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Robert J Lefkowitz - One of the best experts on this subject based on the ideXlab platform.
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essential role of Beta Adrenergic Receptor kinase 1 in cardiac development and function
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Mohamed Jaber, Robert J Lefkowitz, Marc G Caron, Walter J Koch, Howard A Rockman, Richard A Bond, Bradley R Smith, Kathleen K Sulik, John Ross, Bruno GirosAbstract:The Beta-Adrenergic Receptor kinase 1 (Beta ARK1) is a member of the G protein-coupled Receptor kinase (GRK) family that mediates the agonist-dependent phosphorylation and desensitization of G protein-coupled Receptors. We have cloned and disrupted the Beta ARK1 gene in mice by homologous recombination. No homozygote Beta ARK1-/- embryos survive beyond gestational day 15.5. Prior to gestational day 15.5, Beta ARK1-/- embryos display pronounced hypoplasia of the ventricular myocardium essentially identical to the "thin myocardium syndrome" observed upon gene inactivation of several transcription factors (RXR alpha, N-myc, TEF-1, WT-1). Lethality in Beta ARK1-/- embryos is likely due to heart failure as they exhibit a > 70% decrease in cardiac ejection fraction determined by direct in utero intravital microscopy. These results along with the virtual absence of endogenous GRK activity in Beta ARK1-/- embryos demonstrate that Beta ARK1 appears to be the predominant GRK in early embryogenesis and that it plays a fundamental role in cardiac development.
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cardiac function in mice overexpressing the Beta Adrenergic Receptor kinase or a Beta ark inhibitor
Science, 1995Co-Authors: Walter J Koch, Howard A Rockman, Philippe Samama, Raeann Hamilton, Richard A Bond, Carmelo A Milano, Robert J LefkowitzAbstract:Transgenic mice were created with cardiac-specific overexpression of the Beta-Adrenergic Receptor kinase-1 (Beta ARK1) or a Beta ARK inhibitor. Animals overexpressing Beta ARK1 demonstrated attenuation of isoproterenol-stimulated left ventricular contractility in vivo, dampening of myocardial adenylyl cyclase activity, and reduced functional coupling of Beta-Adrenergic Receptors. Conversely, mice expressing the Beta ARK inhibitor displayed enhanced cardiac contractility in vivo with or without isoproterenol. These animals demonstrate the important role of Beta ARK in modulating in vivo myocardial function. Because increased amounts of Beta ARK1 and diminished cardiac Beta-Adrenergic responsiveness characterize heart failure, these animals may provide experimental models to study the role of Beta ARK in heart disease.
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pleckstrin homology domain mediated membrane association and activation of the Beta Adrenergic Receptor kinase requires coordinate interaction with g Beta gamma subunits and lipid
Journal of Biological Chemistry, 1995Co-Authors: Julie A Pitcher, Kazushige Touhara, E S Payne, Robert J LefkowitzAbstract:The pleckstrin homology (PH) domain is an approximately 100-amino-acid region of sequence homology present in numerous proteins of diverse functions, which forms a discrete structural module. Several ligands capable of binding to PH domain-containing proteins have been identified including phosphatidylinositol 4,5-bisphosphate (PIP2) and the G Beta gamma subunits of heterotrimeric G proteins (G Beta gamma), which bind to the amino and carboxyl termini of the PH domain, respectively. Here we report that the binding of G Beta gamma and lipid to the PH domain of the Beta-Adrenergic Receptor kinase (Beta ARK) synergistically enhances agonist-dependent Receptor phosphorylation and that both PH domain-binding ligands are required for membrane association of the kinase. PIP2 and to a lesser extent phosphatidylinositol 4-phosphate, phosphatidylinositol, and phosphatidic acid were the only lipids tested capable, in the presence of G Beta gamma, of enhancing Beta ARK activity. In contrast, the Km and Vmax for phosphorylation of a soluble Beta ARK substrate (casein) was not altered in either the presence or absence of G Beta gamma and/or PIP2. A fusion protein of the Beta ARK containing an intact PH domain inhibits G Beta gamma/PIP2-dependent Beta ARK activity. In contrast, a mutant fusion protein in which a tryptophan residue, invariant in all PH domain sequences, is mutated to alanine shows no inhibitory activity. The requirement for the simultaneous presence of two PH domain binding ligands represents a previously unappreciated mechanism for effecting membrane localization of a protein and may have relevance to other PH domain-containing proteins.
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the binding site for the Beta gamma subunits of heterotrimeric g proteins on the Beta Adrenergic Receptor kinase
Journal of Biological Chemistry, 1993Co-Authors: Walter J Koch, W. C. Stone, James Inglese, Robert J LefkowitzAbstract:Abstract The Beta gamma subunits of heterotrimeric G proteins play important roles in regulating Receptor-stimulated signal transduction processes. Recently appreciated among these is their role in the signaling events that lead to the phosphorylation and subsequent desensitization of muscarinic cholinergic (Haga, K., and Haga, T. (1992) J. Biol. Chem. 267, 2222-2227) and Beta-Adrenergic (Pitcher, J. A., Inglese, J., Higgins, J. B., Arriza, J. L., Casey, P. J., Kim, C., Benovic, J. L., Kwatra, M. M., Caron, M. G., and Lefkowitz, R. J. (1992) Science 257, 1264-1267) Receptors. Beta gamma mediates the membrane targeting of the Beta-Adrenergic Receptor kinase (Beta ARK), in response to Receptor activation, through a specific Beta ARK-Beta gamma interaction. This process utilizes the membrane-anchoring properties of the isoprenylated gamma subunit of Beta gamma. In the present study, we have employed three distinct approaches to identify the region within the carboxyl terminus of Beta ARK which binds Beta gamma and thereby results in membrane translocation. We studied the ability of Beta gamma to enhance the enzymatic activity of a series of truncated mutants of bovine Beta ARK1, the ability of glutathione S-transferase fusion proteins containing various lengths of the carboxyl terminus of Beta ARK to bind Beta gamma subunits, and the ability of synthetic peptides comprised of Beta ARK sequences to inhibit Beta gamma activation of Beta ARK1. We find that the minimal Beta gamma binding domain of Beta ARK is localized to a 125-amino acid residue stretch, the distal end of which is located 19 residues from the carboxyl terminus. A single 28-mer peptide (Trp643 to Ser670) derived from this sequence effectively inhibited Beta gamma activation of Beta ARK1, with an IC50 of 76 microM. The identification of this "Beta gamma binding domain" on Beta ARK and the development of peptide inhibitors provide important tools for the study of G protein-coupled Receptor desensitization, as well as for the investigation of Beta gamma activation of other G protein-effector systems.
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overexpression of Beta arrestin and Beta Adrenergic Receptor kinase augment desensitization of Beta 2 Adrenergic Receptors
Journal of Biological Chemistry, 1993Co-Authors: S Pippig, Robert J Lefkowitz, Marc G Caron, S Andexinger, Kiefer W Daniel, M Puzicha, Martin J LohseAbstract:Abstract Receptor-specific or homologous desensitization of Beta 2-Adrenergic Receptors is thought to be effected via phosphorylation of the Receptor by the Beta-Adrenergic Receptor kinase (Beta ARK), followed by binding of Beta-arrestin. We have generated stably transfected Chinese hamster ovary cell lines overexpressing either of the two regulatory proteins and also expressing low or high levels of Beta 2-Adrenergic Receptors (approximately 80 and approximately 600 fmol/mg of membrane protein). In these cells, we studied the process of desensitization induced by the Beta-Adrenergic Receptor agonist isoproterenol. In cells expressing high levels of Beta 2-Adrenergic Receptors, desensitization to high concentrations of isoproterenol (previously shown to be mediated by both Beta ARK and protein kinase A) amounted to approximately 50% in control cells, approximately 80% in Beta ARK-overexpressing cells, and approximately 90% in Beta-arrestin-overexpressing cells. In cells expressing low levels of Beta 2-Adrenergic Receptors, these values were approximately 50, approximately 60, and approximately 60%, respectively. Desensitization to low concentrations of isoproterenol (previously shown to be essentially protein kinase A-mediated and not Receptor-specific, i.e. heterologous) was not affected by overexpression of either Beta ARK or Beta-arrestin. These data suggest that in cells expressing high levels of Beta 2-Adrenergic Receptors, Beta-arrestin and Beta ARK become limiting for homologous Receptor desensitization. They provide further support for the involvement of these two proteins in the regulation of Beta 2-Adrenergic Receptor function.
David L Hare - One of the best experts on this subject based on the ideXlab platform.
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A nurse-led up-titration clinic improves chronic heart failure optimization of Beta-Adrenergic Receptor blocking therapy--a randomized controlled trial.
BMC Research Notes, 2014Co-Authors: Andrea Driscoll, Piyush M. Srivastava, Jackie Gibcus, Deidre Toia, David L HareAbstract:Beta-Adrenergic blockade has been shown to improve left ventricular function, reduce hospital admissions and improve survival in chronic heart failure with reduced ejection fraction (HFrEF), with mortality reduction starting early after Beta-Adrenergic Receptor blocker initiation and being dose-related. The aim of this pilot study was to determine the effectiveness of a nurse-led titration clinic in improving the time required for patients to reach optimal doses of the Beta-Adrenergic Receptor blocking agents. We conducted a prospective pilot randomized controlled trial. Twenty eight patients with CHF were randomized to optimisation of Beta-Adrenergic Receptor blocker therapy over six months by either a nurse-led titration (NLT) clinic, led by a nurse specialist with the support of a cardiologist in a CHF clinic, or by their primary care physician (usual care (UC)). The primary endpoint was time to maximal Beta-Adrenergic Receptor blocker dose. The secondary end-point was the proportion of patients reaching the target dose of Beta-Adrenergic Receptor blocker by six months. The patients were predominantly men (72%), age 67 ± 16 years; New York Heart Association (NYHA) functional class I (32%), II (44%) and III (20%); baseline left ventricular ejection fraction 33 ± 10%, and a low mean Charlson co-morbidity score of 2.5 ± 1.4. The time to maximum dose was shorter in the NLT group compared to the UC group (90 ± 14 vs 166 ± 8 days, p
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a nurse led up titration clinic improves chronic heart failure optimization of Beta Adrenergic Receptor blocking therapy a randomized controlled trial
BMC Research Notes, 2014Co-Authors: Andrea Driscoll, Piyush M. Srivastava, Jackie Gibcus, Deidre Toia, David L HareAbstract:Beta-Adrenergic blockade has been shown to improve left ventricular function, reduce hospital admissions and improve survival in chronic heart failure with reduced ejection fraction (HFrEF), with mortality reduction starting early after Beta-Adrenergic Receptor blocker initiation and being dose-related. The aim of this pilot study was to determine the effectiveness of a nurse-led titration clinic in improving the time required for patients to reach optimal doses of the Beta-Adrenergic Receptor blocking agents. We conducted a prospective pilot randomized controlled trial. Twenty eight patients with CHF were randomized to optimisation of Beta-Adrenergic Receptor blocker therapy over six months by either a nurse-led titration (NLT) clinic, led by a nurse specialist with the support of a cardiologist in a CHF clinic, or by their primary care physician (usual care (UC)). The primary endpoint was time to maximal Beta-Adrenergic Receptor blocker dose. The secondary end-point was the proportion of patients reaching the target dose of Beta-Adrenergic Receptor blocker by six months. The patients were predominantly men (72%), age 67 ± 16 years; New York Heart Association (NYHA) functional class I (32%), II (44%) and III (20%); baseline left ventricular ejection fraction 33 ± 10%, and a low mean Charlson co-morbidity score of 2.5 ± 1.4. The time to maximum dose was shorter in the NLT group compared to the UC group (90 ± 14 vs 166 ± 8 days, p < 0.0005). At six months, in the NLT group there were nine patients (82%) on high dose and one patient (9%) on low dose Beta-Adrenergic Receptor blocker compared to the UC group with five (42%) patients reaching maximum dose and five (42%) patients on low dose (p = 0.04). The patients allocated to the NLT group also had significantly less worsening of depression between baseline and six months (p = 0.006). A NLT clinic improves optimisation of Beta-Adrenergic Receptor blocker therapy through increasing the proportion of patients reaching maximal dose and facilitating rapid up-titration of Beta-Adrenergic Receptor blocker agents in patients with chronic HFrEF. Australian Clinical Trials Registry ( ACTRN012606000383561 ).
Andrea Driscoll - One of the best experts on this subject based on the ideXlab platform.
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A nurse-led up-titration clinic improves chronic heart failure optimization of Beta-Adrenergic Receptor blocking therapy--a randomized controlled trial.
BMC Research Notes, 2014Co-Authors: Andrea Driscoll, Piyush M. Srivastava, Jackie Gibcus, Deidre Toia, David L HareAbstract:Beta-Adrenergic blockade has been shown to improve left ventricular function, reduce hospital admissions and improve survival in chronic heart failure with reduced ejection fraction (HFrEF), with mortality reduction starting early after Beta-Adrenergic Receptor blocker initiation and being dose-related. The aim of this pilot study was to determine the effectiveness of a nurse-led titration clinic in improving the time required for patients to reach optimal doses of the Beta-Adrenergic Receptor blocking agents. We conducted a prospective pilot randomized controlled trial. Twenty eight patients with CHF were randomized to optimisation of Beta-Adrenergic Receptor blocker therapy over six months by either a nurse-led titration (NLT) clinic, led by a nurse specialist with the support of a cardiologist in a CHF clinic, or by their primary care physician (usual care (UC)). The primary endpoint was time to maximal Beta-Adrenergic Receptor blocker dose. The secondary end-point was the proportion of patients reaching the target dose of Beta-Adrenergic Receptor blocker by six months. The patients were predominantly men (72%), age 67 ± 16 years; New York Heart Association (NYHA) functional class I (32%), II (44%) and III (20%); baseline left ventricular ejection fraction 33 ± 10%, and a low mean Charlson co-morbidity score of 2.5 ± 1.4. The time to maximum dose was shorter in the NLT group compared to the UC group (90 ± 14 vs 166 ± 8 days, p
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a nurse led up titration clinic improves chronic heart failure optimization of Beta Adrenergic Receptor blocking therapy a randomized controlled trial
BMC Research Notes, 2014Co-Authors: Andrea Driscoll, Piyush M. Srivastava, Jackie Gibcus, Deidre Toia, David L HareAbstract:Beta-Adrenergic blockade has been shown to improve left ventricular function, reduce hospital admissions and improve survival in chronic heart failure with reduced ejection fraction (HFrEF), with mortality reduction starting early after Beta-Adrenergic Receptor blocker initiation and being dose-related. The aim of this pilot study was to determine the effectiveness of a nurse-led titration clinic in improving the time required for patients to reach optimal doses of the Beta-Adrenergic Receptor blocking agents. We conducted a prospective pilot randomized controlled trial. Twenty eight patients with CHF were randomized to optimisation of Beta-Adrenergic Receptor blocker therapy over six months by either a nurse-led titration (NLT) clinic, led by a nurse specialist with the support of a cardiologist in a CHF clinic, or by their primary care physician (usual care (UC)). The primary endpoint was time to maximal Beta-Adrenergic Receptor blocker dose. The secondary end-point was the proportion of patients reaching the target dose of Beta-Adrenergic Receptor blocker by six months. The patients were predominantly men (72%), age 67 ± 16 years; New York Heart Association (NYHA) functional class I (32%), II (44%) and III (20%); baseline left ventricular ejection fraction 33 ± 10%, and a low mean Charlson co-morbidity score of 2.5 ± 1.4. The time to maximum dose was shorter in the NLT group compared to the UC group (90 ± 14 vs 166 ± 8 days, p < 0.0005). At six months, in the NLT group there were nine patients (82%) on high dose and one patient (9%) on low dose Beta-Adrenergic Receptor blocker compared to the UC group with five (42%) patients reaching maximum dose and five (42%) patients on low dose (p = 0.04). The patients allocated to the NLT group also had significantly less worsening of depression between baseline and six months (p = 0.006). A NLT clinic improves optimisation of Beta-Adrenergic Receptor blocker therapy through increasing the proportion of patients reaching maximal dose and facilitating rapid up-titration of Beta-Adrenergic Receptor blocker agents in patients with chronic HFrEF. Australian Clinical Trials Registry ( ACTRN012606000383561 ).
Martin J Lohse - One of the best experts on this subject based on the ideXlab platform.
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Expression of Beta-arrestins and Beta-Adrenergic Receptor kinases in the failing human heart.
Circulation research, 1994Co-Authors: Martin Ungerer, E Erdmann, M Bohm, G. Parruti, M Puzicha, A Deblasi, Martin J LohseAbstract:The Beta-Adrenergic Receptor system of the failing human heart is markedly desensitized. We have recently postulated that this desensitization may in part be caused by an increase in Beta-Adrenergic Receptor kinase (Beta ARK) expression. Beta ARK is thought to effect desensitization by acting in concert with an inhibitor protein, called Beta-arrestin. Two isoforms have been identified both for Beta ARK and for Beta-arrestin. In the present study, we have investigated the expression of the individual isoforms of Beta-arrestin and of Beta ARK in left ventricles from failing and control human hearts. mRNAs for all four proteins, Beta-arrestin-1, Beta-arrestin-2, Beta ARK-1, and Beta ARK-2, were identified in human heart. Quantitation by reverse-transcription polymerase chain reactions showed that in heart failure there were no changes of the mRNA levels for Beta-arrestin-1 and Beta-arrestin-2, a slight (< 50%) increase of the mRNA for Beta ARK-2, and a threefold increase for Beta ARK-1 mRNA. At the protein level, Beta-arrestin-1 was readily detected by Western blotting in human heart. Its absolute values were approximately 350 fmol/mg cytosolic protein, and its expression was not changed in heart failure. Beta-Arrestin-2 levels were too low to be detectable using the same methods. Beta ARK levels as determined by enzymatic activity were approximately 20 fmol/mg cytosolic protein (Beta ARK-1 plus Beta ARK-2) and thus almost 20-fold lower than those of Beta-arrestin. Beta ARK levels were increased approximately twofold in heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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overexpression of Beta arrestin and Beta Adrenergic Receptor kinase augment desensitization of Beta 2 Adrenergic Receptors
Journal of Biological Chemistry, 1993Co-Authors: S Pippig, Robert J Lefkowitz, Marc G Caron, S Andexinger, Kiefer W Daniel, M Puzicha, Martin J LohseAbstract:Abstract Receptor-specific or homologous desensitization of Beta 2-Adrenergic Receptors is thought to be effected via phosphorylation of the Receptor by the Beta-Adrenergic Receptor kinase (Beta ARK), followed by binding of Beta-arrestin. We have generated stably transfected Chinese hamster ovary cell lines overexpressing either of the two regulatory proteins and also expressing low or high levels of Beta 2-Adrenergic Receptors (approximately 80 and approximately 600 fmol/mg of membrane protein). In these cells, we studied the process of desensitization induced by the Beta-Adrenergic Receptor agonist isoproterenol. In cells expressing high levels of Beta 2-Adrenergic Receptors, desensitization to high concentrations of isoproterenol (previously shown to be mediated by both Beta ARK and protein kinase A) amounted to approximately 50% in control cells, approximately 80% in Beta ARK-overexpressing cells, and approximately 90% in Beta-arrestin-overexpressing cells. In cells expressing low levels of Beta 2-Adrenergic Receptors, these values were approximately 50, approximately 60, and approximately 60%, respectively. Desensitization to low concentrations of isoproterenol (previously shown to be essentially protein kinase A-mediated and not Receptor-specific, i.e. heterologous) was not affected by overexpression of either Beta ARK or Beta-arrestin. These data suggest that in cells expressing high levels of Beta 2-Adrenergic Receptors, Beta-arrestin and Beta ARK become limiting for homologous Receptor desensitization. They provide further support for the involvement of these two proteins in the regulation of Beta 2-Adrenergic Receptor function.
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altered expression of Beta Adrenergic Receptor kinase and Beta 1 Adrenergic Receptors in the failing human heart
Circulation, 1993Co-Authors: Martin Ungerer, John S. Elce, E Erdmann, M Bohm, Martin J LohseAbstract:BACKGROUNDIn chronic heart failure, the positive inotropic effects of Beta-Adrenergic Receptor agonists are greatly reduced, in part as a result of two alterations of the cardiac Beta-Adrenergic Receptors: loss of their function (Receptor uncoupling) and reduction of their number (downregulation). In vitro studies have shown that a major mechanism leading to Beta-Adrenergic Receptor uncoupling involves phosphorylation of the Receptors by the specific Beta-Adrenergic Receptor kinase (Beta ARK).METHODS AND RESULTSWe have therefore investigated expression of Beta ARK and Beta-Adrenergic Receptors in samples from the left ventricles of patients with dilated cardiomyopathy or ischemic cardiomyopathy and from nonfailing control ventricles. Contractile responses to Beta-Receptor stimulation were decreased in the failing hearts compared with control hearts, whereas those to forskolin and calcium remained unchanged. The messenger RNA (mRNA) levels of Beta ARK, Beta 1- and Beta 2-Receptors, and of glyceraldehyde ph...
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cloning expression and chromosomal localization of Beta Adrenergic Receptor kinase 2 a new member of the Receptor kinase family
Journal of Biological Chemistry, 1991Co-Authors: Jeffrey L. Benovic, Martin J Lohse, Marc G Caron, Jeffrey L Arriza, W. C. Stone, J J Onorato, Nancy A Jenkins, D J Gilbert, Neal G Copeland, Robert J LefkowitzAbstract:Abstract The Beta-Adrenergic Receptor kinase (Beta ARK) specifically phosphorylates the agonist-occupied form of the Beta-Adrenergic and related G protein-coupled Receptors. Structural features of this enzyme have been elucidated recently by the isolation of a cDNA that encodes bovine Beta ARK. Utilizing a catalytic domain fragment of the Beta ARK cDNA to screen a bovine brain cDNA library we have isolated a clone encoding a Beta ARK-related enzyme which we have termed Beta ARK2. Overall, this enzyme has 85% amino acid identity with Beta ARK, with the protein kinase catalytic domain having 95% identity. The ability of Beta ARK2 to phosphorylate various substrates was studied after expression in COS 7 cells. Although Beta ARK2 is essentially equiactive with Beta ARK in phosphorylating an acid-rich synthetic model peptide it was only approximately 50% as active when the substrate was the agonist-occupied Beta 2-Adrenergic Receptor and only approximately 20% as active toward light-bleached rhodopsin. As with Beta ARK, phosphorylation of the Receptor substrates by Beta ARK2 was completely stimulus dependent. RNA blot analysis with selected bovine tissues reveals an mRNA of 8 kilobases with a distribution similar to that of Beta ARK. More detailed RNA analysis using a ribonuclease protection assay in various rat tissues suggests that the Beta ARK2 message is present at much lower levels (typically 10-20%) than the Beta ARK message. In the rat the Beta ARK2 mRNA is localized predominantly in neuronal tissues although low levels are also observed in various peripheral tissues. The Beta ARK2 gene has been localized to a region of mouse chromosome 5 whereas the Beta ARK gene is localized on mouse chromosome 19. These data suggest the existence of a "family" of Receptor kinases which may serve broadly to regulate Receptor function.
Edward D Frohlich - One of the best experts on this subject based on the ideXlab platform.
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role of Beta Adrenergic Receptor blocking agents in hypertensive diseases personal thoughts as the controversy persists
Therapeutic Advances in Cardiovascular Disease, 2009Co-Authors: Edward D FrohlichAbstract:The long history of the Beta-Adrenergic Receptor blockers for the treatment of hypertension is fraught with many controversies. The first compound had severe untoward effects preventing their use until propranolol was introduced. It was found effective for treatment of angina pectoris since not all patients with hypertension responded to monotherapy with a meaningful reduction of pressure. Nevertheless, the Beta-blockers were most effective in: younger patients, especially with hyperkinetic circulation; with co-morbid diseases (e.g. coronary arterial disease with or without prior myocardial infarction); or when used with a diuretic. Subsequently with the advent of meta-analysis to evaluate more generalized experience, controversy resumed with statements made to exclude Beta-blockers for initial hypertensive therapy. Support for this argument was gained with reports of patients developing ‘dysglycemia’ with treatment. However, exclusion of any one therapeutic class for a multifactorial disease such as hype...