35,307 research outputs found
The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist
No full textNebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β2-AR, and likely β1-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β1- and/or β2-ARs. © 2013 Erickson et al
Personal Papers (MS 80-0002)
No full textLetter from T. G. Blocker to I. H. Kempner discussing the Constitutional Amendments mentioned in Kempner's letter of February 13. He states that Dallas enthusiastically supports the amendment, and he knows of no opposition. He sees no reason to oppose the bill, even though it doesn't directly apply to their situation
William Tarn, Hellenistic Civilisation. Third Edition revised by the Author and G. T. Griffith
No full textNachtergael Georges. William Tarn, Hellenistic Civilisation. Third Edition revised by the Author and G. T. Griffith. In: L'antiquité classique, Tome 44, fasc. 2, 1975. p. 782
William Tarn, Hellenistic Civilisation. Third Edition revised by the Author and G. T. Griffith
No full textNachtergael Georges. William Tarn, Hellenistic Civilisation. Third Edition revised by the Author and G. T. Griffith. In: L'antiquité classique, Tome 44, fasc. 2, 1975. p. 782
27 Topical eye treatment with p-blocker abolishes sweat secretion triggered by intradermal isoprenaline plus aminophylline: a clinical observation
No full textObjectives: Two new versions of the sweat test have recently been developed with claimed advantages of being sensitive enough to quantify residual CFTR function and to measure efficacy of basic therapies. Methods: Rates of water evaporation (kg water/hr/m2 ) and of volume of sweat per gland (nL/min) were measured in a healthy female, 61 yrs, following the reported test protocols. Results: Cholinergic stimulation gave normal results (maximal evaporimetric response 5 min after intradermal injection of carbachol: 95.1 kg water/hr/m2 and gland secretion rate obtained 10 min after methacholine injection: 1.8 nL/min). However, the β-adrenergic (isoprenaline plus aminophylline) stimulation, induced in the presence of atropine to block cholinergic stimulation, was abolished (β-adrenergic/cholinergic ratio: 0 and 5.8% of the normal values for evaporimetry and bubble test, respectively), eliciting a diagnosis of CF. The results were confirmed by repeating each test at least twice. Sweat chloride after pilocarpine iontophoresis using a coulometric method was 24 mmol/L. PCR-based screening showed no CFTR mutation. History of current medications possibly interfering with the pharmacological agents used during the tests revealed long-term (>12 yrs) treatment of a well-controlled primary angle closure glaucoma consisting on a daily topical use of β-blocker carteol 2% (1 drop/left eye). No apparent symptom of β-blocker intoxication is present (heart rate: 66 beats/min, regular sinus rhythm, no symptom of asthma). Conclusion: Much attention should be paid to the use of medications that may interfere with the pharmacological steps of the β-secretion tests. The clinical observation confirms the proof-of-concept that the second phase of both tests directly evaluates β-adrenergic sweat production that is very sensitive to β-blocker treatment, even at topical eye use, leading to false positive test results. Acknowledgement: Supported by the Belgian and Italian CF Foundations
Prior beta blocker treatment decreases leukocyte responsiveness to injury
No full textFollowing injury, leukocytes are released from hematopoietic organs and migrate to the site of damage to regulate tissue inflammation and repair; however, leukocytes lacking beta(2)-adrenergic receptor (beta(2)-AR) expression have marked impairments in these processes. Beta blockade is a common strategy for the treatment of many cardiovascular etiologies; therefore, the objective of our study was to assess the impact of prior beta blacker treatment on baseline leukocyte parameters and their responsiveness to acute injury. In a temporal and beta-adrenergic receptor isoform-dependent manner, chronic beta blocker infusion increased splenic vascular cell adhesion molecule 1 expression and leukocyte accumulation (monocytes/macrophages, mast cells, and neutrophils) and decreased chemokine receptor 2 (CCR2) expression and migration of bone marrow and peripheral blood leukocytes (PBLs) to, as well as infiltration into, the heart following acute cardiac injury. Further, CCR2 expression and migratory responsiveness were significantly reduced in the PBLs of patients receiving beta blocker therapy compared with beta blocker-naive patients. These results highlight the ability of chronic beta blocker treatment to alter baseline leukocyte characteristics that decrease leukocytes' responsiveness to acute injury and suggest that prior beta blockade may act to reduce the severity of innate immune responses
Selective tumor cell death induced by irradiated riboflavin through recognizing DNA G-T mismatch
No full textRiboflavin (vitamin B2) has been thought to be a promising antitumoral agent in photodynamic therapy, though the further application of the method was limited by the unclear molecular mechanism. Our work reveals that riboflavin was able to recognize G-T mismatch specifically and induce singlestrand breaks in duplex DNA targets efficiently under irradiation. In the presence of riboflavin, the photo-irradiation could induce the death of tumor cells that are defective in mismatch repair system selectively, highlighting the G-T mismatch as potential drug target for tumor cells. Moreover, riboflavin is a promising leading compound for further drug design due to its inherent specific recognition of the G-T mismatch
Intraindividual comparison of human radial and internal thoracic arteries in vitro and the effect of preoperative calcium blocker therapy
No full textThe patency rate of radial artery (RA) conduits is considerably lower than that of internal thoracic artery (ITA) grafts and the evidence suggests that this is due to a clinically suspected higher incidence of vasospasm. The aim of this study was, therefore, to compare intraindividually the pharmacological reactivity of RA with that of ITA. Both RA and ITA were taken from the same patients and investigated in parallel. Changes in tone were monitored isometrically on ring preparations from both arteries in organ baths with modified Krebs-Henseleit solution containing 1.25 mm calcium chloride at 1 g passive preload. In intraindividual comparisons maximal receptor-mediated contractile responses to noradrenaline and endothelin-1 and endothelium-dependent acetylcholine-induced relaxant responses revealed no differences between both arteries. By contrast, depolarization-induced contractions to potassium chloride (KCl) appeared to be significantly higher in RA than in ITA. Further analysis, however, revealed that this difference was due to preoperative calcium entry blocker (Ca(2+)eB) therapy. Compared with control tissues, maximal responses to KCl were significantly attenuated in the ITA but unchanged in RA when arteries were obtained from patients with preoperative Ca(2+)eB therapy. The present results suggested that functional responses to pharmacological stimuli of both RA and ITA were quite similar. Preoperative Ca(2+)eB therapy, however, attenuated markedly responses to KCl of the ITA leaving those of RA unchanged. These results, demonstrating a lower sensitivity to Ca(2+)eB of RA, therefore suggested that in addition to Ca(2+)eB other classes of drug may be more effective at reducing the propensity of RA conduits to vasospasm
Targeting gut T cell Ca2+ release-activated Ca2+ channels inhibits T cell cytokine production and T-box transcription factor T-bet in inflammatory bowel disease
No full textProlonged Ca(2+) entry through Ca(2+) release-activated Ca(2+) (CRAC) channels is crucial in activating the Ca(2+)-sensitive transcription factor NFAT, which is responsible for directing T cell proliferation and cytokine gene expression. To establish whether targeting CRAC might counteract intestinal inflammation, we evaluated the in vitro effect of a selective CRAC inhibitor on T cell cytokine production and T-bet expression by lamina propria mononuclear cells (LPMC) and biopsy specimens from inflammatory bowel disease (IBD) patients. The inhibitory activity of the CRAC blocker was investigated through patch-clamp experiments on rat basophilic leukemia cells and fluorometric imaging plate reader intracellular Ca(2+) assays using thapsigargin-stimulated Jurkat T cells and its detailed selectivity profile defined using a range of in vitro radioligand binding and functional assays. Anti-CD3/CD28-stimulated LPMC and biopsy specimens from 51 patients with IBD were cultured with a range of CRAC inhibitor concentrations (0.01-10 microM). IFN-gamma, IL-2, IL-8, and IL-17 were analyzed by ELISA. T-bet was determined by immunoblotting. We found that the CRAC blocker concentration-dependently inhibited CRAC current in rat basophilic leukemia cells and thapsigargin-induced Ca(2+) influx in Jurkat T cells. A concentration-dependent reduction in T-bet expression and production of IFN-gamma, IL-2, IL-17, but not IL-8, was observed in IBD LPMC and biopsy specimens treated with the CRAC inhibitor. In conclusion, we provide evidence that the suppression of CRAC channel function may dampen the increased T cell response in the inflamed gut, thus suggesting a promising role for CRAC inhibitor drugs in the therapeutic management of patients with IBD
f(G,T) and its Cosmological Implications
No full textA coupled formulation of the Gauss-Bonnet invariant term G and the
energy momentum trace T term provide a modified f(G,T) gravity,
has been analyzed in this study. The functional form for the
f(G,T) gravity has been taken as f(G,T)=αT+ βGThe presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
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