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Angewandte Chemie (International Ed. in... Feb 2021Adrenoceptors are ubiquitous and mediate important autonomic functions as well as modulating arousal, cognition, and pain on a central level. Understanding these...
Adrenoceptors are ubiquitous and mediate important autonomic functions as well as modulating arousal, cognition, and pain on a central level. Understanding these physiological processes and their underlying neural circuits requires manipulating adrenergic neurotransmission with high spatio-temporal precision. Here we present a first generation of photochromic ligands (adrenoswitches) obtained via azologization of a class of cyclic amidines related to the known ligand clonidine. Their pharmacology, photochromism, bioavailability, and lack of toxicity allow for broad biological applications, as demonstrated by controlling locomotion in zebrafish and pupillary responses in mice.
Topics: Adrenergic Agents; Animals; Chromogenic Compounds; Ligands; Mice; Mice, Nude; Molecular Structure; Receptors, Adrenergic; Zebrafish
PubMed: 33103317
DOI: 10.1002/anie.202010553 -
The role of lactate in sepsis and COVID-19: Perspective from contracting skeletal muscle metabolism.Experimental Physiology Jul 2022What is the topic of this review? Lactate is considered an important substrate for mitochondria in the muscles, heart and brain during exercise and is the main... (Review)
Review
NEW FINDINGS
What is the topic of this review? Lactate is considered an important substrate for mitochondria in the muscles, heart and brain during exercise and is the main gluconeogenetic precursor in the liver and kidneys. In this light, we review the (patho)physiology of lactate metabolism in sepsis and coronavirus disease 2019 (COVID-19). What advances does it highlight? Elevated blood lactate is strongly associated with mortality in septic patients. Lactate seems unrelated to tissue hypoxia but is likely to reflect mitochondrial dysfunction and high adrenergic stimulation. Patients with severe COVID-19 exhibit near-normal blood lactate, indicating preserved mitochondrial function, despite a systemic hyperinflammatory state similar to sepsis.
ABSTRACT
In critically ill patients, elevated plasma lactate is often interpreted as a sign of organ hypoperfusion and/or tissue hypoxia. This view on lactate is likely to have been influenced by the pioneering exercise physiologists around 1920. August Krogh identified an oxygen deficit at the onset of exercise that was later related to an oxygen 'debt' and lactate accumulation by A. V. Hill. Lactate is considered to be the main gluconeogenetic precursor in the liver and kidneys during submaximal exercise, but hepatic elimination is attenuated by splanchnic vasoconstriction during high-intensity exercise, causing an exponential increase in blood lactate. With the development of stable isotope tracers, lactate has become established as an important energy source for muscle, brain and heart tissue, where it is used for mitochondrial respiration. Plasma lactate > 4 mM is strongly associated with mortality in septic shock, with no direct link between lactate release and tissue hypoxia. Herein, we provide evidence for mitochondrial dysfunction and adrenergic stimulation as explanations for the sepsis-induced hyperlactataemia. Despite profound hypoxaemia and intense work of breathing, patients with severe coronavirus disease 2019 (COVID-19) rarely exhibit hyperlactataemia (> 2.5 mM), while presenting a systemic hyperinflammatory state much like sepsis. However, lactate dehydrogenase, which controls the formation of lactate, is markedly elevated in plasma and strongly associated with mortality in severe COVID-19. We briefly review the potential mechanisms of the lactate dehydrogenase elevation in COVID-19 and its relationship to lactate metabolism based on mechanisms established in contracting skeletal muscle and the acute respiratory distress syndrome.
Topics: Adrenergic Agents; COVID-19; Humans; Hypoxia; Lactate Dehydrogenases; Lactic Acid; Muscle, Skeletal; Oxygen; Sepsis
PubMed: 34058787
DOI: 10.1113/EP089474 -
Journal of Musculoskeletal & Neuronal... 2008Evidence that leptin regulates bone turnover in part through a central nervous system (CNS)/beta-adrenergic system relay has driven attention towards the potential... (Review)
Review
Evidence that leptin regulates bone turnover in part through a central nervous system (CNS)/beta-adrenergic system relay has driven attention towards the potential therapeutic benefits of beta-adrenergic blockade to improve bone mass and strength. beta2- adrenergic receptor-mediated signaling in osteoblasts inhibits bone formation and triggers RANKL-mediated osteoclastogenesis and bone resorption. Mouse models of adrenergic-deficiency, particularly the mouse lacking the beta2-adrenergic receptor, have increased bone mass, more specifically increased trabecular bone volume. In turn, beta-blockers, such as propranolol, were reported to inhibit ovariectomy-induced bone loss. In contrast, a number of experiments in mice and rats suggest that inhibition of beta-adrenergic receptor-mediated signaling does not improve, and could actually be detrimental, for bone mass and microstructure. In humans, epidemiological observations suggested that users of beta-blockers have higher bone mineral density (BMD) and/or a reduced risk of fractures, yet not all studies were concordant. Here we review the evidence for a role of the adrenergic system in the regulation of bone metabolism in vitro and in vivo and provide some new evidence for a dual role of beta-adrenergic receptors 1 and 2 on bone turnover. Furthermore, we will examine the similarities and disparities that may exist in the effects of beta-adrenergic and PTH stimulation on bone metabolism.
Topics: Adrenergic Agents; Adrenergic Agonists; Adrenergic Antagonists; Animals; Bone Remodeling; Bone Resorption; Bone and Bones; Humans; Osteoclasts; Osteoporosis; Parathyroid Hormone; Receptors, Adrenergic; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 18622078
DOI: No ID Found -
Therapeutic Advances in Cardiovascular... Aug 2009beta-blockers are among the most widely used drugs in the prevention and treatment of cardiovascular disease, although they are associated with increased peripheral... (Review)
Review
beta-blockers are among the most widely used drugs in the prevention and treatment of cardiovascular disease, although they are associated with increased peripheral resistance. Third-generation beta-blockers avoid this adverse effect by inducing vasodilation through different mechanisms. In particular, nebivolol, a highly selective blocker of beta(1)-adrenergic receptors, is the only beta-blocker known to induce vascular production of nitric oxide, the main endothelial vasodilator. The specific mechanism of nebivolol is particularly relevant in hypertension, where nitric oxide dysfunction occurs. Indeed, nebivolol is able to reverse endothelial dysfunction. Nebivolol induces nitric oxide production via activation of beta(3)-adrenergic receptors, which can explain the good metabolic profile observed after treatment with this drug. Moreover, nebivolol can also stimulate the beta(3)-adrenergic receptor-mediated production of nitric oxide in the heart, and this stimulation can result in a greater protection against heart failure. In conclusion, nebivolol has a unique profile among antihypertensive drugs, adding to a very high selectivity against beta(1) adrenergic receptors, and an agonist action on beta(3) receptors and nitric oxide (NO), which has led to clinically significant improvements in hypertensive patients.
Topics: Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Antihypertensive Agents; Benzopyrans; Cardiovascular Diseases; Endothelium, Vascular; Ethanolamines; Humans; Myocardium; Nebivolol; Nitric Oxide; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-3; Signal Transduction; Vasodilation; Vasodilator Agents
PubMed: 19443516
DOI: 10.1177/1753944709104496 -
Nature Communications Dec 2022The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in...
The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in brown adipose tissue (BAT) and beige adipocytes remains to be investigated. Here we show that a previously uncharacterized adipokine (UPF0687 protein / human C20orf27 homolog) we named as Adissp (Adipose-secreted signaling protein) is a key regulator for white adipose tissue (WAT) thermogenesis and glucose homeostasis. Adissp expression is adipose-specific and highly BAT-enriched, and its secretion is stimulated by β3-adrenergic activation. Gain-of-functional studies collectively showed that secreted Adissp promotes WAT thermogenesis, improves glucose homeostasis, and protects against obesity. Adipose-specific Adissp knockout mice are defective in WAT browning, and are susceptible to high fat diet-induced obesity and hyperglycemia. Mechanistically, Adissp binds to a putative receptor on adipocyte surface and activates protein kinase A independently of β-adrenergic signaling. These results establish BAT-enriched Adissp as a major upstream signaling component in thermogenesis and offer a potential avenue for the treatment of obesity and diabetes.
Topics: Mice; Animals; Humans; Adipose Tissue, Brown; Adipokines; Thermogenesis; Adipose Tissue, White; Obesity; Glucose; Adrenergic Agents; Adipocytes, Brown; Energy Metabolism
PubMed: 36496438
DOI: 10.1038/s41467-022-35335-w -
International Journal of Molecular... Aug 2023The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for... (Review)
Review
The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of the tumor microenvironment, nor-adrenaline (NA) is poured in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surfaces of cancer and immune cells and are often involved in the activation of pro-tumoral signaling pathways. Beta2-adrenergic receptors (β2-ARs) are an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate regulatory immune cells and inhibit effector immune cells. Blocking β2-AR increases activation, proliferation, and cytokine release of T lymphocytes. Moreover, β2-AR deficiency during metabolic reprogramming of T cells increases mitochondrial membrane potential and biogenesis. In the view of the available research data, the immunosuppressive role of β2-AR in T cells presents it as a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged the contemporary knowledge about adrenergic-stress-mediated β2-AR activation on T lymphocytes inside tumor milieu.
Topics: Receptors, Chimeric Antigen; T-Lymphocytes; Adrenergic Agents; Norepinephrine; Cell- and Tissue-Based Therapy; Epinephrine
PubMed: 37629018
DOI: 10.3390/ijms241612837 -
The Journal of Clinical Investigation Nov 2018Bone metabolism is controlled by endocrine, paracrine, and inflammatory signals that continuously operate in health and disease. While these signals are critical for...
Bone metabolism is controlled by endocrine, paracrine, and inflammatory signals that continuously operate in health and disease. While these signals are critical for skeletal adaptation during development, longitudinal growth, and repair, disturbances such as sex hormone deficiency or chronic inflammation have unambiguously been linked to bone loss and skeletal fragility across species. In the current issue of the JCI, Khosla et al. evaluated the role of sympathetic outflow and present evidence to support the idea that the sympathetic nervous system regulates bone metabolism in humans, primarily via the β1-adrenergic receptor.
Topics: Adrenergic Agents; Bone Density; Bone and Bones; Humans; Norepinephrine; Sympathetic Nervous System
PubMed: 30277473
DOI: 10.1172/JCI122992 -
Neuroimmunomodulation 2023The immune system is embedded in a network of regulatory systems to keep homeostasis in case of an immunologic challenge. Neuroendocrine immunologic research has... (Review)
Review
The immune system is embedded in a network of regulatory systems to keep homeostasis in case of an immunologic challenge. Neuroendocrine immunologic research has revealed several aspects of these interactions over the past decades, e.g., between the autonomic nervous system and the immune system. This review will focus on evidence revealing the role of the sympathetic nervous system (SNS) in chronic inflammation, like colitis, multiple sclerosis, systemic sclerosis, lupus erythematodes, and arthritis with a focus on animal models supported by human data. A theory of the contribution of the SNS in chronic inflammation will be presented that spans these disease entities. One major finding is the biphasic nature of the sympathetic contribution to inflammation, with proinflammatory effects until the point of disease outbreak and mainly anti-inflammatory influence thereafter. Since sympathetic nerve fibers are lost from sites of inflammation during inflammation, local cells and immune cells achieve the capability to endogenously produce catecholamines to fine-tune the inflammatory response independent of brain control. On a systemic level, it has been shown across models that the SNS is activated in inflammation as opposed to the parasympathetic nervous system. Permanent overactivity of the SNS contributes to many of the known disease sequelae. One goal of neuroendocrine immune research is defining new therapeutic targets. In this respect, it will be discussed that at least in arthritis, it might be beneficial to support β-adrenergic and inhibit α-adrenergic activity besides restoring autonomic balance. Overall, in the clinical setting, we now need controlled interventional studies to successfully translate the theoretical knowledge into benefits for patients.
Topics: Animals; Humans; Sympathetic Nervous System; Inflammation; Immune System; Arthritis; Adrenergic Agents
PubMed: 37231902
DOI: 10.1159/000530969 -
British Journal of Anaesthesia Jul 2014Electroconvulsive therapy (ECT) is associated with at least transient episodes of hypertension and tachycardia. Beta-blocking agents may be indicated to prevent... (Review)
Review
Electroconvulsive therapy (ECT) is associated with at least transient episodes of hypertension and tachycardia. Beta-blocking agents may be indicated to prevent cardiovascular complications and may shorten seizure duration. This review evaluates studies that used beta-blocking agents during ECT to determine which agent has the most favourable outcomes on cardiovascular variables and seizure duration. A Medline database search was made using the combined keywords 'adrenergic beta-antagonists' and 'electroconvulsive therapy'. The search was restricted to double-blind randomized controlled trials and yielded 29 original studies. With the use of esmolol, significant attenuating effects were found on cardiovascular parameters in the first 5 min after stimulation; its shortening effects on seizure duration may be dose-related. With the use of labetalol, findings on cardiovascular effects were inconsistent during the first minutes after stimulation but were significant after 5 min and thereafter; seizure duration was scarcely studied. Landiolol attenuates heart rate but with inconsistent findings regarding arterial pressure (AP); seizure duration was mostly unaffected. Esmolol appears to be effective in reducing the cardiovascular response, although seizure duration may be affected with higher dosages. Landiolol can be considered a suitable alternative, but effects on AP need further investigation. Labetalol has been studied to a lesser extent and may have prolonged cardiovascular effects. The included studies varied in design, methodology, and the amount of exact data provided in the publications. Further study of beta-blocking agents in ECT is clearly necessary.
Topics: Adrenergic beta-Antagonists; Cardiovascular Diseases; Electroconvulsive Therapy; Humans; Labetalol; Morpholines; Propanolamines; Randomized Controlled Trials as Topic; Urea
PubMed: 24942714
DOI: 10.1093/bja/aeu153 -
JACC. Cardiovascular Imaging Dec 2020
Topics: Adrenal Gland Neoplasms; Adrenergic Agents; Humans; Pheochromocytoma; Predictive Value of Tests; Ventricular Function, Left; Ventricular Remodeling
PubMed: 33221239
DOI: 10.1016/j.jcmg.2020.09.011