Adrenergic Antagonists Research Articles

Remyelinating activities of Carvedilol or alpha lipoic acid in the Cuprizone-Induced rat model of demyelination.

Multiple sclerosis (MS) is a complex and multifactorial neurodegenerative disease with unknown etiology, MS is featured by multifocal demyelinated lesions distributed throughout the brain. It is assumed to result from an interaction between genetic and environmental factors, including nutrition. Therefore, different therapeutic approaches are aiming to stimulate remyelination which could be defined as an endogenous regeneration and repair of myelin in the central nervous system. Carvedilol is an adrenergic receptor antagonist. Alpha lipoic acid (ALA) is a well-known antioxidant. Herein, we investigated the remyelination potential of Carvedilol or ALA post-Cuprizone (CPZ) intoxication. Carvedilol or ALA (20mg/kg/d) was administrated orally for two weeks at the end of the five weeks of CPZ (0.6%) administration. CPZ provoked demyelination, enhanced oxidative stress, and stimulated neuroinflammation. Histological investigation of CPZ-induced brains showed obvious demyelination in the corpus callosum (CC). Both Carvedilol and ALA demonstrated remyelinating activities, with corresponding upregulation of the expression of MBP and PLP, the major myelin proteins, downregulation of the expression of TNF-α and MMP-9, and decrement of serum IFN-γ levels. Moreover, both Carvedilol and ALA alleviated oxidative stress, and ameliorated muscle fatigue. This study highlights the neurotherapeutic potential of Carvedilol or ALA in CPZ-induced demyelination, and offers a better model for the exploring of neuroregenerative strategies. The current study is the first to demonstrate a pro-remyelinating activity for Carvedilol, as compared to ALA, which might represent a potential additive benefit in halting demyelination and alleviating neurotoxicity. However, we could declare that Carvedilol showed a lower neuroprotective potential than ALA.

Data-Driven Taxonomy for Antipsychotic Medication: A New Classification System

BackgroundGlobally, there are more than 25 licensed antipsychotic medications. Antipsychotics are commonly described as either typical or atypical, but this dichotomous classification does not reflect the diversity of their pharmacological and clinical profiles. There is a need for a data-driven antipsychotic classification scheme suitable for clinicians and researchers that maps onto both pharmacological and clinical effects. Receptor affinity provides one starting point for such a scheme. MethodsWe analyzed affinities of 27 antipsychotics for 42 receptors from 3325 in vitro receptor binding studies. We used a clustering algorithm to group antipsychotics based on receptor affinity. Using a machine learning model, we examined the ability of this grouping to predict antipsychotic-induced clinical effects quantified according to an umbrella review of clinical trial and treatment guideline data. ResultsClustering resulted in 4 groups of antipsychotics. The predominant receptor affinity and clinical effect “fingerprints” of these 4 groups were defined as follows: group 1, muscarinic (M2–M5) receptor antagonism (cholinergic and metabolic side effects); group 2, dopamine (D2) partial agonism and adrenergic antagonism (overall low side-effect burden); group 3, serotonergic and dopaminergic antagonism (overall moderate side-effect burden); and group 4, dopaminergic antagonism (extrapyramidal side effects and hyperprolactinemia). Groups 1 and 4 were more efficacious than groups 2 and 3. The classification was shown to predict out-of-sample clinical effects of individual drugs. ConclusionsA receptor affinity–based grouping not only reflects compound pharmacology but also detects meaningful clinical differences. This approach has the potential to benefit both patients and researchers by guiding treatment and informing drug development.

Novel prognostication biomarker adipophilin reveals a metabolic shift in uveal melanoma and new therapeutic opportunities.

Metastatic uveal melanoma remains incurable at present. We previously demonstrated that loss of BAP1 gene expression in tumour cells triggers molecular mechanisms of immunosuppression in the tumour microenvironment (TME) of metastatic uveal melanoma. Adipophilin is a structural protein of lipid droplets involved in fat storage within mammalian cells, and its expression has been identified in uveal melanoma. We comprehensively evaluated adipophilin expression at the RNA (PLIN2) and protein levels of 80 patients of the GDC-TCGA-UM study and in a local cohort of 43 primary uveal melanoma samples respectively. PLIN2 expression is a survival prognosticator biomarker in uveal melanoma. Loss of adipophilin expression is significantly associated with monosomy 3 status and nuclear BAP1 losses in uveal melanoma tumours. Integrative transcriptomic and secretome studies show a relationship between transient loss of adipophilin expression and increased levels of tumour-associated macrophages and hypoxia genes, suggesting PLIN2-dependent changes in oxygen and lipid metabolism in the TME of low and high-metastatic risk uveal melanoma. We designed four adipophilin-based multigene signatures for uveal melanoma prognostication using a transcriptomic and secretome survival-functional network approach. Adipophilin-based multigene signatures were validated in BAP1-positive and BAP1-negative uveal melanoma cell lines using a next-generation RNA sequencing approach. We identified existing small molecules, mostly adrenergic, retinoid, and glucocorticoid receptor agonists, MEK, and RAF inhibitors, with the potential to reverse this multigene signature expression in uveal melanoma. Some of these molecules were able to impact tumour cell viability, and carvedilol, an adrenergic receptor antagonist, restored PLIN2 levels, mimicking the expression of normoxia/lipid storage signatures and reversing the expression of hypoxia/lipolysis signatures in co-cultures of uveal melanoma cells with human macrophages. These findings open up a new research line for understanding the lipid metabolic regulation of immune responses, with implications for therapeutic innovation in uveal melanoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

BAY-6096: A Potent, Selective, and Highly Water-Soluble Adrenergic α2B Antagonist.

After acute myocardial infarction, early reperfusion is the most effective strategy for reducing cardiac damage and improving clinical outcome. However, restoring blood flow to the ischemic myocardium can paradoxically induce injury by itself (reperfusion injury), with microvascular dysfunction being one contributing factor. α2B adrenergic receptors have been hypothesized to be involved in this process. To assess α2B-related pharmacology, we identified a novel α2B antagonist by HTS. The HTS hit showed limited α2A selectivity as well as low solubility and was optimized toward BAY-6096, a potent, selective, and highly water-soluble α2B antagonist. Key aspects of the optimization were the introduction of a permanently charged pyridinium moiety to achieve very good aqueous solubility and the inversion of an amide to prevent genotoxicity. BAY-6096 dose-dependently reduced blood pressure increases in rats induced by an α2B agonist, demonstrating the role of α2B receptors in vascular constriction in rats.

Prophylaxis Pharmacological Management for Patients with Intraoperative Floppy Iris Syndrome Risk Due to ?1-Adrenergic Receptor Antagonists Use

Introduction: Intraoperative floppy iris syndrome (IFIS) remains a challenge that increases the risk of complications in patients undergoing cataract surgery who use ?1-adrenergic receptor antagonists. To date, no definite consensus on a preventive strategy for IFIS is available. The aim of this review is to assess various pharmacological managements to prevent IFIS in high-risk patients. Methods: This review was based on Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines. A systematic search using PubMed, Science Direct, Cochrane Library, and WorldCat database was performed. Quality of each study was evaluated using Cochrane Risk of Bias 2.0 (RoB 2.0), Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I), or Newcastle- Ottawa Scale (NOS). Results: The search identified 1589 articles of which 7 met the eligibility criteria. Experimental and observational studies between 2010 and 2018 were included. Pharmacological managements included in this review are administered in varying routes. Phenylephrine, lidocaine, a combination of lidocaine and epinephrine are given intracamerally. Other pharmacological managements included are sub-tenon injection of lidocaine, topical atropine, a combination of topical atropine with intracameral epinephrine, combined irrigation solution of phenylephrine and ketorolac, and mydriatic cocktail- soaked wick sponges. Conclusion: Various pharmacological managements for IFIS prophylaxis have shown promising potential. However, studies that evaluate the efficacy of each agent and comparison between these strategies are still limited. Further research is needed to determine the best prophylaxis strategy to reduce the incidence of IFIS.

Antipsychotic-induced priapism: case report and review of the literature.

IntroductionPriapism is a painful and prolonged penile erection in the absence of sexual stimulation. It is a urology emergency that, if not treated, may cause erectile dysfunction. Pharmacologically induced priapism is the most common form of priapism and almost half of all cases are caused by antipsychotic (AP) drugs. Considering priapism is a rare but important side effect, it is of major importance that psychiatrists be aware of it. Thus, we herein report the case of a 46-year-old man that developed priapism upon receiving intramuscular APs in a psychiatric emergency setting.ObjectivesTo alert for the importance of priapism as a potential side effect of AP drugs and to understand the physiological mechanisms involved in antipsychotic-induced priapism.MethodsA non-systematic review of the literature was carried out on PubMed. We looked for reviews and case reports published in the last 10 years containing the terms “priapism”, “antipsychotics” and “psychopharmacology priapism”. We also present a clinical case of antipsychotics-induced priapism.ResultsWe report the case of a 46-year-old man that was brought to the Psychiatric ER by police authorities due to disruptive and aggressive behaviour, a sense of increased energy and power and delusional speech of grandiose and persecutory content. No clinical records of psychosis or bipolar disorder were known, and the patient had never been medicated with AP drugs. The patient was involuntarily admitted to the psychiatric inward for treatment. Due to the aggravation of his aggressive behaviour, with potential danger for himself, other patients and the nursing staff, he was medicated with 5 mg of haloperidol and 25 mg of chlorpromazine. About an hour later the patient developed a painful erection that lasted at least for 4 hours. He was promptly sent to the Urology ER where an intracavernosal aspiration followed by injection of phenylephrine was needed to reverse priapism. APs are the most common cause of drug-induced priapism. Even though typical APs were pointed as more prone to cause this side effect, it is now known that atypical APs, including third-generation ones such as aripiprazole, may also cause priapism. It is thought that the α1- adrenergic antagonist action of most APs inhibits the contraction of smooth muscle in the corpus cavernosum of the penis, impeding venous outflow and thus causing ischemic priapism. To reduce the risk, the dosage of the AP may be reduced or changed to an AP with lower affinity for α1- adrenergic receptors.ConclusionsPriapism is a rare but important side effect of APs. Being aware of it and of its physiological mechanism is of major importance when treating patients with APs.Disclosure of InterestNone Declared

Guanfacine inhibits interictal epileptiform events and sodium currents in prefrontal cortex pyramidal neurons

BackgroundGuanfacine (an alpha-2A receptor agonist) is a commonly used drug with recognized efficacy in the treatment of attention deficit hyperactivity disorder (ADHD). This study aimed to assess the effects of guanfacine on short-lasting (interictal) epileptiform discharges in cortical neurons. Moreover, we assessed the effects of guanfacine on voltage-gated sodium currents.MethodsWe conducted patch-clamp recordings in prefrontal cortex pyramidal neurons obtained from young rats. Interictal epileptiform events were evoked in cortical slices in a zero magnesium proepileptic extracellular solution with an elevated concentration of potassium ions.ResultsInterictal epileptiform discharges were spontaneous depolarisations, which triggered action potentials. Guanfacine (10 and 100 µM) inhibited the frequency of epileptiform discharges. The effect of guanfacine on interictal events persisted in the presence of alpha-2 adrenergic receptor antagonist idazoxan. The tested drug inhibited neuronal excitability. Tonic NMDA currents were not influenced by guanfacine. Recordings from dispersed neurons showed that the tested drug (10 and 100 µM) inhibited persistent and fast inactivating voltage-gated sodium currents.ConclusionsThis study shows that guanfacine inhibits interictal discharges in cortical neurons independently of alpha-2A adrenergic receptors. This effect may be mediated by voltage-gated sodium currents. Inhibition of interictal activity by guanfacine may be of clinical importance because interictal events often occur in patients with ADHD and may contribute to symptoms of this disease.Graphical abstract

Dexmedetomidine Protects against Airway Inflammation and Airway Remodeling in a Murine Model of Chronic Asthma through TLR4/NF-κB Signaling Pathway.

Asthma is a common respiratory disease characterized by chronic airway inflammation. Dexmedetomidine (DEX), a highly selective α2 adrenergic receptor agonist, has been shown to participate in regulating inflammatory states and thus exert organ protective actions. However, the potential of DEX in asthma is still unknown. This study is aimed at investigating the role of DEX in a mouse model of house dust mite- (HDM-) induced asthma and exploring its underlying mechanism. Here, we found that DEX treatment significantly ameliorated airway hyperresponsiveness, airway inflammation, and airway remodeling in the asthmatic mice, which were similar to the efficacy of the reference anti-inflammatory drug dexamethasone. In addition, DEX reversed the increased expression of toll-like receptor 4 (TLR4) and its downstream signaling adaptor molecule nuclear factor-κB (NF-κB) in the lung tissue of asthmatic mice. Furthermore, these protective effects of DEX were abolished by yohimbine, an α2 adrenergic receptor antagonist. These results indicate that DEX is capable of ameliorating airway inflammation and remodeling in asthmatic mice, and this protective effect is associated with the inhibition of the TLR4/NF-κB signaling pathway.

The Role of Non-Selective Beta-Blockers (NSBBs) in Liver Cirrhosis

Non-selective beta-blockers (NSBBs) are one of the recommended treatments for portal hypertension in liver cirrhosis (LC). NSBB plays the role of primary as well as secondary prophylactic upper gastrointestinal bleeding in LC. NSBB therapy has been shown to effectively reduce the risk of variceal bleeding, reduction of portal pressure, and treat other complications of portal hypertension. The safety of NSBB therapy in cirrhosis requires a good therapeutic guide and considers the side effects. The indication of NSBB administration is adjusted according to the cirrhosis stage and the specific pathophysiology that occurs in cirrhosis. Conventional NSBBs such as propranolol and nadolol which are antagonists of β1 and β2 adrenergic receptors would induce decreased cardiac output and splanchnic vasoconstriction. Carvedilol is an NSBB with the addition of α1-adrenergic activity in reducing portal pressure stronger than conventional NSBB, so carvedilol can cause greater systemic arterial pressure reduction when compared to conventional NSBB. The appropriate treatment strategies can be applied in the use of NSBB to prevent more severe complications and reduce morbidity and mortality.

Nicotine suppresses central post-stroke pain via facilitation of descending noradrenergic neuron through activation of orexinergic neuron

Central post-stroke pain (CPSP) is a type of central neuropathic pain, whose underlying mechanisms remain unknown. We previously reported that bilateral carotid artery occlusion (BCAO)-induced CPSP model mice showed mechanical hypersensitivity and decreased mRNA levels of preproorexin, an orexin precursor, in the hypothalamus. Recently, nicotine was shown to regulate the neuronal activity of orexin in the lateral hypothalamus (LH) and suppress inflammatory and neuropathic pain. In this study, we evaluated whether nicotine could suppress BCAO-induced mechanical allodynia through the activation of orexinergic neurons. Mice were subjected to BCAO for 30 min. Mechanical hypersensitivity was assessed by the von Frey test. BCAO mice showed hypersensitivity to mechanical stimuli three days after BCAO surgery. The intracerebroventricular injection of nicotine suppressed BCAO-induced mechanical hypersensitivity in a dose-dependent manner. These effects were inhibited by α7 or α4β2-nicotinic receptor antagonists. After nicotine injection, the level of c-fos, a neuronal activity marker, increased in the LH and locus coeruleus (LC) of Sham and BCAO mice. Increased number of c-Fos-positive cells partly colocalized with orexin A-positive cells in the LH, as well as tyrosine hydroxylase-positive cells in the LC.Orexinergic neurons project to the LC area. Nicotine-induced antinociception tended to cancel by the pretreatment of SB334867, an orexin receptor1 antagonist into the LC. Intra-LH microinjection of nicotine attenuated BCAO-induced mechanical hypersensitivity. Nicotine-induced antinociception was inhibited by intrathecal pre-treatment with yohimbine, an α2 adrenergic receptor antagonist. These results indicated that nicotine may suppress BCAO-induced mechanical hypersensitivity through the activation of the descending pain control system via orexin neurons.

The β2-adrenergic receptor in the apical membrane of intestinal enterocytes senses sugars to stimulate glucose uptake from the gut.

The presence of sugar in the gut causes induction of SGLT1, the sodium/glucose cotransporter in intestinal epithelial cells (enterocytes), and this is accompanied by stimulation of sugar absorption. Sugar sensing was suggested to involve a G-protein coupled receptor and cAMP - protein kinase A signalling, but the sugar receptor has remained unknown. We show strong expression and co-localization with SGLT1 of the β2-adrenergic receptor (β 2-AR) at the enterocyte apical membrane and reveal its role in stimulating glucose uptake from the gut by the sodium/glucose-linked transporter, SGLT1. Upon heterologous expression in different reporter systems, the β 2-AR responds to multiple sugars in the mM range, consistent with estimated gut sugar levels after a meal. Most adrenergic receptor antagonists inhibit sugar signaling, while some differentially inhibit epinephrine and sugar responses. However, sugars did not inhibit binding of I125-cyanopindolol, a β 2-AR antagonist, to the ligand-binding site in cell-free membrane preparations. This suggests different but interdependent binding sites. Glucose uptake into everted sacs from rat intestine was stimulated by epinephrine and sugars in a β 2-AR-dependent manner. STD-NMR confirmed direct physical binding of glucose to the β 2-AR. Oral administration of glucose with a non-bioavailable β 2-AR antagonist lowered the subsequent increase in blood glucose levels, confirming a role for enterocyte apical β 2-ARs in stimulating gut glucose uptake, and suggesting enterocyte β 2-AR as novel drug target in diabetic and obese patients. Future work will have to reveal how glucose sensing by enterocytes and neuroendocrine cells is connected, and whether β 2-ARs mediate glucose sensing also in other tissues.

Beta-blockers in cardiac arrhythmias-Clinical pharmacologist's point of view.

β-blockers is a vast group of antiarrhythmic drugs which differ in their pharmacokinetic and chemical properties. Some of them block β-adrenergic receptors selectively while the others work non-selectively. Consequently, they reduce the influence of the sympathetic nervous system on the heart, acting negatively inotropic, chronotropic, bathmotropic and dromotropic. Although they have been present in medicine since the beginning of the 1960s, they still play a crucial role in the treatment of cardiac arrhythmias. They are also first-line group of drugs used to control the ventricular rate in patients with the most common arrhythmia-atrial fibrillation. Previous reports indicate that infection with SARS-CoV-2 virus may constitute an additional risk factor for arrhythmia. Due to the aging of the population in developed countries and the increase in the number of patients with cardiac burden, the number of people suffering from cardiac arrhythmias will increase in the upcoming years. As a result the role of above-mentioned beta-blockers will remain significant. Particularly noteworthy is propranolol-the oldest beta adrenergic antagonist, which in recent years has found additional applications due to its unique properties. In this article, we reviewed the accessible literature and summarized the current guidelines on the use of beta-blockers in the treatment of cardiac arrhythmias.

A proteome-wide atlas of drug mechanism of action.

Defining the cellular response to pharmacological agents is critical for understanding the mechanism of action of small molecule perturbagens. Here, we developed a 96-well-plate-based high-throughput screening infrastructure for quantitative proteomics and profiled 875 compounds in a human cancer cell line with near-comprehensive proteome coverage. Examining the 24-h proteome changes revealed ligand-induced changes in protein expression and uncovered rules by which compounds regulate their protein targets while identifying putative dihydrofolate reductase and tankyrase inhibitors. We used protein-protein and compound-compound correlation networks to uncover mechanisms of action for several compounds, including the adrenergic receptor antagonist JP1302, which we show disrupts the FACT complex and degrades histone H1. By profiling many compounds with overlapping targets covering a broad chemical space, we linked compound structure to mechanisms of action and highlighted off-target polypharmacology for molecules within the library.

Pharmacodynamic benefits of combined renin angiotensin system inhibition and alpha-1 adrenergic antagonism in the management of hypertension and cardiovascular disease in people with African ancestry

Abstract Genetic differences exist between Blacks and whites through sympathetic-vascular transduction signaling mechanisms. However, the lack of benefit of alpha-1 blockers in whites may not be applicable in Africans. The angiotensin II (Ang II) and alpha-1 receptor pathways are critical for vasoconstriction in Blacks. This article reviewed the consequence of the dual blockade among Nigerians, those with and without cardiovascular disease. Both receptors exhibited crosstalk and mutual regulations. Synergistic inhibition of Forearm vasoconstriction and hypotensive response to enalapril + prazosin (alpha-1 blocker [A1B]) occurred (P < 0.05). High efficacy of dual blockade by angiotensin converting enzyme inhibitor (ACEI) + A1B was reported in hypertensive urgency, hypertensive crises, and heart failure (HF) with reduced ejection fraction congestive HF compared to ACEI (P < 0.05). The high efficacy of dual blockade by ACEI + A1B + diuretics is beneficial for widespread use in Nigerians with cardiovascular disease.

Abruptly Stopping an Adamantane Management for Fatigue in an Elderly Multiple Sclerosis Patient Provoked Acute Withdrawal Symptoms (AWS); A Case Report

Introduction: Health care workers are continuously being burdened with acute conditions especially with the current pandemic of Covid-19. Staying home and feeling trapped can be particularly detrimental to patients with history of depression or psychotic as well as multiple sclerosis. We present a case of a 63-year-old patient with Multiple Sclerosis whose condition is being managed with mainly dopamine agonists. Withdrawal symptoms arose acutely after abrupt cessation of Amantadine; a dopamine agonist. Amantadine is thought to work by raising the amount of dopamine available to brain cells. The purpose of this research is to report a case of a 63-yearold Multiple Sclerosis patient who presented with Acute Withdrawal Syndrome (AWS) after being managed with Amantadine for two years and abruptly stopping the medication. Case Presentation: A 63-year-old woman with past medical history of stroke and multiple sclerosis reported symptoms of AWS after abruptly stopping amantadine use for multiple sclerosis. The patient was on cyclobenzaprine for spasticity, gabapentin and lamotrigine for neuropathic pain and seizure disorder respectively. She also had a history of hypertension and hyperlipidemia and presented with 1-week history of nausea and vomiting followed by visual hallucination, tremor, slurred speech and lethargy. On presentation, the patient was afebrile and hemodynamically stable. This patient denies blurred vision and severe fatigue with bathing or exercise. Upon further evaluation, patient did not report electrical sensation down her limbs or back especially with neck flexion. The initial labs were remarkable for hemoglobin of 8.5mg/dL and hypokalemia of 3.2mmol/L. We suspected vasculitis of CNS. One of the proposed pathophysiology for this is the extensive inflammatory damage to the blood brain barrier, allowing inflammatory cell recruitment into the CNS. The patient was admitted for acute altered mental status with waxing and wanning symptoms. Her acute delirium symptoms lead to the withdrawal of amantadine and cyclobenzaprine. Within about 48-70 hours later, patient developed severe agitation requiring emergent intubation. EEG showed generalized medium voltage delta, theta, and fast activity throughout indicative of diffuse cerebral dysfunction, but no lateralized or epileptic activity was seen. CT brain was negative for acute stroke or bleed. The patient underwent lumbar puncture, and was started on empiric coverage with IV acyclovir, vancomycin, and ceftriaxone for possible meningoencephalitis along with methylprednisolone for possible multiple sclerosis flare vs autoimmune encephalitis. MRI showed stable extensive white matter T2 hyperintense lesions. CSF was negative for infectious processes, and vancomycin, ceftriaxone, and acyclovir were discontinued. The patient continued to require sedation for severe agitation. The severe agitation was suspected to be due to discontinuation of her home medications, one of which was amantadine. The amantadine was resumed with improvement of her mental status within 24 hours. Patient was extubated within 48 hours of initiation of amantadine and was transferred to the floor for continuity of care and eventually discharged home after 15 days of hospitalization. Conclusion: Acute Withdrawal Syndrome (AWS) symptoms are often as a result of abrupt cessation of a medication(s) particularly central acting agents like clonidine, beta adrenergic antagonists as well as diuretics but Amantadine is starting to be a strong culprit since it is also thought to act centrally as a dopamine agonist. Clinicians should always be mindful of AWS especially from patients on long term central acting medications that have been abruptly stopped.

Beta 2 Adrenergic Receptor Selective Antagonist Enhances Mechanically Stimulated Bone Anabolism in Aged Mice.

The anabolic response of aged bone to skeletal loading is typically poor. Efforts to improve mechanotransduction in aged bone have met with limited success. This study investigated whether the bone response to direct skeletal loading is improved by reducing sympathetic suppression of osteoblastic bone formation via β2AR. To test this possibility, we treated aged wild-type C57BL/6 mice with a selective β2AR antagonist, butaxamine (Butax), before each of nine bouts of cantilever bending of the right tibia. Midshaft periosteal bone formation was assessed by dynamic histomorphometry of loaded and contralateral tibias. Butax treatment did not alter osteoblast activity of contralateral tibias. Loading alone induced a modest but significant osteogenic response. However, when loading was combined with Butax pretreatment, the anabolic response was significantly elevated compared with loading preceded by saline injection. Subsequent studies in osteoblastic cultures revealed complex negative interactions between adrenergic and mechanically induced intracellular signaling. Activation of β2AR by treatment with the β1, β2-agonist isoproterenol (ISO) before fluid flow exposure diminished mechanically stimulated ERK1/2 phosphorylation in primary bone cell outgrowth cultures and AKT phosphorylation in MC3T3-E1 pre-osteoblast cultures. Expression of mechanosensitive Fos and Ptgs2 genes was enhanced with ISO treatment and reduced with flow in both MC3T3-E1 and primary cultures. Finally, co-treatment of MC3T3-E1 cells with Butax reversed these ISO effects, confirming a critical role for β2AR in these responses. In combination, these results demonstrate that selective inhibition of β2AR is sufficient to enhance the anabolic response of the aged skeleton to loading, potentially via direct effects upon osteoblasts. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats.

Inhaled irritant air pollutants may trigger stress-related metabolic dysfunction associated with altered circulating adrenal-derived hormones. We used implantable telemetry in rats to assess real-time changes in circulating glucose during and after exposure to ozone and mechanistically linked responses to neuroendocrine stress hormones. First, using a cross-over design, we monitored glucose during ozone exposures (0.0, 0.2, 0.4, and ) and nonexposure periods in male Wistar Kyoto rats implanted with glucose telemeters. A second cohort of unimplanted rats was exposed to ozone (0.0, 0.4 or 0.8 ppm) for 30 min, 1 h, 2 h, or 4 h with hormones measured immediately post exposure. We assessed glucose metabolism in sham and adrenalectomized rats, with or without supplementation of adrenergic/glucocorticoid receptor agonists, and in a separate cohort, antagonists. Ozone () was associated with significantly higher blood glucose and lower core body temperature beginning 90 min into exposure, with reversal of effects 4-6 h post exposure. Glucose monitoring during four daily 4-h ozone exposures revealed duration of glucose increases, adaptation, and diurnal variations. Ozone-induced glucose changes were preceded by higher levels of adrenocorticotropic hormone, corticosterone, and epinephrine but lower levels of thyroid-stimulating hormone, prolactin, and luteinizing hormones. Higher glucose and glucose intolerance were inhibited in rats that were adrenalectomized or treated with adrenergic plus glucocorticoid receptor antagonists but exacerbated by agonists. We demonstrated the temporality of neuroendocrine-stress-mediated biological sequalae responsible for ozone-induced glucose metabolic dysfunction and mechanism in a rodent model. Stress hormones assessment with real-time glucose monitoring may be useful in identifying interactions among irritant pollutants and stress-related illnesses. https://doi.org/10.1289/EHP11088.

COVID-19-associated Guillain–Barrè Syndrome and Urinary Dysfunction: A case report

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can cause multiple systemic and neurological complications, including Guillain- Barrè Syndrome (GBS). In this report we describe for the first time, urinary dysfunction in a patient with COVID- 19. We reported a 41-years- old female patient with complaints of an increased generalized muscular weakness associated with progressive difficulty in walking. Four days earlier, patient complained of fever, diarrhea, and general weakness, and the RT-PCR was positive for COVID-19 infection. Due to the worsening of neurological symptoms, a neurophysiological examination on nervous conduction was performed and the diagnosis was suggestive of GBS. Two weeks later, patient developed two consecutive episodes of acute urinary retention that requested the placement of indwelling transurethral catheter. Patient started assuming selective alpha-1 adrenergic antagonist in association with 4 clean intermittent catheterization/ die. Four months later, women continued the therapy and the ultrasound evaluation revealed non- pathologic post- void residual volume. Therefore, patient started to void spontaneously again and alpha- blockers were discontinued. We report for the first time a case of severe voiding disorder in a patient with COVID-19 associated GBS. Timely bladder drainage should be adopted to avoid irreversible detrusor damage.

Abstract 9933: Shifting Paradigms in Rhythm versus Rate Control in Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials

Introduction: Atrial fibrillation is the most common cardiac arrhythmia and is an independent risk factor for mortality across a wide age range in both men and women. Management methods of atrial fibrillation have been thoroughly investigated through numerous trials exploring various treatment modalities. There has been a preference for rate control as the initial approach, but recent studies, particularly the EAST-AFNET 4 trial, point out several clinical settings in which rhythm control is preferable. To evaluate new paradigms in the acute management of atrial fibrillation, our meta-analysis provides a current, curated examination of the major landmark trials in the management of atrial fibrillation along with the most recent randomized controlled trials that have been published since 2022. Methods: A literature search was performed on May 2022 using PubMed and OVID Medline databases for study identification. Combinations of the search terms atrial fibrillation, rate control, adrenergic beta antagonists, rhythm control, anti-arrhythmia drugs, and catheter ablation were combined to conduct the literature search. Boolean operators AND and OR were used to combine terms. Results: There were no significant differences in the effects of rate and rhythm control on any outcome: all-cause mortality (RR: 0.996; CI: 0.674-1.376), cardiovascular mortality (RR: 0.957; CI: 0.601-1.413), arrhythmic/sudden death mortality (RR: 0.954; CI: 0.445-1.816), stroke/transient ischemic attack (RR: 1.011; CI: 0.535-1.78), and systemic embolism (RR: 1.275; CI: 0.541-2.625). Conclusions: Updated data pooled from randomized control trials in patients with atrial fibrillation suggests that rhythm and rate control strategies have no statistically significant differences on major clinical outcomes. Additional studies will be required to investigate factors favorable for rhythm-control strategies and to determine contemporary best clinical practices.

Impact of intraoperative floppy IRIS syndrome in cataract surgery by phacoemulsification: Analysis of 622 cases

BackgroundSmall pupil syndromes, including IFIS, increase the risk of complications during cataract surgery if proper surgical planning is not performed. Tamsulosin is associated with a very significant increase in the risk of IFIS, due to the prolonged inactivation of alpha-1 adrenergic receptors in the smooth muscle fiber of the iris. Material and methodsSingle-center prospective observational study, carried out at the Hospital de l'Esperança - Parc de Salut Mar. Results622 eyes of 502 patients were included, of which 337 (62%) were women. The mean age of the sample is 74.8 years. 61 cases of IFIS (11%) were observed, of which 13 received treatment with Tamsulosin and 1 with Doxazosin. 23 cases of IFIS were observed in female patients. The female:male ratio was approximately 1:3. 19 cases (3%) of severe IFIS were observed, of which 6 received treatment with alpha-antagonists, with no statistically significant correlation.The mean surgical time was 13.80 min (Standard Deviation - SD: 4.01 min) in patients without IFIS and 16.93 min (SD: 4.32 min) in patients with IFIS. The relationship between the duration of the surgical procedure in minutes and the presence of IFIS was statistically significant, applying a 'two-tailed' or bilateral t-Student test with a p value of 0.01. ConclusionRegardless of the degree of severity, the diagnosis of IFIS lengthens the surgical time in cataract surgery. This represents yet another piece of evidence that supports the use of less selective alpha-1 adrenergic antagonist treatments than Tamsulosin or the performance of cataract surgery before starting these treatments.