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The Journal of Toxicological Sciences Feb 1990Employing propranolol as a non-selective beta-blocker, atenolol, acebutolol and metoprolol as selective beta 1-blockers, butoxamine as a selective beta 2-blocker,...
Employing propranolol as a non-selective beta-blocker, atenolol, acebutolol and metoprolol as selective beta 1-blockers, butoxamine as a selective beta 2-blocker, labetalol as an alpha- and beta-blocker, and phentolamine as an alpha-blocker, we compared the effects of these adrenoceptor-blocking agents to reduce the degree of the myocardial injury induced by epinephrine in mice. Epinephrine in a single dose of 4 mg/kg/day, s.c., daily for 7 days, caused widely extended lesions, necrosis and fibrosis in the myocardial fibers, and degeneration in the residual myocardial fibers. The adrenoceptor-blocking agents in a dose of 10 mg/kg/day, s.c., given 30 minutes prior to epinephrine to each mouse daily for 7 days, had reduced the degree of the myocardial injury induced by epinephrine. The blockers, all, effectively suppressed the injury. Although metoprolol and butoxamine were less effective on the protection of the cardiotoxicity than phentolamine, the other blockers prevented the cardiotoxicity with the same degree as phentolamine did. These findings suggest that not only alpha- but also beta 1- and beta 2-adrenoceptors play critical roles in producing the myocardial injury.
Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Epinephrine; Heart; Male; Mice; Myocardium
PubMed: 1970836
DOI: 10.2131/jts.15.1 -
Journal of Bone and Mineral Research :... May 2019Normal bone mass is maintained by balanced bone formation and resorption. Myosin X (Myo10), an unconventional "myosin tail homology 4-band 4.1, ezrin, radixin, moesin"...
Normal bone mass is maintained by balanced bone formation and resorption. Myosin X (Myo10), an unconventional "myosin tail homology 4-band 4.1, ezrin, radixin, moesin" (MyTH4-FERM) domain containing myosin, is implicated in regulating osteoclast (OC) adhesion, podosome positioning, and differentiation in vitro. However, evidence is lacking for Myo10 in vivo function. Here we show that mice with Myo10 loss of function, Myo10 , exhibit osteoporotic deficits, which are likely due to the increased OC genesis and bone resorption because bone formation is unchanged. Similar deficits are detected in OC-selective Myo10 conditional knockout (cko) mice, indicating a cell autonomous function of Myo10. Further mechanistic studies suggest that Unc-5 Netrin receptor B (Unc5b) protein levels, in particular its cell surface level, are higher in the mutant OCs, but lower in RAW264.7 cells or HEK293 cells expressing Myo10. Suppressing Unc5b expression in bone marrow macrophages (BMMs) from Myo10 mice by infection with lentivirus of Unc5b shRNA markedly impaired RANKL-induced OC genesis. Netrin-1, a ligand of Unc5b, increased RANKL-induced OC formation in BMMs from both wild-type and Myo10 mice. Taken together, these results suggest that Myo10 plays a negative role in OC formation, likely by inhibiting Unc5b cell-surface targeting, and suppressing Netrin-1 promoted OC genesis. © 2019 American Society for Bone and Mineral Research.
Topics: Acebutolol; Animals; HEK293 Cells; Humans; Mice; Mice, Knockout; Myosins; Netrin Receptors; Netrin-1; Osteoclasts; Osteoporosis; RANK Ligand; RAW 264.7 Cells
PubMed: 30645777
DOI: 10.1002/jbmr.3667 -
British Journal of Clinical Pharmacology Mar 1984We have measured the psychological effects of acebutolol and atenolol in sixteen patients with essential hypertension. The drugs were administered in a randomized,... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
We have measured the psychological effects of acebutolol and atenolol in sixteen patients with essential hypertension. The drugs were administered in a randomized, placebo-controlled, double-blind manner, in single daily doses of 100 mg atenolol, 400 mg acebutolol or placebo for periods of 6 weeks, each drug period being separated by a placebo period. At each 2 weekly clinic visit, a questionnaire designed for assessment of state anxiety and state arousal was administered for self-completion. Arousal was significantly reduced by atenolol over the whole 6 weeks of administration. It was not affected by acebutolol. Anxiety was significantly reduced by acebutolol but only at the first of the three 2 weekly assessments on treatment. It was not affected by atenolol. Differences in the psychological effects of these two beta-adrenoceptor blockers are discussed in terms of their lipid solubility and haemodynamic effects.
Topics: Acebutolol; Adult; Aged; Anxiety; Arousal; Atenolol; Double-Blind Method; Female; Humans; Male; Middle Aged
PubMed: 6712870
DOI: 10.1111/j.1365-2125.1984.tb02356.x -
Biomolecules & Therapeutics Sep 2018The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation,...
The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.
PubMed: 29129046
DOI: 10.4062/biomolther.2017.123 -
British Journal of Clinical Pharmacology Feb 1976
Topics: Absorption; Acebutolol; Humans; Hydrogen-Ion Concentration; Kidney; Male; Mouth Mucosa
PubMed: 9955
DOI: 10.1111/j.1365-2125.1976.tb00590.x -
British Heart Journal Jun 1979To assess the effects of intravenously administered acebutolol (1-20 mg every 4 hours for 24 hours) on cardiac rhythm and performance, we studied 72 patients with...
To assess the effects of intravenously administered acebutolol (1-20 mg every 4 hours for 24 hours) on cardiac rhythm and performance, we studied 72 patients with evolving myocardial infarction. Twenty-five patients were treated with acebutolol beginning 6 hours after the first increase in the level of plasma creatine kinase. Enzymatically estimated infarct size was compared with that of 25 controls matched for predicted infarct size. Observed infarct sizes were not significantly different in the 2 groups (37 +/- 5 and 30 +/- 5 CK-gram equivalents, respectively). Mean heart rate, diastolic blood pressure, and cardiac output declined from control values during treatment with acebutolol, but remained within the normal range. Mean pulmonary artery pressure and pulmonary artery occlusive pressure were unchanged. In a group of 22 treated patients matched with 22 control subjects for frequency of ventricular extrasystoles, acebutolol effected a prompt reduction in frequencies of ventricular extrasystoles and repetitive arrhythmias, whereas values were not significantly changed in controls during the corresponding intervals. Accordingly, acebutolol may be a useful antiarrhythmic agent in selected patients with acute myocardial infarction with adversely altering haemodynamic stability or enzymatically estimated infarct size.
Topics: Acebutolol; Acute Disease; Adult; Aged; Arrhythmias, Cardiac; Creatine Kinase; Electrocardiography; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction
PubMed: 465240
DOI: 10.1136/hrt.41.6.654 -
British Journal of Pharmacology Jan 2018Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in...
BACKGROUND AND PURPOSE
Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible.
EXPERIMENTAL APPROACH
Previous PBPK model development of enantiomers of a series of seven racemic β-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design.
KEY RESULTS
Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments.
CONCLUSIONS AND IMPLICATIONS
PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.
Topics: Adrenergic beta-Antagonists; Animals; Injections, Intravenous; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 29053169
DOI: 10.1111/bph.14071 -
British Journal of Clinical Pharmacology Mar 19811 The acute cardiovascular effects of acebutolol were measured at constant paced heart rate in thirteen patients investigated for possible coronary artery disease, six...
1 The acute cardiovascular effects of acebutolol were measured at constant paced heart rate in thirteen patients investigated for possible coronary artery disease, six of whom showed significant coronary stenosis with regional myocardial dysfunction, seven of whom proved normal. Acebutolol 0.75 mg/kg i.v. was given to three patients with coronary artery disease and three normals, and 1 mg/kg i.v. to the other patients.2 Measurements were made of cardiac output, left ventricular and arterial pressures, and left ventricular angiography. Isovolumic and ejection phase parameters of left ventricular function, and systemic vascular resistance were derived. Plasma levels of acebutolol were measured. 3 The acute effects of acebutolol were a slight fall in cardiac output, LV dp/dt and dP/dt/P. There was no change in LV or arterial pressures, no consistent change in LVEDP or EDV, and no consistent change in ejection fraction or mean VCF. These changes imply a small negative inotropic effect, more marked at the higher dose. 4 The effects of acebutolol differed in patients with ischaemic heart disease compared with normals in that LVEDP and EDV increased, mean VCF decreased and cardiac output was lowered more. 5 These data are consistent with myocardial and vascular effects of beta-adrenoceptor blockade more marked at the higher dose and more marked in patients with ischaemic heart disease.
Topics: Acebutolol; Adult; Aged; Blood Pressure; Cardiac Output; Coronary Disease; Female; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Vascular Resistance
PubMed: 7213527
DOI: 10.1111/j.1365-2125.1981.tb00532.x -
British Medical Journal (Clinical... Oct 1981Systolic blood pressure, heart rate, and blood glucose concentration were measured in the first three days of life in 10 infants born to mothers who had received...
Systolic blood pressure, heart rate, and blood glucose concentration were measured in the first three days of life in 10 infants born to mothers who had received acebutolol, a cardioselective beta-adrenergic-blocking agent, for hypertension in pregnancy and compared with values in 10 infants whose mothers had received methyldopa. The blood pressure was expressed as a percentage of the expected value. Blood pressure was significantly lower in the infants of the mothers given acebutolol (p less than 0.02, less than 0.01, and less than 0.01 respectively during the three days of observation). Heart rate was also lower, but the significance was only at the 0.05 level. Blood glucose was not significantly different between the two groups. These results suggest that care should be taken in prescribing beta-adrenergic-blocking drugs during pregnancy.
Topics: Acebutolol; Blood Glucose; Blood Pressure; Female; Heart Rate; Humans; Hypertension; Infant, Newborn; Maternal-Fetal Exchange; Methyldopa; Pregnancy; Pregnancy Complications, Cardiovascular; Prospective Studies
PubMed: 6794766
DOI: 10.1136/bmj.283.6299.1077 -
British Journal of Pharmacology Dec 19921. The outward K+ current induced by KRN2391 (K+ channel opener) in Xenopus oocytes is blocked by glibenclamide. We have investigated the effects of various classes...
1. The outward K+ current induced by KRN2391 (K+ channel opener) in Xenopus oocytes is blocked by glibenclamide. We have investigated the effects of various classes (I-IV) of antiarrhythmic drugs on this KRN2391-induced response. 2. All class I antiarrhythmic drugs (Na+ channel blockers) tested concentration-dependently suppressed KRN2391-induced responses with the rank order of potency (IC50 in microM), disopyramide (17.8) > aprindine (29.5) > propafenone (63.1) > ajmaline (145) > quinidine (151). Flecainide, SUN1165, lignocaine, mexiletine and procainamide were much less potent (IC50, 450- > 1000 microM) than quinidine. 3. The class II antiarrhythmic drugs (beta-blockers), timolol, (-)- and (+/-)- propranolol, and (+)- propranolol (a non-beta-blocker) inhibited KRN2391-induced K+ currents in a concentration-dependent manner with values for IC50 (microM) of 79, 131, 151 and 129, respectively, whilst butoxamine, oxprenolol, alprenolol, pindolol, nadolol, metoprolol and acebutolol were either weak (IC50, 300 microM-600 microM) or virtually inactive (IC50, > 1000 microM). 4. The class III antiarrhythmic drugs, amiodarone and (+)-sotalol scarcely affected KRN2391 responses. 5. All class IV drugs (Ca2+ antagonists) tested suppressed KRN2391-induced responses in a concentration-dependent manner with an IC50 of 6.3 microM for bepridil, 38 microM for prenylamine, 85 microM for verapamil and 135 microM for diltiazem. 6. In conclusion, antiarrhythmic drugs of classes I, II and IV potently blocked glibenclamide-sensitive K+ channels in Xenopus oocytes.
Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Calcium Channel Blockers; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiology; Female; Glyburide; Oocytes; Potassium Channels; Pyridines; Sodium Channels; Xenopus laevis
PubMed: 1361399
DOI: 10.1111/j.1476-5381.1992.tb13407.x