β-Blockers in Metabolic and Endocrine Perspectives

2020 ◽  
Vol 6 (1) ◽  
pp. 62-68
Author(s):  
Mohamad Arif ◽  
Nur Anna Chalimah Sadyah
Keyword(s):  
Adrenergic Receptor ◽  
Receptor Activation ◽  
Metabolic Effects ◽  
Protein Activation ◽  
Thyroid Hormone Metabolism ◽  
G Protein Activation ◽  
Receptor Blockers ◽  
Initial Generation ◽  
Β Blocker ◽  
Β Blockers

Catecholamine, through α-adrenergic receptor and β-adrenergic receptor activation, plays many roles in body’s physiological and pathophysiologicalprocesses. β-adrenergic receptor has different effect pursuant to receptor type, receptor location and G protein activation in the receptor. Beta receptor blockers (β-blockers) are a drug commonly used for cardiovascular disease. There are 3 different generations of β-blockers. In addition to their great advantages in cardiovascular, β-blockers also have metabolic and endocrine effects. β-blocker may influence sugar and insulin, fat, melatonin, cancer, blood uric acid and thyroid hormone metabolism. These metabolic effects may be disadvantageous, which mostly takes place with initial generation β-blockers. Third generation β-blockers do not show disadvantageous metabolic effect. However, early generation β-blockers may be advantageous in certain condition.

scholarly journals The role of nebivolol in the management of hypertensive patients: from pharmacological profile to treatment guidelines

2021 ◽  
Author(s):  
Claudio Ferri
Keyword(s):  
Treatment Guidelines ◽  
Metabolic Effects ◽  
Third Generation ◽  
Pharmacological Profile ◽  
Good Tolerability ◽  
Hypertensive Patients ◽  
Β Blocker ◽  
Β Blockers ◽  
Treatment Step

According to the most recent international guidelines, β-blockers maintain a central role in the management of hypertension, being recommended at any treatment step when there is a specific indication, such as heart failure, angina, postacute myocardial infarction, atrial fibrillation or pregnancy. However, β-blockers are not a homogeneous class: individual molecules differ in terms of pharmacological and clinical profile and are therefore suitable for different patient subtypes. In particular nebivolol, a third generation β1-selective β-blocker with vasodilating properties, neutral metabolic effects and good tolerability, proved to have advantages over other β-blockers, which makes the drug suitable in a wide variety of hypertensive patients with or without comorbidities.

scholarly journals Agonist-induced formation of unproductive receptor-G12complexes

2020 ◽  
Vol 117 (35) ◽  
pp. 21723-21730
Author(s):  
Najeah Okashah ◽  
Shane C. Wright ◽  
Kouki Kawakami ◽  
Signe Mathiasen ◽  
Joris Zhou ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Receptor Activation ◽  
Receptor Internalization ◽  
Protein Association ◽  
Protein Activation ◽  
Protein Receptor ◽  
G Protein Activation

G proteins are activated when they associate with G protein-coupled receptors (GPCRs), often in response to agonist-mediated receptor activation. It is generally thought that agonist-induced receptor-G protein association necessarily promotes G protein activation and, conversely, that activated GPCRs do not interact with G proteins that they do not activate. Here we show that GPCRs can form agonist-dependent complexes with G proteins that they do not activate. Using cell-based bioluminescence resonance energy transfer (BRET) and luminescence assays we find that vasopressin V2receptors (V2R) associate with both Gsand G12heterotrimers when stimulated with the agonist arginine vasopressin (AVP). However, unlike V2R-Gscomplexes, V2R-G12complexes are not destabilized by guanine nucleotides and do not promote G12activation. Activating V2R does not lead to signaling responses downstream of G12activation, but instead inhibits basal G12-mediated signaling, presumably by sequestering G12heterotrimers. Overexpressing G12inhibits G protein receptor kinase (GRK) and arrestin recruitment to V2R and receptor internalization. Formyl peptide (FPR1 and FPR2) and Smoothened (Smo) receptors also form complexes with G12that are insensitive to nucleotides, suggesting that unproductive GPCR-G12complexes are not unique to V2R. These results indicate that agonist-dependent receptor-G protein association does not always lead to G protein activation and may in fact inhibit G protein activation.

Abstract P328: β-Blockers Can Enhance Short-Term Receptor Sensitivity in Silico and in Vitro

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Robert Amanfu ◽  
Jeffrey Saucerman
Keyword(s):  
Signaling Pathway ◽  
Adrenergic Receptor ◽  
Acute Stress ◽  
Receptor Signaling ◽  
Receptor Model ◽  
Receptor Sensitivity ◽  
Binding Studies ◽  
Receptor Signaling Pathway ◽  
Β Blocker ◽  
Β Blockers

A key feature of heart failure is the chronic elevation of circulating catecholamines which desensitizes the β-adrenergic receptor signaling pathway, rendering patients incapable of increasing cardiac output in response to acute stress (eg. exercise). β-adrenergic receptor blockers (β-blockers) are commonly used to treat this condition, but precisely how they work is still controversial and poorly understood. Two opposing theories are that β-blockers work by 1) blocking the harmful consequences of chronic signaling or 2) paradoxically increasing receptor sensitivity. To investigate whether β-blockers function by increasing receptor sensitivity, we extended a published computational model of the β 1 -adrenergic receptor signaling pathway developed in our lab by using a ternary complex receptor module. This receptor model includes the spontaneous switching between the active and inactive conformations of the receptor that is crucial for accurate representation of β-blockers. Parameter values were determined from literature to model 11 agonists and 10 β-blockers. The new receptor model was validated against ligand binding studies and adenylyl cyclase assays from literature. Chronic and acute stresses were modeled as low and high (100X greater) concentrations of the agonist isoproterenol. Simulations indicate that when the β-blocker propranolol is present during chronic stress, cAMP levels are increased upon application of an acute stress, elevating intracellular calcium levels and contractility. This suggests that in addition to blocking the harmful consequences of chronic signaling, β-blockers may sensitize the response to acute stress. Preliminary data from calcium imaging experiments in isolated cardiac ventricular cells confirm this prediction. Simulations with a range of commonly used β-blockers indicate that individual drugs differ significantly in their ability to enhance receptor sensitivity. In addition, simulation of the Gly389Arg polymorphism suggests that the Arg389 variant has reduced sensitization to acute stress in the presence of propranolol. These simulations are a first step towards evaluating personalized β-blocker therapies with computational models.

scholarly journals Use of β-Blockers, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Risk of Breast Cancer Recurrence: A Danish Nationwide Prospective Cohort Study

2013 ◽  
Vol 31 (18) ◽  
pp. 2265-2272 ◽  
Author(s):  
Gitte Vrelits Sørensen ◽  
Patricia A. Ganz ◽  
Steven W. Cole ◽  
Lars A. Pedersen ◽  
Henrik Toft Sørensen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Angiotensin Converting Enzyme ◽  
Ace Inhibitor ◽  
Cancer Recurrence ◽  
Breast Cancer Recurrence ◽  
Converting Enzyme ◽  
Receptor Selectivity ◽  
Receptor Blockers ◽  
Β Blocker ◽  
Β Blockers

Purpose To estimate associations between use of β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort. Patients and Methods We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. β-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year. Results Compared with never users, users of any β-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual β-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3). Conclusion Our data do not support the hypothesis that β-blockers attenuate breast cancer recurrence risk.

scholarly journals Induction of Cardiac Fibrosis by β-Blocker in G Protein-independent and G Protein-coupled Receptor Kinase 5/β-Arrestin2-dependent Signaling Pathways

2012 ◽  
Vol 287 (42) ◽  
pp. 35669-35677 ◽  
Author(s):  
Michio Nakaya ◽  
Satsuki Chikura ◽  
Kenji Watari ◽  
Natsumi Mizuno ◽  
Koji Mochinaga ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Cardiac Fibrosis ◽  
Receptor Kinase ◽  
Biased Agonism ◽  
Β Blocker ◽  
Β Blockers ◽  
G Protein Coupled ◽  
Dependent Pathway

G-protein coupled receptors (GPCRs) have long been known as receptors that activate G protein-dependent cellular signaling pathways. In addition to the G protein-dependent pathways, recent reports have revealed that several ligands called “biased ligands” elicit G protein-independent and β-arrestin-dependent signaling through GPCRs (biased agonism). Several β-blockers are known as biased ligands. All β-blockers inhibit the binding of agonists to the β-adrenergic receptors. In addition to β-blocking action, some β-blockers are reported to induce cellular responses through G protein-independent and β-arrestin-dependent signaling pathways. However, the physiological significance induced by the β-arrestin-dependent pathway remains much to be clarified in vivo. Here, we demonstrate that metoprolol, a β1-adrenergic receptor-selective blocker, could induce cardiac fibrosis through a G protein-independent and β-arrestin2-dependent pathway. Metoprolol, a β-blocker, increased the expression of fibrotic genes responsible for cardiac fibrosis in cardiomyocytes. Furthermore, metoprolol induced the interaction between β1-adrenergic receptor and β-arrestin2, but not β-arrestin1. The interaction between β1-adrenergic receptor and β-arrestin2 by metoprolol was impaired in the G protein-coupled receptor kinase 5 (GRK5)-knockdown cells. Metoprolol-induced cardiac fibrosis led to cardiac dysfunction. However, the metoprolol-induced fibrosis and cardiac dysfunction were not evoked in β-arrestin2- or GRK5-knock-out mice. Thus, metoprolol is a biased ligand that selectively activates a G protein-independent and GRK5/β-arrestin2-dependent pathway, and induces cardiac fibrosis. This study demonstrates the physiological importance of biased agonism, and suggests that G protein-independent and β-arrestin-dependent signaling is a reason for the diversity of the effectiveness of β-blockers.

Effects of β-adrenergic receptor blockers on cardiac function: a comparative study in male versus female ratsThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue).

2009 ◽  
Vol 87 (4) ◽  
pp. 310-317 ◽  
Author(s):  
Erkan Tuncay ◽  
Ali Aytac Seymen ◽  
Pinar Sam ◽  
Hakan Gurdal ◽  
Belma Turan
Keyword(s):  
Adrenergic Receptor ◽  
Left Ventricular ◽  
Female Rats ◽  
Male Rats ◽  
Clinical Effects ◽  
Male And Female ◽  
Male And Female Rats ◽  
Receptor Blockers ◽  
Propranolol Treatment ◽  
Β Blockers

In heart disease, differences exist between women and men with respect to the impact of risk factors, symptoms, and therapeutic responses. The use of β-adrenergic receptor blockers is now well established in the treatment of mild and moderate systolic heart failure. Although there are significant differences among agents, their clinical effects are predictable. To address the question of sex disparities in the heart, however, we investigated the effect of treatment with the nonselective β-blockers timolol and propranolol on mechanical and electrical function of heart preparations from male and female rats. We examined the long-term effects of intragastric treatment with timolol (5 mg/kg per day) or propranolol (25 mg/kg per day) for 7 months on the hemodynamic and intracellular action potential parameters of the heart. Chronic administration of timolol but not propranolol produced a significant increase in the baseline activity of the left ventricular developed pressure (LVDP) in both male and female rats with no significant effect on the left ventricular end-diastolic pressure. Timolol or propranolol treatment of male rats and timolol but not propranolol treatment of female rats induced significant shortening in the repolarization phases of action potentials recorded from left ventricular papillary muscle strips of the hearts. The responses of LVDP to β-adrenergic stimulation were similar in timolol- or propranolol-treated or untreated male rats. On the other hand, timolol treatment markedly increased, and propranolol treatment significantly decreased, the responses of increase in LVDP in female rats. Our results suggest that although treatment with β-blockers for 7 months confirmed the role of the β-adrenergic pathway in heart function, there are marked differences in the effects of individual β-blockers on heart physiology. Sex differences should be taken into consideration when using β-blockers during experimental studies and clinical therapy.

The C-terminal of the α1b-adreneroceptor is a key determinant for its structure integrity and biological functions

2021 ◽  
Author(s):  
Ying Liu ◽  
Yu-Ting Shao ◽  
Richard Ward ◽  
Li Ma ◽  
Hao-Xin Gui ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Phosphorylation Sites ◽  
Biological Functions ◽  
Protein Activation ◽  
G Protein Activation ◽  
Signaling Function ◽  
Signal Changes ◽  
C 30 ◽  
C 50

Abstract The C-terminal of GPCRs is now recognized as being important for G protein activation and signaling function. To detect the role of C-terminal tail in receptor activation, we used the α1b-AR, which has a long C-terminal of 164 amino acids. We constructed the intramolecular FRET sensors, in which the C-terminal was truncated to 10 (∆C-10), 20 (∆C-20), 30 (∆C-30), 50 (∆C-50), 70 (∆C-70) or 90 (∆C-90). The truncated mutants of ∆C-10, ∆C-20 or ∆C-30 cannot induce FRET signal changes and downstream ERK1/2 phosphorylation. However, the truncated mutants of ∆C-50, ∆C-70 or ∆C-90 induce significant FRET signal changes and downstream ERK1/2 phosphorylation, especially ∆C-90. This is particularly true in the case of the ∆C-90, ∆C-70, or ∆C-50 which retained the potential phosphorylation sites (Ser401, Ser404, Ser408 or Ser410). The ∆C-90 showed an increase in agonist-induced FRET signal changes and ERK1/2 phosphorylation in PKC- or endocytosis-dependent and EGFR-, src- or β-arrestin 2-independent.

Phe303in TMVI of the α1B-Adrenergic Receptor Is a Key Residue Coupling TM Helical Movements to G-protein Activation†

Biochemistry ◽  
2002 ◽  
Vol 41 (2) ◽  
pp. 588-596 ◽  
Author(s):  
Songhai Chen ◽  
Fang Lin ◽  
Ming Xu ◽  
Robert M. Graham
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
Protein Activation ◽  
G Protein Activation
Sign in / Sign up

Export Citation Format

Share Document