181,239 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 Daniel W. Kempner to C. A. Blocker confirming his order to work on the car
Personal Papers (MS 80-0002)
No full textLetter from Daniel W. Kempner to C. A. Blocker asking for him to watch over his car
Personal Papers (MS 80-0002)
No full textLetter from Daniel W. Kempner to C. A. Blocker asking if he will remind him to get it from the factory
Personal Papers (MS 80-0002)
No full textLetter from Daniel W. Kempner to C. A. Blocker providing a list of all the repairs and service he would like done to his car
Personal Papers (MS 80-0002)
No full textLetter from Daniel W. Kempner to C. A. Blocker informing that the samples are enclosed and the tan herringbone is $90.00
Factors associated with β-blocker initiation and discontinuation in a population-based cohort of seniors newly diagnosed with heart failure
No full textCatherine Girouard,1–3 Jean-Pierre Grégoire,1–3 Paul Poirier,2,4 Jocelyne Moisan1–3 1Chair on Adherence to Treatments, Université Laval, 2Faculty of Pharmacy, Université Laval, 3Population Health and Optimal Health Practices Research Unit, CHU de Québec Research Center, 4Quebec Heart and Lung Institute-Université Laval, Quebec City, QC, Canada Purpose: β-Blockers (bisoprolol, carvedilol, and metoprolol) are the cornerstone of heart failure (HF) management. The incidence rate of β-blocker initiation and discontinuation and their associated factors among seniors with a first HF diagnosis were assessed.Methods: A population-based inception cohort study that included all individuals aged ≥65 years with a first HF diagnosis in Quebec was conducted. β-Blockers initiation among 91,131 patients who were not using β-blockers at the time of HF diagnosis and discontinuation among those who initiated a β-blocker after HF diagnosis were assessed. Stepwise Cox regression analyses were used to calculate hazard ratios (HR) and to identify factors associated with β-blocker initiation and discontinuation.Results: After HF diagnosis, 32,989 (36.2%) individuals initiated a β-blocker. Of these, 15,408 (46.7%) discontinued their β-blocker during the follow-up. Individuals more likely to initiate a β-blocker were those diagnosed in a recent calendar year (2009: HR, 2.11; 95% confidence interval [CI], 2.00–2.23) and diagnosed by a cardiologist (HR, 1.38; 95% CI, 1.34–1.42). Individuals less likely to initiate were those aged ≥90 years (HR, 0.65; 95% CI, 0.61–0.68) and those with chronic obstructive pulmonary disease (HR, 0.66; 95% CI, 0.64–0.68). Individuals more likely to discontinue were those with more than nine medical consultations (HR, 1.14; 95% CI, 1.10–1.18) and those with dementia (HR, 1.13; 95% CI, 1.01–1.27). Individuals less likely to discontinue were those diagnosed in a recent calendar year (2009: HR 0.74; 95% CI, 0.65–0.82) and those exposed to another β-blocker before HF diagnosis (HR, 0.88; 95% CI, 0.85–0.91).Conclusion: Quebec seniors seem to be underexposed to β-blocker following HF diagnosis. Among those who initiate β-blocker use, discontinuation is high. Better understanding of the underlying causes is needed to help target interventions to improve the management of HF. Keywords: heart failure, β-blocker initiation, β-blocker discontinuation, cohort study, drug us
Rufus C. and Eunice Blocker
No full textPhotograph of Rufus C. and Eunice Blocker. These two are the first two extension agents in the county. He was called the "Farm Demonstrator" and she taught girls how to can foods
Comanopa Blocker 1979
No full textGenus Comanopa Blocker, 1979 Type species Stragania puertoricensis Caldwell, 1952. Diagnosis Forewing (Fig. 1) with vein separating appendix and first apical cell incomplete (evanescent apically). Male pygofer (Fig. 6) with process (pygofer hooks) arising near apex, extending anterad, similar to Penestragania Beamer & Lawson, 1945. Subgenital plate (Fig. 8) simple, slightly reduced in size, similar to Momoria Blocker, 1979. Style (Fig. 9) reduced in length. Connective (Fig. 9) like a narrow semicircular band.Published as part of Domahovski, Alexandre C., 2021, Two new species of Hyalojassini (Hemiptera: Cicadellidae: Iassinae) to the genera Comanopa Blocker and Gehundra Blocker, description of the male of G. sordida (Baker) and key to species, pp. 112-129 in European Journal of Taxonomy 746 (1) on page 114, DOI: 10.5852/ejt.2021.746.1323, http://zenodo.org/record/471618
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