-
Pharmacological Research Jan 2023Activation of brown adipose tissue (BAT) with the β3-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of...
Activation of brown adipose tissue (BAT) with the β3-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is associated with cardiometabolic health in humans. In contrast, exposure to cold or treatment with the clinically used β3-adrenergic receptor agonist mirabegron to activate BAT exacerbates atherosclerosis in apolipoprotein E (ApoE)- and low-density lipoprotein receptor (LDLR)-deficient mice, both lacking a functional ApoE-LDLR pathway crucial for lipoprotein remnant clearance. We, therefore, investigated the effects of mirabegron treatment on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a humanized lipoprotein metabolism model with a functional ApoE-LDLR clearance pathway. Mirabegron activated BAT and induced white adipose tissue (WAT) browning, accompanied by selectively increased fat oxidation and attenuated fat mass gain. Mirabegron increased the uptake of fatty acids derived from triglyceride (TG)-rich lipoproteins by BAT and WAT, which was coupled to increased hepatic uptake of the generated cholesterol-enriched core remnants. Mirabegron also promoted hepatic very low-density lipoprotein (VLDL) production, likely due to an increased flux of fatty acids from WAT to the liver, and resulted in transient elevation in plasma TG levels followed by a substantial decrease in plasma TGs. These effects led to a trend toward lower plasma cholesterol levels and reduced atherosclerosis. We conclude that BAT activation by mirabegron leads to substantial metabolic benefits in APOE*3-Leiden.CETP mice, and mirabegron treatment is certainly not atherogenic. These data underscore the importance of the choice of experimental models when investigating the effect of BAT activation on lipoprotein metabolism and atherosclerosis.
Topics: Animals; Humans; Mice; Adipose Tissue, Brown; Adrenergic Agonists; Apolipoproteins E; Atherosclerosis; Cholesterol; Fatty Acids; Lipoproteins, LDL; Liver; Triglycerides; Receptors, LDL
PubMed: 36574856
DOI: 10.1016/j.phrs.2022.106634 -
Journal of Animal Physiology and Animal... May 2021The objective was to conduct a systematic review to evaluate the effects of dietary supplementation with beta-adrenergic agonists on calpains and calpastatin activity in...
The objective was to conduct a systematic review to evaluate the effects of dietary supplementation with beta-adrenergic agonists on calpains and calpastatin activity in bovine muscle and changes in meat tenderness. A survey was conducted in June 2019 on Science Direct, Web of Science, Scopus, PubMed and Capes Periodicals, using four keyword combinations: agonist and calpain and cattle; agonist and calpain and bovine; agonist and calpain and heifers; agonist and calpain and steers. Thirteen studies were selected, 54% concluded that supplementation with beta-adrenergic agonists increases calpastatin activity, 23% observed increase in their gene expression and 23% reported no effect on activity or expression of this enzyme. Nine studies evaluated the influence of beta-adrenergic agonists supplementation on meat texture and all found an increase in shear force values. There is strong evidence that beta-adrenergic agonists may increase calpastatin activity in the muscle, causing damage to meat tenderness.
Topics: Adrenergic beta-Agonists; Animals; Calpain; Cattle; Female; Meat; Muscle, Skeletal; Muscles; Proteolysis
PubMed: 33452737
DOI: 10.1111/jpn.13479 -
Communications Biology Nov 2022Vesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission....
Vesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission. VMAT2 inhibitors are approved for symptomatic treatment of tardive dyskinesia and Huntington's chorea, but despite being much-studied inhibitors their exact binding site and mechanism behind binding and inhibition of monoamine transport are not known. Here we report the identification of several approved drugs, notably β2-adrenergic agonists salmeterol, vilanterol and formoterol, β2-adrenergic antagonist carvedilol and the atypical antipsychotic ziprasidone as inhibitors of rat VMAT2. Further, plausible binding modes of the established VMAT2 inhibitors reserpine and tetrabenazine and hit compounds salmeterol and ziprasidone were identified using molecular dynamics simulations and functional assays using VMAT2 wild-type and mutants. Our findings show VMAT2 as a potential off-target of treatments with several approved drugs in use today and can also provide important first steps in both drug repurposing and therapy development targeting VMAT2 function.
Topics: Animals; Rats; Adrenergic Agonists; Antipsychotic Agents; Piperazines; Vesicular Monoamine Transport Proteins; Adrenergic Antagonists
PubMed: 36418492
DOI: 10.1038/s42003-022-04121-1 -
Endocrine, Metabolic & Immune Disorders... 2020Mirabegron is a β3-agonist drug approved by the FDA for use in 2012 and administered in overactive bladder. Activating of adrenergic receptors leads to the relaxation... (Review)
Review
Mirabegron is a β3-agonist drug approved by the FDA for use in 2012 and administered in overactive bladder. Activating of adrenergic receptors leads to the relaxation of the detrusor muscle. According to the latest research and reports, it also has lipolytic activity, affecting the reduction of mainly brown adipose tissue (BAT) but also of white adipose tissue (WAT). This results in a decrease in body weight and triglyceride concentration and an increase in lipoprotein lipase activity, as well as in the level of free fatty acids or adipokines in the plasma. The drug indirectly participates in the regulation of carbohydrate metabolism, influencing the increase in insulin sensitivity, supporting cellular uptake of glucose. However, due to the elevation of blood pressure and pulse, as a supplement, the drug should be taken with care to avoid cardiovascular complications. In our review, below, we present a description and discussion of available studies in terms of mirabegron action on the exercise capacity of the body in the context of its potential use as a doping agent.
Topics: Acetanilides; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adrenergic beta-3 Receptor Agonists; Animals; Exercise Tolerance; Humans; Lipolysis; Thiazoles; Urinary Bladder, Overactive
PubMed: 32416711
DOI: 10.2174/1871530320666200516164434 -
Frontiers in Endocrinology 2021Liraglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist used as an anti-hyperglycemic agent in type 2 diabetes treatment and recently approved for...
AIMS
Liraglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist used as an anti-hyperglycemic agent in type 2 diabetes treatment and recently approved for obesity management. Weight loss is attributed to appetite suppression, but therapy may also increase energy expenditure. To further investigate the effect of GLP-1 signaling in thermogenic fat, we assessed adipose tissue oxygen consumption and type 2 deiodinase (D2) activity in mice treated with liraglutide, both basally and after β3-adrenergic treatment.
METHODS
Male C57BL/6J mice were randomly assigned to receive liraglutide (400 μg/kg, n=12) or vehicle (n=12). After 16 days, mice in each group were co-treated with the selective β3-adrenergic agonist CL316,243 (1 mg/kg, n=6) or vehicle (n=6) for 5 days. Adipose tissue depots were assessed for gene and protein expression, oxygen consumption, and D2 activity.
RESULTS
Liraglutide increased interscapular brown adipose tissue (iBAT) oxygen consumption and enhanced β3-adrenergic-induced oxygen consumption in iBAT and inguinal white adipose tissue (ingWAT). These effects were accompanied by upregulation of UCP-1 protein levels in iBAT and ingWAT. Notably, liraglutide increased D2 activity without significantly upregulating its mRNA levels in iBAT and exhibited additive effects to β3-adrenergic stimulation in inducing D2 activity in ingWAT.
CONCLUSIONS
Liraglutide exhibits additive effects to those of β3-adrenergic stimulation in thermogenic fat and increases D2 activity in BAT, implying that it may activate this adipose tissue depot by increasing intracellular thyroid activation, adding to the currently known mechanisms of GLP-1A-induced weight loss.
Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adrenergic beta-3 Receptor Agonists; Animals; Dioxoles; Enzyme Activation; Glucagon-Like Peptide 1; Iodide Peroxidase; Liraglutide; Male; Mice; Mice, Inbred C57BL; Obesity; Oxygen Consumption; RNA, Messenger; Receptors, Adrenergic, beta-3; Thermogenesis; Uncoupling Protein 1; Iodothyronine Deiodinase Type II
PubMed: 35069450
DOI: 10.3389/fendo.2021.803363 -
Psychopharmacology Bulletin Oct 2020This evidence-based systematic review will focus on the use of dexmedetomidine and its role as adjuvant anesthetics in regional blocks to help better guide physicians in... (Review)
Review
PURPOSE OF REVIEW
This evidence-based systematic review will focus on the use of dexmedetomidine and its role as adjuvant anesthetics in regional blocks to help better guide physicians in their practice. This review will cover background and mechanism of dexmedetomidine as well as the use in various regional blocks.
RECENT FINDINGS
Local anesthetics are preferred for nerve blocks over opioids; however, both due come with its own side effects. Local anesthetics may be toxic as they disrupt cell membrane and proteins, but by using adjuvants such as dexmedetomidine, that can prolong sensory and motor blocks can reduce total amount of local anesthetics needed. Dexmedetomidine is an alpha-2-adrenergic agonist used as additive for regional nerve block. It has a relatively low side effect profile and have been researched in various regional blocks (intrathecal, paravertebral, axillary, infraclavicular brachial plexus, interscalene). Dexmedetomidine shows promising results as adjuvant anesthetics in most regional blocks.
SUMMARY
Many studies have been done and many show promising results for the use of dexmedetomidine in regional blocks. It may significantly increase in duration of sensory and motor blocks that correlates with lower pain scores and less need of morphine in various regional blocks.
Topics: Adrenergic alpha-2 Receptor Agonists; Anesthesia, Conduction; Anesthetics, Local; Brachial Plexus Block; Dexmedetomidine
PubMed: 33633422
DOI: No ID Found -
The contribution of autonomic mechanisms to pain in temporomandibular disorders: A narrative review.Journal of Oral Rehabilitation Nov 2022Temporomandibular disorders (TMD) are diagnosed based on symptom presentation and, like other functional pain disorders, often lack definitive pathology. There is a... (Review)
Review
BACKGROUND
Temporomandibular disorders (TMD) are diagnosed based on symptom presentation and, like other functional pain disorders, often lack definitive pathology. There is a strong association between elevated stress levels and the severity of TMD-related pain, which suggests that alterations in autonomic tone may contribute to this pain condition.
OBJECTIVES
This narrative review examines the association between altered autonomic function and pain in TMD.
METHODS
Relevant articles were identified by searching PubMed and through the reference list of those studies.
RESULTS
TMD sufferers report an increased incidence of orthostatic hypotension. As in other chronic musculoskeletal pain conditions, TMD is associated with increased sympathetic tone, diminished baroreceptor reflex sensitivity and decreased parasympathetic tone. It remains to be determined whether ongoing pain drives these autonomic changes and/or is exacerbated by them. To examine whether increased sympathetic tone contributes to TMD-related pain through β adrenergic receptor activation, clinical trials with the beta blocker propranolol have been undertaken. Although evidence from small studies suggested propranolol reduced TMD-related pain, a larger clinical trial did not find a significant effect of propranolol treatment. This is consistent with human experimental pain studies that were unable to demonstrate an effect of β adrenergic receptor activation or inhibition on masticatory muscle pain. In preclinical models of temporomandibular joint arthritis, β adrenergic receptor activation appears to contribute to inflammation and nociception, whereas in masticatory muscle, α adrenergic receptor activation has been found to induce mechanical sensitisation. Some agents used to treat TMD, such as botulinum neurotoxin A, antidepressants and α adrenergic receptor agonists, may interact with the autonomic nervous system as part of their analgesic mechanism.
CONCLUSION
Even if dysautonomia turns out to be a consequence rather than a causative factor of painful TMD, the study of its role has opened up a greater understanding of the pathogenesis of this condition.
Topics: Adrenergic Agonists; Analgesics; Antidepressive Agents; Autonomic Nervous System; Botulinum Toxins, Type A; Clinical Trials as Topic; Humans; Pain; Propranolol; Receptors, Adrenergic; Temporomandibular Joint Disorders
PubMed: 36098708
DOI: 10.1111/joor.13370 -
Journal of the American Academy of... Apr 2023The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications.
METHOD
A total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pretreatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pretreatment clinical and EEG measures predicted treatment-related change in ADHD severity.
RESULTS
Higher pretreatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pretreatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (R= 0.34-0.41) as clinical measures alone (R = 0.14-.21).
CONCLUSION
We identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD.
CLINICAL TRIAL REGISTRATION INFORMATION
Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; https://clinicaltrials.gov; NCT00429273.
Topics: Male; Child; Humans; Attention Deficit Disorder with Hyperactivity; Guanfacine; Methylphenidate; Adrenergic alpha-2 Receptor Agonists; Treatment Outcome; Central Nervous System Stimulants; Double-Blind Method
PubMed: 35963559
DOI: 10.1016/j.jaac.2022.08.001 -
Scientific Reports Mar 2022Metabolic reprogramming contributes to oncogenesis, tumor growth, and treatment resistance in pancreatic ductal adenocarcinoma (PDAC). Here we report the effects of...
Metabolic reprogramming contributes to oncogenesis, tumor growth, and treatment resistance in pancreatic ductal adenocarcinoma (PDAC). Here we report the effects of (R,S')-4'-methoxy-1-naphthylfenoterol (MNF), a GPR55 antagonist and biased β-adrenergic receptor (β-AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and β-AR in (R,S')-MNF signaling was explored further in PANC-1 cells. Moreover, the effect of (R,S')-MNF on tumor growth was determined in a PANC-1 mouse xenograft model. PANC-1 cells treated with (R,S')-MNF showed marked attenuation in GPR55 signal transduction and function combined with increased β-AR/Gα/adenylyl cyclase/PKA signaling, both of which contributing to lower MEK/ERK, PI3K/AKT and YAP/TAZ signaling. (R,S')-MNF administration significantly reduced PANC-1 tumor growth and circulating L-lactate concentrations. Global metabolic profiling of (R,S')-MNF-treated tumor tissues revealed decreased glycolytic metabolism, with a shift towards normoxic processes, attenuated glutamate metabolism, and increased levels of ophthalmic acid and its precursor, 2-aminobutyric acid, indicative of elevated oxidative stress. Transcriptomics and immunoblot analyses indicated the downregulation of gene and protein expression of HIF-1α and c-Myc, key initiators of metabolic reprogramming in PDAC. (R,S')-MNF treatment decreased HIF-1α and c-Myc expression, attenuated glycolysis, shifted fatty acid metabolism towards β-oxidation, and suppressed de novo pyrimidine biosynthesis in PANC-1 tumors. The results indicate a potential benefit of combined GPR55 antagonism and biased β-AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism.
Topics: Adrenergic Agonists; Animals; Cell Line, Tumor; Cell Proliferation; Fenoterol; Humans; Mice; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Receptors, Adrenergic, beta-2; Receptors, Cannabinoid; Signal Transduction
PubMed: 35256673
DOI: 10.1038/s41598-022-07600-x -
Kyobu Geka. the Japanese Journal of... Sep 2023The number of elderly patients in thoracic surgery is increasing. The percentage of patients over the age of 80 in surgical cases of malignant diseases such as lung...
The number of elderly patients in thoracic surgery is increasing. The percentage of patients over the age of 80 in surgical cases of malignant diseases such as lung cancer and mediastinal tumors is increasing every year. It is also true that the indications for surgery have been expanding as surgery itself has become less invasive, such as thoracoscopic and robotic surgery. However, it is not uncommon for patients over 80 years of age to have some organ dysfunction and many comorbidities. Therefore, when performing surgery for lung cancer and other diseases, it is important to assess the patient's ability to tolerate surgery, including respiratory and cardiac functions, and to perform risk management. To prevent postoperative complications and improve the accuracy of perioperative management, respiratory rehabilitation should be conducted before and after surgery, and not only smoking cessation instruction but also inhalation training using incentive spirometry( IS), breathing exercises, and the use of inhalers such as long-acting β2 agonist (LABA)/long-acting muscaring antagonist (LAMA) for patients with chronic obstructive pulmonary disease( COPD) are useful.
Topics: Humans; Aged, 80 and over; Aged; Muscarinic Antagonists; Adrenergic beta-2 Receptor Agonists; Administration, Inhalation; Respiratory Therapy; Pulmonary Disease, Chronic Obstructive; Lung Neoplasms; Drug Therapy, Combination
PubMed: 38056855
DOI: No ID Found