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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"Landiolol hydrochloride, which is launched in Japan, is an ultra-short-acting beta-blocker with a very short half-life of approximately 4 min, a high beta1/beta2 selectivity ratio of about 255, and less of a negative inotropic effect than esmolol, which provides a response at 0–2 min after administration [7–11]. The selectivity ratio of landiolol is higher than other beta blockers, such as bisoprorol (13.5), atenolol (4.7), metoprolol (2.3) , and esmolol (42.5) , and is at least about six times greater than other beta blockers. "
[Show abstract][Hide abstract]ABSTRACT: Postoperative atrial fibrillation (POAF) is one of the most common complications after cardiac surgery. Patients who develop POAF have a prolonged stay in the intensive care unit and hospital and an increased risk of postoperative stroke. Many guidelines for the management of cardiac surgery patients, therefore, recommend perioperative administration of beta-blockers to prevent and treat POAF. Landiolol is an ultra-short acting beta-blocker, and some randomized controlled trials of landiolol administration for the prevention of POAF have been conducted in Japan. This meta-analysis evaluated the effectiveness of landiolol administration for the prevention of POAF after cardiac surgery.
The Medline/PubMed and BioMed Central databases were searched for randomized controlled trials comparing cardiac surgery patients who received perioperative landiolol with a control group (saline administration, no drug administration, or other treatment). Two independent reviewers selected the studies for inclusion. Data regarding POAF and safety outcomes were extracted. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method (fixed effects model).
Six trials with a total of 560 patients were included in the meta-analysis. Landiolol administration significantly reduced the incidence of POAF after cardiac surgery (OR 0.26, 95% CI 0.17-0.40). The effectiveness of landiolol administration was similar in three groups: all patients who underwent coronary artery bypass grafting (CABG) (OR 0.27, 95% CI 0.17-0.43), patients who underwent CABG compared with a control group who received saline or nothing (OR 0.28, 95% CI 0.17-0.45), and all patients who underwent cardiac surgery compared with a control group who received saline or nothing (OR 0.27, 95% CI 0.17-0.42). Only two adverse events associated with landiolol administration were observed (2/302, 0.7%): hypotension in one patient and asthma in one patient.
Landiolol administration reduces the incidence of POAF after cardiac surgery and is well tolerated.
Full-text · Article · Apr 2014 · Advances in Therapy
"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. "
[Show abstract][Hide abstract]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.
Full-text · Article · Apr 2014 · Archiv für Experimentelle Pathologie und Pharmakologie
"Treatment with carazolol did increase the phosphorylation of S262, but not that of either S345/S346 or S355/S356. Earlier it was shown by Baker that carazolol treatment indeed stimulate intracellular accumulation of cyclic AMP in CHO cells . Forskolin significantly increased the phosphorylation of S262. "
[Show abstract][Hide abstract]ABSTRACT: Protein phosphorylation of G-protein-coupled receptors (GPCR) is central to the myriad of functions that these ubiquitous receptors perform in biology. Although readily addressable with the use of phospho-specific antibodies, analysis phosphorylation at the level of stoichiometry requires receptor isolation and advanced proteomics. We chose two key sites of potential phosphorylation of human beta2-adrenergic receptor (beta2AR residues S355 and S356) to ascertain the feasibility of applying targeted mass spectrometry to establishing the stoichiometry of the phosphorylation.
We stimulated HEK293 cells stably expressing Flag-tagged beta2AR-eGFP with 10 muM beta-adrenergic agonist (isoproterenol) and made use of proteomics and targeted mass spectrometry (MS) to quantify the molar ration of phosphorylation on S355 and S356 versus non-phosphorylated receptor in agonist-treated cells.
Phosphorylation of either S355 or S356 residue occurred only for agonist-occupied beta2AR. The results demonstrated that pS356 is the dominant site of protein phosphorylation. The abundance of the p356 was 8.6-fold more than that of pS355. Calculation of the molar ratio of phosphorylated (pS355 plus pS356) versus non-phosphorylated receptor reveals that at high occupancy of the receptor only 12.4% of the beta2AR is phosphorylated at these sites.
Application of advanced proteomics and use of the most sensitive targeted MS strategy makes possible the detection and quantification of phosphorylation of very low abundance peptide digests of beta2AR. Establishing the stoichiometry of two key sites of agonist-stimulated phosphorylation with beta2AR is an essential first-step to global analysis of the stoichiometry of GPCR phosphorylation.