RESUMO
Neuromodulators act on multiple timescales to affect neuronal activity and behavior. They function as synaptic fine-tuners and master coordinators of neuronal activity across distant brain regions and body organs. While much research on neuromodulation has focused on roles in promoting features of wakefulness and transitions between sleep and wake states, the precise dynamics and functions of neuromodulatory signaling during sleep have received less attention. This review discusses research presented at our minisymposium at the 2024 Society for Neuroscience meeting, highlighting how norepinephrine, dopamine, and acetylcholine orchestrate brain oscillatory activity, control sleep architecture and microarchitecture, regulate responsiveness to sensory stimuli, and facilitate memory consolidation. The potential of each neuromodulator to influence neuronal activity is shaped by the state of the synaptic milieu, which in turn is influenced by the organismal or systemic state. Investigating the effects of neuromodulator release across different sleep substates and synaptic environments offers unique opportunities to deepen our understanding of neuromodulation and explore the distinct computational opportunities that arise during sleep. Moreover, since alterations in neuromodulatory signaling and sleep are implicated in various neuropsychiatric disorders and because existing pharmacological treatments affect neuromodulatory signaling, gaining a deeper understanding of the less-studied aspects of neuromodulators during sleep is of high importance.
Assuntos
Neurotransmissores , Sono , Humanos , Animais , Sono/fisiologia , Neurotransmissores/fisiologia , Encéfalo/fisiologia , Norepinefrina/fisiologia , Norepinefrina/metabolismo , Acetilcolina/metabolismo , Acetilcolina/fisiologia , Dopamina/metabolismo , Dopamina/fisiologia , Vigília/fisiologiaRESUMO
The objective of this investigation was to assess the impact of elevated catecholamine concentrations, induced through cold-water hand immersion, on the oxygen consumption (VÌO2) kinetics during intense exercise, and to contrast this effect with that of the priming effect. Ten active participants underwent three 8-minute constant work rate exercises (CWR) at ∆25%, with one CWR preceded by hand cooling (2 min at 0 °C, HC) and two consecutive CWR to induced priming effect on the second bout (SB). Pulmonary gas exchange and blood samples were analyzed to measure levels of epinephrine (E) and norepinephrine (NE). Results demonstrated a significant increase in the primary phase amplitude of VÌO2 kinetics in response to both hand HC (33.9 mL.min-1.kg-1; CI [32.2;35.7], p < 0.001) and SB (34.6 mL.min-1.kg-1; CI [33.0;36.3], p < 0.001) relative to the control (32.7 mL.min-1.kg-1; CI [31.5;35.1]). Additionally, the amplitude of the VÌO2 slow component was reduced for both HC (3.2 mL.min-1.kg-1; CI [2.2;4.1], p = 0.018) and SB (2.9 mL.min-1.kg-1; CI [1.8;4.2], p = 0.009) in comparison to control (3.9 mL.min-1.kg-1; CI [2.9;4.2]). These findings suggest that the increase in E and NE induced by hand cooling prior to exercise modifies VÌO2 kinetics in a manner akin to the priming effect. This research underscores the potential role of catecholamines in facilitating the priming effect and its subsequent impact on VÌO2 kinetics. However, further studies are necessary to clearly establish this link.
Assuntos
Epinefrina , Exercício Físico , Mãos , Norepinefrina , Consumo de Oxigênio , Humanos , Masculino , Adulto , Cinética , Norepinefrina/sangue , Norepinefrina/metabolismo , Epinefrina/sangue , Epinefrina/metabolismo , Mãos/fisiologia , Adulto Jovem , Exercício Físico/fisiologia , Temperatura Baixa , Feminino , Oxigênio/metabolismo , Troca Gasosa Pulmonar/fisiologiaRESUMO
BACKGROUND: Exploring clinical trial data using alternative methods may enhance original study's findings and provide new insights. The SOAP II trial has been published more than 10 years ago; but there is still some speculation that some patients may benefit from dopamine administration for shock management. We aimed to reanalyse the trial under different approaches and evaluate for heterogeneity in treatment effect (HTE). METHODS: All patients enrolled in SOAP II were eligible for reanalysis. We used a variety of methods including the win-ratio (WR), a Bayesian reanalysis stratified according to shock type, and both a risk-based and effect-based explorations for HTE. The methods were applied to different endpoints, including a hierarchy of death, new use of renal-replacement therapy (RRT), and new-onset arrhythmia; 28-day mortality; a composite endpoint (mortality, new use of RRT, and new-onset arrhythmia), and days alive and free of ICU at 28-days (DAFICU28). RESULTS: A total of 1679 patients were included (average age was 64.9 years, 57% male, 62% with septic and 17% with cardiogenic shock). All analysis favoured norepinephrine over dopamine. Under the WR approach, dopamine had fewer wins compared to norepinephrine (WR 0.79; 95% confidence intervals [CI] 0.68-0.92; p = 0.003), evident in both cardiogenic and septic shock subgroups. The Bayesian reanalysis for type of shock showed, for dopamine, a probability of harm of 0.95 for mortality, > 0.99 probability of harm for composite endpoint, and 0.91 probability of harm for DAFICU28. The fewer DAFICU28 with dopamine was more apparent in those with cardiogenic shock (0.92). Under the risk-based HTE, there was a high probability that dopamine resulted fewer DAFICU28 in the highest quartile of predicted mortality risk. The effect-based HTE assessment model did not recommended dopamine over norepinephrine for any combination of possible modifiers including age, type of shock, presence of cardiomyopathy, and SOFA score. Receiving dopamine when the effect-based model recommended norepinephrine was associated with an absolute increase in composite endpoint of 6%. CONCLUSION: The harm associated with the use of dopamine for the management of shock appears to be present in both septic and cardiogenic shock patients. There was no suggestion of any subgroup in which dopamine was found to be favourable over norepinephrine.
Assuntos
Teorema de Bayes , Dopamina , Norepinefrina , Humanos , Dopamina/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Norepinefrina/uso terapêutico , Idoso , Choque/tratamento farmacológicoRESUMO
Macrophages play a multifaceted role in maintaining tissue homeostasis, fighting infections, and regulating cold-induced thermogenesis. The brown adipose tissue (BAT) is crucial for maintaining body temperature during cold exposure. Cold stress triggers the sympathetic nervous system to release norepinephrine (NE), which activates BAT via ß3-adrenergic receptors, initiating lipolysis and glycolysis. BAT-infiltrating macrophages can either hinder or enhance thermogenesis by controlling the interplay between BAT cells and sympathetic nerves. In this study we report on a unique population of CD3+F4/80+ dual lineage co-expressing (DE) cells within the interscapular BAT (iBAT), that increased following chronic adrenergic stimulation. In forward scatter/side scatter plots, they formed a cluster distinct from lymphocytes, appearing larger and more complex. These CD3+F4/80+ DE cells demonstrated the lack of T cell markers CD62L and TCRß and expressed higher levels of Ly6C, F4/80, and CD11b markers compared to T cells and CD3- macrophages. Furthermore, analysis revealed two subpopulations within the CD3+F4/80+ DE population based on MHCII expression, with the proportion of MHCII-low subset increasing with adrenergic stimulation. This novel DE population within iBAT, unequivocally identified by the its unique surface marker profile, warrants further investigation into the intricate mechanisms governing adaptive thermogenesis regulation.
Assuntos
Tecido Adiposo Marrom , Complexo CD3 , Macrófagos , Termogênese , Animais , Tecido Adiposo Marrom/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Complexo CD3/metabolismo , Norepinefrina/farmacologia , Norepinefrina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos beta 3/metabolismoRESUMO
INTRODUCTION: Mental fatigue (MF) significantly affects both cognitive and physical performance. However, the precise mechanisms, particularly concerning neurotransmission, require further investigation. An implication of the role of dopamine (DA) and noradrenaline (NA) is stated, but empirical evidence for this theory still needs to be provided. To address this gap, we aim to investigate the role of brain neurotransmission in elucidating if, and how prolonged cognitive activity induces MF and its subsequent impact on cognitive performance. METHODS: This study (registration number: G095422N) will adopt a randomized cross-over design with sixteen healthy participants aged 18-35 years. The sessions include a familiarization, two experimental (DA: 20mg Methylphenidate; NA: 8mg Reboxetine) conditions, and one placebo (lactose tablet: 10mg) condition. A 60-minute individualized Stroop task will be used to investigate whether, and how the onset of MF changes under the influence of reuptake inhibitors. Attention and response inhibition will be assessed before and after the MF-inducing task using a Go/NoGo task. The integration of physiological (electroencephalography, heart rate), behavioral (attention, response inhibition), and subjective indicators (scales and questionnaires) will be used to detect the underlying mechanisms holistically. Data analysis will involve linear mixed models with significance at p<0.05. DISCUSSION: The integration of diverse techniques and analyses offers a comprehensive perspective on the onset and impact of MF, introducing a novel approach. Future research plans involve extending this protocol to explore the connection between brain neurotransmission and physical fatigue. This protocol will further advance our understanding of the complex interplay between the brain and fatigue.
Assuntos
Encéfalo , Estudos Cross-Over , Fadiga Mental , Metilfenidato , Transmissão Sináptica , Humanos , Fadiga Mental/fisiopatologia , Adulto , Adolescente , Adulto Jovem , Encéfalo/fisiologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Metilfenidato/farmacologia , Masculino , Feminino , Reboxetina , Cognição/fisiologia , Norepinefrina/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Atenção/fisiologia , Atenção/efeitos dos fármacos , Eletroencefalografia , Dopamina/metabolismoRESUMO
BACKGROUND: In pediatric critical care, vasoactive/inotropic support is widely used in patients with heart failure, but it remains controversial because the influence of multiple medications and the interplay between their inotropic and vasoactive effects on a given patient are hard to predict. Robust evidence supporting their use and quantifying their effects in this group of patients is scarce. STUDY QUESTION: The aim of this study was to characterize the effect of vasoactive medications on various cardiovascular parameters in pediatric patient with decreased ejection fraction. STUDY DESIGN: Clinical-data based physiologic simulator study. MEASURE AND OUTCOMES: We used a physics-based computer simulator for quantifying the response of cardiovascular parameters to the administration of various types of vasoactive/inotropic medications in pediatric patients with decreased ejection fraction. The simulator allowed us to study the impact of increasing medication dosage and the simultaneous administration of some vasoactive agents. Correlation and linear regression analyses yielded the quantified effects on the vasoactive/inotropic support. RESULTS: Cardiac output and systemic venous saturation significantly increased with the administration of dobutamine and milrinone in isolation, and combination of milrinone with dobutamine, dopamine, or epinephrine. Both parameters decreased with the administration of epinephrine and norepinephrine in isolation. No significant change in these hemodynamic parameters was observed with the administration of dopamine in isolation. CONCLUSIONS: Milrinone and dobutamine were the only vasoactive medications that, when used in isolation, improved systemic oxygen delivery. Milrinone in combination with dobutamine, dopamine, or epinephrine also increased systemic oxygen delivery. The induced increment on afterload can negatively affect systemic oxygen delivery.
Assuntos
Cardiotônicos , Simulação por Computador , Dobutamina , Epinefrina , Insuficiência Cardíaca Sistólica , Monitorização Hemodinâmica , Milrinona , Humanos , Criança , Milrinona/uso terapêutico , Milrinona/administração & dosagem , Milrinona/farmacologia , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Cardiotônicos/administração & dosagem , Dobutamina/farmacologia , Dobutamina/administração & dosagem , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Insuficiência Cardíaca Sistólica/fisiopatologia , Epinefrina/administração & dosagem , Monitorização Hemodinâmica/métodos , Dopamina/farmacologia , Dopamina/administração & dosagem , Dopamina/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Norepinefrina/administração & dosagem , Norepinefrina/uso terapêutico , Norepinefrina/farmacologia , Masculino , Volume Sistólico/efeitos dos fármacos , Feminino , Pré-Escolar , Quimioterapia CombinadaRESUMO
Introduction: The use of push-dose vasopressors to treat anesthesia-induced hypotension is a common evidence-based practice among anesthesiologists. In more recent years, the use of push-dose vasopressors has transitioned to the emergency department (ED) and critical care setting. There is debate on the best choice of a push-dose vasopressor, with push-dose epinephrine or phenylephrine being more commonly used. This scoping review evaluated publications regarding the clinical use of push-dose norepinephrine. Methods: We queried research studies in both PubMed and Google Scholar on the use of push-dose norepinephrine in human subjects, with numerous randomized controlled trials that compare norepinephrine to other vasopressors including phenylephrine, ephedrine, and epinephrine. Results: A large majority of the studies were performed in the setting of spinal anesthesia prior to cesarean section, while several involved the administration of general anesthesia, with limited-to-no literature in the emergency and critical care setting. Of the 27 studies that we included in the review, 17 were randomized controlled trials. These studies demonstrated that norepinephrine was safe and effective. Conclusion: Prior research has demonstrated the superiority of norepinephrine as a pressor of choice for various shock states. In this review, the safety and efficacy of push-dose norepinephrine is demonstrated, and favorable hemodynamic markers are shown in comparison to other agents. In addition, there are some safety and efficiency benefits to using push-dose norepinephrine from an administration standpoint, as well as clinically in decreased need for repeat doses. Further high-quality studies in the emergency and critical care realm would be beneficial to confirm these findings.
Assuntos
Hipotensão , Norepinefrina , Vasoconstritores , Humanos , Norepinefrina/administração & dosagem , Vasoconstritores/administração & dosagem , Vasoconstritores/uso terapêutico , Hipotensão/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Serviço Hospitalar de Emergência , Epinefrina/administração & dosagem , Epinefrina/uso terapêutico , Fenilefrina/administração & dosagem , Fenilefrina/uso terapêuticoRESUMO
PURPOSE: To explore the effects of a single dose of uridine adenosine tetraphosphate (Up4A) administered through the tail vein, on the blood pressure of mice. METHODS: The mice were separated into three groups: the Up4A group, the norepinephrine (NA) group, and the α, ß-methylene adenosine triphosphate (α, ß-meATP) group. Each group of mice were injected drugs through the tail vein at 1, 3, 10, and 30 nmol/kg doses in an ascending order. Additionally, six mice were injected Up4A through the tail vein at 20, 40, 60, and 80 nmol/kg doses in an ascending order. The administration intervals for each dose were 20 min. RESULTS: Mice in these groups experienced a rapid increase in blood pressure, reaching its peak within 10 s after drug administration. It took approximately 120 s for the blood pressure to return to baseline levels after the administration of the drugs in both the NA and α, ß-meATP groups. After higher doses of Up4A were administered to the mice, their blood pressure exhibited biphasic changes. Initially, blood pressure of the mice rapidly dropped to a minimum within 10 s, then rose rapidly to a peak within 30 s. Subsequently, it gradually declined, taking around 10 min to return to the levels before the drug administration. CONCLUSION: Compared to NA and α, ß-meATP, Up4A, which contains purine and pyrimidine components, displayed a weaker blood pressure-elevating potency. Through its corresponding structure, Up4A exerted vasodilatory and vasoconstrictive effects throughout the entire experiment resulting in biphasic changes in blood pressure.
Assuntos
Pressão Sanguínea , Fosfatos de Dinucleosídeos , Animais , Pressão Sanguínea/efeitos dos fármacos , Camundongos , Fosfatos de Dinucleosídeos/farmacologia , Fosfatos de Dinucleosídeos/administração & dosagem , Masculino , Injeções Intravenosas , Norepinefrina/farmacologia , Norepinefrina/administração & dosagem , Relação Dose-Resposta a Droga , Trifosfato de Adenosina/análogos & derivadosRESUMO
Caffeine, a methylxanthine alkaloid, works as a nonselective adenosine receptor antagonist. It is the most widely used psychostimulant drug worldwide. However, caffeine overdose can lead to acute intoxication, posing a clinical problem. Hyperthermia and hyperactivity are associated issues with acute caffeine intoxication; however, no definitive treatment exists. This study aimed to assess the ability of risperidone to attenuate caffeine-induced hyperthermia and hyperactivity while elucidating the unknown mechanisms of caffeine intoxication. The rats received intraperitoneal injections of saline, risperidone (0.25 mg/kg, 0.5 mg/kg), WAY-100635, ketanserin, haloperidol, sulpiride, or SCH 23390, 5 min after the administration of caffeine (25 mg/kg). Subcutaneous temperature and activity counts were measured using nano tag ® for up to 90 min. In vivo microdialysis was used to determine the effect of risperidone on caffeine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline (NA) concentrations in the anterior hypothalamus. Rats were injected with caffeine (25 mg/kg), followed by saline or risperidone (0.5 mg/kg) 5 min later. The levels of DA, 5-HT, and noradrenaline were measured every 15 min for up to 90 min after caffeine administration. Risperidone and 5-HT2A receptor antagonist ketanserin attenuated caffeine-induced hyperthermia and hyperactivity. Haloperidol and dopamine D1 antagonist SCH-23390 exacerbated hyperthermia without any effect on the hyperactivity. In the microdialysis study, risperidone treatment further attenuated caffeine-induced 5-HT elevation, but not DA and NA. Our results indicate that risperidone attenuates caffeine-induced hyperthermia and hyperactivity by blocking 5-HT2A receptor activity and may be potentially useful for treating caffeine intoxication.
Assuntos
Cafeína , Hipertermia , Risperidona , Serotonina , Animais , Cafeína/farmacologia , Risperidona/farmacologia , Masculino , Hipertermia/induzido quimicamente , Serotonina/metabolismo , Ratos Sprague-Dawley , Dopamina/metabolismo , Ratos , Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Norepinefrina/metabolismoRESUMO
A simple and efficient method for obtaining monospecies and binary Staphylococcus aureus and Staphylococcus epidermidis cultures in sodium alginate gel matrix mimicking the natural microenvironment of the nasal cavity was proposed. The cultures were used for studying the effect of norepinephrine on monospecies and binary communities of two types of bacteria, S. aureus (invasive strain) and S. epidermis (commensal strain). After 24-h incubation, S. aureus predominated in the binary community, but later it was replaced by S. epidermis. Norepinephrine at higher concentrations accelerated this process without principally changing it. The model can be used to develop more effective complex antimicrobial drugs.
Assuntos
Alginatos , Norepinefrina , Staphylococcus aureus , Staphylococcus epidermidis , Alginatos/farmacologia , Staphylococcus epidermidis/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Norepinefrina/farmacologia , Ácidos Hexurônicos/farmacologia , Ácido Glucurônico/farmacologia , Géis/farmacologia , Catecolaminas/farmacologia , Catecolaminas/metabolismo , Antibacterianos/farmacologiaRESUMO
Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level1. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target1. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states-the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.
Assuntos
Microscopia Crioeletrônica , Modelos Moleculares , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Humanos , Sítios de Ligação , Especificidade por Substrato , Ligação Proteica , Norepinefrina/metabolismoRESUMO
Tissues often experience hypoxia at sites of inflammation due to malperfusion, massive immune cell recruitment, and increased oxygen consumption. Organisms adapt to these hypoxic conditions through the transcriptional activation of various genes. In fact, there is significant crosstalk between the transcriptional responses to hypoxia and inflammatory processes. This interaction, named inflammatory hypoxia, plays a crucial role in various diseases including malignancies, chronic inflammatory lung diseases, and sepsis. To further elucidate the crosstalk between hypoxia and inflammation in vivo and assess its potential for innovative therapies, our study aimed at investigating the impact of acute hypoxic conditions on inflammation-induced immune responses. To this end, we exposed healthy human subjects to hypoxia either before (hypoxia priming) or after a single intravenous (i.v.) injection of 0.4 ng/kg LPS. Our data show that hypoxia exposure prior to LPS injection (hypoxia priming) amplified the proinflammatory response. This was reflected by an increase in body temperature, plasma noradrenaline levels, and the production of proinflammatory cytokines (i.e., IL-6 and TNF-α), compared with LPS control conditions. These effects were not observed when participants were exposed to hypoxia after LPS administration, demonstrating that the interaction between hypoxia and inflammation highly depends on the timing of both stimuli. Our findings suggest that acute hypoxia (i.e., hypoxia priming) modulates transient inflammation, leading to an enhanced proinflammatory response in healthy human subjects. This highlights the need for further investigations to understand the pathology of various hypoxia-inducible factor (HIF)-associated inflammatory diseases and to develop suitable, innovative therapies.NEW & NOTEWORTHY To our knowledge, this is the first in vivo study investigating the effects of hypoxia preceding (hypoxia priming) or following LPS administration on the endotoxin-induced inflammatory response in healthy human subjects. The data show that hypoxia priming amplified the proinflammatory response, reflected by an increased body temperature, increased plasma noradrenaline levels, and higher production of proinflammatory cytokines (i.e., IL-6 and TNF-α) compared with LPS control conditions.
Assuntos
Citocinas , Voluntários Saudáveis , Hipóxia , Inflamação , Lipopolissacarídeos , Humanos , Masculino , Adulto , Lipopolissacarídeos/farmacologia , Hipóxia/metabolismo , Adulto Jovem , Inflamação/metabolismo , Inflamação/imunologia , Citocinas/metabolismo , Interleucina-6/metabolismo , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/metabolismo , Norepinefrina/sangue , Temperatura Corporal/efeitos dos fármacos , EndotoxinasRESUMO
OBJECTIVE: Mean arterial pressure (MAP) plays a significant role in regulating tissue perfusion and urine output (UO). The optimal MAP target in critically ill patients remains a subject of debate. We aimed to explore the relationship between MAP and UO. DESIGN: A retrospective observational study. SETTING: A general ICU in a tertiary medical center. PATIENTS: All critically ill patients admitted to the ICU for more than 10 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: MAP values and hourly UO were collected in 5,207 patients. MAP levels were categorized into 10 groups of 5 mm Hg (from MAP < 60 mm Hg to MAP > 100 mg Hg), and 656,423 coupled hourly mean MAP and UO measurements were analyzed. Additionally, we compared the UO of individual patients in each MAP group with or without norepinephrine (NE) support or diuretics, as well as in patients with acute kidney injury (AKI).Hourly UO rose incrementally between MAP values of 65-100 mm Hg. Among 2,226 patients treated with NE infusion, mean UO was significantly lower in the MAP less than 60 mm Hg group (53.4 mL/hr; 95% CI, 49.3-57.5) compared with all other groups (p < 0.001), but no differences were found between groups of 75 less than or equal to MAP. Among 2500 patients with AKI, there was a linear increase in average UO from the MAP less than 60 mm Hg group (57.1 mL/hr; 95% CI, 54.2-60.0) to the group with MAP greater than or equal to 100 mm Hg (89.4 mL/hr; 95% CI, 85.7-93.1). When MAP was greater than or equal to 65 mm Hg, we observed a statistically significant trend of increased UO in periods without NE infusion. CONCLUSIONS: Our analysis revealed a linear correlation between MAP and UO within the range of 65-100 mm Hg, also observed in the subgroup of patients treated with NE or diuretics and in those with AKI. These findings highlight the importance of tissue perfusion to the maintenance of diuresis and achieving adequate fluid balance in critically ill patients.
Assuntos
Pressão Arterial , Estado Terminal , Unidades de Terapia Intensiva , Humanos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Idoso , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/urina , Injúria Renal Aguda/diagnóstico , Norepinefrina/urina , Micção/efeitos dos fármacos , Micção/fisiologiaRESUMO
Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.
Assuntos
Tecido Adiposo Marrom , Adiposidade , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Obesidade , Ocitocina , Sistema Nervoso Simpático , Animais , Ocitocina/farmacologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/inervação , Masculino , Camundongos , Obesidade/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Adiposidade/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos , Camundongos Obesos , Metabolismo Energético/efeitos dos fármacos , Norepinefrina/metabolismoRESUMO
Hypoglycemia is common in people with type 1 diabetes. Sometimes, severe hypoglycemia can be fatal. The underlying mechanisms by which severe hypoglycemia can lead to death are unclear. The sympathetic nervous system is thought to be proarrhythmic. We hypothesized that norepinephrine is the main mediator of severe hypoglycemia-induced fatal cardiac arrhythmias. To test this hypothesis, adult, non-diabetic Sprague-Dawley rats were subjected to hyperinsulinemic-severe hypoglycemic clamps (3 h, 10-15 mg/dL) during two different experiments: (1) intracerebroventricular (ICV) norepinephrine (n = 26) or artificial cerebrospinal fluid (aCSF) (n = 20) infusion or (2) blockade of norepinephrine release by intraperitoneal reserpine (n = 20) or control (n = 29). In experiment 1, brain norepinephrine infusion during severe hypoglycemia led to a 2.5-fold increase in third-degree heart block and a 24% incidence of ST elevation compared to no ST elevation in aCSF controls. In experiment 2, reserpine successfully reduced plasma and cardiac norepinephrine levels. During severe hypoglycemia, reserpine completely prevented second and third-degree heart block and T wave increases, a marker of myocardial infarction, compared to controls. In conclusion, norepinephrine increases while reserpine, used to reduce norepinephrine nerve terminal release, reduces heart block and markers of myocardial infarction during severe hypoglycemia.
Assuntos
Bloqueio Cardíaco , Hipoglicemia , Norepinefrina , Ratos Sprague-Dawley , Animais , Norepinefrina/metabolismo , Norepinefrina/líquido cefalorraquidiano , Masculino , Hipoglicemia/metabolismo , Ratos , Bloqueio Cardíaco/fisiopatologia , Reserpina/farmacologiaRESUMO
Research on sex differences has increased across various fields, including cancer and its treatment domains. Reports have indicated sex differences in cancer incidence, survival rates, and the efficacy of anticancer drugs. However, such reports are limited, and in-depth assessments of the underlying mechanisms are still in progress. Although various chemotherapeutic regimens are applicable for breast cancer treatment, reports have surfaced regarding weight gain in female patients undergoing fluorouracil, epirubicin, cyclophosphamide (FEC) or cyclophosphamide, methotrexate, fluorouracil (CMF) therapy. We hypothesized the potential of 5-fluorouracil (5-FU) in weight gain and sex-related differences. To address this, we conducted experiments in mice to confirm weight gain and sex differences following 5-FU administration, and elucidate the underlying mechanisms. Our findings revealed weight gain and increased food intake in female mice following 5-FU administration. Additionally, female mice receiving 5-FU exhibited increased norepinephrine and α1- and α2-adrenergic receptor expression, reduced estradiol levels, and increased ghrelin levels. These results indicate 5-FU administration-induced sex differences in weight gain and implicate increased food intake because of increased norepinephrine and α1- and α2-adrenergic receptor expression, reduced estradiol levels, and a subsequent increase in ghrelin levels, which contribute to weight gain in female patients undergoing CMF therapy.
Assuntos
Fluoruracila , Grelina , Caracteres Sexuais , Aumento de Peso , Animais , Feminino , Aumento de Peso/efeitos dos fármacos , Masculino , Antimetabólitos Antineoplásicos , Ingestão de Alimentos/efeitos dos fármacos , Camundongos , Estradiol/sangue , Norepinefrina/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Although the locus ceruleus (LC) is recognized as a crucial modulator for attention and perception by releasing norepinephrine into various cortical regions, the impact of LC-noradrenergic (LC-NE) modulation on auditory discrimination behavior remains elusive. In this study, we firstly recorded local field potential and single-unit activity in multiple cortical regions associated with auditory-motor processing, including the auditory cortex, posterior parietal cortex, secondary motor cortex, anterior cingulate cortex, prefrontal cortex, and orbitofrontal cortex (OFC), in response to optogenetic activation (40â Hz and 0.5â s) of the LC-NE neurons in awake mice (male). We found that phasic LC stimulation induced a persistent high gamma oscillation (50-80â Hz) in the OFC. Phasic activation of LC-NE neurons also resulted in a corresponding increase in norepinephrine levels in the OFC, accompanied by a pupillary dilation response. Furthermore, when mice were performing a go/no-go auditory discrimination task, we optogeneticaly activated the neural projections from LC to OFC and revealed a shortened latency in behavioral responses to sound stimuli and an increased false alarm rate. These impulsive behavioral responses may be associated with the gamma neural activity in the OFC. These findings have broadened our understanding of the neural mechanisms involved in the role of LC in auditory-motor processing.
Assuntos
Percepção Auditiva , Discriminação Psicológica , Locus Cerúleo , Optogenética , Animais , Locus Cerúleo/fisiologia , Camundongos , Masculino , Percepção Auditiva/fisiologia , Discriminação Psicológica/fisiologia , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Estimulação Acústica/métodos , Ritmo Gama/fisiologia , Neurônios/fisiologia , Córtex Cerebral/fisiologiaRESUMO
Prader-Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/-p) animals. Compared to WT mice, Ndn + m/-p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/-p and WT mice, but Ndn + m/-p mice were less anxious. After acute restraint, Ndn + m/-p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/-p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/-p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.
Assuntos
Modelos Animais de Doenças , Locus Cerúleo , Síndrome de Prader-Willi , Animais , Locus Cerúleo/fisiopatologia , Camundongos , Síndrome de Prader-Willi/fisiopatologia , Feminino , Masculino , Proteínas do Tecido Nervoso/genética , Norepinefrina/metabolismo , Ansiedade/fisiopatologia , Ansiedade/etiologia , Camundongos Endogâmicos C57BL , Aprendizagem em Labirinto/fisiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Interação Social , Proteínas NuclearesRESUMO
Pain perception is the consequence of a complex interplay between activation and inhibition. Noradrenergic pain modulation inhibits nociceptive transmission and pain perception. The main source of norepinephrine (NE) in the central nervous system is the Locus Coeruleus (LC), a small but complex cluster of cells in the pons. The aim of this study is to review the literature on the LC-NE inhibitory system, its influence on chronic pain pathways and its frequent comorbidities. The literature research showed that pain perception is the consequence of nociceptive and environmental processing and is modulated by the LC-NE system. If perpetuated in time, nociceptive inputs can generate neuroplastic changes in the central nervous system that reduce the inhibitory effects of the LC-NE complex and facilitate the development of chronic pain and frequent comorbidities, such as anxiety, depression or sleeping disturbances. The exact mechanisms involved in the LC functional shift remain unknown, but there is some evidence that they occur through plastic changes in the medial and lateral pathways and their brain projections. Additionally, there are other influencing factors, like developmental issues, neuroinflammatory glial changes, NE receptor affinity and changes in LC neuronal firing rates.
Assuntos
Dor Crônica , Locus Cerúleo , Norepinefrina , Locus Cerúleo/metabolismo , Humanos , Dor Crônica/fisiopatologia , Dor Crônica/metabolismo , Animais , Norepinefrina/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Neurônios/fisiologia , Percepção da Dor/fisiologiaRESUMO
BACKGROUND: Spinal anaesthesia is a common anaesthetic method for caesarean sections but often results in hypotension, posing potential risks to maternal and neonatal health. Norepinephrine, as a vasopressor, may be effective in preventing and treating this hypotension. This systematic review and meta-analysis aims to systematically evaluate the efficacy and safety of prophylactic norepinephrine infusion for the treatment of hypotension following spinal anaesthesia in caesarean sections. METHODS: Literature searches were conducted in PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, and VIP databases for relevant studies on prophylactic administration of norepinephrine for the treatment of hypotension after spinal anaesthesia in caesarean delivery. Reference lists of included articles were also searched. The latest search update was on March 20, 2024. Meta-analysis was conducted using R software. The methods recommended by the Cochrane Handbook, Begge's and Egger's tests were used for risk of bias evaluation of the included literature. RESULTS: Nine studies were finally included in this study. The results showed that prophylactic administration of norepinephrine was superior to the control group in four aspects of treating hypotension after spinal anaesthesia in caesarean delivery: the incidence of hypotension was reduced [RR = 0.34, 95%CI (0.27-0.43), P < 0.01]; the incidence of severe hypotension was reduced [RR = 0.32, 95%CI (0.21-0.51), P < 0.01]; and maternal blood pressure was more stable with MDPE [MD = -5.00, 95%CI (-7.80--2.21), P = 0.06] and MDAPE [MD = 4.11, 95%CI (1.38-6.85), P < 0.05], the incidence of nausea and vomiting was reduced [RR = 0.52, 95%CI (0.35-0.77), P < 0.01]. On the other hand, the incidence of reactive hypertension was higher than the control group [RR = 3.58, 95%CI (1.94-6.58), P < 0.01]. There was no difference between the two groups in one aspects: newborn Apgar scores [MD = -0.01, 95%CI (-0.10-0.09, P = 0.85)]. CONCLUSION: Prophylactic administration of norepinephrine is effective in treating hypotension after spinal anaesthesia in caesarean delivery patients; however, it does not provide improved safety and carries a risk of inducing reactive hypertension.
Hypotension, or low blood pressure, after spinal anaesthesia can threaten the health of both mothers and their babies during caesarean sections. Norepinephrine is a drug that affects heart rate less and does not easily cross the placental barrier, which may reduce its potential negative effects on the baby. However, there are not many studies on using norepinephrine as a preventive measure. Our study systematically evaluated the use of prophylactic norepinephrine infusion to prevent hypotension in caesarean section patients. We found that it is effective in preventing low blood pressure but does not show improved safety and carries some risk of causing high pressure as a reaction.