Beta-1 adrenergic receptors

The in vitro effect of nifedipine and atenolol, either alone or in combination, on the proliferation and migration of rat aortic smooth muscle cells was investigated. Nifedipine inhibited the replication of arterial myocytes in concentrations ranging between 10 and 100 microM. The inhibition, evaluated as cell number, was dose- and time-dependent with an IC50 of 39 and 34 microM after 48 and 72 h, respectively; the cell doubling time increased with drug concentrations up to 118 h versus 28 h for controls. Atenolol alone failed to reduce arterial myocyte proliferation, and did not influence the effect of nifedipine on cell proliferation. Nifedipine and atenolol alone inhibited in a dose-dependent manner rat aortic myocytes migration induced by fibrinogen as chemotactic agent. When the combination nifedipine-atenolol was investigated, an additive inhibitory effect on cell migration was observed. These results provide in vitro support for a potential effect of this drug association on early steps of atherogenesis.[3]

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Hem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in β-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to β-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by β-blockers in Hem-ECs. Conclusion: Our data suggest that autophagy may be ascribed among the mechanisms of action of β-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis [4].

Compared with BP before medication, all 3 doses of combined atenolol and amlodipine significantly decreased the BP at 24 h after administration, except for the low dose on diastolic BP. Compared with the control group, all 3 doses of combined atenolol and amlodipine significantly reduced the average BP levels for the 24 h period after administration; furthermore, the high and intermediate doses also significantly decreased the BPV levels for the same period. The q values calculated by probability sum analysis for systolic and diastolic BP for the 24 h period after administration were 2.29 and 1.45, respectively, and for systolic and diastolic BPV for the same period they were 1.41 and 1.60, respectively. Conclusion: There is significant synergism between atenolol and amlodipine in lowering and stabilizing BP in 2K1C renovascular hypertensive rats [5].

Fresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 μM to 150 μM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy [4].

Aim: To test the synergistic effects of atenolol and amlodipine on lowering blood pressure (BP) and reducing blood pressure variability (BPV) in 2-kidney, one-clip (2K1C) renovascular hypertensive rats. Methods: Forty-eight 2K1C renovascular hypertensive rats were randomly divided into 6 groups. They were respectively given 0.8% carboxymethylcellulose sodium (control), atenolol (10.0 mg/kg), amlodipine (1.0 mg/kg), and combined atenolol and amlodipine (low dose: 5.0+0.5 mg/kg; intermediate dose: 10.0+1.0 mg/kg; high dose: 20.0+2.0 mg/kg). The drugs were given via a catheter in a gastric fistula. BP was recorded for 25 h from 1 h before drug administration to 24 h after administration.[5]

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Animals and RVHR preparation [5]
Male Sprague–Dawley rats (160–180 g) were anesthetized with a combination of ketamine (40 mg/kg) and diazepam (6 mg/kg). The right renal artery of each animal was isolated through a flank incision as described previously, and a silver clip (0.2 mm internal gap) was placed on the renal artery. Five weeks after placement of the clip, the systolic blood pressure (SBP) of rats was measured by using the tail-cuff method (CB10). In total, 48 RVHR whose SBP was greater than 160 mmHg were used in this study. Rats were kept in a controlled temperature (23 °C– 25 °C) and lighting (light 08:00–20:00, dark 20:00–08:00) environment, and had free access to food and tap water. All the animals used in this work received humane care in compliance with institutional animal care guidelines.

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BP and BPV measurement [5]
SBP, diastolic blood pressure (DBP) and heart period (HP) were continuously recorded using a previously described technique. Briefly, rats were anesthetized by injection (ip) with a combination of ketamine (40 mg/kg) and diazepam (6 mg/kg). A floating polyethylene catheter was inserted into the lower abdominal aorta via the left femoral artery for BP measurement, and another catheter was placed into the stomach via a mid-abdominal incision for drug administration. The catheters were exteriorized through the interscapular skin. After a 2-d recovery period, the animals were placed for BP recording in individual cylindrical cages containing food and water. The aortic catheter was connected to a BP transducer via a rotating swivel that allowed the animals to move freely in the cage. After approximately 14-h habituation, at 9:00 o’clock the BP signal was begun to be digitized by a microcomputer. One hour later, at 10:00 o’clock the drug was given via the catheter in the gastric fistula. SBP, DBP, and HP values were recorded beat-to-beat for 25 h, up to 10:00 o’clock on the second day. The mean values of these parameters during a designated period were calculated and served as SBP, DBP and HP values. The standard deviation of all values obtained over 24 h was denoted as the quantitative parameter of variability; that is, SBP variability (SBPV), DBP variability (DBPV), and HP variability (HPV) for each rat.

Absorption, Distribution and Excretion
Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, with the remainder being excreted unchanged in the feces. Administering atenolol with food can decrease the AUC by about 20%. While atenolol can cross the blood-brain barrier, it does so slowly and to a small extent.
85% is eliminated by the kidneys following IV administration with 10% appearing in the feces.
Total Vd of 63.8-112.5 L. Atenolol distributes into a central volume of 12.8-17.5 L along with two peripheral compartments with a combined volume of 51-95 L. Distribution takes about 3 hrs for the central compartment, 4 hrs for the shallower peripheral compartment, and 5-6 hrs for the deeper peripheral compartment.
Total clearance is estimated at 97.3-176.3 mL/min with a renal clearance of 95-168 mL/min.
In animals, atenolol is well distributed into most tissues and fluids except brain and /cerebrospinal fluid/. Unlike propranolol, only a small portion of atenolol is apparently distributed into the CNS.
Approximately 5-15% of atenolol is bound to plasma protein.
Atenolol readily crosses the placenta, and has been detected in cord blood. During continuous administration, fetal serum concentrations of the drug are probably equivalent to those in maternal serum. Atenolol is distributed into milk; peak milk concentrations of the drug are higher than peak serum concentrations after an individual dose, and the area under the milk concentration-time (AUC) is substantially greater than that of the serum AUC in lactating women receiving the drug continuously.
Atenolol is rapidly but incompletely absorbed from the GI tract. Only about 50-60% of an oral dose of atenolol is absorbed. In healthy adults, peak plasma concentrations of 1-2 ug/ml are achieved 2-4 hours after oral administration of a single 200 mg dose of atenolol. An approximately fourfold interindividual variation in plasma concentrations attained has been reported with a specific oral dose of atenolol. Peak plasma atenolol concentrations are achieved within 5 minutes following direct IV injection of the drug, and decline rapidly during an initial distribution phase; after the first 7 hours, plasma concentrations reportedly decline with an elimination half-life similar to that of orally administered drug.
For more Absorption, Distribution and Excretion (Complete) data for ATENOLOL (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Minimal metabolism in the liver. The sole non-conjugated metabolite is the product of a hydroxylation reaction at the carbon between the amide and benzene groups. The only other metabolite to be confirmed is a glucuronide conjugate. These metabolites make up 5-8% and 2% of the renally excreted dose with 87-90% appearing as unchanged drug. The hydroxylated metabolite is exerts 1/10th the beta-blocking activity of atenolol.
Minimal hepatic metabolism; removable by hemodialysis; very low lipid solubility.
Little or no metabolism of atenolol occurs in the liver. Approximately 40-50% of an oral dose of the drug is excreted in urine unchanged. The remainder is excreted unchanged in feces, principally as unabsorbed drug. About 1-12% of atenolol is reportedly removed by hemodialysis.
Hepatic (minimal)
Route of Elimination: Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. Unlike propranolol or metoprolol, but like nadolol, atenolol undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion.
Half Life: 6-7 hours

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Biological Half-Life
6-7 hrs.
In patients with normal renal function, atenolol has a plasma half-life (t1/2) of 6-7 hours. Children with normal renal function may exhibit a shorter elimination half-life. In one study in children ages 5-16 (mean: 8.9) with arhythmias and normal renal and hepatic function, the terminal elimination half-life averaged 4.6 hours. Plasma t1/2 of the drug increases to 16-27 hours in patients with creatinine clearances of 15-35 ml/minute per 1.73 sq m and exceeds 27 hours with progressive renal impairment.
The half-life in the elderly was significantly longer (8.8 + or - 0.9 hr) compared with that in the young (5.8 + or - 1.1 hr) (p < 0.01).

Toxicity Summary
Like metoprolol, atenolol competes with sympathomimetic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart and vascular smooth muscle, inhibiting sympathetic stimulation. This results in a reduction in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex orthostatic hypotension. Higher doses of atenolol also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles.

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Toxicity Data
LD50: 2000-3000 mg/kg(oral, mice).

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Interactions
Concomitant administration of atenolol with reserpine may increase the incidence of hypotension and bradycardia as compared with atenolol alone, because of reserpine's catecholamine-depleting activity. Atenolol also is additive with and may potentiate the hypotensive actions of other hypotensive agents (e.g., hydralazine, methylodpa).
It has been shown that paradoxical pressor response to a beta adrenoceptor antagonist occurs in conscious rats pretreated with an alpha adrenoceptor antagonist. This study examines the influence of anaesthetic agents on mean arterial pressure response to a beta blocker. ... IV injections of all three beta blockers caused dose dependent increases in mean arterial pressure in urethane anesthetized rats. In halothane anesthetized rats, propranolol and atenolol did not alter mean arterial pressure ... In the presence of pentobarbitone, none of the beta blockers raised mean arterial pressure. ... /When/ propranolol or atenolol were iv injected in pentobarbitone anesthetized rats treated with both phentolamine and adrenaline, /they both/ ... raised the mean arterial pressure. /These/ results show that anesthetic agents differentially affect the mean arterial pressure response to a beta blocker.
In a recent study in which metabolic characteristics of newly detected obese and nonobese hypertensive subjects were compared with those of normotensive subjects, insulin sensitivity was decreased, fasting insulin values and insulin values after an intravenous glucose tolerance test were increased, and fasting and intravenous glucose tolerance glucose values were increased in both hypertensive groups. ... The effects of various antihypertensive agents on these metabolic variables have been assessed in prospective trials. Treatment with the beta 1 selective blocking agents metoprolol and atenolol was associated with decreased insulin sensitivity and increased fasting values of insulin and glucose.
A double blind, randomized, crossover study of the pharmacokinetics of nifedipine and atenolol was conducted in 15 healthy male subjects (mean age 32 yr) who received a single oral tablet containing 50 mg atenolol, a sustained action tablet containing 20 mg nifedipine, both the atenolol and nifedipine tablets together, or an oral capsule containing 50 mg atenolol and 20 mg sustained release nifedipine. There was no difference between atenolol alone, given with nifedipine tablet or in the combination tablet with respect to time to maximum blood concentration or elimination half-life. ... /In conclusion,/ the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and the bioavailability of both drugs in the fixed combination is equivalent to that of the single tablets.
For more Interactions (Complete) data for ATENOLOL (14 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse oral 2000 mg/kg
LD50 Rat oral 3000 mg/kg
LD50 Mouse iv 98.7 mg/kg
LD50 Rat iv 59.24 mg/kg

[1]. Atenolol: a review of its pharmacological properties and therapeutic efficacy in angina pectoris and hypertension. Drugs. 1979;17(6):425-460.

[2]. (+/-)[125Iodo] cyanopindolol, a new ligand for beta-adrenoceptors: identification and quantitation of subclasses of beta-adrenoceptors in guinea pig. Naunyn Schmiedebergs Arch Pharmacol. 1981;317(4):277-285.

[3].Effect of the nifedipine-atenolol association on arterial myocyte migration and proliferation. Pharmacol Res. 1993 May-Jun;27(4):299-307.

[4].Β-blockers activate autophagy on infantile hemangioma-derived endothelial cells in vitro. Vascul Pharmacol. 2022 Oct;146:107110.

[5].Synergistic effects of atenolol and amlodipine for lowering and stabilizing blood pressure in 2K1C renovascular hypertensive rats. Acta Pharmacol Sin. 2005 Nov;26(11):1303-8.

Therapeutic Uses
Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics
Atenolol has been used with good results alone or in conjunction with a benzodiazepine in the management of acute alcohol withdrawal in a limited number of patients.
Atenolol ... /is/ indicated in the treatment of classic angina pectoris, also referred to as "effort-associated angina". /Included in US product labeling/
Atenolol /is/ used in the treatment of mitral value prolapse syndrome. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for ATENOLOL (12 total), please visit the HSDB record page.

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Drug Warnings
Atenolol should be used with caution and in reduced dosage in patients with impaired renal function, especially when creatinine clearance is less than 35 ml/minute per 1.73 sq m. ... Patients receiving atenolol after hemodialysis /should/ be administered the drug under close supervision in a hospital setting, since marked hypotension may occur.
Atenolol is contraindicated in patients with sinus bradycardia, AV block greater than first degree, cardiogenic shock, and overt cardiac failure.
Atenolol should be used with caution in patients undergoing major surgery involving general anesthesia. The necessity of withdrawing beta-adrenergic blocking therapy prior to major surgery is controversial. Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received beta-adrenergic blocking agents.
Abrupt withdrawal of atenolol may exacerbate angina symptoms and/or precipitate myocardial infarction and venticular arrhythmias in patients with coronary artery disease, or may precipitate thyroid storm in patients with thyrotoxicosis. Therefore, patients receiving atenolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their physician.
For more Drug Warnings (Complete) data for ATENOLOL (12 total), please visit the HSDB record page.

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Pharmacodynamics
Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload. The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature. Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects. Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers. Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system. The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease. Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control.

C14H22N2O3

266.34

266.163

C, 63.13; H, 8.33; N, 10.52; O, 18.02

29122-68-7

Atenolol-d7;1202864-50-3; 51706-40-2 (HCl); 29122-68-7;93379-54-5 (S isomer); 56715-13-0 (R isomer)

2249

White to off-white solid powder

1.1±0.1 g/cm3

508.0±50.0 °C at 760 mmHg

154°C

261.1±30.1 °C

0.0±1.4 mmHg at 25°C

1.540

0.1

3

4

8

19

263

0

O(C1C([H])=C([H])C(C([H])([H])C(N([H])[H])=O)=C([H])C=1[H])C([H])([H])C([H])(C([H])([H])N([H])C([H])(C([H])([H])[H])C([H])([H])[H])O[H]

METKIMKYRPQLGS-UHFFFAOYSA-N

InChI=1S/C14H22N2O3/c1-10(2)16-8-12(17)9-19-13-5-3-11(4-6-13)7-14(15)18/h3-6,10,12,16-17H,7-9H2,1-2H3,(H2,15,18)

2-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]acetamide

Atenolol; Blokium; Normiten; atenolol; 29122-68-7; Prenormine; Blokium; Myocord; Normiten; (RS)-Atenolol; Tenormine; Tenormin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~375.46 mM)
H2O : ~8.33 mg/mL (~31.28 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.39 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.39 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 36.67 mg/mL (137.68 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)