Baker JG.The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. Br J Pharmacol 144:317-322

Institute of Cell Signalling, C Floor Medical School, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.
British Journal of Pharmacology (Impact Factor: 4.99). 03/2005; 144(3):317-22. DOI: 10.1038/sj.bjp.0706048
Source: PubMed

ABSTRACT Beta-adrenoceptor antagonists ("beta-blockers") are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at beta1-adrenoceptors), while the worrisome side effects of bronchospasm result from airway beta2-adrenoceptor blockade. The aim of this study was to determine the selectivity of beta-antagonists for the human beta-adrenoceptor subtypes. (3)H-CGP 12177 whole cell-binding studies were undertaken in CHO cell lines stably expressing either the human beta1-, beta2- or the beta3-adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background. In this study, the selectivity of well-known subtype-selective ligands was clearly demonstrated: thus, the selective beta1 antagonist CGP 20712A was 501-fold selective over beta2 and 4169-fold selective over beta3; the beta2-selective antagonist ICI 118551 was 550- and 661-fold selective over beta1 and beta3, respectively, and the selective beta3 compound CL 316243 was 10-fold selective over beta2 and more than 129-fold selective over beta1. Those beta2-adrenoceptor agonists used clinically for the treatment of asthma and COPD were beta2 selective: 29-, 61- and 2818-fold for salbutamol, terbutaline and salmeterol over beta1, respectively. There was little difference in the affinity of these ligands between beta1 and beta3 adrenoceptors. The clinically used beta-antagonists studied ranged from bisoprolol (14-fold beta1-selective) to timolol (26-fold beta2-selective). However, the majority showed little selectivity for the beta1- over the beta2-adrenoceptor, with many actually being more beta2-selective. This study shows that the beta1/beta2 selectivity of most clinically used beta-blockers is poor in intact cells, and that some compounds that are traditionally classed as "beta1-selective" actually have higher affinity for the beta2-adrenoceptor. There is therefore considerable potential for developing more selective beta-antagonists for clinical use and thereby reducing the side-effect profile of beta-blockers.

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    • "The effects of forskolin and butaprost were not additive to that of the β 2 adrenoceptor agonist olodaterol (Fig. 3b). Finally, the selective β 2 -adrenoceptor antagonist ICI 118551 (Baker 2005) prevented the stimulatory (Fig. 4) as well as the inhibitory (Fig. 6) effects of the β 2 -adrenoceptor agonists but did not affect the upregulation caused by forskolin (Fig. 4). After inhibition of de novo RNA synthesis by actinomycin D, the stimulatory effect of formoterol was abolished, whereas in presence of cycloheximide, which by its own caused already a marked increase in β 2 -adrenoceptor mRNA, formoterol elicited a further marked increase (Fig. 5), resulting in an almost 9-fold increase when cycloheximide and the β 2 -adrenoceptor agonist were concomitantly present. "
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    ABSTRACT: Based on their bronchodilatory effect, β2-adrenoceptor agonists constitute essential elements in the treatment of bronchial asthma and COPD. As treatment with β2-adrenoceptor agonists has been associated with worsening of airway hyper-reactivity, possibly because of loss of β-adrenoceptor function, molecular mechanism of the regulation of β2-adrenoceptor expression were studied. MRC-5 human lung fibroblasts were cultured in absence or presence of test substances followed by β2-adrenoceptor messenger RNA (mRNA) determination by qPCR. After inhibition of mRNA synthesis by actinomycin D, β2-adrenoceptor mRNA decreased with a half-life of 23 min, whereas inhibition of protein synthesis by cycloheximide caused an about 5- and 6-fold increase within 1.5 and 4 h, respectively. β2-Adrenoceptor mRNA was increased by about 100 % after 1 h exposure to formoterol or olodaterol but decreased by about 60 % after 4 h agonist exposure. Both effects of β2-adrenoceptor agonists were mimicked by forskolin, a direct activator of adenylyl cyclase and cholera toxin, which stimulates adenylyl cyclase by permanent activation of Gs. β2-Adrenoceptor agonist-induced upregulation of β2-adrenoceptor mRNA was blocked by the β2-adrenoceptor antagonist ICI 118551 and prevented by actinomycin D, but not by cycloheximide. Moreover, in presence of cycloheximide, β2-adrenoceptor agonist-induced reduction in β2-adrenoceptor mRNA was converted into stimulation, resulting in a more than 10-fold increase. In conclusion, expression of β2-adrenoceptors in human lung fibroblasts is highly regulated at transcriptional level. The β2-adrenoceptor gene is under strong inhibitory control of short-living suppressor proteins. β2-Adrenoceptor activation induces via adenylyl cyclase - cyclic adenosine monophosphate (cAMP) signaling a rapid in onset direct stimulation of the β2-adrenoceptor gene transcription, an effect opposed by a delayed upregulation of inhibitory factors.
    Archiv für Experimentelle Pathologie und Pharmakologie 04/2014; 387(7). DOI:10.1007/s00210-014-0971-7 · 2.36 Impact Factor
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    • "Hence, we examined whether epinephrine-stress induced PMN trafficking to wound sites and impaired wound healing was mediated by a β 2 AR-dependent mechanism. We therefore evaluated the role of β 2 ARdependent signaling on PMN trafficking and wound size using a pharmacological agonist (salbutamol) and antagonist (ICI 118,551) specific for the β 2 AR (Baker, 2005) in wounded EGFP-lys-mice. Treatment of mice with salbutamol (3 mg/kg/day) resulted in a delay in wound healing and prolonged trafficking of PMN to the wound, equivalent to that induced by epinephrine-stress (Figs.3a and 3b). "
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    ABSTRACT: Stress-induced hormones can alter the inflammatory response to tissue injury, however, the precise mechanism by which epinephrine influences inflammatory response and wound healing is not well defined. Here we demonstrate that epinephrine alters the neutrophil (PMN)-dependent inflammatory response to a cutaneous wound. Using non-invasive real-time imaging of genetically-tagged PMNs in a murine skin wound, chronic, epinephrine-mediated stress was modeled by sustained delivery of epinephrine. Prolonged systemic exposure of epinephrine resulted in persistent PMN trafficking to the wound site via an IL-6 mediated mechanism, and this in turn impaired wound repair. Further, we demonstrate that β2 adrenergic receptor-dependent activation of pro-inflammatory macrophages is critical for epinephrine-mediated IL-6 production. This study expands our current understanding of stress hormone-mediated impairment of wound healing and provides an important mechanistic link to explain how epinephrine stress exacerbates inflammation via increased number and lifetime of PMNs.Journal of Investigative Dermatology accepted article preview online, 11 October 2013. doi:10.1038/jid.2013.415.
    Journal of Investigative Dermatology 10/2013; 134(3). DOI:10.1038/jid.2013.415 · 6.37 Impact Factor
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    • "It has, however, to be noted that another study group using the same disease model, but the 129S6/SvEvTac mouse strain and different methods of evaluating retinopathy, did not show any effect of propranolol on VEGF expression and on pathologic neovascularization (Chen et al. 2012). Moreover, propranolol has only low affinity for β 3 -adrenoceptors (Baker 2005), indicating that these data may be explained by β 1 -or β 2 adrenoceptor engagement. Thus, a reevaluation of the findings in this ischemic model is needed. "
    Archiv für Experimentelle Pathologie und Pharmakologie 01/2013; 386(4). DOI:10.1007/s00210-013-0835-6 · 2.36 Impact Factor
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