11,522 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
Discontinuous dynamics in North Sea cod Gadus morhua caused by ecosystem change
No full textMarine ecosystems worldwide experience abrupt changes and regime shifts in structure and functioning due to the interacting effects of multiple stressors. North Sea cod Gadus morhua is a key example of a species being strongly overexploited for decades, causing an abrupt stock decrease below scientifically advised sustainable levels. Despite reductions in fishing pressure in recent years, populations of North Sea cod have not yet recovered. Why recovery is hindered and especially how ecosystem dynamics interacted with fishing to create a stable low cod stock is an open question. Here, we sequentially apply change point and principle component analyses as well as stochastic cusp modelling to a long-term time series (1963−2018) to show that North Sea cod recovery is limited due to an interaction of fishing pressure, internal stock dynamics and external environmental changes. We found that cod biomass experienced nonlinear, discontinuous dynamics, given the interaction of fishing pressure and climate change-induced increases in temperatures, wind magnitude and the North Atlantic Oscillation. Our results further demonstrate discontinuity in cod biomass due to low recruitment caused by a discontinuous relationship between stock biomass and environmental changes characterized by climate and zooplankton variables. Our study indicates that climate-induced changes in the environment have trapped North Sea cod in a depleted state, limiting the probability that the population will regain its role as a main target species for fisheries. Hence, we highlight the importance of incorporating discontinuous dynamics in fisheries management approaches to achieve sustainable exploitation levels and to identify thresholds of drivers to favour policies to prevent regime shifts
Personal Papers (MS 80-0002)
No full textLetter from C. A. Blocker to Daniel W. Kempner enclosing a copy of the repair order to benefit the insurance compan
A LTE RX front-end with digitally programmable multi-band blocker cancellation in 28nm CMOS
No full textThis paper presents a LTE receiver front-end with a feedback digital filter in the baseband to perform multiband blocker cancellation. The programmable filter provides 34.9dB attenuation of TX leakage and variable attenuation of an additional blocker anywhere in the frequency range 17.5MHz-107.5MHz. The receiver front-end operates at 1.8GHz with a noise figure of 3.9dB, IIP3 of -5dBm, and consumes only 20.4-37.5mW, the lowest among state-of-the-art designs
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
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