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1 β‐Adrenoceptor antagonists (‘β‐blockers’) are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at β1‐adrenoceptors), while the worrisome side effects of bronchospasm result from airway β2‐adrenoceptor blockade. The aim of this study was to determine the selectivity of β‐antagonists for the human β‐adrenoceptor subtypes. 2 3H‐CGP 12177 whole cell‐binding studies were undertaken in CHO cell lines stably expressing either the human β1‐, β2‐ or the β3‐adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background. 3 In this study, the selectivity of well‐known subtype‐selective ligands was clearly demonstrated: thus, the selective β1 antagonist CGP 20712A was 501‐fold selective over β2 and 4169‐fold selective over β3; the β2‐selective antagonist ICI 118551 was 550‐ and 661‐fold selective over β1 and β3, respectively, and the selective β3 compound CL 316243 was 10‐fold selective over β2 and more than 129‐fold selective over β1. 4 Those β2‐adrenoceptor agonists used clinically for the treatment of asthma and COPD were β2 selective: 29‐, 61‐ and 2818‐fold for salbutamol, terbutaline and salmeterol over β1, respectively. There was little difference in the affinity of these ligands between β1 and β3 adrenoceptors. 5 The clinically used β‐antagonists studied ranged from bisoprolol (14‐fold β1‐selective) to timolol (26‐fold β2‐selective). However, the majority showed little selectivity for the β1‐ over the β2‐adrenoceptor, with many actually being more β2‐selective. 6 This study shows that the β1/β2 selectivity of most clinically used β‐blockers is poor in intact cells, and that some compounds that are traditionally classed as ‘β1‐selective’ actually have higher affinity for the β2‐adrenoceptor. There is therefore considerable potential for developing more selective β‐antagonists for clinical use and thereby reducing the side‐effect profile of β‐blockers. British Journal of Pharmacology (2005) 144, 317–322. doi:10.1038/sj.bjp.0706048

Background Takotsubo cardiomyopathy (TCM) is a left ventricular dysfunction resembling acute coronary syndrome. Its prognosis is generally favorable; however, a subset of patients may present with severe complications. TCM is a rare side‐effect of modified electroconvulsive therapy (ECT); it has been reported in 22 female and two male patients. Eight cases of ECT reinitiation after TCM have been reported (all females), with the shortest duration being 3 weeks. Case Presentation We report the case of a 61‐year‐old man with a history of major depressive disorder and no history of heart disease or previous ECT treatment. Antidepressants had been ineffective, and ECT was indicated. After the third ECT session, the patient complained of chest pain and shortness of breath. Electrocardiography revealed ST elevation, and catheter angiography was used to diagnose TCM. The patient had mild heart failure but remained stable. Recognizing that ECT was effective, the patient asked for it to be reinitiated. We confirmed that the cardiac function had been normalized, applied a bisoprolol fumarate patch as a preventive measure, and reinitiated ECT 14 days after the onset of TCM. ECT was performed five times, with no recurrence of TCM and a marked improvement in depression. Conclusion We describe a male patient with major depressive disorder who underwent reinitiation of ECT 2 weeks after ECT‐induced TCM. Therefore, TCM should be recognized as a side‐effect of ECT, even in men. Moreover, depending on whether the patient's condition is stable, ECT can be successfully performed in patients with TCM. We report the case of a male patient with major depressive disorder who underwent reinitiation of modified electroconvulsive therapy (ECT) 2 weeks after ECT‐induced Takotsubo cardiomyopathy(TCM). As a result, TCM should be recognized as a side‐effect of ECT, even in men. Furthermore, depending on the case and condition of the patient, ECT can be successfully performed in patients who have recently experienced TCM.

Breast cancer is the most common cancer diagnosed in women. It is associated with multiple symptoms in both patients and caregivers, such as stress, anxiety, depression, sleep disturbance, and fatigue. Stress appears to promote cancer progression via activation of the sympathetic nervous system releasing epinephrine and norepinephrine as well as activation of hypothalamic-pituitary-adrenal axis releasing cortisol. These stress hormones have been shown to promote the proliferation of cancer cells. This review focuses on stress-reducing strategies which may decrease cancer progression by abrogating these pathways, with a main focus on the β-adrenergic signaling pathway. Patients utilize both non-pharmacologic and pharmacologic strategies to reduce stress. Non-pharmacologic stress-reduction strategies include complementary and alternative medicine techniques, such as meditation, yoga, acupuncture, exercise, use of natural products, support groups and psychology counseling, herbal compounds, and multivitamins. Pharmacologic strategies include abrogating the β2-adrenergic receptor signaling pathway to antagonize epinephrine and norepinephrine action on tumor and immune cells. β-Blocker drugs may play a role in weakening the pro-migratory and pro-metastatic effects induced by stress hormones in cancer and strengthening the anti-tumor immune response. Preclinical models have shown that non-selective β1/2-blocker use is associated with a decrease in tumor growth and metastases and clinical studies have suggested their positive impact on decreasing breast cancer recurrence and mortality. Thus, non-pharmacological approaches, along with pharmacological therapies part of clinical trials are available to cancer patients to reduce stress, and have promise to break the cycle of cancer and stress.

A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a β₂-adrenergic receptor (β₂AR) agonist enhances skeletal muscle strength and hypertrophy; however, its clinical utility is limited by side effects such as cardiac arrhythmias mediated by G protein signaling. We recently reported that clenbuterol-induced increases in contractility and skeletal muscle hypertrophy were lost in β-arrestin 1 knockout mice, implying that arrestins, multifunctional adapter and signaling proteins, play a vital role in mediating the skeletal muscle effects of β₂AR agonists. Carvedilol, classically defined as a βAR antagonist, is widely used for the treatment of chronic systolic heart failure and hypertension, and has been demonstrated to function as a β-arrestin-biased ligand for the β₂AR, stimulating β-arrestin-dependent but not G protein-dependent signaling. In this study, we investigated whether treatment with carvedilol could enhance skeletal muscle strength via β-arrestin-dependent pathways. In a murine model, we demonstrate chronic treatment with carvedilol, but not other β-blockers, indeed enhances contractile force in skeletal muscle and this is mediated by β-arrestin 1. Interestingly, carvedilol enhanced skeletal muscle contractility despite a lack of effect on skeletal muscle hypertrophy. Our findings suggest a potential unique clinical role of carvedilol to stimulate skeletal muscle contractility while avoiding the adverse effects with βAR agonists. This distinctive signaling profile could present an innovative approach to treating sarcopenia, frailty, and secondary muscle wasting.

The β-blocker carvedilol has been shown to prevent skin carcinogenesis in vitro and in vivo. Since systemic absorption of the β-blocker may cause cardiovascular disturbance, we developed a carvedilol loaded transfersome for skin-targeted delivery. Transfersomes were prepared using phospholipids and surfactants at various ratios and characterized. One formulation (F18) selected for further analysis was composed of carvedilol, soy phosphatidylcholine, and Tween-80 at a ratio of 1:3:0.5, which had a particle size of 115.6 ± 8.7 nm, a zeta potential of 11.34 ± 0.67 mV, and an encapsulation efficiency of 93.7 ± 5.1%. F18 inhibited EGF-induced neoplastic transformation of mouse epidermal JB6 P+ cells at non-toxic concentrations, while only high concentrations induced cytotoxicity in JB6 P+ and human keratinocytes HaCaT. Compared to the free drug, F18 released through the dialysis membrane and permeated through the porcine ear skin at a slower rate, but similarly depositing the drug in the epidermis and dermis of the skin. Consistently, surface application of F18 on reconstructed full-thickness human skin showed slower drug permeation, while it suppressed ultraviolet-induced DNA damage, inflammatory gene expression, and apoptosis. These data indicate that transfersome is a promising topical delivery system of carvedilol for preventing ultraviolet-induced skin damage and carcinogenesis.

An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking β-blockers have better outcomes. Clinical trials testing whether β-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon.

This retrospective study compared cardiovascular (CV) outcomes between initial β‐blocker (BB) + calcium channel blocker (CCB) dual therapy (“B + C”) and other initial dual therapies in Chinese newly diagnosed hypertensive patients. In this study, all patients in a regional electronic database with newly diagnosed hypertension from January 01, 2012 to December 31, 2016 who received any initial optimal dual therapy recommended by the Chinese hypertension guideline were included. 1:2 propensity score matching (PSM) was used to balance baseline characteristics between patients receiving B + C and patients receiving other initial dual therapies (“Others”). The primary outcome was major adverse cardiovascular events (MACE) that occurred from January 01, 2012 to December 31, 2017, consisting of non‐fatal stroke, non‐fatal myocardial infarction (MI), non‐fatal chronic heart failure (CHF), and all‐cause death. Cox proportional hazard models were used to compare these CV outcomes in the 2 matched cohorts. After the PSM, 6227 patients receiving B + C and 12 454 patients receiving Others were included. Compared to patients receiving Others, patients receiving B + C had a significantly lower risk of MACE (hazard ratio [HR] 0.85; 95% confidential interval [CI] 0.78–0.92; p < .001), non‐fatal stroke (HR 0.89; 95% CI 0.81–0.98; p = .018) and non‐fatal CHF (HR 0.74; 95% CI 0.63–0.86; p < .0001). Additionally, differences in risks of non‐fatal MI and all‐cause death between the 2 treatment cohorts were not statistically significant. In conclusion, BB + CCB initial dual therapy was associated with a lower risk of MACE, stroke, and CHF than other optimal initial dual therapies recommended by the Chinese hypertension guideline in Chinese newly diagnosed hypertensive patients.

Background β-blocker s may protect against catecholaminergic myocardial injury in critically ill patients. Long-term β-blocker users are known to have lower lactate concentrations and favorable sepsis outcomes. However, the effects of β1-selective and nonselective β-blockers on sepsis outcomes have not been compared. This study was conducted to investigate the impacts of different β-blocker classes on the mortality rate in septic patients. Methods We retrospectively screened 2678 patients admitted to the medical or surgical intensive care unit (ICU) between December 2015 and July 2017. Data from patients who met the Sepsis-3 criteria at ICU admission were included in the analysis. Premorbid β-blocker exposure was defined as the prescription of any β-blocker for at least 1 month. Bisoprolol, metoprolol, and atenolol were classified as β1-selective β-blockers , and others were classified as nonselective β-blockers . All patients were followed for 28 days or until death. Results Among 1262 septic patients, 209 (16.6%) patients were long-term β-blocker users. Patients with premorbid β-blocker exposure had lower heart rates, initial lactate concentrations, and ICU mortality. After adjustment for disease severity, comorbidities, blood pressure, heart rate, and laboratory data, reduced ICU mortality was associated with premorbid β1-selective [adjusted hazard ratio, 0.40; 95% confidence interval (CI), 0.18–0.92; P = 0.030], but not non-selective β-blocker use. Conclusion Premorbid β1-selective, but not non-selective, β-blocker use was associated with improved mortality in septic patients. This finding supports the protective effect of β1-selective β-blockers in septic patients. Prospective studies are needed to confirm it.

Andersen–Tawil syndrome (ATS) is a rare disorder characterized by a triad of ventricular arrhythmia (VA), dysmorphic features, and periodic paralysis. Due to the rarity of this condition, less is known about physiologic effect of pregnancy to ATS and arrhythmia. There is no established guideline for peripartum or postpartum treatment and prevention of arrhythmia in ATS; thus, the clinical management is challenging. We reported two KCNJ2‐associated ATS patients who got pregnant and underwent vaginal birth safely. Both individuals had VA, micrognathia without periodic paralysis. β‐blocker plus flecainide could be an effective treatment combination when monotherapy failed to control arrhythmia. VA of two pregnant patients with ATS could be controlled by either physiologic changes associated pregnancy or the combination treatment of β‐blocker and flecainide.

In this study, an animal model of moderate‐severe traumatic brain injury (TBI) was treated with an acute dose of propranolol followed by a delayed dose of human mesenchymal stem cells (MSCs), resulting in improved short‐ and long‐term measurements. These results reinforce the inevitable clinical trial of MSCs to treat TBI by demonstrating, among other benefits, a notable decrease in chronic neuroinflammation and demonstrating that MSCs and propranolol are compatible treatments that improve overall outcome. More than 6.5 million patients are burdened by the physical, cognitive, and psychosocial deficits associated with traumatic brain injury (TBI) in the U.S. Despite extensive efforts to develop neuroprotective therapies for this devastating disorder, there have been no successful outcomes in human clinical trials to date. Retrospective studies have shown that β‐adrenergic receptor blockers, specifically propranolol, significantly decrease mortality of TBI through mechanisms not yet fully elucidated but are thought to counterbalance a hyperadrenergic state resulting from a TBI. Conversely, cellular therapies have been shown to improve long‐term behavior following TBI, likely by reducing inflammation. Given the nonredundancy in their therapeutic mechanisms, we hypothesized that a combination of acute propranolol followed by mesenchymal stem cells (MSCs) isolated from human bone marrow would have additive effects in treating a rodent model of TBI. We have found that the treatments are well‐tolerated individually and in combination with no adverse events. MSCs decrease BBB permeability at 96 hours after injury, inhibit a significant accumulation of activated microglia/macrophage in the thalamic region of the brain both short and long term, and enhance neurogenesis short term. Propranolol decreases edema and reduces the number of fully activated microglia at 7 days and the number of semiactivated microglia at 120 days. Combinatory treatment improved cognitive and memory functions 120 days following TBI. Therefore, the results here suggest a new, efficacious sequential treatment for TBI may be achieved using the β‐blocker propranolol followed by MSC treatment. Significance Despite continuous efforts, traumatic brain injury (TBI) remains the leading cause of death and disability worldwide in patients under the age of 44. In this study, an animal model of moderate‐severe TBI was treated with an acute dose of propranolol followed by a delayed dose of human mesenchymal stem cells (MSCs), resulting in improved short‐ and long‐term measurements. These results have direct translational application. They reinforce the inevitable clinical trial of MSCs to treat TBI by demonstrating, among other benefits, a notable decrease in chronic neuroinflammation. More importantly, these results demonstrate that MSCs and propranolol, which is increasingly being used clinically for TBI, are compatible treatments that improve overall outcome.