformation. A recent mutagenesis study identified transmembrane region (TM)4 of the β1-adrenoceptor as key for this low-affinity conformation. Others suggested that TM4 has a role in β1-adrenoceptor oligomerization. Here, assessment of the dissociation rate of a fluorescent analog of CGP 12177 [bordifluoropyrromethane-tetramethylrhodamine-(±)CGP 12177 (BODIPY-TMR-CGP)] at the human β1-adrenoceptor expressed in Chinese hamster ovary cells revealed negative cooperative interactions between 2 distinct β1-adrenoceptor conformations. The dissociation rate of 3 nM BODIPY-TMR-CGP was 0.09 ± 0.01 min−1 in the absence of competitor ligands, and this was enhanced 2.2- and 2.1-fold in the presence of 1 µM CGP 12177 and 1 µM propranolol, respectively. These effects on the BODIPY-TMR-CGP dissociation rate were markedly enhanced in β1-adrenoceptor homodimers constrained by bimolecular fluorescence complementation (9.8- and 9.9-fold for 1 µM CGP 12177 and 1 µM propranolol, respectively) and abolished in β1-adrenoceptors containing TM4 mutations vital for the second conformation pharmacology. This study suggests that negative cooperativity across a β1-adrenoceptor homodimer may be responsible for generating the low-affinity pharmacology of the secondary β1-adrenoceptor conformatio
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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