Β-adrenergic Blockers Research Articles

Timolol Maleate Microspheres: An Ingenious Carrier for Sustained Release Antihypertensive Formulation

Background: Timolol maleate is classified as a BCS Class I drug and functions as a non-selective β-adrenergic receptor blocker. Its ability to lower heart rate and cardiac output has led to its widespread use in the treatment of hypertension. Objective: Timolol maleate has a short half-life and is rapidly cleared from the body, which limits its therapeutic effectiveness, requiring frequent dosing and potentially affecting patient adherence. To overcome these challenges, sustained-release microspheres of Timolol maleate were developed using the ion gelation method. Method: The ion gelation technique was employed to create the microspheres due to its various advantages, including ease of use, scalability and gentle processing conditions. Results: All batches exhibited a comparatively lower swelling index in 0.1M HCl (pH 1.2) than in SIF (pH 6.8). It was observed that increasing the concentration of sodium alginate resulted in higher drug content. The microspheres were sized between 400 and 900 μm and demonstrated excellent flow characteristics. An optimized batch achieved an entrapment efficiency of 88.83% and released 92.15% of the drug over 7 hrs. Furthermore, stability studies conducted according to ICH Q1A(R2) for 3 months at 5±3°C and 25±2°C/60±5% RH indicated no significant changes in evaluation parameters. Conclusion: The optimized Timolol maleate-loaded microspheres effectively provided sustained drug release through the membrane over 7 hrs. This study contributes to the development of improved drug delivery systems for better hypertension management, addressing the unmet needs in patient compliance. Keywords: Timolol Maleate, Microspheres, Ion gelation method, Sodium alginate, Calcium chloride, Sustained release, Hypertension

Evaluation of β-Blocker-Induced Bradyarrhythmia Using an Analysis of the Japanese Adverse Drug Event Report Database.

β-Adrenergic receptor blockers (β-blockers) are used to treat hypertension, ischemic heart disease, chronic heart failure, and tachyarrhythmia. The main side effects of treatment include bradycardia, atrioventricular block, and hypotension. Bradycardia may result in pacemaker implantation as well as the discontinuation of β-blockers. Bradycardia is difficult to confirm at a single institution because it diagnosed only by symptoms when electrocardiogram (ECG) are not routinely performed. Previous studies reported an increase in bradycardia in heart failure patients treated with β-blockers; however, limited information is currently available for non-heart failure patients. Bradycardia induced by β-blockers has not yet been comprehensively examined. Therefore, the present study investigated data on the incidence and duration of bradyarrhythmia caused by β-blockers using the Japanese Adverse Drug Event Report database (JADER). Cases of adverse effects associated with this medication were extracted from JADER and Fisher's exact test was performed to assess whether each β-blocker caused bradyarrhythmia. In addition, only data from patients who reported bradyarrhythmia after β-blocker treatment were extracted, and the Weibull distribution was used to analyze the time-to-onset of bradyarrhythmia. Thirteen β-blockers caused bradyarrhythmia and signals were observed for 12 drugs, except nadolol. Bradyarrhythmia induced by oral β-blockers was more likely to be of the early failure type, and developed within 2 months of treatment initiation with most β-blockers. A comprehensive analysis of bradyarrhythmia with β-blockers suggests that careful monitoring is needed, particularly early in the initiation of treatment.

Targeting Sodium in Heart Failure.

A dominant event determining the course of heart failure (HF) includes the disruption of the delicate sodium (Na+) and water balance leading to (Na+) and water retention and edema formation. Although incomplete decongestion adversely affects outcomes, it is unknown whether interventions directly targeting (Na+), such as strict dietary (Na+) restriction, intravenous hypertonic saline, and diuretics, reverse this effect. As a result, it is imperative to implement (Na+)-targeting interventions in selected HF patients with established congestion on top of quadruple therapy with angiotensin receptor neprilysin inhibitor, β-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor, which dramatically improves outcomes. The limited effectiveness of (Na+)-targeting treatments may be partly due to the fact that the current metrics of HF severity have a limited capacity of foreseeing and averting episodes of congestion and guiding (Na+)-targeting treatments, which often leads to dysnatremias, adversely affecting outcomes. Recent evidence suggests that spot urinary sodium measurements may be used as a guide to monitor (Na+)-targeting interventions both in chronic and acute HF. Further, the classical (2)-compartment model of (Na+) storage has been displaced by the (3)-compartment model emphasizing the non-osmotic accumulation of (Na+), chiefly in the skin. 23(Na+) magnetic resonance imaging (MRI) enables the accurate and reliable quantification of tissue (Na+). Another promising approach enabling tissue (Na+) monitoring is based on wearable devices employing ion-selective electrodes for electrolyte detection, including (Na+) and (Cl-). Undoubtably, further studies using 23(Na+)-MRI technology and wearable sensors are required to learn more about the clinical significance of tissue (Na+) storage and (Na+)-related mechanisms of morbidity and mortality in HF.

β-Adrenergic blockade attenuates adverse adipose tissue responses after burn.

Severe burn injuries are defined by a prolonged hypermetabolic response characterized by increases in resting energy expenditure, systemic catabolism, and multi-organ dysfunction. The sustained elevation of catecholamines following a burn injury is thought to significantly contribute to this hypermetabolic response, leading to changes in adipose tissue such as increased lipolysis and the browning of subcutaneous white adipose tissue (WAT). Failure to mitigate these adverse changes within the adipose tissue has been shown to exacerbate the post-burn hypermetabolic response and lead to negative outcomes. Propranolol, a non-selective β-blocker, has been clinically administered to improve outcomes of pediatric and adult burn patients, but there is inadequate knowledge of its effects on the distinct adipose tissue depots. In this study, we investigated the adipose depot-specific alterations that occur in response to burn injury. Moreover, we explored the therapeutic effects of β-adrenoceptor blockade via the drug propranolol in attenuating these burn-induced pathophysiological changes within the different fat depots. Using a murine model of thermal injury, we show that burn injury induces endoplasmic reticulum (ER) stress in the epididymal (eWAT) but not in the inguinal (iWAT) WAT depot. Conversely, burn injury induces the activation of key lipolytic pathways in both eWAT and iWAT depots. Treatment of burn mice with propranolol effectively mitigated adverse burn-induced alterations in the adipose by alleviating ER stress in the eWAT and reducing lipolysis in both depots. Furthermore, propranolol treatment in post-burn mice attenuated UCP1-mediated subcutaneous WAT browning following injury. Overall, our findings suggest that propranolol serves as an effective therapeutic intervention to mitigate the adverse changes induced by burn injury, including ER stress, lipotoxicity, and WAT browning, in both adipose tissue depots. KEY MESSAGES: Burn injury adversely affects adipose tissue metabolism via distinct changes in both visceral and subcutaneous adipose depots. Propranolol, a non-selective β-adrenergic blocker, attenuates many of the adverse adipose tissue changes mediated by burn injury.

Non-invasive assessment of proarrhythmic risks associated with isoprenaline and the dietary supplement ingredient synephrine using human induced pluripotent stem cell-derived cardiomyocytes.

There have been conflicting reports about the proarrhythmic risk of p-synephrine (SYN). To address this, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with the microelectrode array (MEA) system have been utilized to assess arrhythmia risks, particularly in the context of adrenomimetic drugs. This study aims to determine whether MEA recordings from hiPSC-CMs could predict the proarrhythmic risk of adrenomimetic drugs and to investigate the cardiovascular effects and mechanisms of SYN. We employed MEA recordings to assess the electrophysiological properties of hiPSC-CMs and conducted concentration-response analyses to evaluate the effects of SYN and Isoprenaline (ISO) on beating rate and contractility. A risk scoring system for proarrhythmic risks was established based on hiPSC-CMs in this study. ISO, a classic beta-adrenergic drug, was also evaluated. Furthermore, the study evaluated the risk of SYN and recorded the concentration-response of beating rate, contractility and the change in the presence or absence of selective β1, β2 and β3 adrenergic blockers. Our results suggested that ISO carries a high risk of inducing arrhythmias, aligning with existing literature. SYN caused a 30% prolongation of the field potential duration (FPD) at a concentration of 206.326 μM, a change significantly different from baseline measurements and control treatments. The half maximal effective concentration (EC50) of SYN (3.31 μM) to affect hiPSC-CM beating rate is much higher than that of ISO (18.00 nM). The effect of SYN at an EC50 of 3.31 μM is about ten times more potent in hiPSC-CMs compared to neonatal rat cardiomyocytes (34.12 μM). SYN increased the contractility of cardiomyocytes by 29.97 ± 11.65%, compared to ISO's increase of 50.56 ± 24.15%. β1 receptor blockers almost eliminated the beating rate increase induced by both ISO and SYN, while neither β2 nor β3 blockers had a complete inhibitory effect. The MEA and hiPSC-CM system could effectively predict the risk of adrenomimetic drugs. The study concludes that the proarrhythmia risk of SYN at conventional doses is low. SYN is more sensitive in increasing beating rate and contractility in human cardiomyocytes compared to rats, primarily activating β1 receptor.

Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases

Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment (TME). Herein, elevated neutrophil extracellular traps (NETs) and cancer-associated neurotransmitters (CANTs, e.g., catecholamines) are firstly identified as two of the dominant inducements. Further, an injectable fibrin-alginate hydrogel with high tissue adhesion has been constructed to specifically co-deliver NETs inhibitor (DNase I)-encapsulated PLGA nanoparticles and an unselective β-adrenergic receptor blocker (propranolol). The two components (i.e., fibrin and alginate) can respond to two triggers (thrombin and Ca2+, respectively) in postoperative bleeding to gelate, shaping into an interpenetrating network (IPN) featuring high strength. The continuous release of DNase I and PR can wreck NETs and antagonize catecholamines to decrease microvessel density, blockade myeloid-derived suppressor cells, secrete various proinflammatory cytokines, potentiate natural killer cell function and hamper cytotoxic T cell exhaustion. The reprogrammed TME significantly suppress locally residual and distant tumors, induce strong immune memory effects and thus inhibit lung metastasis. Thus, targetedly degrading NETs and blocking CANTs enabled by this in-situ IPN-based hydrogel drug depot provides a simple and efficient approach against SR-induced cancer recurrence and metastasis.

Parotid hypersalivation after inferior salivatory nucleus glutamate/NMDA receptor excitation in the rat

Although salivation is essential during eating behavior, little is known about the brainstem centers that directly control the salivary glands. With regard to the inferior salivatory nucleus (ISN), the site of origin of the parasympathetic preganglionic cell bodies that innervate the parotid glands, previous anatomical studies have located it within the rostrodorsal medullary reticular formation. However, to date there is no functional data that shows the secretory nature of the somas grouped in this region. To activate only the somas and rule out the activation of the efferent fibers from and the afferent fibers to the ISN, in exp. 1, NMDA neurotoxin was administered to the rostrodorsal medullary region and the secretion of saliva was recorded during the following hour. Results showed an increased secretion of parotid saliva but a total absence of submandibular-sublingual secretion. In exp. 2, results showed that the hypersecretion of parotid saliva after NMDA microinjection was completely blocked by the administration of atropine (a cholinergic blocker) but not after administration of dihydroergotamine plus propranolol (α and β-adrenergic blockers, respectively). These findings suggest that the somata of the rostrodorsal medulla are secretory in nature, controlling parotid secretion via a cholinergic pathway. The data thus functionally supports the idea that these cells constitute the ISN.

Feasibility Study of Single-Photon Emission Computed Tomography with Iodine-123 Labeled Metaiodobenzylguanidine for Preclinical Evaluation of Labetalol as a β-Adrenergic Receptor Blocker.

Among clinically used radiopharmaceuticals, iodine-123 labeled metaiodobenzylguanidine ([123I]mIBG) serves for diagnosing neuroendocrine tumors and obtaining images of myocardial sympathetic innervation. mIBG, a structural analogue of norepinephrine (NE), a neurotransmitter acting in peripheral and central nerves, follows a pathway similar to NE, transmitting signals through the NE transporter (NET) located at synaptic terminals. It moves through the body without decomposing, enabling noninvasive image evaluation. In this study, we aimed to quantify [123I]mIBG uptake in the adrenal glands using small animal single-photon emission computed tomography/computed tomography (SPECT/CT) images post [123I]mIBG administration. We investigated the possibility of assessing the effectiveness of β-adrenergic receptor blockers by quantifying SPECT/CT images and biodistribution results to determine the degree of [123I]mIBG uptake in the adrenal glands treated with labetalol, a known β-adrenergic receptor blocker. Upon intravenous administration of [123I]mIBG to mice, SPECT/CT images were acquired over time to confirm the in vivo distribution pattern, revealing a clear uptake in the adrenal glands. Labetalol inhibited the uptake of [123I]mIBG in cell lines expressing NET. A decrease in [123I]mIBG uptake in the adrenal glands was observed in the labetalol-treated group compared with the normal group through SPECT/CT imaging and biodistribution studies. These results demonstrate that SPECT/CT imaging with [123I]mIBG could be applicable for evaluating the preclinical efficacy of new antihypertensive drug candidates such as labetalol, a β-adrenergic receptor blocker.

Dronedarone Enhances the Antibacterial Activity of Polymyxin B and Inhibits the Quorum Sensing System by Interacting with LuxS.

Quorum sensing (QS) is considered an appealing target for interference with bacterial infections. β-Adrenergic blockers are promising anti-QS agents but do not have antibacterial activity. We assessed the potential ability of adrenergic receptor inhibitors to enhance the antibacterial activity of polymyxin B (PB) against Klebsiella pneumoniae and determined that dronedarone has the most potent activity both in vitro and in vivo. We found that dronedarone increases the thermal stability of LuxS, decreases the production of AI-2, and affects the biofilm formation of K. pneumoniae. We also identified the direct binding of dronedarone to LuxS. However, the mechanism by which dronedarone enhances the antibacterial activity of PB has not been elucidated and is worthy of further exploration. Our study provides a basis for the future development of drug combination regimens.

Lipase mediated new chemo-enzymatic synthesis of (RS)-, (R)-, and (S)-bunolol.

The β-adrenergic receptor blocking agents are an important class of drug molecules. The present study reports a new chemo and chemo-enzymatic synthetic process for (RS)-, (R)-, and (S)-bunolol, one of the potent β-adrenergic receptor blocker. In chemo-enzymatic process, CAL L4777 lipase was employed for enantioselective kinetic resolution to synthesize the enantiopure (R)-alcohol and (S)-ester from the corresponding racemic alcohol. Thereafter, the corresponding (R)-alcohol and deacylated (S)-ester were treated with tert-butylamine to produce (S)- and (R)-bunolol, respectively. In chemical approach, epichlorohydrin (RS-, R-, and S-) was used as a starting material via respective (RS)-, (S)-, and (R)-glycidyl ether as intermediates for synthesis of enantiomeric (RS)-, (R)-, and (S)-bunolol. In comparison between two approaches, it was found that the chemo-enzymatic process was more effective and resulted in enantiomeric excess of 98% with 35% yield.

Pharmacotherapy of glaucoma in terms of evidence-based medicine

Glaucoma is a disease associated with increased intraocular pressure (IOP). Of the pharmacological agents for treating glaucoma, there are drugs of the first (most effective and safe) and second-line treatment. First-line treatment includes prostaglandin analogs and beta-blockers. The currently used prostaglandin analogs (latanoprost, bimatoprost, tafluprost and travoprost) are PG F2α analogs that act through stimulation of FP receptors. They are distinguished by the optimal ratio of effectiveness and risk of side effects. They are convenient for the patient because for the therapeutic effect, it is enough to prescribe 1 time per day. As a result, it is rational to start the treatment of glaucoma with a drug in this group. In terms of pharmacoeconomics, the most affordable prostaglandin drug is latanoprost, which is generally as effective as other prostaglandin analogs. β-adrenergic blockers reduce the production of intraocular fluid, the formation of which is controlled by β1- and β2-adrenergic receptors. Therefore, non-selective β-blockers (timolol, levobunolol, metipranolol, and carteolol) have a pharmacodynamic advantage over selective β1-adrenergic antagonists (betaxolol). Conducted clinical studies of β-blockers have shown that given the cost, efficacy and safety, timolol was the most preferable treatment for glaucoma. In the presence of medical contraindications to the use of first-line drugs or to enhance their effectiveness, α2-agonists (apraclonidine and brimonidine), carbonic anhydrase inhibitors (usually local action: dorzolamide and brinzolamide), M-cholinomimetics (pilocarpine, carbachol and echothiopate), and also Rho-kinase inhibitors (ripasudil)

Influence of experimental heart failure therapy with different generations of β-adrenergic blockers on Cardiac Electrical Activity (ECG) and Autonomic Regulation of Heart Rhythm (ARHR)

Abstract: In the complex treatment of chronic heart failure (CHF) β-adrenoblockers (carvedilol, nebivolol, bisoprolol, metoprolol) are used, which due to their pharmacological properties increase the survival rate of patients, improve cardio- and haemodynamic parameters, metabolism. However, modern realities in medicine require creation of new more effective and safe β-adrenoblockers. In this regard, the potential drug Hypertirl is of interest. The aim was to evaluate the cardioprotective effect of 1-(b-phenylethyl)-4-amino-1,2,4-triazolium bromide (Hypertril) on cardiac electrical activity and autonomic regulation of heart rhythm in a model of CHF in comparison with β-adrenoblockers of different generations (Nebivolol, Carvedilol, Bisoprolol, Metoprolol). Materials and methods: Chronic heart failure was induced by 14-day administration of doxorubicin in a cumulative dose of 15 mg/kg to white mongrel rats weighing 190–220g (total 85). The investigated drugs were administered after doxorubicin course for 30 days: Hypertril at an experimentally substantiated dose of 3.5 mg/kg, Metoprolol succinate 15 mg/kg, Nebivolol 10 mg/kg, Carvedilol 50 mg/kg, Bisoprolol 10 mg/kg. At the end of drug administration under thiopental anaesthesia (40 mg/kg), electrocardiogram (ECG) and autonomic regulation of heart rhythm (ARHR) were analysed using a computer analyser CardioCom-2000plus (KAI-Medica, Ukraine). The results of the study were calculated using a standard statistical package “STATISTICA for Windows 6.0” (StatSoftInc., №AXXR712D833214FAN5), “SPSS 16.0” and “Microsoft Office Excell 2003”. Results and discussion: Hypertril administration resulted in a negative chronotropic effect, normalisation of atrial (P) and ventricular (R) spike amplitude, ST segment inversion below isoline, increased amplitude of ventricular myocardial repolarisation T. Myocardial repolarisation spike were observed, as well as normalised the duration of atrial (P) and ventricular depolarisation phase (QRS complex) to the intact value and restored the duration of electrical diastole (TR interval). Hypertril reduced systolic and diastolic myocardial dysfunction in animals with CHF. Hypertril restored autonomic mechanisms of heart rhythm regulation and balanced activity of sympathetic and parasympathetic parts of autonomic nervous system in the control of cardiac function. Conclusion: The obtained results demonstrated the undoubted advantage of the new original molecule (Hypertril) over basic β-adrenoblockers (Metoprolol, Nebivolol, Carvedilol and Bisoprolol) and experimentally justify further in-depth study to create on its basis a drug for the treatment of CHF.

ß1-adrenergic blockers preserve neuromuscular function by inhibiting the production of extracellular traps during systemic inflammation in mice.

Severe inflammation via innate immune system activation causes organ dysfunction. Among these, the central nervous system (CNS) is particularly affected by encephalopathies. These symptoms are associated with the activation of microglia and a potential infiltration of leukocytes. These immune cells have recently been discovered to have the ability to produce extracellular traps (ETs). While these components capture and destroy pathogens, deleterious effects occur such as reduced neuronal excitability correlated with excessive ETs production. In this study, the objectives were to determine (1) whether immune cells form ETs in the CNS during acute inflammation (2) whether ETs produce neuromuscular disorders and (3) whether an immunomodulatory treatment such as β1-adrenergic blockers limits these effects. We observed an infiltration of neutrophils in the CNS, an activation of microglia and a production of ETs following lipopolysaccharide (LPS) administration. Atenolol, a β1-adrenergic blocker, significantly decreased the production of ETs in both microglia and neutrophils. This treatment also preserved the gastrocnemius motoneuron excitability. Similar results were observed when the production of ETs was prevented by sivelestat, an inhibitor of ET formation. In conclusion, our results demonstrate that LPS administration increases neutrophils infiltration into the CNS, activates immune cells and produces ETs that directly impair neuromuscular function. Prevention of ETs formation by β1-adrenergic blockers partly restores this function and could be a good target in order to reduce adverse effects in severe inflammation such as sepsis but also in other motor related pathologies linked to ETs production.

Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.

Regulation of Soluble E-Cadherin Signaling in Non-Small-Cell Lung Cancer Cells by Nicotine, BDNF, and β-Adrenergic Receptor Ligands.

The ectodomain of the transmembrane protein E-cadherin can be cleaved and released in a soluble form referred to as soluble E-cadherin, or sE-cad, accounting for decreased E-cadherin levels at the cell surface. Among the proteases implicated in this cleavage are matrix metalloproteases (MMP), including MMP9. Opposite functions have been reported for full-length E-cadherin and sE-cad. In this study, we found increased MMP9 levels in the media of two non-small cell lung cancer (NSCLC) cell lines, A549 and H1299, treated with BDNF, nicotine, or epinephrine that were decreased upon cell treatment with the β-adrenergic receptor blocker propranolol. Increased MMP9 levels correlated with increased sE-cad levels in A549 cell media, and knockdown of MMP9 in A549 cells led to downregulation of sE-cad levels in the media. Previously, we reported that A549 and H1299 cell viability increased with nicotine and/or BDNF treatment and decreased upon treatment with propranolol. In investigating the function of sE-cad, we found that immunodepletion of sE-cad from the media of A549 cells untreated or treated with BDNF, nicotine, or epinephrine reduced activation of EGFR and IGF-1R, decreased PI3K and ERK1/2 activities, increased p53 activation, decreased cell viability, and increased apoptosis, while no effects were found using H1299 cells under all conditions tested.

ВЗАИМОСВЯЗЬ ПОКАЗАТЕЛЕЙ НАПРЯЖЕННОСТИ СИМПАТОАДРЕНАЛОВОЙ СИСТЕМЫ У ПАЦИЕНТОВ С ФИБРИЛЛЯЦИЕЙ ПРЕДСЕРДИЙ ДО И ПОСЛЕ ХИРУРГИЧЕСКОГО ЛЕЧЕНИЯ

Introduction. It is known that cardiovascular diseases, including cardiac arrhythmias, are accompanied by increased activation of the sympathetic-adrenal system (SAS). Hyperactivation of the SAS causes an increase in the level of circulating catecholamines - adrenaline and norepinephrine, resulting in desensitization of β-adrenergic receptors (β-AR), aggravation of myocardial contractile dysfunction and the development of arrhythmia. Indicators of SAS tension are β-adrenergic reactivity of erythrocyte membranes (β-ARM) and the level of circulating catecholamines. One of the most common arrhythmias is atrial fibrillation (AF), which leads to a decrease in the quality of life, disability and high mortality. Therefore, among patients with AF, it is important to study the functional viability of β-AR in different periods of the disease. Purpose: to evaluate β-ARM and the level of adrenaline, norepinephrine in patients with AF before and after surgical treatment. Materials and methods. The sample included 47 patients - 31 men and 16 women, the age in the sample was 51 (26; 77) years. All patients were diagnosed with AF based on ECG and 24-hour monitoring. Among the entire sample, 59.6% of patients had paroxysmal, 25.5% persistent, 14.9% long-term persistent forms of AF. All patients underwent surgical treatment of AF using radiofrequency or cryoablation. β-ARM was determined by the method of assessing changes in erythrocyte osmotic resistance as a result of blockade of β-AR in vitro with a selective β-adrenergic blocker (Β-ARM, AGAT, Russia). Plasma epinephrine and norepinephrine concentrations were determined by enzyme-linked immunosorbent assay using Adrenalin ELISA and Noradrenalin ELISA kits (Tecan IBL International, Germany). The parameters were studied in all patients before treatment, in 44 patients after 3 days, in 18 patients after 3 months and in 9 patients after 12 months after ablation. The significance of changes in β-ARM and catecholamine levels before and after ablation was assessed using the Wilcoxon test. The strength of the linear relationship between quantitative indicators was assessed using the Spearman rank correlation coefficient. Results. In the study sample, there were no statistically significant changes in β-ARM and adrenaline levels before and at different times after ablation. Thus, the level of β-ARM before surgery was 18.2 (12.6; 25.4), after 3 days - 22.3 (14.4; 26.6), after 3 months - 20.3 (9.3 ; 29.3), and 12 months after the operation - 27.7 (16.8; 36.7). The level of adrenaline before surgery, 3 days, 3 months and 12 months after surgery was 4.4 (3.7; 6.9), 4.7 (3.0; 6.4), 4.6 (2 .5; 6.6), 5.6 (9.1; 8.8). However, an increase in the level of norepinephrine was found 12 months after ablation compared with the values before treatment and 3 days after treatment by 1.7 and 1.8 times, respectively (p = 0.028). The level of norepinephrine before surgery, 3 days, 3 months and 12 months after surgery was 40.9 (18.7; 56.6), 38.6 (14.8; 49.6), 46.7 (25 .6; 57.3), 69.3 (65.1; 80.1). Before surgery, β-ARM and norepinephrine levels were linearly correlated (r = 0.335, p = 0.037), but after treatment, the linear correlation disappeared. At 3 and 12 months after ablation, there was a strong linear correlation between adrenaline and norepinephrine levels (r = 0.611, p = 0.012; r = 0.786, p = 0.036, respectively). Conclusion. In the sample of patients with AF, β-ARM and norepinephrine levels were linearly correlated before treatment, but after ablation, the correlation disappeared. At the same time, the values of β-ARM do not change statistically significantly, and the level of norepinephrine increases during a 12-month follow-up. Thus, 12 months after treatment in patients with AF, the activity of the CAS increases, but the functional viability of beta-AR does not change significantly.

Advanced Progress of the Relationship Between Antihypertensive Drugs and Bone Metabolism.

Hypertension and osteoporosis are common comorbidities among elderly individuals. Drug therapy has been widely used in clinical practice as the preferred antihypertensive treatment. Therefore, antihypertensive drugs have become some of the most commonly prescribed drugs in healthcare settings. However, antihypertensive drugs have different effects on bone metabolism. The results of animal and clinical studies on the effects of antihypertensive drugs on osteoporosis or fracture risk are controversial and have aroused widespread concern among clinicians. Recent studies found that angiotensin receptor blockers, selective β-adrenergic receptor blockers, and thiazide diuretics might improve bone trabecular number and bone mineral density by stimulating osteoblast differentiation, reducing osteoclast generation, and other mechanism. Furthermore, nonselective β-adrenergic receptor blockers and dihydropyridine calcium channel blockers were found to have no significant relationship with bone mineral density or bone strength, and α-adrenergic receptor blockers and loop diuretics might increase fracture risk by decreasing bone mineral density. This article aimed to review previous animal experiments, clinical studies, and meta-analyses focusing on the effects of different antihypertensive drugs on bone metabolism, and to provide a new approach for the prevention and treatment of osteoporosis.

β-blockers as the First Line of Treatment for Hypertension Management.

β-adrenergic blocker group of medicines has been traditionally used to control high blood pressure since propranolol was discovered by Sir James Black almost 50 years ago. They were the drug of choice in hypertension (HTN) associated with ischemic heart disease, tachyarrhythmias including atrial fibrillation (AF), and anxiety. Congestive cardiac failure was a relative contraindication, but with major advances in science, it became an absolute indication. However, with the advent of newer antihypertensives, especially calcium channel blocker (CCBs) and renin-angiotensin-aldosterone inhibitors, comparative studies were done, and depending on the outcomes of these trials, β-blockers (BBs) were downgraded to fourth or fifth-line therapy, except in the conditions mentioned above, along with HTN in pregnancy. But clinicians never rejected BBs as important antihypertensives, as evidenced by various real-world data. Also, many investigators found the unfairness of the trial designs where BBs were poor performers. The fact that all BBs are not similar, and differ widely in various properties, added to the question of downgrading all BBs on the basis of trials mostly with atenolol, which is also used once daily. Moreover, trials like ASCOT could not show the reduction of most of the events after long-term follow-up with the use of newer antihypertensives. Added to the issue is the fact that the majority of the trials used BBs with diuretics, and selecting BBs as the sole nonperformer appears to be unjustified and illogical. The recent European Society of HTN (ESH) guideline reemphasized the fact that all the five major classes of antihypertensives, including BBs, can be used as first-line medicine and also can be used interchangeably. Moreover, apart from the traditional indications of BBs, this guideline listed nineteen other conditions, including high heart rate (HR), chronic obstructive pulmonary disease (COPD), and obstructive sleep apnoea, as the conditions where BBs are preferred agents as antihypertensive. So, the life history of BBs in HTN has completed a full cycle, and they are ready now for prime time again. How to cite this article: Ray S, Saboo B, Joshi S, et al. β-blockers as the First Line of Treatment for Hypertension Management. J Assoc Physicians India 2023;71(9):95-100.

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder that may lead patients to sudden cell death through the occurrence of ventricular arrhythmias. ACM is characterised by the progressive substitution of cardiomyocytes with fibrofatty scar tissue that predisposes the heart to life-threatening arrhythmic events. Cardiac mesenchymal stromal cells (C-MSCs) contribute to the ACM by differentiating into fibroblasts and adipocytes, thereby supporting aberrant remodelling of the cardiac structure. Flecainide is an Ic antiarrhythmic drug that can be administered in combination with β-adrenergic blockers to treat ACM due to its ability to target both Nav1.5 and type 2 ryanodine receptors (RyR2). However, a recent study showed that flecainide may also prevent fibro-adipogenic differentiation by inhibiting store-operated Ca2+ entry (SOCE) and thereby suppressing spontaneous Ca2+ oscillations in C-MSCs isolated from human ACM patients (ACM C-hMSCs). Herein, we briefly survey ACM pathogenesis and therapies and then recapitulate the main molecular mechanisms targeted by flecainide to mitigate arrhythmic events, including Nav1.5 and RyR2. Subsequently, we describe the role of spontaneous Ca2+ oscillations in determining MSC fate. Next, we discuss recent work showing that spontaneous Ca2+ oscillations in ACM C-hMSCs are accelerated to stimulate their fibro-adipogenic differentiation. Finally, we describe the evidence that flecainide suppresses spontaneous Ca2+ oscillations and fibro-adipogenic differentiation in ACM C-hMSCs by inhibiting constitutive SOCE.

The Efficacy of Carvedilol in Comparison to Propranolol in Reducing the Hepatic Venous Pressure Gradient and Decreasing the Risk of Variceal Bleeding in Adult Cirrhotic Patients: A Systematic Review.

The most common cause of portal hypertension is liver cirrhosis. Portal hypertension causes many complications in cirrhotic patients; a significant complication is the formation of varices and the subsequent life-threatening variceal bleeding due to elevated portal venous pressures. Hepatic venous pressure gradient (HVPG) is the gold standard for measuring portal hypertension and guides management. Pharmacological treatments lower the HVPG, preventing the progression of varices and subsequent variceal bleeding. The pharmacological treatments frequently used in primary and secondary prophylaxis of a variceal bleed are nonselective beta (β)-adrenergic blockers. Propranolol was the first nonselective β-adrenergic blocker used for lowering HVPG and has been well studied. However, in the past decade, clinical trials have shown that carvedilol has been more effective. This study aims to establish whether carvedilol is more effective than propranolol in reducing the hepatic venous pressure gradient and decreasing the risk of variceal bleeding in adult cirrhotic patients. A systematic review has been conducted to gather relevant clinical trials comparing drugs and their effects on HVPG. Four databases: PubMed (Medical Literature Analysis and Retrieval System Online (MEDLINE)), Google Scholar, the Cochrane Library, and ScienceDirect, were analyzed, and records from January 1, 1999, to January 1, 2023, were chosen. There were a total of 1,235 potentially eligible records across the four databases. Using the eligibility criteria for this systematic review, seven studies of 533 patients were included. Across all seven clinical trials, it was found that carvedilol reduced HVPG more than propranolol and decreased the risk of variceal bleeding in adult cirrhotic patients.