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Pharmacological Research Aug 2019Sympathetic activity plays an important role in modulation of cardiac rhythm. Indeed, while exerting positive tropic effects in response to physiologic and pathologic... (Review)
Review
Sympathetic activity plays an important role in modulation of cardiac rhythm. Indeed, while exerting positive tropic effects in response to physiologic and pathologic stressors, β-adrenergic stimulation influences cardiac electrophysiology and can lead to disturbances of the heart rhythm and potentially lethal arrhythmias, particularly in pathological settings. For this reason, β-blockers are widely utilized clinically as antiarrhythmics. In this review, the molecular mechanisms of β-adrenergic action in the heart, the cellular and tissue level cardiac responses to β-adrenergic stimulation, and the clinical use of β-blockers as antiarrhythmic agents are reviewed. We emphasize the complex interaction between cardiomyocyte signaling, contraction, and electrophysiology occurring over multiple time- and spatial-scales during pathophysiological responses to β-adrenergic stimulation. An integrated understanding of this complex system is essential for optimizing therapies aimed at preventing arrhythmias.
Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Humans; Myocardium
PubMed: 31100336
DOI: 10.1016/j.phrs.2019.104274 -
Annals of Medicine Dec 2022Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant... (Review)
Review
Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant pharmacological potential and could be exploited for research by medicinal chemists. It is an indole alkaloid obtained from various natural/synthetic sources. The research on yohimbine started early, and its use as a stimulant and aphrodisiac by humans has been reported for a long time. The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre and postsynaptic α-adrenergic receptors and has a moderate affinity for 1 and 2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A>, 5HT-1B > 1-D > D3 > D2 receptors. The current review highlights some significant findings that contribute to developing yohimbine-based drugs. It also highlights the therapeutic potential of yohimbine against selected human diseases. However, further research is recommended on the pharmacokinetics, molecular mechanisms, and drug safety requirements using well-designed randomized clinical trials to produce yohimbine as a pharmaceutical agent for human use.Key MessagesYohimbine is a natural indole alkaloid with significant pharmacological potential.Humans have used it as a stimulant and aphrodisiac from a relatively early time.It blocks the pre- and postsynaptic α2-adrenergic receptors that could be exploited for managing erectile dysfunction, myocardial dysfunction, inflammatory disorders, and cancer.
Topics: Male; Humans; Yohimbine; Adrenergic alpha-Antagonists; Aphrodisiacs; Receptors, Adrenergic, alpha-2; Pharmaceutical Preparations
PubMed: 36263866
DOI: 10.1080/07853890.2022.2131330 -
American Family Physician Mar 2020More than 70% of adults treated for primary hypertension will eventually require at least two antihypertensive agents, either initially as combination therapy or as... (Review)
Review
More than 70% of adults treated for primary hypertension will eventually require at least two antihypertensive agents, either initially as combination therapy or as add-on therapy if monotherapy and lifestyle modifications do not achieve adequate blood pressure control. Four main classes of medications are used in combination therapy for the treatment of hypertension: thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). ACEIs and ARBs should not be used simultaneously. In black patients, at least one agent should be a thiazide diuretic or a calcium channel blocker. Patients with heart failure with reduced ejection fraction should be treated initially with a beta blocker and an ACEI or ARB (or an angiotensin receptor-neprilysin inhibitor), followed by add-on therapy with a mineralocorticoid receptor antagonist and a diuretic based on volume status. Treatment for patients with chronic kidney disease and proteinuria should include an ACEI or ARB plus a thiazide diuretic or a calcium channel blocker. Patients with diabetes mellitus should be treated similarly to those without diabetes unless proteinuria is present, in which case combination therapy should include an ACEI or ARB.
Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Drug Therapy, Combination; Humans; Hypertension
PubMed: 32163253
DOI: No ID Found -
Nature Cancer Oct 2022Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of...
Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of predictors of response. Here, from bulk and single-cell transcriptomic analyses, we identify a subset of neuroblastomas enriched for transcripts associated with immune activation and inhibition and show that these are predominantly characterized by gene expression signatures of the mesenchymal lineage state. By contrast, tumors expressing adrenergic lineage signatures are less immunogenic. The inherent presence or induction of the mesenchymal state through transcriptional reprogramming or therapy resistance is accompanied by innate and adaptive immune gene activation through epigenetic remodeling. Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage.
Topics: Humans; Cell Lineage; Adrenergic Agents; Immune Checkpoint Inhibitors; Neuroblastoma; Cytokines; Phenotype
PubMed: 36138189
DOI: 10.1038/s43018-022-00427-5 -
Nature Nov 2022G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated...
G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)-a master regulator of cell proliferation and survival. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood. Here we investigated how spatially organized β-adrenergic receptor (βAR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors, we show that βAR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gα and requires ligand-stimulated βAR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gα, RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal βAR and Gα signalling blunted nuclear ERK activity, MYC gene expression and cell proliferation. These results reveal a non-canonical mechanism for the spatial regulation of ERK through GPCR signalling and identify a functionally important endosomal signalling axis.
Topics: Adrenergic Agents; Cell Proliferation; Endosomes; Extracellular Signal-Regulated MAP Kinases; Genes, myc; GTP-Binding Protein alpha Subunits, Gs; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 36289326
DOI: 10.1038/s41586-022-05343-3 -
Drug Design, Development and Therapy 2023Peripheral nerve block technology is important to balanced anesthesia technology. It can effectively reduce opioid usage. It is the key to enhance clinical... (Review)
Review
Peripheral nerve block technology is important to balanced anesthesia technology. It can effectively reduce opioid usage. It is the key to enhance clinical rehabilitation as an important part of the multimodal analgesia scheme. The emergence of ultrasound technology has accelerated peripheral nerve block technology development. It can directly observe the nerve shape, surrounding tissue, and diffusion path of drugs. It can also reduce the dosage of local anesthetics by improving positioning accuracy while enhancing the block's efficacy. Dexmedetomidine is a highly selective drug α-adrenergic receptor agonist. Dexmedetomidine has the characteristics of sedation, analgesia, anti-anxiety, inhibition of sympathetic activity, mild respiratory inhibition, and stable hemodynamics. Numerous studies have revealed that dexmedetomidine in peripheral nerve blocks can shorten the onset time of anesthesia and prolong the time of sensory and motor nerve blocks. Although dexmedetomidine was approved by the European Drug Administration for sedation and analgesia in 2017, it has not yet been approved by the US Food and Drug Administration (FDA). It is used as a non-label drug as an adjuvant. Therefore, the risk-benefit ratio must be evaluated when using these drugs as adjuvants. This review explains the pharmacology and mechanism of dexmedetomidine, the effect of dexmedetomidine on various peripheral nerve block as an adjuvant, and compare it with other types of adjuvants. We summarized and reviewed the application progress of dexmedetomidine as an adjuvant in nerve block and look forward to its future research direction.
Topics: United States; Dexmedetomidine; Adjuvants, Immunologic; Anesthetics, Local; Nerve Block; Adrenergic alpha-2 Receptor Agonists; Peripheral Nerves
PubMed: 37220544
DOI: 10.2147/DDDT.S405294 -
Science (New York, N.Y.) Sep 2022Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic...
Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new αAR agonists chemotypes that lack the sedation conferred by known αAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G and G signaling. Experimental structures of αAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC) of 52 nanomolar] and two analogs, '7075 and PS75 (EC 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.
Topics: Adrenergic alpha-2 Receptor Agonists; Analgesics, Non-Narcotic; Animals; Dexmedetomidine; Drug Design; Drug Discovery; Humans; Ligands; Mice; Molecular Docking Simulation; Pain; Pain Management; Structure-Activity Relationship
PubMed: 36173843
DOI: 10.1126/science.abn7065 -
Journal of the American College of... Dec 2021The use of β-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The use of β-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and observational cohort studies.
OBJECTIVES
This study aimed to investigate the effects of metoprolol on left ventricular outflow tract (LVOT) obstruction, symptoms, and exercise capacity in patients with obstructive HCM.
METHODS
This double-blind, placebo-controlled, randomized crossover trial enrolled 29 patients with obstructive HCM and New York Heart Association (NYHA) functional class II or higher symptoms from May 2018 to September 2020. Patients received metoprolol or placebo for 2 consecutive 2-week periods in random order. The effect parameters were LVOT gradients, NYHA functional class, Canadian Cardiovascular Society (CCS) angina class, Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and cardiopulmonary exercise testing.
RESULTS
Compared with placebo, the LVOT gradient during metoprolol was lower at rest (25 mm Hg [interquartile range (IQR): 15-58 mm Hg] vs 72 mm Hg [IQR: 28-87 mm Hg]; P = 0.007), at peak exercise (28 mm Hg [IQR: 18-40 mm Hg] vs 62 mm Hg [IQR: 31-113 mm Hg]; P < 0.001), and postexercise (45 mm Hg [IQR: 24-100 mm Hg] vs 115 mm Hg [IQR: 55-171 mm Hg]; P < 0.0001). During metoprolol treatment, 14% of patients were in NYHA functional class III or higher compared with 38% of patients receiving placebo (P < 0.01). Similarly, no patients were in CCS class III or higher during metoprolol treatment compared with 10% during placebo treatment (P < 0.01). These findings were confirmed by higher KCCQ-OSS during metoprolol treatment (76.2 ± 16.2 vs 73.8 ± 19.5; P = 0.039). Measures of exercise capacity, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide did not differ between the study arms.
CONCLUSIONS
Compared with placebo, metoprolol reduced LVOT obstruction at rest and during exercise, provided symptom relief, and improved quality of life in patients with obstructive HCM. Maximum exercise capacity remained unchanged. (The Effect of Metoprolol in Patients with Hypertrophic Obstructive Cardiomyopathy [TEMPO]; NCT03532802).
Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Cardiomyopathy, Hypertrophic; Cross-Over Studies; Double-Blind Method; Exercise Tolerance; Female; Humans; Male; Metoprolol; Middle Aged; Ventricular Outflow Obstruction
PubMed: 34915981
DOI: 10.1016/j.jacc.2021.07.065 -
Signal Transduction and Targeted Therapy Jul 2023Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous...
Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day; and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. These results implicate that the adrenergic signals could serve as potential targets for fracture management.
Topics: Mice; Animals; Fracture Healing; Bone Marrow; Myelopoiesis; Mice, Knockout; Brain Injuries, Traumatic; Adrenergic Agents
PubMed: 37402714
DOI: 10.1038/s41392-023-01457-w -
Nature Communications Mar 2023The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we...
The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC.
Topics: Humans; Child; Neuroblastoma; Transcription Factors; Chromatin; Cell Nucleus; Chromosome Aberrations; Adrenergic Agents; DNA Helicases; Nuclear Proteins; SOXC Transcription Factors; Histone Demethylases
PubMed: 36882421
DOI: 10.1038/s41467-023-36735-2