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CMAJ : Canadian Medical Association... May 2024
Topics: Humans; Analgesics, Opioid; Xylazine; Illicit Drugs; Canada; Opioid-Related Disorders
PubMed: 38740412
DOI: 10.1503/cmaj.231603-f -
Developmental Cell Nov 2023The autonomic nervous system plays a pivotal role in cardiac repair. Here, we describe the mechanistic underpinning of adrenergic signaling in fibrotic and regenerative...
The autonomic nervous system plays a pivotal role in cardiac repair. Here, we describe the mechanistic underpinning of adrenergic signaling in fibrotic and regenerative response of the heart to be dependent on immunomodulation. A pharmacological approach identified adrenergic receptor alpha-1 as a key regulator of macrophage phenotypic diversification following myocardial damage in zebrafish. Genetic manipulation and single-cell transcriptomics showed that the receptor signals activation of an "extracellular matrix remodeling" transcriptional program in a macrophage subset, which serves as a key regulator of matrix composition and turnover. Mechanistically, adrenergic receptor alpha-1-activated macrophages determine activation of collagen-12-expressing fibroblasts, a cellular determinant of cardiac regenerative niche, through midkine-mediated paracrine crosstalk, allowing lymphatic and blood vessel growth and cardiomyocyte proliferation at the lesion site. These findings identify the mechanism of adrenergic signaling in macrophage phenotypic and functional determination and highlight the potential of neural modulation for regulation of fibrosis and coordination of myocardial regenerative response.
Topics: Animals; Zebrafish; Adrenergic Agents; Myocardium; Extracellular Matrix; Macrophages; Fibrosis; Fibroblasts; Receptors, Adrenergic; Myocytes, Cardiac
PubMed: 37875117
DOI: 10.1016/j.devcel.2023.09.011 -
Nature Neuroscience Oct 2023Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated from oligodendrocyte precursor cells (OPCs) that express neurotransmitter...
Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated from oligodendrocyte precursor cells (OPCs) that express neurotransmitter receptors. However, the mechanisms that affect OPC activity in vivo and the physiological roles of neurotransmitter signaling in OPCs are unclear. In this study, we generated a transgenic mouse line that expresses membrane-anchored GCaMP6s in OPCs and used longitudinal two-photon microscopy to monitor OPC calcium (Ca) dynamics in the cerebral cortex. OPCs exhibit focal and transient Ca increases within their processes that are enhanced during locomotion-induced increases in arousal. The Ca transients occur independently of excitatory neuron activity, rapidly decline when OPCs differentiate and are inhibited by anesthesia, sedative agents or noradrenergic receptor antagonists. Conditional knockout of α1A adrenergic receptors in OPCs suppresses spontaneous and locomotion-induced Ca increases and reduces OPC proliferation. Our results demonstrate that OPCs are directly modulated by norepinephrine in vivo to enhance Ca dynamics and promote population homeostasis.
Topics: Mice; Animals; Oligodendrocyte Precursor Cells; Calcium; Norepinephrine; Mice, Transgenic; Oligodendroglia; Cerebral Cortex; Cell Proliferation; Arousal; Cell Differentiation
PubMed: 37697112
DOI: 10.1038/s41593-023-01426-0 -
Journal of Neuroinflammation Nov 2023Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common...
BACKGROUND
Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma.
METHODS
Sox10/Rpl22 mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH sympathetic neurons and glial-restricted Sox10/JellyOP/Rpl22 mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI.
RESULTS
With ~ 4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glial reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic-driven enteric glial reactivity.
CONCLUSIONS
Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.
Topics: Animals; Mice; Gliosis; Adrenergic Agents; Neuroglia; Signal Transduction; Sympathetic Nervous System; Enteric Nervous System
PubMed: 37941007
DOI: 10.1186/s12974-023-02937-0 -
Naunyn-Schmiedeberg's Archives of... May 2024Mirtazapine (MTZ) is an antidepressant drug with an exceptional pharmacological profile. It also has an excellent safety and tolerability profile. The present review... (Review)
Review
Mirtazapine (MTZ) is an antidepressant drug with an exceptional pharmacological profile. It also has an excellent safety and tolerability profile. The present review provides a pharmacological update on MTZ and summarizes the research findings of MTZ's effects on different diseases. MTZ is hypothesized to have antidepressant effects because of the synergy between noradrenergic and serotonergic actions and is effective in treating major depressive disorder and depression associated with epilepsy, Alzheimer's disease, stroke, cardiovascular disease, and respiratory disease. In cancer patients, MTZ significantly reduced sadness, nausea, sleep disruption, and pain and improved quality of life. Also, it has promising effects on Parkinson's disease, schizophrenia, dysthymia, social anxiety disorder, alcohol dependency, posttraumatic stress disorder, panic disorder, pain syndromes, obsessive-compulsive disorder, and sleep disorders. Additionally, MTZ is potentially therapeutic in different situations associated with depression, such as liver, kidney, cardiovascular, respiratory, infertility, heavy metal-induced neurotoxicity, and pruritus. Potent antioxidative, anti-inflammatory, and anti-apoptotic bioactivities mediate these promising effects. These positive outcomes of the scientific investigations motivate more and more clinical trials for a golden exceptional antidepressant in different conditions.
Topics: Humans; Mirtazapine; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic
PubMed: 37943296
DOI: 10.1007/s00210-023-02818-6 -
JAMA Network Open Nov 2023The most prescribed class of medications for benign prostatic hyperplasia (BPH) is α-blockers (ABs). However, the cardiovascular safety profile of these medications...
IMPORTANCE
The most prescribed class of medications for benign prostatic hyperplasia (BPH) is α-blockers (ABs). However, the cardiovascular safety profile of these medications among patients with BPH is not well understood.
OBJECTIVE
To compare the safety of ABs vs 5-α reductase inhibitors (5-ARIs) for risk of adverse cardiovascular outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This active comparator, new-user cohort study was conducted using insurance claims data from a 20% random sample of Medicare beneficiaries from 2007 to 2019 to evaluate the 1-year risk of adverse cardiovascular outcomes. Males aged 66 to 90 years were indexed into the cohort at new use of an AB or 5-ARI. Twelve months of continuous enrollment and at least 1 diagnosis code for BPH within 12 months prior to initiation were required. Data were analyzed from January 2007 through December 2019.
EXPOSURES
Exposure was defined by a qualifying prescription fill for an AB or 5-ARI after at least 12 months without a prescription for these drug classes.
MAIN OUTCOMES AND MEASURES
Follow-up began at a qualified refill for the study drug. Primary study outcomes were hospitalization for heart failure (HF), composite major adverse cardiovascular events (MACE; hospitalization for stroke, myocardial infarction, or death), composite MACE or hospitalization for HF, and death. Inverse probability of treatment and censoring-weighted 1-year risks, risk ratios (RRs), and risk differences (RDs) were estimated for each outcome.
RESULTS
Among 189 868 older adult males, there were 163 829 patients initiating ABs (mean [SD] age, 74.6 [6.2] years; 579 American Indian or Alaska Native [0.4%], 5890 Asian or Pacific Islander [3.6%], 9179 Black [5.6%], 10 610 Hispanic [6.5%], and 133 510 non-Hispanic White [81.5%]) and 26 039 patients initiating 5-ARIs (mean [SD] age, 75.3 [6.4] years; 76 American Indian or Alaska Native [0.3%], 827 Asian or Pacific Islander [3.2%], 1339 Black [5.1%], 1656 Hispanic [6.4%], and 21 605 non-Hispanic White [83.0%]). ABs compared with 5-ARIs were associated with an increased 1-year risk of MACE (8.95% [95% CI, 8.81%-9.09%] vs 8.32% [95% CI, 7.92%-8.72%]; RR = 1.08 [95% CI, 1.02-1.13]; RD per 1000 individuals = 6.26 [95% CI, 2.15-10.37]), composite MACE and HF (RR = 1.07; [95% CI, 1.03-1.12]; RD per 1000 individuals = 7.40 [95% CI, 2.88-11.93 ]), and death (RR = 1.07; [95% CI, 1.01-1.14]; RD per 1000 individuals = 3.85 [95% CI, 0.40-7.29]). There was no difference in risk for HF hospitalization alone.
CONCLUSIONS AND RELEVANCE
These results suggest that ABs may be associated with an increased risk of adverse cardiovascular outcomes compared with 5-ARIs. If replicated with more detailed confounder data, these results may have important public health implications given these medications' widespread use.
Topics: United States; Male; Humans; Aged; 5-alpha Reductase Inhibitors; Prostatic Hyperplasia; Cohort Studies; Medicare; Cardiovascular System; Heart Failure; Adrenergic alpha-Antagonists
PubMed: 37962887
DOI: 10.1001/jamanetworkopen.2023.43299 -
Drug Design, Development and Therapy 2023This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of... (Review)
Review
This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D, 5-hydroxytryptamine (5-HT), and 5-HT receptors and a partial agonistic effect on the 5-HT receptor with low affinities for muscarinic M, histamine H, and a adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT and 5-HT receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.
Topics: Humans; Lurasidone Hydrochloride; Schizophrenia; Serotonin; Isoindoles; Thiazoles; Antipsychotic Agents; Weight Gain
PubMed: 37789971
DOI: 10.2147/DDDT.S366769 -
Journal of Hypertension Nov 2023Maternal cardiovascular diseases, including hypertension and cardiac conditions, are associated with poor fetal outcomes. A range of adrenergic antihypertensive and... (Review)
Review
Maternal cardiovascular diseases, including hypertension and cardiac conditions, are associated with poor fetal outcomes. A range of adrenergic antihypertensive and cardioprotective medications are often prescribed to pregnant women to reduce major maternal complications during pregnancy. Although these treatments are not considered teratogenic, they may have detrimental effects on fetal growth and development, as they cross the fetoplacental barrier, and may contribute to placental vascular dysregulation. Medication risk assessment sheets do not include specific advice to clinicians and women regarding the safety of these therapies for use in pregnancy and the potential off-target effects of adrenergic medications on fetal growth have not been rigorously conducted. Little is known of their effects on the fetoplacental vasculature. There is also a dearth of knowledge on adrenergic receptor activation and signalling within the endothelium and vascular smooth muscle cells of the human placenta, a vital organ in the maintenance of adequate blood flow to satisfy fetal growth and development. The fetoplacental circulation, absent of sympathetic innervation, and unique in its reliance on endocrine, paracrine and autocrine influence in the regulation of vascular tone, appears vulnerable to dysregulation by adrenergic antihypertensive and cardioprotective medications compared with the adult peripheral circulation. This semi-systematic review focuses on fetoplacental vascular expression of adrenergic receptors, associated cell signalling mechanisms and predictive consequences of receptor activation/deactivation by antihypertensive and cardioprotective medications.
Topics: Adult; Female; Humans; Pregnancy; Adrenergic Agents; Antihypertensive Agents; Fetus; Placenta; Placental Circulation
PubMed: 37694528
DOI: 10.1097/HJH.0000000000003532 -
Veterinary Immunology and... Jun 2024Polymorphonuclear cells (PMN) provide a rapid response to infection and tissue damage and stress can modify these critical innate immune defences. The study of...
Polymorphonuclear cells (PMN) provide a rapid response to infection and tissue damage and stress can modify these critical innate immune defences. The study of adrenergic receptor (AR) expression and function in bovine PMNs is limited but both neutrophils and eosinophils express numerous AR genes but differ significantly in their expression of individual AR genes. A flow cytometric technique was developed to differentiate between bovine neutrophils and eosinophils so both neutrophil and eosinophil responses to adrenergic agonists could be analysed. Neutrophils and eosinophils displayed significantly different changes in CD11b, L-selectin, and CD44 expression when activated by bovine serum opsonized zymosan and recombinant bovine interferon gamma. The responses of activated and resting neutrophils and eosinophils were then compared following stimulation with endogenous adrenergic agonists, epinephrine (E) norepinephrine (NE), and synthetic agonists targeting α1-, α2-, or β-ARs. Both resting and activated neutrophils and eosinophils displayed differences in iROS, CD44, and L-selectin expression following stimulation with E and NE. Resting neutrophils displayed pro-inflammatory responses to both E and NE, while resting eosinophils displayed a pro-inflammatory response to only NE. No single synthetic adrenergic agonist fully recapitulated responses observed with either E or NE and responses to adrenergic agonists were dose-dependent. In conclusion, bovine eosinophils and neutrophils responded to multiple adrenergic agonists by altering expression of proteins involved in immune surveillance and pro-inflammatory responses. Significant differences in neutrophil and eosinophil responses to adrenergic agonists are consistent with their differences in AR gene expression. This highlights the importance of analysing separately these two PMN subpopulations when investigating the effects of either endogenous or synthetic AR agonists.
Topics: Animals; Cattle; Neutrophils; Eosinophils; L-Selectin; Norepinephrine; Epinephrine; Adrenergic Agonists; Hyaluronan Receptors; Flow Cytometry; CD11b Antigen; Neutrophil Activation; Receptors, Adrenergic
PubMed: 38669937
DOI: 10.1016/j.vetimm.2024.110758 -
Journal of Biomedical Science Jul 2023Sustained, chronic activation of β-adrenergic receptor (β-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and...
BACKGROUND
Sustained, chronic activation of β-adrenergic receptor (β-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and Epac2) as key mediators. This study aimed to evaluate whether CD44, a transmembrane receptor mediating various cellular responses, participates in Epac-dependent arrhythmias.
METHODS
The heart tissue from CD44 knockout (CD44) mice, cultured HL-1 myocytes and the tissue of human ventricle were used for western blot, co-immunoprecipitaiton and confocal studies. Line-scanning confocal imaging was used for the study of cellular Ca sparks on myocytes. Optical mapping and intra-cardiac pacing were applied for arrhythmia studies on mice's hearts.
RESULTS
In mice, isoproterenol, a β-AR agonist, upregulated CD44 and Epac1 and increased the association between CD44 and Epac1. Isoproterenol upregulated the expression of phospho-CaMKII (p-CaMKII), phospho-ryanodine receptor (p-RyR), and phospho-phospholamban (p-PLN) in mice and cultured myocytes; these effects were attenuated in CD44 mice compared with wild-type controls. In vitro, isoproterenol, 8-CPT-cAMP (an Epac agonist), and osteopontin (a ligand of CD44) significantly upregulated the expression of p-CaMKII, p-RyR, and p-PLN; this effect was attenuated by CD44 small interfering RNA (siRNA). In myocytes, resting Ca sparks were induced by isoproterenol and overexpressed CD44, which were prevented by inhibiting CD44. Ex vivo optical mapping and in vivo intra-cardiac pacing studies showed isoproterenol-induced triggered events and arrhythmias in ventricles were prevented in CD44 mice. The inducibility of ventricular arrhythmias (VAs) was attenuated in CD44 HF mice compared with wild-type HF controls. In patients, CD44 were upregulated, and the association between CD44 and Epac1 were increased in ventricles with reduced contractility.
CONCLUSION
CD44 regulates β-AR- and Epac1-mediated Ca-handling abnormalities and VAs. Inhibition of CD44 is effective in reducing VAs in HF, which is potentially a novel therapeutic target for preventing the arrhythmias and sudden cardiac death in patients with diseased hearts.
Topics: Humans; Mice; Animals; Receptors, Adrenergic, beta; Isoproterenol; Guanine Nucleotide Exchange Factors; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Myocytes, Cardiac; Calcium; Arrhythmias, Cardiac; Calcium Signaling; Adrenergic Agents; Hyaluronan Receptors
PubMed: 37452346
DOI: 10.1186/s12929-023-00944-0