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European Heart Journal Dec 2020Clinical guidelines recommend early intravenous β-blockers during ongoing myocardial infarction; however, it is unknown whether all β-blockers exert a similar...
AIMS
Clinical guidelines recommend early intravenous β-blockers during ongoing myocardial infarction; however, it is unknown whether all β-blockers exert a similar cardioprotective effect. We experimentally compared three clinically approved intravenous β-blockers.
METHODS AND RESULTS
Mice undergoing 45 min/24 h ischaemia-reperfusion (I/R) received vehicle, metoprolol, atenolol, or propranolol at min 35. The effect on neutrophil infiltration was tested in three models of exacerbated inflammation. Neutrophil migration was evaluated in vitro and in vivo by intravital microscopy. The effect of β-blockers on the conformation of the β1 adrenergic receptor was studied in silico. Of the tested β-blockers, only metoprolol ameliorated I/R injury [infarct size (IS) = 18.0% ± 0.03% for metoprolol vs. 35.9% ± 0.03% for vehicle; P < 0.01]. Atenolol and propranolol had no effect on IS. In the three exacerbated inflammation models, neutrophil infiltration was significantly attenuated only in the presence of metoprolol (60%, 50%, and 70% reductions vs. vehicle in myocardial I/R injury, thioglycolate-induced peritonitis, and lipopolysaccharide-induced acute lung injury, respectively). Migration studies confirmed the particular ability of metoprolol to disrupt neutrophil dynamics. In silico analysis indicated different intracellular β1 adrenergic receptor conformational changes when bound to metoprolol than to the other two β-blockers.
CONCLUSIONS
Metoprolol exerts a disruptive action on neutrophil dynamics during exacerbated inflammation, resulting in an infarct-limiting effect not observed with atenolol or propranolol. The differential effect of β-blockers may be related to distinct conformational changes in the β1 adrenergic receptor upon metoprolol binding. If these data are confirmed in a clinical trial, metoprolol should become the intravenous β-blocker of choice for patients with ongoing infarction.
Topics: Adrenergic beta-Antagonists; Animals; Atenolol; Humans; Inflammation; Metoprolol; Mice; Myocardial Infarction
PubMed: 33026079
DOI: 10.1093/eurheartj/ehaa733 -
Journal of Neurology, Neurosurgery, and... Oct 1979Three different beta-adrenoreceptor antagonists--propranolol, sotalol, and atenolol--were compared in a double-blind study with placebo in nine patients with essential... (Clinical Trial)
Clinical Trial Comparative Study
Three different beta-adrenoreceptor antagonists--propranolol, sotalol, and atenolol--were compared in a double-blind study with placebo in nine patients with essential tremor. All three drugs produced an equal reduction in standing pulse rate but atenolol was less effective in reducing tremor than propranolol and sotalol. These results suggest that the reduction in tremor produced by beta-adrenoreceptor antagonists is mediated by an effect on peripheral beta 2-adrenoreceptors.
Topics: Adult; Aged; Atenolol; Blood Pressure; Double-Blind Method; Female; Humans; Male; Middle Aged; Placebos; Propanolamines; Propranolol; Pulse; Sotalol; Tremor
PubMed: 512665
DOI: 10.1136/jnnp.42.10.904 -
Circulation. Cardiovascular Genetics Apr 2014The 5-amino acid (AA) signature, including isoleucine, leucine, valine, tyrosine, and phenylalanine, has been associated with incident diabetes mellitus and insulin... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The 5-amino acid (AA) signature, including isoleucine, leucine, valine, tyrosine, and phenylalanine, has been associated with incident diabetes mellitus and insulin resistance. We investigated whether this same AA signature, single-nucleotide polymorphisms in genes in their catabolic pathway, was associated with development of impaired fasting glucose (IFG) after atenolol treatment.
METHODS AND RESULTS
Among 234 European American participants enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study and treated with atenolol for 9 weeks, we prospectively followed a nested cohort that had both metabolomics profiling and genotype data available for the development of IFG. We assessed the association between baseline circulating levels of isoleucine, leucine, valine, tyrosine, and phenylalanine, as well as single-nucleotide polymorphisms in branched-chain amino-acid transaminase 1 (BCAT1) and phenylalanine hydroxylase (PAH) with development of IFG. All baseline AA levels were strongly associated with IFG development. Each increment in standard deviation of the 5 AAs was associated with the following odds ratio and 95% confidence interval for IFG based on a fully adjusted model: isoleucine 2.29 (1.31-4.01), leucine 1.80 (1.10-2.96), valine 1.77 (1.07-2.92), tyrosine 2.13 (1.20-3.78), and phenylalanine 2.04 (1.16-3.59). The composite P value was 2×10(-5). Those with PAH (rs2245360) AA genotype had the highest incidence of IFG (P for trend=0.0003).
CONCLUSIONS
Our data provide important insight into the metabolic and genetic mechanisms underlying atenolol-associated adverse metabolic effects. Clinical Trial Registration- http://www.clinicaltrials.gov; Unique Identifier: NCT00246519.
Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Amino Acids; Atenolol; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Hypertension; Male; Middle Aged; Young Adult
PubMed: 24627569
DOI: 10.1161/CIRCGENETICS.113.000421 -
Japanese Journal of Pharmacology Oct 1990Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on cardiohemodynamics and coronary circulation were investigated in two kinds of anesthetized... (Comparative Study)
Comparative Study
Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on cardiohemodynamics and coronary circulation were investigated in two kinds of anesthetized open-chest dog preparations in comparison with those of atenolol and propranolol. When administered intravenously, betaxolol, atenolol and propranolol produced dose-dependent decreases in the heart rate (HR), maximum left ventricular dP/dt [+)dP/dt), cardiac output (CO) and mean arterial pressure (MAP). Although all three drugs were almost equipotent in decreasing HR, betaxolol was much less potent than atenolol and propranolol in decreasing (+)dP/dt. Betaxolol decreased the total peripheral resistance (TPR), whereas atenolol and propranolol increased it. In another series of experiments, when administered intravenously, betaxolol, atenolol and propranolol all produced a decrease in the myocardial oxygen consumption (MVO2) and an increase in the atrioventricular conduction time (AVCT). All three drugs were nearly equipotent in decreasing MVO2, although betaxolol was less potent than the other two drugs at higher doses (greater than 300 micrograms/kg). Prolongation of AVCT with propranolol was stronger than those with betaxolol and atenolol. These results suggest that, unlike atenolol and propranolol, the decrease in TPR as well as beta 1-adrenoceptor blockade may be responsible for both the hypotensive effect of betaxolol and the decrease in MVO2 with betaxolol. The result that the cardiodepressant effect of betaxolol was much less potent than those of atenolol and propranolol suggests that betaxolol would be more beneficial than the others in the treatment of ischemic heart disease.
Topics: Animals; Atenolol; Betaxolol; Blood Pressure; Cardiac Output; Coronary Circulation; Dogs; Female; Heart; Heart Rate; Hemodynamics; Male; Propranolol
PubMed: 2077180
DOI: 10.1254/jjp.54.113 -
Nephrology, Dialysis, Transplantation :... Mar 2014The purpose of this study was to determine among maintenance hemodialysis patients with echocardiographic left ventricular hypertrophy and hypertension whether in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The purpose of this study was to determine among maintenance hemodialysis patients with echocardiographic left ventricular hypertrophy and hypertension whether in comparison with a β-blocker-based antihypertensive therapy, an angiotensin converting enzyme-inhibitor-based antihypertensive therapy causes a greater regression of left ventricular hypertrophy.
METHODS
Subjects were randomly assigned to either open-label lisinopril (n = 100) or atenolol (n = 100) each administered three times per week after dialysis. Monthly monitored home blood pressure (BP) was controlled to <140/90 mmHg with medications, dry weight adjustment and sodium restriction. The primary outcome was the change in left ventricular mass index (LVMI) from baseline to 12 months.
RESULTS
At baseline, 44-h ambulatory BP was similar in the atenolol (151.5/87.1 mmHg) and lisinopril groups, and improved similarly over time in both groups. However, monthly measured home BP was consistently higher in the lisinopril group despite the need for both a greater number of antihypertensive agents and a greater reduction in dry weight. An independent data safety monitoring board recommended termination because of cardiovascular safety. Serious cardiovascular events in the atenolol group occurred in 16 subjects, who had 20 events, and in the lisinopril group in 28 subjects, who had 43 events {incidence rate ratio (IRR) 2.36 [95% confidence interval (95% CI) 1.36-4.23, P = 0.001]}. Combined serious adverse events of myocardial infarction, stroke and hospitalization for heart failure or cardiovascular death in the atenolol group occurred in 10 subjects, who had 11 events and in the lisinopril group in 17 subjects, who had 23 events (IRR 2.29, P = 0.021). Hospitalizations for heart failure were worse in the lisinopril group (IRR 3.13, P = 0.021). All-cause hospitalizations were higher in the lisinopril group [IRR 1.61 (95% CI 1.18-2.19, P = 0.002)]. LVMI improved with time; no difference between drugs was noted.
CONCLUSIONS
Among maintenance dialysis patients with hypertension and left ventricular hypertrophy, atenolol-based antihypertensive therapy may be superior to lisinopril-based therapy in preventing cardiovascular morbidity and all-cause hospitalizations. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number: NCT00582114).
Topics: Adult; Aged; Antihypertensive Agents; Atenolol; Double-Blind Method; Early Termination of Clinical Trials; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Myocardial Infarction; Renal Dialysis; Treatment Failure
PubMed: 24398888
DOI: 10.1093/ndt/gft515 -
The British Journal of General Practice... Jun 2008
Topics: Adrenergic beta-Antagonists; Atenolol; Bisoprolol; Carbazoles; Carvedilol; Heart; Heart Failure; Humans; Natriuretic Peptide, Brain; Propanolamines
PubMed: 18505613
DOI: 10.3399/bjgp08X299317 -
British Journal of Pharmacology Feb 2007Postsystolic wall thickening (PSWT) is part of thickening that occurs after end-systole and represents wasted effort as it does not contribute to ejection. The effects... (Comparative Study)
Comparative Study
BACKGROUND AND PURPOSE
Postsystolic wall thickening (PSWT) is part of thickening that occurs after end-systole and represents wasted effort as it does not contribute to ejection. The effects of antianginal drugs on PSWT remain to be established. We compared the effects on PSWT of two agents that reduce heart rate, the beta-blocker atenolol and the selective inhibitor of If current, ivabradine.
EXPERIMENTAL APPROACH
Six dogs were prepared to measure wall thickening by sonomicrometry in the conscious state, at rest and during exercise, after administration of saline, atenolol (1 mg.kg-1) or ivabradine (1 mg.kg-1).
KEY RESULTS
Atenolol and ivabradine similarly reduced heart rate vs saline at rest (about 10-20%) and during exercise (about 30%). Atenolol but not ivabradine decreased dP/dtmax. Concomitantly, PSWT increased with atenolol vs saline at rest (0.35+/-0.07 vs 0.21+/-0.03 mm, respectively) and during exercise (0.30+/-0.04 vs 0.15+/-0.04 mm, respectively). In contrast, ivabradine did not alter PSWT. Importantly, atenolol but not ivabradine increased the ratio of postsystolic to systolic wall thickening by 80+/-23%. This enhanced thickening during diastole with atenolol was accompanied by impeded isovolumic relaxation of the left ventricle, as illustrated by the significant correlation between the isovolumic relaxation time constant tau and the postsystolic to systolic wall thickening ratio. None of these effects of atenolol were abolished when heart rate was controlled with atrial pacing.
CONCLUSION AND IMPLICATIONS
For a similar heart rate reduction at rest and during exercise, ivabradine, but not atenolol, did not alter PSWT and preserved the part of thickening contributing to ejection.
Topics: Adrenergic beta-Antagonists; Animals; Atenolol; Benzazepines; Cardiovascular Agents; Dogs; Heart Rate; Heart Ventricles; Ivabradine; Myocardium; Physical Conditioning, Animal
PubMed: 17179940
DOI: 10.1038/sj.bjp.0706996 -
Perioperative β-blockade: atenolol is associated with reduced mortality when compared to metoprolol.Anesthesiology Apr 2011The Atenolol study of 1996 provided evidence that perioperative β-blockade reduced postsurgical mortality. In 1998, the indications for perioperative β-blockade were... (Comparative Study)
Comparative Study
BACKGROUND
The Atenolol study of 1996 provided evidence that perioperative β-blockade reduced postsurgical mortality. In 1998, the indications for perioperative β-blockade were codified as the Perioperative Cardiac Risk Reduction protocol and implemented at the San Francisco Veterans Affairs Medical Center. The current study tested the following hypothesis: Is there a difference in mortality rates between patients receiving perioperative atenolol and metoprolol?
METHODS
Epidemiologic analysis of the operations performed at the San Francisco Veterans Affairs Medical Center since 1996 was performed. High-risk inpatients with perioperative β-blockade were divided into two groups: patients who received perioperative atenolol only and those who received metoprolol only. Patients who switched between the two chronic oral β-blocker medications were excluded. IV administration of β-blockers was ignored. Propensity matching analysis was used to correct for population differences in risk factors.
RESULTS
There were 38,779 operations performed from 1996 to 2008, with 24,739 inpatient procedures. Based on analysis of inpatient medication use, 3,787 patients received atenolol only (1,011) or metoprolol only (2,776). Thirty-day mortality (atenolol 1% vs. metoprolol 3%, P < 0.0008) and 1-yr mortality (atenolol 7% vs. metoprolol 13%, P < 0.0001) differed between the two β-blockers. Analysis based on inpatient and outpatient β-blocker use showed a similar pattern. Propensity matching that corrected for multiple cardiac risk factors found an odds ratio (OR) of 2.1 [95% CI 1.5-2.9], P < 0.0001 for increased 1-yr mortality with metoprolol for inpatient use.
CONCLUSION
Perioperative β-blockade using atenolol is associated with reduced mortality compared with metoprolol.
Topics: Adrenergic beta-Antagonists; Aged; Atenolol; Female; Humans; Male; Metoprolol; Middle Aged; Perioperative Care; Randomized Controlled Trials as Topic; Risk Assessment; Surgical Procedures, Operative
PubMed: 21372680
DOI: 10.1097/ALN.0b013e3182110e83 -
Clinical Cardiology Jun 1991Although silent ischemia may be linked to increases in cardiovascular morbidity and mortality, the long-term effects of a strategy aimed at the detection and treatment... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Although silent ischemia may be linked to increases in cardiovascular morbidity and mortality, the long-term effects of a strategy aimed at the detection and treatment of this asymptomatic condition have not been fully explored. We therefore have developed the Atenolol Silent Ischemia Trial (ASIST), the first multicenter, randomized, prospective study of the prognostic implications of silent ischemia in asymptomatic and minimally symptomatic patients with coronary artery disease. Inclusion criteria for study patients were documented coronary artery disease, evidenced angiographically or by previous myocardial infarction, and transient ischemia, evidenced by abnormalities of regional wall motion, stress thallium-201, or exercise electrocardiogram. The main objective of ASIST is to assess the influence of frequency and duration of symptomatic and asymptomatic ischemic episodes on the occurrence of fatal and nonfatal cardiac events. Atenolol, a beta 1-selective adrenergic blocker, was chosen as the therapeutic intervention because of its potential benefits in treating both symptomatic and asymptomatic ischemia. Ambulatory electrocardiographic monitoring will be used to measure the frequency and duration of ischemic episodes during daily life. The predictive ability of short-term (4-week) effects on long-term (52-week) response to atenolol treatment is also being assessed, along with the economic impact of this diagnostic and therapeutic strategy. Given the current emphasis on reducing morbidity and mortality associated with coronary artery disease, ASIST results should shed light onto the long-term management and prognostic implications of this otherwise asymptomatic condition.
Topics: Atenolol; Clinical Protocols; Coronary Disease; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Humans; Prognosis; Prospective Studies; Single-Blind Method
PubMed: 1810681
DOI: 10.1002/clc.4960140627 -
PloS One 2013Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between...
Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.
Topics: Adult; Black or African American; Antihypertensive Agents; Atenolol; Cluster Analysis; Female; Genomics; Humans; Hypertension; Male; Metabolic Networks and Pathways; Metabolome; Metabolomics; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Risk Factors; White People
PubMed: 23536766
DOI: 10.1371/journal.pone.0057639