Β-adrenergic Agonist Research Articles

N-cadherin antagonism is bronchoprotective in severe asthma models.

Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and β-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. No drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. We find that N-cadherin, a membrane cell-cell adhesion protein up-regulated in ASM from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation, prevented bronchoconstriction, and actively promoted bronchodilation of airways ex vivo. ADH-1 inhibited ASM contraction by disrupting N-cadherin-δ-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma.

Formoterol dynamically alters endocannabinoid tone in the periaqueductal gray inducing headache

BackgroundHeadache is a pain disorder present in populations world-wide with a higher incidence in females. Specifically, the incidences of medication overuse headache (MOH) have increased worldwide. Comorbidities of MOH include photosensitivity, anxiety, “brain fog”, and decreased physical activity. The FDA-approved long-lasting selective β2-adrenergic receptor agonist, formoterol, is currently approved for use in severe asthma and chronic obstructive pulmonary disease. Recently, interest in repurposing formoterol for use in other disorders including Alzheimer’s disease, and neuropathic pain after spinal cord injury and traumatic brain injury has gained traction. Thus, revisiting known side-effects of formoterol, like headache and anxiety, could inform treatment paradigms. The endocannabinoid (eCB) system is implicated in the etiology of preclinical headache, with observed decreases in the circulating levels of endogenous cannabinoids, referred to as Clinical Endocannabinoid Deficiency. As cross-talk between the eCB system and adrenergic receptors has been reported, this study investigated the role of the eCB system and ability of formoterol to induce headache-like periorbital allodynic behavior.MethodsFemale 8-week-old C57Bl/6J mice were treated daily with formoterol (0.3 mg/kg, i.p.) for up to 42-days, during which they were assessed for periorbital allodynia, open field/novel object recognition, and photosensitivity. At the end of the study, the periaqueductal grey (PAG), a brain region known to contribute to both headache induction and maintenance, was collected and subjected to LC-MS to quantify endocannabinoid levels.ResultsMice exhibited periorbital allodynia at nearly all time points tested and photosensitivity from 28-days onward. Levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptor 1 (CB1R) expression were altered by both age and upon treatment with formoterol. Administration of FAAH/MAGL inhibitors, to target the eCB system, and a non-selective cannabinoid receptor agonist, WIN 55,212 reversed the formoterol-induced periorbital allodynia.ConclusionsThese results suggest that formoterol is dysregulates eCB tone to drive headache-like periorbital allodynic behaviors. These results could help inform preventative treatment options for individuals receiving formoterol, as well as provide information on the interaction between the eCB and adrenergic system.Graphical

Upregulation of inhibitor of DNA binding 1 and 3 is important for efficient thermogenic response in human adipocytes.

Brown and beige adipocytes can be activated by β-adrenergic agonist via cAMP-dependent signaling. Performing RNA-sequencing analysis in human cervical area-derived adipocytes, we found that dibutyryl-cAMP, which can mimic in vivo stimulation of browning and thermogenesis, enhanced the expression of browning and batokine genes and upregulated several signaling pathway genes linked to thermogenesis. We observed that the expression of inhibitor of DNA binding and cell differentiation (ID) 1 and particularly ID3 was strongly induced by the adrenergic stimulation. The degradation of ID1 and ID3 elicited by the ID antagonist AGX51 during thermogenic activation prevented the induction of proton leak respiration that reflects thermogenesis and abrogated cAMP analogue-stimulated upregulation of thermogenic genes and mitochondrial complex I, II, and IV subunits, independently of the proximal cAMP-PKA signaling pathway. The presented data suggests that ID proteins contribute to efficient thermogenic response of adipocytes during adrenergic stimulation.

Dietary energy level and β2-adrenergic agonist supplementation on growth performance, dietary energy, carcass traits, and visceral mass of hairy lambs

Context The beta-agonist zilpaterol (ZH) is a feed additive that improves growth performance via protein accretion during the finishing phase of ruminant fattening. However, evaluating the possible interaction between ZH and nutrients of the diet has received limited attention. Aims We investigated the changes in growth performance and carcass traits in response to ZH supplementation of hairy lambs fed finishing diets with different energy concentration. Methods Forty-eight Pelibuey × Katahdin crossbred male lambs (43.8 ± 6.3 kg) were used in a 34-day feeding trial to evaluate the interaction between diet energy density [8.37 (LE) and 8.79 (HE) MJ of net energy for maintenance (NEm) per kilogram of diet] and zilpaterol hydrochloride supplementation (ZH, dosed at 0 or 6 mg ZH/kg) on growth performance, carcass traits, and visceral mass. All diets contained 14.5% crude protein (CP). Key results There was no interaction of energy level and ZH in any of the variables evaluated. HE increased average daily gain (ADG) and gain efficiency (GF) without affecting the observed-to-expected dietary NE. Zilpaterol supplementation increased ADG, GF, and observed-to-expected dietary NE. Both HE and ZH increased carcass weight. HE increased carcass fat, whereas ZH decreased it. HE increased dressing percentage. ZH increased longissimus muscle area, the muscle:fat ratio in the shoulder, and leg whole-cut proportion. Visceral mass was not affected by energy level. ZH decreased visceral fat. Conclusions Increasing diet energy from 8.37 to 8.79 MJ NEm/kg enhanced growth performance and carcass traits but did not improve dietary energy utilization. Supplemental ZH enhanced growth performance, dietary-energy utilization and carcass traits of lambs. Implications ZH supplementation is a tool to enhance growth performance by improving protein accretion and reducing carcass fat. Response to ZH supplementation is independent of the differences in energy density of finishing diets.

The role of progesterone preparations in the prevention of premature birth: a modern view of the problem

Despite significant progress achieved in healthcare, preterm birth is an urgent problem in modern obstetrics. The preterm birth can be caused by various risk factors: for example, an ascending infection can trigger the onset of uterine contractions, cervical shortening followed by infection of the fetal membranes, amniotic fluid, and, in rare cases, the fetus itself. In most cases, the infectious and inflammatory process is the etiopathogenetic factor of isthmic-cervical insufficiency (ICI), one of the common causes of late miscarriages and preterm births. The period between 14 and 20 weeks of gestation is the most critical time for the development of ICI. The dynamic ultrasound cervicometry once every 7–14 days from week 16 through week 24 of pregnancy is recommended to the patients with ICI, as well as pregnant women in the high-risk group. Most professional societies guidelines addressing this issue recommend all pregnant women to perform routine transvaginal cervicometry during the second ultrasound screening for the timely formation of risk groups and optimization of approaches to the patient management. The following groups of drugs are used to prevent preterm birth: micronized progesterone, slow calcium channel blockers, β-adrenergic agonists, and non-steroidal anti-inflammatory drugs. The use of progesterone drugs to prevent preterm birth has generated much debate. Thus, the availability of several forms of progesterone and various routes of administration determine the complexity of the drug therapy. Micronized progesterone is the only progesterone drug that was approved for use after 20 weeks of gestation. The vaginal micronized progesterone has been found to be highly effective in the prevention of preterm birth, significantly reduce neonatal mortality and improve infant morbidity outcomes.

β3-adrenergic agonist counters oxidative stress and Na+-K+ pump inhibitory S-glutathionylation of placental cells: Implications for preeclampsia.

Oxidative stress from placental ischemia/reperfusion and hypoxia/reoxygenation (H/R) in preeclampsia is accompanied by Na+-K+ pump inhibition and S-glutathionylation of its β1 subunit (GSS-β1), a modification that inhibits the pump. β3-adrenergic receptor (β3-AR) agonists can reverse GSS-β1. We examined effects of the agonist CL316,243 on GSS-β1 and sources of H/R-induced oxidative stress in immortalized first trimester human trophoblast (HTR-8/SVneo) and freshly isolated placental explants from normal term pregnancies. H/R increased GSS-β1 and, reflecting compromised α1/β1 subunit interaction, it reduced α1/β1 pump subunit co-immunoprecipitation. H/R increased p47phox/p22phox NADPH oxidase subunit co-immunoprecipitation reflecting membrane translocation of cytosolic p47phox that is needed to activate NADPH oxidase. Fluorescence of O2•--sensitive dihydroethidium increased in parallel. H/R increased S-glutathionylation of endothelial nitric oxide synthase (GSS-eNOS) that uncouples NO synthesis towards synthesis of O2•- and reduced trophoblast migration. Oxidative stress induced by tumor necrosis factor α (TNF-α) increased soluble fms-like tyrosine kinase receptor 1 (sFlt-1) trophoblast release, a marker of preeclampsia, and reduced trophoblast integration into endothelial cellular networks. CL316,243 eliminated H/R-induced GSS-β1 and decreases of α1/β1 subunit coimmunoprecipitation, eliminated NADPH oxidase activation and increases in GSS-eNOS, restored trophoblast migration, eliminated increased sFlt-1 release and restored trophoblast integration in endothelial cell networks. H/R induced GSS-β1, α1/β1 subunit co-immunoprecipitation and NADPH oxidase activation of placental explants reflected effects of H/R for trophoblasts and CL316,243 eliminated these changes. We conclude a β3-AR agonist counters key pathophysiological features of preeclampsia in vitro. β3 agonists already in human use for another purpose are potential candidates for re-purposing to treat preeclampsia.

Effect of isoproterenol, a β-adrenergic agonist, on the differentiation of insulin-producing pancreatic β cells derived from human pluripotent stem cells

Research on islet replacement through the differentiation of functionally matured insulin-producing β-like cells for the treatment of diabetes presents a significant challenge. Neural signals in β cell differentiation significantly impact the pancreatic microenvironment in glucose metabolism, but they are not fully understood. In this study, isoproterenol, a β adrenoreceptor agonist, was introduced into pancreatic progenitor cells, derived from human pluripotent stem cells in vitro, undergoing endocrine differentiation, using 2-dimensional (2D) and 3-dimensional (3D) differentiation protocols. This resulted in increased insulin and C-peptide secretion, along with elevated expression of key pancreatic beta cell transcription factors, including PDX-1, NKX6.1, and MAFA, and improved function, demonstrated by increased responsiveness to glucose determined via a glucose-stimulated insulin secretion test. Moreover, RNA transcriptome analysis of isoproterenol-treated endocrine progenitors facilitated the identification of biological pathways and genes that contribute to mature beta cell differentiation efficiency correlated with neural signals, such as adrenoceptor beta 1, calcium/calmodulin dependent protein kinase II alpha, phospholipase C delta 4, and neurotrophic receptor tyrosine kinase 1. Among those genes, calcium/calmodulin dependent protein kinase II alpha was suggested as the most notable gene involved in the isoproterenol mechanism through inhibitor assays. This study illustrates that isoproterenol significantly enhances endocrine differentiation and underscores its effects on stem cell-derived beta cell maturation, emphasizing its therapeutic potential for the treatment of diabetes.

Impact of noradrenergic inhibition on neuroinflammation and pathophysiology in mouse models of Alzheimer's disease.

Norepinephrine (NE) modulates cognitive function, arousal, attention, and responses to novelty and stress, and also regulates neuroinflammation. We previously demonstrated behavioral and immunomodulatory effects of beta-adrenergic pharmacology in mouse models of Alzheimer's disease (AD). The current studies were designed to block noradrenergic signaling in 5XFAD mice through 1 ) chemogenetic inhibition of the locus coeruleus (LC), 2) pharmacologic blocking of β-adrenergic receptors, and 3) conditional deletion of β1- or β2-adrenergic receptors (adrb1 or adrb2) in microglia. First, brain-wide AD pathology was mapped in 3D by imaging immunolabeled, cleared 5XFAD brains to assess the overlap between Aβ pathology, reactive microglia, and the loss of tyrosine hydroxylase (TH) expression in the catecholaminergic system. To examine the effects of inhibiting the LC NE system in the 5XFAD model, inhibitory (Gi) DREADD receptors were expressed specifically in LC NE neurons. LC NE neurons were chronically inhibited through the subcutaneous pump administration of the DREADD agonist clozapine-N-oxide (CNO). Plasma and brains were collected for assessment of neuroinflammation and pathology. A separate cohort of 5XFAD mice was chronically dosed with the beta-adrenergic antagonist propranolol or vehicle and evaluated for behavior, as well as post-mortem neuroinflammation and pathology. Finally, we used 5XFAD mice with conditional deletion of either adrb1 or adrb2 in microglia to assess neuroinflammation and pathology mediated by β-adrenergic signaling. Using iDISCO, light sheet fluorescence microscopy, and novel analyses, we detected widespread microgliosis and amyloid pathology, along with modest TH downregulation in fibers across multiple brain regions, in contrast to the spatially limited TH downregulation observed in neurons. Both chemogenetic inhibition of LC adrenergic signaling and pharmacological inhibition of beta-adrenergic receptors potentiated neuroinflammation without altering amyloid beta pathology. Conditional deletion of adrb1 in microglia did not affect neuroinflammation. Conditional deletion of adrb2 in microglia attenuated inflammation and pathology in females but had no effect in males. Overall, these data support previous observations demonstrating the immunomodulatory effects of beta-adrenergic signaling in the pathophysiology of brain disorders and suggest that adrenergic receptors on cell types other than microglia, such as astrocytes, may predominantly mediate the disease-modifying effects of β-adrenergic agonists in the brain.

FDG Uptake in Brown Adipose Tissue Activated by a Long-Acting β2-Adrenergic Receptor Agonist Inhaler Prescribed for Bronchial Asthma.

We herein report a case of an elderly woman in whom brown adipose tissue (BAT) was visible on 18 F-FDG PET imaging performed in the summer. In this patient, none of the well-known factors that induce BAT activation in adults, including cold exposure, catecholamine-producing tumors, or β3-adrenergic receptor agonists administration, were present. Daily inhalation of a long-acting β2-adrenergic agonist for treatment of her bronchial asthma was considered the cause of her BAT visualization. This case suggests the need to consider β2-adrenergic receptor agonists as a cause of BAT visualization.

New Brønsted–Lowry acid Co(II) complexes: Synthesis, characterization, and investigation of electrochemical application for sensing of salbutamol

In recent years, the employment of transition metal complexes for working electrode surface modification for sensor fabrication has become an area of research direction. Based on this, in this study, three Co(II) complexes: Co(phen)Cl2 (CoC12H8N2Cl2) (C1), and Brønsted–Lowry acids Co(phen)(HTA)Cl (CoC16H13N2O6Cl)(C2), and Co(phen)(HTA)2 (CoC20H18N2O12)(C3) were synthesized and characterized using various techniques such as UV–Vis, FT-IR, ICP OES, TGA, DTA, pXRD as well as electrolytic conductivity, and acid-base property analysis. C and C3 were found polycrystalline whose size falls within the nano range of 50 and 51 nm, respectively. The synthesis was intended to get materials for voltammetrically modifying glassy carbon electrodes for the determination of salbutamol. Salbutamolis a short-acting β2adrenergic receptor agonist that is applied for opening the medium and large airways in the lungs and eventually treats asthma among other problems. The electrochemical application of the synthesized materials was studied by fabricating through electropolymerization of C1, C2, and C3 on glassy carbon electrodes. The poly(C1)/GCE, poly(C2)/GCE, and poly(C3)/GCE) revealed effective surface area is 0.174 cm2, 0.183 cm2, and 0.281 cm2, respectively, and electrochemical catalysis of the materials increased with the number of the tartrate. The Rct values are 5686, 242, 216, and 185 Ω cm2, while the Cdl values are 9.93 × 10−8, 5.35 × 10−6, 1.25 × 10−5, and 2.72 × 10−5, for bare GCE, poly(C1)/GCE, poly(C2)/GCE and poly(C3)/GCE, respectively. Similarly, the rate of charge transfer (k°) increased significantly on the modified electrode compared to the bare GCE. Salbutamol demonstrated a single well-shaped irreversible oxidative peak at the modified electrodes in the ascending order of poly(C1)/GCE, poly(C2)/GCE, and poly(C3)/GCE when compared to a bare GCE.

The β2-adrenergic biased agonist nebivolol inhibits the development of Th17 and the response of memory Th17 cells in an NF-κB-dependent manner.

Adrenergic receptors regulate metabolic, cardiovascular, and immunological functions in response to the sympathetic nervous system. The effect of β2-adrenergic receptor (AR) as a high expression receptor on different subpopulations of T cells is complex and varies depending on the type of ligand and context. While traditional β2-AR agonists generally suppress T cells, they potentially enhance IL-17A production by Th17 cells. The effects of pharmacological drugs that count as biased agonists of AR like nebivolol are not completely understood. We investigated the impact of nebivolol on human memory CD4+ T (Th1, Th2, Th17) cells and polarized naive Th17 cells, highlighting its potential for IL-17A suppression via a non-canonical β2-AR cell signaling pathway. The effects of nebivolol were tested on healthy human peripheral blood mononuclear cells, purified memory Th cells, and polarized naive Th17 cells activated with anti-CD3/anti-CD28/anti-CD2 ImmunoCult reagent. IFN-γ, IL-4, and IL-17A, which are primarily derived from Th1, Th2, and Th17 cells, respectively, were quantified by ELISA and flow cytometry. IL-10 was measured by ELISA. Gene expression of RORC, ADRB1, ADRB2, and ADRB3 was evaluated by qPCR. The ADRB2 gene was knocked out in memory Th cells using CRISPR/Cas9. Protein expression of phosphorylated serine133-CREB and phosphorylated NF-κB p65 was assessed by Western blot. Proliferation was assessed by fluorescent dye loading and flow cytometry. Nebivolol treatment decreased IL-17A and IFN-γ secretion by activated memory Th cells and elevated IL-4 levels. Nebivolol reduced the proportion of IL-17A+ Th cells and downregulated RORC expression. Unlike the β2-AR agonist terbutaline, nebivolol inhibited the shift of naive CD4+ T cells toward the Th17 phenotype. IL-10 and the proliferation index remained unchanged. Nebivolol-treated β2-knockout memory Th cells showed significant inhibition of β2-AR-mediated signaling, evidenced by the absence of IL-17A suppression compared to controls. Phosphorylation of the NF-κB p65 subunit was inhibited by nebivolol, but CREB phosphorylation was not changed, suggesting a selective transcriptional control. The findings demonstrate that nebivolol acts through a β2-AR-mediated signaling pathway, as a distinctive anti-inflammatory agent capable of selectively shifting Th17 cells and suppressing the phosphorylation of NF-κB. This highlights nebivolol's potential for therapeutic interventions in chronic autoimmune conditions with elevated IL-17A levels.

TongGuanWan Alleviates Doxorubicin- and Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis by Modulating Apoptotic and Fibrotic Pathways.

Heart failure, a major public health issue, often stems from prolonged stress or damage to the heart muscle, leading to cardiac hypertrophy. This can progress to heart failure and other cardiovascular problems. Doxorubicin (DOX), a common chemotherapy drug, and isoproterenol (ISO), a β-adrenergic agonist, both induce cardiac hypertrophy through different mechanisms. This study investigates TongGuanWan (TGW,), a traditional herbal remedy, for its effects on cardiac hypertrophy and fibrosis in DOX-induced H9c2 cells and ISO-induced mouse models. TGW was found to counteract DOX-induced increases in H9c2 cell surface area (n = 8, p < 0.01) and improve biomarkers like ANP (n = 3, p < 0.01)) and BNP (n = 3, p < 0.01). It inhibited the MAPK pathway (n = 4, p < 0.01) and GATA-4/calcineurin/NFAT-3 signaling, reduced inflammation by decreasing NF-κB p65 translocation, and enhanced apoptosis-related factors such as caspase-3 (n = 3, p < 0.01), caspase-9 (n = 3, p < 0.01), Bax (n = 3, p < 0.01), and Bcl-2 (n = 3, p < 0.01). Flow cytometry showed TGW reduced apoptotic cell populations. In vivo, TGW reduced heart (n = 8~10, p < 0.01), and left ventricle weights (n = 6~7), cardiac hypertrophy markers (n = 3, p < 0.01), and perivascular fibrosis in ISO-induced mice, with Western blot analysis confirming decreased levels of fibrosis-related factors like fibronectin, α-SMA (n = 3, p < 0.05), and collagen type I (n = 3, p < 0.05). These findings suggest TGW has potential as a therapeutic option for cardiac hypertrophy and fibrosis.

Chromogranin B Protects Human Umbilical Endothelial Cells against Oxidative Stress

Chromogranin B (CgB) is involved in the control of the cardiovascular system through the regulation of catecholamine release. Whether CgB can exert direct actions on the endothelium has not yet been clarified. Here, we aimed to investigate the effects of CgB on cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), glutathione (GSH), nitric oxide (NO) release, and the cytosolic calcium concentration ([Ca2+]c) in human vascular endothelial cells (HUVECs) cultured under both physiological and peroxidative conditions. In HUVECs, experiments were conducted to establish the proper concentration and timing of CgB stimulation. Thereafter, specific assays were used to evaluate the response of HUVECs cultured in physiologic or oxidative stress conditions to CgB in the presence or absence of β-adrenergic receptor agonists and antagonists and intracellular pathways blockers. Analysis of cell viability, mitochondrial membrane potential, and NO release revealed that CgB was able to cause increased effects in HUVECs cultured in physiological conditions. Additionally, the same analyses performed in HUVECs cultured with H2O2, showed protective effects exerted by CgB, which was also able to counteract ROS release and maintain GSH levels. Furthermore, CgB played a dual role on the [Ca2+]c depending on the physiological or peroxidative cell culturing conditions. In conclusion, our data provide new information about the direct role of CgB in the physiological regulation of endothelial function and highlight its potential as a protective agent against peroxidative conditions, such as those found in cardiovascular diseases.

“Muscarinic Receptor Antagonists: From Pharmacology to Folklore: Discovering Medications that Effectively Treat COPD and Asthma”

Acetylcholine is released into M3 muscarinic receptors by parasympathetic neurons, which give them dominating control over the smooth muscle of the airways in the lungs. Anticholinergic medications that inhibit muscarinic receptors have been used to treat respiratory disorders for more than 2,000 years. Clinical outcomes for antimuscarinic medications in asthma were inconsistent, despite pharmacologic data suggesting that they should be quite effective. As a result, the use of muscarinic antagonists decreased after β-adrenergic receptor agonists were found to be effective. Numerous reasons, such as undesirable side effects (which might range from dry mouth to coma) and the identification of other muscarinic receptor subtypes in the lungs that occasionally have conflicting effects, contribute to the lack of efficacy of muscarinic antagonists. Possibly the most significant issue is inefficient dosing as a result of poorly understood variations in administration routes is no reliable method for determining if antagonists block receptors that acetylcholine stimulates physically. Asthma and chronic obstructive pulmonary disease seem to respond well to the development of newer muscarinic receptor antagonists that address the issues of side effects and receptor specificity.

Trends of Overactive Bladder and Pharmacologic Treatment Among U.S. Women.

To evaluate and consider how prescribing practices have changed in relation to high-risk overactive bladder (OAB) medications. The objective of this study was to evaluate trends in the prevalence of OAB and pharmacologic treatment over time in the United States. Data from the National Health and Nutrition Examination Survey (NHANES, 2001-2018, n = 30,478) and the National Ambulatory Medical Care Survey (NAMCS, 2003-2019, n = 251,330) were used to identify women with symptomatic incontinence and overactive bladder (OAB) (NHANES) as well as determine the frequency of prescription use for OAB medications (NHANES and NAMCS) using sampling-based weights. Joinpoint regression was used to determine adjusted annual percent change (APC, adjusting for race, age, body mass index, and insurance status). Trends were assessed overall and by race, age, body mass index, and insurance status. The prevalence of OAB was 31.2% in the final survey year of NHANES (2017-2018). Women aged >65 years had the highest prevalence of OAB at 54% compared with other age groups. There was an overall increase in OAB (APC 1.24 [0.64, 1.84], P = 0.002) over time. Overall, only 3.5% of patients with symptoms of OAB reported pharmacologic treatment in NHANES. The NAMCS demonstrated a significant decrease in anticholinergic prescriptions from 2003 until 2019 (APC -6.44 [-9.77, -2.98], P = 0.001). However, in NHANES, there was no significant change in anticholinergic use (APC 0.62 [-20.2, 26.8], P = 0.944). There was a stable prevalence of β3-adrenergic agonist prescriptions since they were introduced to market (APC 0.65 [-2.24, 3.62], P = 0.616). This study demonstrates an increasing prevalence of OAB and highlights the likely undertreatment of symptomatic patients. The high and increasing prevalence coupled with the relative undertreatment of OAB underscores the importance of screening for this condition.

β-Adrenergic Agonist-Induced Lactic Acidosis: A Case Report.

β-Adrenergic agonist medications such as albuterol are the mainstay for treatment of patients with acute asthma exacerbations. Patients who present to the emergency department with severe symptoms are often treated with multiple albuterol doses in sequence to maximize the impact of the medications, relax bronchoconstriction, and relieve their breathlessness. Patients who present with acute dyspnea have numerous potential causes of hyperlactatemia and acidosis including an uncommonly recognized outcome of albuterol administration. This clinical case report outlines a scenario where a patient who was treated for an acute asthma exacerbation had rising lactate levels despite improving clinically. Causes of elevated lactate levels are discussed, particularly related to β-adrenergic agonist use, and considerations for monitoring and withdrawal of albuterol administration are outlined.

SARS-CoV-2 spike protein acts as a β-adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID.

Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown. Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac β-adrenergic receptor (β-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to β1- and β2-AR, but not to D1-dopamine receptor. These interactions were blocked by β1- and β2-AR blockers. Molecular docking and MST assay of β-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both β-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on β-ARs. Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric β-AR agonist, leading to cardiac β-AR hyperactivity, thus contributing to PASC-CVS.

Chronic β3-AR stimulation activates distinct thermogenic mechanisms in brown and white adipose tissue and improves systemic metabolism in aged mice.

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age-related metabolic dysfunction.

SEDATION AND LARYNGOSPASM IN PEDIATRIC SURGERY

Introduction: The use of anesthetics in pediatrics is essential for diagnostic and therapeutic procedures. The incidence of post-anesthetic respiratory complications is often avoidable with appropriate intervention. Laryngospasm, a reflex obstruction of the vocal cords, is more common in children. Objective: To discuss respiratory complications, with an emphasis on laryngospasm, during the use of anesthetics in pediatric procedures. Method: The Medical Literature Analysis and Retrieval System Online (MEDLINE, via PUBMED), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), and Virtual Health Library (VHL) databases were used. Seven articles were selected that met the systematic review criteria. Results: The incidence of laryngospasm is 0.87% in adults, 1.7% in children, and 2.82% in babies. In children, it occurs mainly during emergence from anesthesia. Risk factors include inadequate anesthesia, respiratory infections and multiple attempts at airway management. Drug combinations such as propofol, ketamine and fentanyl are used to minimize complications. Preventive measures include clearing secretions and adequate depth of anesthesia. Drugs such β2-adrenergic agonists, such as albuterol, are used to reduce respiratory resistance during intubation. Training strategies with low-cost simulators are effective for managing difficult airways in pediatrics. In pediatric surgery, the laryngeal mask is preferred to endotracheal intubation to reduce respiratory complications. Studies indicate that positive communication between anesthesia teams improves performance in critical situations. Conclusion: Laryngospasm is a serious complication in pediatric anesthesia, more common in children due to their anatomy and sensitive reflexes. Risk factors include respiratory infections, asthma, smoking, gastroesophageal reflux, and superficial anesthesia. Prevention involves the proper use of anesthetics, cleaning secretions and careful monitoring. Medications such as propofol, ketamine, and albuterol can reduce adverse effects. Simulator training and effective communication in anesthesia teams improve clinical performance. With proper management, most episodes are resolved without long-term complications.

Influence of β2-adrenergic selective agonist formoterol on the motor unit of a mouse model of a congenital myasthenic syndrome with complete VAChT deletion

Congenital Myasthenic Syndromes (CMS) are a set of genetic diseases that affect the neuromuscular transmission causing muscular weakness. The standard pharmacological treatment aims at ameliorating the myasthenic symptom by acetylcholinesterase inhibitors. Most patients respond well in the short and medium term, however, over time the beneficial effects rapidly fade, and the efficacy of the treatment diminishes. Increasing evidence shows that β2-adrenergic agonists can be a suitable choice for the treatment of neuromuscular disorders, including CMS, as they promote beneficial effects in the neuromuscular system. The exact mechanism on which they rely is not completely understood, although patients and animal models respond well to the treatment, especially over extended periods. Here, we report the use of the long-lasting specific β2-adrenergic agonist formoterol in a myasthenic mouse model (mnVAChT-KD), featuring deletion of VAChT (Vesicular Acetylcholine Transporter) specifically in the α-motoneurons. Our findings demonstrate that formoterol treatment (300 μg/kg/day; sc) for 30 days increased the neuromuscular junction area, induced skeletal muscle hypertrophy and altered fibre type composition in myasthenic mice. Interestingly, β2-adrenergic agonists have shown efficacy even in the absence of ACh (acetylcholine). Our data provide important evidence supporting the potential of β2-adrenergic agonists in treating neuromuscular disorders of pre-synaptic origin and characterized by disruptions in nerve-muscle communication, through a direct and beneficial action within the motor unit.