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 the oral dose is absorbed through the gastrointestinal tract, with the remainder excreted unchanged in the feces. Co-administration with food can reduce the AUC of atenolol by approximately 20%. While atenolol can cross the blood-brain barrier, the process is slow and minimal. Following intravenous administration, 85% of the drug is excreted by the kidneys, and 10% by the feces. The total volume of distribution is 63.8–112.5 L. Atenolol is distributed in the central compartment (12.8–17.5 L) and two peripheral compartments (total volume 51–95 L). Distribution to the central compartment takes approximately 3 hours, to the shallower peripheral compartments approximately 4 hours, and to the deeper peripheral compartments approximately 5–6 hours. The estimated total clearance is 97.3–176.3 mL/min, and the renal clearance is 95–168 mL/min. In animal studies, atenolol distributes well in most tissues and fluids, except for brain tissue and cerebrospinal fluid. Unlike propranolol, atenolol is distributed only in small amounts in the central nervous system. Approximately 5-15% of atenolol is bound to plasma proteins. Atenolol readily crosses the placenta and is detectable in umbilical cord blood. During continuous administration, fetal serum drug concentrations may be comparable to maternal serum drug concentrations. Atenolol is distributed in breast milk; after a single dose, peak drug concentrations in breast milk are higher than in serum, and in lactating women taking the drug continuously, the area under the concentration-time curve (AUC) in breast milk is significantly greater than that in serum. Atenolol is rapidly but incompletely absorbed from the gastrointestinal tract. After oral administration, only about 50-60% of atenolol is absorbed. In healthy adults, peak plasma drug concentrations can reach 1-2 μg/ml 2-4 hours after a single oral dose of 200 mg atenolol. It has been reported that after administration of atenolol at specific doses, inter-individual plasma concentrations vary by approximately fourfold. Following intravenous injection of atenolol, peak plasma concentrations are reached within 5 minutes and decline rapidly during the initial distribution phase; plasma concentrations are reported to decrease after 7 hours, with an elimination half-life similar to that of oral administration. For more complete data on the absorption, distribution, and excretion of atenolol (6 types), please visit the HSDB record page. Metabolites/Metabolites: Minimal metabolism in the liver. The only unconjugated metabolites are products of the carbon atom hydroxylation reaction between the amide group and the benzene ring. The only other confirmed metabolites are glucuronide conjugates. These metabolites account for 5-8% and 2% of the renal excretion dose, respectively, with the remaining 87-90% excreted unchanged. The β-receptor blocking activity of the hydroxylated metabolites is approximately one-tenth that of atenolol. Minimal hepatic metabolism; can be removed by hemodialysis; very low lipid solubility. Atenolol is almost not metabolized in the liver. Approximately 40-50% of orally administered doses of atenolol are excreted unchanged in the urine. The remainder is excreted unchanged in the feces, primarily as unabsorbed drug. It has been reported that approximately 1-12% of atenolol can be removed via hemodialysis.
Hepatic (very little)
Clearance route: Approximately 50% of orally administered doses are absorbed through the gastrointestinal tract, with the remainder excreted unchanged in the feces. Unlike propranolol or metoprolol, but similar to nadolol, atenolol is almost entirely not metabolized by the liver; the absorbed portion is primarily excreted through the kidneys.
Half-life: 6-7 hours
Biological half-life
6-7 hours.
In patients with normal renal function, the plasma half-life (t1/2) of atenolol is 6-7 hours. The elimination half-life may be shorter in children with normal renal function. A study of children aged 5–16 years (mean age: 8.9 years) with cardiac arrhythmias and normal renal and hepatic function showed a mean terminal elimination half-life of 4.6 hours. In patients with creatinine clearance of 15–35 ml/min/1.73 m², the plasma half-life (t1/2) increased to 16–27 hours, and exceeded 27 hours with progressive renal impairment. The half-life in older adults (8.8 ± 0.9 hours) was significantly longer than in younger adults (5.8 ± 1.1 hours) (p < 0.01).

Toxicity Summary
Similar to metoprolol, atenolol competitively binds to β1-adrenergic receptors in cardiac and vascular smooth muscle with sympathomimetic neurotransmitters such as catecholamines, thereby inhibiting sympathetic nerve excitation. This leads to a decrease in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex orthostatic hypotension. Higher doses of atenolol also competitively block β2-adrenergic responses in bronchial and vascular smooth muscle. Toxicity Data
LD50: 2000-3000 mg/kg (oral, mouse). Interactions Due to reserpine's catecholamine-depleting effect, co-administration of atenolol with reserpine may increase the incidence of hypotension and bradycardia compared to atenolol alone. Atenol has an additive effect with other antihypertensive drugs (e.g., hydralazine, hydroquinone) and may enhance their antihypertensive effects. Studies have shown that in conscious rats pretreated with alpha-adrenergic receptor antagonists, beta-adrenergic receptor antagonists induce a paradoxical pressor response. This study investigated the effects of anesthetics on the mean arterial pressure (MAP) response induced by beta-blockers. …In rats anesthetized with urethane, intravenous administration of three beta-blockers resulted in a dose-dependent increase in MAP. In rats anesthetized with halothane, propranolol and atenolol did not alter MAP…In the presence of pentobarbital, none of the beta-blockers increased MAP. When propranolol or atenolol was administered intravenously to rats anesthetized with pentobarbital and concurrently treated with phentolamine and epinephrine, both increased MAP. These results indicate that anesthetics have different effects on the MAP response induced by beta-blockers. In a recent study, researchers compared the metabolic characteristics of newly identified obese and non-obese hypertensive patients with normotensive individuals. The results showed that both groups of hypertensive patients exhibited decreased insulin sensitivity, elevated fasting insulin levels, and elevated insulin levels after both fasting and intravenous glucose tolerance tests. …The effects of various antihypertensive drugs on these metabolic variables have been assessed in prospective trials. Treatment with the β1-selective blockers metoprolol and atenolol was associated with decreased insulin sensitivity and elevated fasting insulin and glucose levels. A double-blind, randomized, crossover study evaluated the pharmacokinetics of nifedipine and atenolol. The study included 15 healthy male subjects (mean age 32 years) who received oral administration of 50 mg atenolol tablets, 20 mg nifedipine extended-release tablets, atenolol and nifedipine combination tablets, or 50 mg atenolol and 20 mg nifedipine extended-release capsules. The results showed no difference in the time to reach peak plasma concentration or elimination half-life between atenolol alone and its combination with nifedipine tablets or other formulations. In conclusion, the fixed-dose combination of nifedipine and atenolol is bioequivalent to the free combination, and the bioavailability of both drugs in the fixed-dose combination is comparable to that in the single-dose formulation.
For more complete interaction data (14 in total) on atenolol, please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice: 2000 mg/kg
Oral LD50 in rats: 3000 mg/kg
Intravenous LD50 in mice: 98.7 mg/kg
Intravenous LD50 in rats: 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-blockers; antiarrhythmics; antihypertensives; sympathomimetic agents. In a small number of patients, atenolol, alone or in combination with benzodiazepines, has shown good efficacy in treating acute alcohol withdrawal symptoms. Atenolol…is indicated for the treatment of classic angina, also known as “exertional angina.” (Included on the US product label) Atenolol is indicated for the treatment of mitral valve prolapse syndrome. /Not included on the US product label/ For more complete data on the therapeutic uses of atenolol (of 12), please visit the HSDB record page. Drug Warnings Atenolol should be used with caution and at reduced doses in patients with impaired renal function, especially when creatinine clearance is below 35 ml/min/1.73 m². …Patients receiving atenolol after hemodialysis should be closely monitored in a hospital setting as significant hypotension may occur. Atenolol is contraindicated in patients with sinus bradycardia, first-degree or higher atrioventricular block, cardiogenic shock, and significant heart failure. Atenolol should be used with caution in patients undergoing major surgery under general anesthesia. Whether β-adrenergic blockers need to be discontinued before major surgery remains controversial. Some patients treated with β-adrenergic blockers experience severe, persistent hypotension and difficulty in restoring or maintaining a heartbeat during surgery. Abrupt discontinuation of atenolol may worsen angina symptoms in patients with coronary artery disease and/or induce myocardial infarction and ventricular arrhythmias, or induce thyroid storm in patients with thyrotoxicosis. Therefore, patients taking atenolol (especially those with ischemic heart disease) should be advised not to interrupt or stop treatment without a physician's permission. For more complete data on drug warnings for atenolol (12 in total), please visit the HSDB record page.

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Pharmacodynamics
Atenolol is a cardiac-selective beta-blocker, therefore its effects are primarily cardiac. As a sympathetic antagonist, it inhibits the increase in heart rate, myocardial conductivity, and contractility caused by increased norepinephrine release from the peripheral nervous system. The decrease in contractility and heart rate together lead to a reduction in cardiac output, resulting in a compensatory increase in peripheral vascular resistance in the short term. With long-term use of atenolol, this response gradually returns to baseline levels. More importantly, the reduction in myocardial work also reduces oxygen consumption, thus exerting a therapeutic effect by reducing oxygen supply-demand mismatch in cases of coronary artery blood flow restriction (e.g., coronary atherosclerosis). Reduced oxygen consumption, especially after exercise, can reduce the frequency of angina symptoms and may improve the survival rate of residual myocardium after myocardial infarction.
By blocking adrenergic β-receptors, atenolol reduces the frequency of sinoatrial node potentials, slows electrical conduction, slows the conduction velocity of atrioventricular node potentials, and decreases the frequency of ectopic potentials. These effects benefit arrhythmias (such as atrial fibrillation) by controlling the rate of action potential generation and promoting more effective coordinated contraction. Since a certain level of sympathetic activity is necessary to maintain cardiac function, the decrease in contractility caused by atenolol may induce or worsen heart failure, especially under volume overload. The effects of atenolol on blood pressure have been confirmed, although less potent than other β-blockers, but the mechanism remains unclear. As a β1-selective drug, it does not exert its effects through the vasodilatory effects of non-selective drugs. Nevertheless, it persistently reduces peripheral vascular resistance, thereby lowering blood pressure and cardiac output. It is believed that the antihypertensive effect of atenolol may be related to its effects on the central nervous system (CNS) or its inhibition of the renin-aldosterone-angiotensin system, rather than a direct effect on the vascular system. The central nervous system effects of atenolol are similar to those of other beta-blockers, but are milder due to its weaker ability to cross the blood-brain barrier. It may cause fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms of these adverse reactions are not yet clear, but they must be taken seriously due to their clinical significance. Atenolol also has some effects on the respiratory system, but far less than non-selective beta-blockers. It interacts with β2 receptors in the airways, causing bronchoconstriction by blocking sympathetic-mediated bronchial smooth muscle relaxation. This effect can interfere with beta-agonist therapy used to treat asthma and chronic obstructive pulmonary disease. Unlike some other beta-blockers, atenolol has no intrinsic sympathomimetic or membrane-stabilizing effects and does not alter 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.)