Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 81.106
Filtrar
1.
Rev. colomb. anestesiol ; 49(4): e200, Oct.-Dec. 2021. tab, graf
Artigo em Inglês | LILACS, COLNAL | ID: biblio-1341236

RESUMO

Abstract Introduction Vasopressors are essential in the management of various types of shock. Objective To establish the trend of vasopressors use in the intensive care units (ICU) in a population of patients affiliated with the Colombian Health System, 2010-2017. Methods Observational trial using a population database of patients hospitalized in eleven ICUs in various cities in Colombia. The drugs dispensed to hospitalized patients over 18 years old, from January 2010 until December 2017 were considered. A review and analysis of the vasopressors dispensed per month was conducted, taking into account sociodemographic and pharmacological variables (vasopressor used and daily doses defined per 100/beds/day (DBD). Results 81,348 dispensations of vasopressors, equivalent to 26,414 treatments in 19,186 patients receiving care in 11 hospitals from 7 cities were reviewed. The mean age of patients was 66.3±18.1 years and 52.6 % were males. Of the total number of treatments recorded, 17,658 (66.8 %) were with just one vasopressor. Norepinephrine was the most frequently prescribed drug (75.9 % of the prescriptions dispensed; 60.5 DBD), followed by adrenaline (26.6 %; 41.6 DBD), dopamine (19.4%), dobutamine (16.0 %), vasopressin (8.5 %) and phenylephrine (0.9 %). The use of norepinephrine increased from 2010 to 2017 (+6.19 DBD), whilst the use of other drugs decreased, particularly the use of adrenaline (-60.6 DBD) and dopamine (-10.8 DBD). Conclusions Norepinephrine is the most widely used vasopressor showing a growing trend in terms of its use during the study period, which is supported by evidence in favor of its effectiveness and safety in patients with shock.


Resumen Introducción Los fármacos vasopresores son fundamentales en el manejo de los diferentes tipos de choque. Objetivo Determinar la tendencia de utilización de fármacos vasopresores en unidades de cuidados intensivos (UCI) en una población de pacientes afiliados al Sistema de Salud de Colombia, 2010-2017. Métodos Estudio observacional, a partir de una base de datos poblacional con pacientes hospitalizados en once UCI de diferentes ciudades de Colombia. Se obtuvieron las dispensaciones de pacientes mayores de 18 años hospitalizados desde enero de 2010 hasta diciembre de 2017. Se hizo revisión y análisis de la dispensación mensual de vasopresores. Se consideraron variables sociodemográficas y farmacológicas (medicamento vasopresor usado y dosis diarias definidas por 100 camas/día [DCD]). Resultados Se revisaron 81.348 dispensaciones de vasopresores, equivalentes a 26.414 terapias en 19.186 pacientes atendidos en 11 hospitales de 7 ciudades, cuya edad promedio fue 66,3±18,1 años y el 52,6 % eran hombres. Del total de terapias registradas, 17.658 (66,8 %) fueron con un solo vasopresor. La norepinefrina fue el más comúnmente prescrito (75,9 % de las dispensaciones; 60,5 DCD), seguido por adrenalina (26,6 %; 41,6 DCD), dopamina (19,4 %), dobutamina (16,0 %), vasopresina (8,5 %) y fenilefrina (0,9 %). El uso de norepinefrina se incrementó de 2010 a 2017 (+6,19 DCD), mientras que el de otros fármacos disminuyó, especialmente adrenalina (-60,6 DCD) y dopamina (-10,8 DCD). Conclusiones La norepinefrina es el fármaco vasopresor más utilizado y el que ha demostrado una tendencia de uso incremental durante el periodo de estudio, lo cual está respaldado por evidencia a favor de su efectividad y seguridad en pacientes con choque.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Choque , Vasoconstritores , Vasopressinas , Unidades de Terapia Intensiva , Fenilefrina , Preparações Farmacêuticas , Dopamina , Epinefrina , Norepinefrina , Dobutamina , Uso de Medicamentos , Dosagem , Prescrições
2.
BMJ Case Rep ; 14(11)2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34764114

RESUMO

A middle-aged woman was diagnosed with postural orthostatic tachycardia syndrome based on her clinical symptoms, elevated norepinephrine levels and positive tilt-table test. The patient was refractory to conventional treatment and improved only after she was treated with methylated B vitamins for her heterozygous catechol-O-methyltransferase Val158Met polymorphism.


Assuntos
Síndrome da Taquicardia Postural Ortostática , Complexo Vitamínico B , Catecol O-Metiltransferase/genética , Feminino , Frequência Cardíaca , Humanos , Pessoa de Meia-Idade , Norepinefrina , Síndrome da Taquicardia Postural Ortostática/tratamento farmacológico , Síndrome da Taquicardia Postural Ortostática/genética , Teste da Mesa Inclinada , Complexo Vitamínico B/uso terapêutico
4.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(9): 1116-1120, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34839872

RESUMO

OBJECTIVE: To observe the effect of early rehabilitation exercise on blood pressure of elderly patients with septic shock. METHODS: A single-center, prospective, randomized controlled study was conducted in elderly patients with septic shock who were hospitalized in the department of critical care medicine of Huangshan Shoukang Hospital (High-tech Zone Central Hospital of Huangshan) from December 2018 to November 2020. According to the principle of simple random, all patients were divided into control group and intervention group. Both groups were treated with lower limb barometry to prevent deep vein thrombosis, 3 times a day, 30 minutes each time. After comprehensive treatment in the intensive care unit (ICU), the severity of patients was gradually improved, the hemodynamics was relatively stable, and the norepinephrine was reduced to 0.5 µg×kg-1×min-1. The control group continued to receive lower limb barometric treatment without rehabilitation training, while the intervention group began rehabilitation training when the dose of norepinephrine was reduced to 0.5 µg×kg-1×min-1. The duration of norepinephrine use, the length of ICU stay, and the occurrence of adverse events during rehabilitation training in intervention group was recorded. RESULTS: Seventy-two patients were included in the final analysis, 35 in intervention group and 37 in control group. There was no significant difference in gender, age, Oxford acute severity of illness score (OASIS), acute physiology and chronic health evaluation II (APACHE II), mean arterial pressure (MAP) of 3 times and underlying diseases between two groups. Compared with control group, the length of ICU stay and duration of dose of norepinephrine ≤ 0.5 µg×kg-1×min-1 in intervention group were significantly shorter [length of ICU stay (hours): 193.0 (145.5, 312.0) vs. 242.5 (180.0, 483.5), P < 0.05; duration of dose of norepinephrine ≤ 0.5 µg×kg-1×min-1 (hours): 120.0 (72.0, 144.0) vs. 144.5 (120.0, 192.0), Z = 2.976, P = 0.003]. In intervention group, 35 patients did not show acute myocardial infarction, arrhythmia, syncope, central venous catheter detachment, and gastric tube detachment during the rehabilitation period, except 1 patient suffered from naked hematuria due to urinary catheter traction, which disappeared the next day after symptomatic treatment. CONCLUSIONS: The early rehabilitation exercise was beneficial to the recovery of autonomic blood pressure in elderly patients with septic shock, shorten the time of norepinephrine use and ICU stay.


Assuntos
Choque Séptico , Idoso , Pressão Sanguínea , Terapia por Exercício , Humanos , Norepinefrina , Estudos Prospectivos , Choque Séptico/terapia
5.
Int J Mol Sci ; 22(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34639047

RESUMO

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples.


Assuntos
Dopamina/metabolismo , Epinefrina/metabolismo , Norepinefrina/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Catecolaminas/química , Catecolaminas/metabolismo , Dopamina/química , Epinefrina/química , Humanos , Drogas Ilícitas/metabolismo , Inativação Metabólica , Redes e Vias Metabólicas , Modelos Biológicos , Norepinefrina/química , Transtornos Relacionados ao Uso de Substâncias/etiologia
6.
Nat Commun ; 12(1): 6054, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663784

RESUMO

It is commonly assumed that episodic memories undergo a time-dependent systems consolidation process, during which hippocampus-dependent memories eventually become reliant on neocortical areas. Here we show that systems consolidation dynamics can be experimentally manipulated and even reversed. We combined a single pharmacological elevation of post-encoding noradrenergic activity through the α2-adrenoceptor antagonist yohimbine with fMRI scanning both during encoding and recognition testing either 1 or 28 days later. We show that yohimbine administration, in contrast to placebo, leads to a time-dependent increase in hippocampal activity and multivariate encoding-retrieval pattern similarity, an indicator of episodic reinstatement, between 1 and 28 days. This is accompanied by a time-dependent decrease in neocortical activity. Behaviorally, these neural changes are linked to a reduced memory decline over time after yohimbine intake. These findings indicate that noradrenergic activity shortly after encoding may alter and even reverse systems consolidation in humans, thus maintaining vividness of memories over time.


Assuntos
Nível de Alerta , Hipocampo/efeitos dos fármacos , Norepinefrina/farmacologia , Ioimbina/farmacologia , Adulto , Método Duplo-Cego , Feminino , Hipocampo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Consolidação da Memória/efeitos dos fármacos , Memória Episódica , Memória de Longo Prazo/efeitos dos fármacos , Memória de Longo Prazo/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Adulto Jovem
7.
Anal Chem ; 93(44): 14743-14747, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34709796

RESUMO

A long-standing challenge has been the simultaneous sensing of intracellular temperature and norepinephrine (NE) variations to explore signaling pathways and depression pathogeny. Here, we designed a fluorescent probe using poly(N-isopropylacrylamide) and 1-[4-(7-nitro-benzo [1,2,5]oxadiazol-4-yl)-piperazin-1-yl]-propenone (PNIPAm-AANBD) and (E)-1-(4-boronobenzyl)-2-(2-(1,3-dioxo-1H,3H-benzo[de]isochromen-6-yl)vinyl)pyridin-1-ium bromide (PHE) for simultaneously measuring the temperature and NE with high selectivity. The fluorescence intensity of the PNIPAm-AANBD moiety exhibited a good response to temperature changes. The PHE moiety could selectively sense NE due to the naphthalic anhydride group in PHE, which formed naphthalimide upon bonding with the primary amino group of NE. The hydroxyl-terminated ligand recognized the phenolic hydroxyl group of NE through the formation of hydrogen bonds. Using the proposed fluorescent probe, variations in the intracellular temperature and NE during NE reuptake could be simultaneously measured. It was first discovered that with the inhibition of antidepressant drugs, the intracellular temperature increased by 1.2-2.1 °C, and the NE reuptake decreased by about 21.5 µM. The measured variations in intracellular temperature and NE during neurotransmitter reuptake can shed light on the underlying mechanism of neurotransmitter signaling pathways, which may facilitate the treatment of depression.


Assuntos
Corantes Fluorescentes , Norepinefrina , Antidepressivos , Naftalimidas , Temperatura
8.
Artigo em Russo | MEDLINE | ID: mdl-34481450

RESUMO

Antidepressants are one of the most important classes of psychotropic drugs and they are widely used in clinical practice, mainly in psychiatry and neurology. The main indications for the use of antidepressants are depression and anxiety disorders. First-line antidepressants are selective serotonin reuptake inhibitors, as well as serotonin-norepinephrine reuptake inhibitors which due to their dual pharmacological action have an additional effect on pain syndromes that determines their use in the treatment of neuropathic pain and fibromyalgia. A special place among the serotonin-norepinephrine reuptake inhibitors has duloxetine, which is characterized by proven efficacy in the treatment of depression, anxiety disorders, as well as isolated and comorbid pain. The optimal balance of efficacy and tolerability determines the possibility of safe use of duloxetine in patients with severe neurological disorders.


Assuntos
Neurologia , Psiquiatria , Humanos , Norepinefrina , Serotonina , Inibidores de Captação de Serotonina/uso terapêutico
9.
Adv Ther ; 38(10): 5025-5045, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34514552

RESUMO

INTRODUCTION: Hot flushes/flashes (HFs) or other vasomotor symptoms affect between 45 and 97% of women during menopause. Hormone replacement therapy (HRT) is effective at alleviating menopausal symptoms, but some women cannot or prefer not to take HRT. Since current non-hormonal options have suboptimal efficacy/tolerability, there is a pressing need for an effective, well-tolerated alternative. The neurokinin 3 receptor (NK3R) has recently been implicated in the generation of menopausal HFs and represents a novel therapeutic target to ameliorate HF symptoms. This review aims to assess if NK3R antagonists (NK3Ras) are more effective than Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)-currently a common choice for non-hormonal treatment of menopausal HFs. METHODS: Studies were identified after systematically searching Ovid MEDLINE and EMBASE databases based on PRISMA guidelines. Trial quality and bias were assessed. Key efficacy outcomes (HF frequency, HF severity and number of night-time awakenings/night-sweats) and selected safety outcomes were extracted and analysed. RESULTS: Seven SNRI and four NK3Ra placebo-controlled randomised trials (plus four follow-up reports) were included in this review. NK3Ra administration resulted in a larger reduction from baseline in HF frequency, HF severity and night-sweats compared to SNRIs. Five of seven SNRI trials showed a reduction in HF frequency that was statistically significant (by 48-67% from baseline at weeks 8 or 12) whereas all NK3Ra trials showed a statistically significant reduction in HF frequency (by 62-93% from baseline at weeks 2, 4 or 12). While SNRI trials reported poor tolerability, particularly nausea, NK3Ra trials reported good tolerability overall, although two trials reported elevation in transaminases. CONCLUSION: NK3Ras trials show encouraging efficacy and tolerability/safety. Completion of phase 3 NK3Ra trials are required to confirm efficacy and uphold safety/tolerability data but phase 2 results suggest that NK3Ras are more effective than SNRIs for non-hormonal treatment of menopausal HFs.


Assuntos
Inibidores de Captação de Serotonina , Serotonina , Feminino , Humanos , Menopausa , Norepinefrina , Receptores da Neurocinina-3 , Inibidores de Captação de Serotonina/uso terapêutico
10.
Free Radic Biol Med ; 175: 171-183, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34474105

RESUMO

Stress induces emotional arousal causing anxiety, irritability, exaggerated startle behaviour, and hypervigilance observed in patients with trauma and stress-related mental disorders, including acute stress disorder and post-traumatic stress disorder. Central norepinephrine release promotes stress-induced emotional arousal. However, the regulator of emotional arousal remains unknown. Here, we show that the arachidonate-derived metabolite produced by stress-activated leukocyte 12/15-lipoxygenase is remarkably elevated in the plasma and upregulates the central norepinephrine release, resulting in the enhancement of the struggle behaviour (= escape behaviour) in the tail suspension test. Struggle behaviour is mimicking a symptom of emotional arousal. This stress-induced struggle behaviour was absent in 12/15-lipoxygenase deficient mice; however, intravenous administration of a 12/15-lipoxygenase metabolite to these mice after stress exposure rekindled the struggle behaviour. Furthermore, tocotrienols and geranylgeraniol reduced stress-induced 12/15-lipoxygenase metabolite production and suppressed the struggle behaviour. Our findings indicate that arachidonate-derived 12/15-lipoxygenase metabolite is involved in the regulation of stress-enhanced central norepinephrine release and struggle behaviour. In addition, we propose 12/15-lipoxygenase as a potential therapeutic target for the treatment of emotional arousal observed in stress-related mental disorders.


Assuntos
Araquidonato 15-Lipoxigenase , Tocotrienóis , Animais , Ansiedade , Araquidonato 12-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase , Humanos , Leucócitos , Camundongos , Norepinefrina
11.
Behav Neurosci ; 135(5): 629-641, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34582223

RESUMO

Prenatal protein malnutrition (PPM) alters the developing brain including changes in monoaminergic systems and attention. In the present study, we used in vivo microdialysis to examine the relationship between PPM, acute stress, and extracellular serotonin (5HT), dopamine (DA) and norepinephrine (NE) in both hemispheres of lateral orbital frontal cortices (lOFC) in the adult rat. We hypothesized that prenatal protein malnutrition would alter extracellular concentrations of cortical monoamines. The effects of an acute restraint stress were also assessed because PPM alters the brain's response to stress. We used adult male, Long-Evans rats [10 prenatally malnourished (6% casein) and 10 prenatally well-nourished (25% casein)]. Samples were collected from the left and right hemispheres of the lOFC every 20 min for 6 hr total and quantified using high-performance liquid chromatography (HPLC). After 2 hr of sampling, animals were exposed to a 40-min restraint stress. Extracellular levels of NE were significantly higher in PPM animals than in well-nourished controls across both hemispheres at all time-points. In contrast, baseline levels of 5HT and DA levels did not differ between nutritional groups. 5HT levels, but not NE or DA levels, were elevated compared to baseline levels in both nutritional groups and in both hemispheres during the first 20 min of stress exposure. These data highlight the impact of PPM on neuromodulatory systems and the profile of changes in response to acute stress. Additional studies are needed to determine how these basal and stress-related responses impact cognitive performance and whether these differences persist during cognitive testing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Dopamina , Desnutrição , Animais , Feminino , Masculino , Microdiálise , Norepinefrina , Córtex Pré-Frontal , Gravidez , Ratos , Ratos Long-Evans , Serotonina
12.
Pan Afr Med J ; 39: 177, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34584603

RESUMO

Staphylococcal scalded skin syndrom is a bullous dermatosis induced by exfoliating staphylococcal exotoxins. Children are most often affected. We report the case of a 6-month-old infant who had angina in the few days before leading up to bullous erythroderma and whose skin biopsy showed characteristic appearance of staphylococcal scalded skin syndrom. The development was rapidly unfavourable and the infant died in a refractory septic shock chart, despite the introduction of norepinephrine and anti-SAMR antibiotic therapy. The term staphylococcal scalded skin syndrome (SSSS) was separated from the toxic or allergic epidermal necrolysis by Lyell into the opposite anatomical aspect of these two entities: in scalded skin syndrome, Skin detachment is done by cleavage of the superficial part of the epidermis at the granular layer, while in toxic Lyell syndrome, the cleavage sits deeper at the level of the mucous body.


Assuntos
Choque Séptico/etiologia , Síndrome da Pele Escaldada Estafilocócica/diagnóstico , Antibacterianos/administração & dosagem , Biópsia , Evolução Fatal , Humanos , Lactente , Masculino , Norepinefrina/administração & dosagem , Síndrome da Pele Escaldada Estafilocócica/tratamento farmacológico , Síndrome da Pele Escaldada Estafilocócica/fisiopatologia
13.
Eur J Anaesthesiol ; 38(10): 1077-1084, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524157

RESUMO

BACKGROUND: Studies comparing phenylephrine and norepinephrine for the treatment of postspinal hypotension in pre-eclamptic patients are limited. OBJECTIVE: To compare bolus doses of phenylephrine and norepinephrine for treating hypotension in pre-eclamptic mothers undergoing caesarean section under spinal anaesthesia. It was hypothesised that norepinephrine and phenylephrine use would be associated with similar neonatal outcome. DESIGN: Randomised controlled study. SETTING: Single centre, tertiary care, university teaching hospital, from December 2018 to March 2020. PATIENTS: A total of 86 women with pre-eclampsia and a singleton pregnancy who developed postspinal hypotension during caesarean section. INTERVENTIONS: Patients received intravenous phenylephrine (50 µg) or norepinephrine (4 µg) for treatment of hypotension, defined as a fall in baseline systolic BP by ≥ 20% or an absolute value < 100 mmHg. MAIN OUTCOME MEASURES: The primary outcome was umbilical artery pH. Secondary outcomes included Apgar scores, the number of hypotensive episodes, vasopressor requirements, the incidence of tachycardia/bradycardia/arrhythmias/hypertension and maternal complications. RESULTS: Umbilical artery pH was not different between the phenylephrine and norepinephrine groups (7.26 ±â€Š0.06 and 7.27 ±â€Š0.06, respectively; P = 0.903). The median [IQR] number of hypotensive episodes was higher in the norepinephrine than the phenylephrine group: 2 [1 to 3] vs 1 [1 to 2], respectively; P = 0.014. Apgar scores, total number of vasopressor boluses required, systolic BP trends and the incidence of maternal complications were comparable in the two groups. Heart rate (HR) values were lower in phenylephrine group (P = 0.026), and one patient in phenylephrine group and none in the norepinephrine group developed bradycardia (HR < 50 bpm), P = 1.000. CONCLUSIONS: In women with pre-eclampsia undergoing caesarean section, bolus doses of phenylephrine (50 µg) and norepinephrine (4 µg) used to treat hypotension after spinal anaesthesia are equally effective with similar neonatal and maternal outcomes. TRIAL REGISTRATION: CTRI/2018/11/016478.


Assuntos
Anestesia Obstétrica , Raquianestesia , Hipotensão , Pré-Eclâmpsia , Anestesia Obstétrica/efeitos adversos , Raquianestesia/efeitos adversos , Cesárea/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Hipotensão/induzido quimicamente , Hipotensão/diagnóstico , Hipotensão/tratamento farmacológico , Recém-Nascido , Infusões Intravenosas , Norepinefrina , Fenilefrina , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/tratamento farmacológico , Gravidez , Vasoconstritores/uso terapêutico
14.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575863

RESUMO

Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by an exaggerated pro-inflammatory state and lipid metabolism disturbance leading to sequential organ failure. Meldonium is an anti-ischemic and anti-inflammatory agent which negatively interferes with lipid metabolism by shifting energy production from fatty acid oxidation to glycolysis, as a less oxygen-demanding pathway. Thus, we investigated the effects of a four-week meldonium pre-treatment on faecal-induced sepsis in Sprague-Dawley male rats. Surprisingly, under septic conditions, meldonium increased animal mortality rate compared with the meldonium non-treated group. However, analysis of the tissue oxidative status did not provide support for the detrimental effects of meldonium, nor did the analysis of the tissue inflammatory status showing anti-inflammatory, anti-apoptotic, and anti-necrotic effects of meldonium. After performing tissue lipidomic analysis, we concluded that the potential cause of the meldonium harmful effect is to be found in the overall decreased lipid metabolism. The present study underlines the importance of uninterrupted energy production in sepsis, closely drawing attention to the possible harmful effects of lipid-mobilization impairment caused by certain therapeutics. This could lead to the much-needed revision of the existing guidelines in the clinical treatment of sepsis while paving the way for discovering new therapeutic approaches.


Assuntos
Fezes/microbiologia , Metilidrazinas/farmacologia , Sepse/prevenção & controle , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Biomarcadores , Epinefrina/metabolismo , Ácidos Graxos/metabolismo , Inflamação , Metabolismo dos Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos , Lipidômica , Masculino , Norepinefrina/metabolismo , Estresse Oxidativo , Oxigênio/química , Ratos , Ratos Sprague-Dawley , Temperatura , Resultado do Tratamento , Triglicerídeos/metabolismo , Troponina T/sangue
15.
PLoS One ; 16(9): e0256953, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34534237

RESUMO

Our daily activities require vigilance. Therefore, it is useful to externally monitor and predict our vigilance level using a straightforward method. It is known that the vigilance level is linked to pupillary fluctuations via Locus Coeruleus and Norepinephrine (LC-NE) system. However, previous methods of estimating long-term vigilance require monitoring pupillary fluctuations at rest over a long period. We developed a method of predicting the short-term vigilance level by monitoring pupillary fluctuation for a shorter period consisting of several seconds. The LC activity also fluctuates at a timescale of seconds. Therefore, we hypothesized that the short-term vigilance level could be estimated using pupillary fluctuations in a short period and quantified their amplitude as the Micro-Pupillary Unrest Index (M-PUI). We found an intra-individual trial-by-trial positive correlation between Reaction Time (RT) reflecting the short-term vigilance level and M-PUI in the period immediately before the target onset in a Psychomotor Vigilance Task (PVT). This relationship was most evident when the fluctuation was smoothed by a Hanning window of approximately 50 to 100 ms (including cases of down-sampled data at 100 and 50 Hz), and M-PUI was calculated in the period up to one or two seconds before the target onset. These results suggest that M-PUI can monitor and predict fluctuating levels of vigilance. M-PUI is also useful for examining pupillary fluctuations in a short period for elucidating the psychophysiological mechanisms of short-term vigilance.


Assuntos
Nível de Alerta/fisiologia , Locus Cerúleo/fisiologia , Desempenho Psicomotor/fisiologia , Reflexo Pupilar/fisiologia , Vigília/fisiologia , Adulto , Feminino , Humanos , Masculino , Norepinefrina/fisiologia , Pupila/fisiologia , Tempo de Reação/fisiologia , Fatores de Tempo
16.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502543

RESUMO

To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed. Blind patch-clamp recording was performed using slice preparations of SG neurons from the spinal cords of adult rats. Spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were recorded. The ratios of the frequency and amplitude of the sIPSCs and sEPSCs following the introduction of naftopidil compared with baseline, and after the application of naftopidil, serotonin (5-HT), and prazosin, compared with noradrenaline (NA) were evaluated. First, the sIPSC analysis indicated that SG neurons reached their full response ratio for NA at 50 µM. Second, they responded to 5-HT (50 µM) with a response ratio similar to that for NA, but prazosin (10 µM) did not change the sEPSCs and sIPSCs. Third, the highest concentration of naftopidil (100 µM) led to two types of response in the SG neurons, which corresponded with the reactions to 5-HT and prazosin. These results indicate that not all neurons were necessarily activated by naftopidil, and that the micturition reflex may be regulated in a sophisticated manner by inhibitory mechanisms in these interneurons.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Substância Gelatinosa/efeitos dos fármacos , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Naftalenos/farmacologia , Neurônios/fisiologia , Norepinefrina/farmacologia , Piperazinas/farmacologia , Prazosina/farmacologia , Ratos Sprague-Dawley , Serotonina/farmacologia , Substância Gelatinosa/citologia , Substância Gelatinosa/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
17.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576086

RESUMO

The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO/cGMP axis require CRP4. This study uses mice with a targeted deletion of the CRP4 gene (CRP4 KO) to elucidate whether cGMP-elevating agents, which are well known for their vasorelaxant properties, affect vessel tone, and thus, BP through CRP4. Cinaciguat, a NO- and heme-independent activator of the NO-sensitive (soluble) guanylyl cyclase (NO-GC) and NO-releasing agents, relaxed both CRP4-proficient and -deficient aortic ring segments pre-contracted with prostaglandin F2α. However, the magnitude of relaxation was slightly, but significantly, increased in vessels lacking CRP4. Accordingly, CRP4 KO mice presented with hypotonia at baseline, as well as a greater drop in systolic BP in response to the acute administration of cinaciguat, sodium nitroprusside, and carbachol. Mechanistically, loss of CRP4 in VSMCs reduced the Ca2+-sensitivity of the contractile apparatus, possibly involving regulatory proteins, such as myosin phosphatase targeting subunit 1 (MYPT1) and the regulatory light chain of myosin (RLC). In conclusion, the present findings confirm that the adapter protein CRP4 interacts with the NO-GC/cGMP/cGKI pathway in the vasculature. CRP4 seems to be part of a negative feedback loop that eventually fine-tunes the NO-GC/cGMP axis in VSMCs to increase myofilament Ca2+ desensitization and thereby the maximal vasorelaxant effects attained by (selected) cGMP-elevating agents.


Assuntos
Pressão Sanguínea , Vasos Sanguíneos/fisiologia , GMP Cíclico/metabolismo , Proteínas com Domínio LIM/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Feminino , Masculino , Camundongos Knockout , Modelos Biológicos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Norepinefrina/farmacologia , Transdução de Sinais , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores/farmacologia
18.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502154

RESUMO

To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellular stress, and functions in the CNS in glial cells, neurons, and cerebrovascular endothelial cell in multiple anti-inflammatory and neuroprotective ways. We now know that depression is associated with neurodegeneration in the subgenual prefrontal cortex and hippocampus, decreased neuroplasticity, and defective neurogenesis. Brain-derived neurotrophic factor (BDNF) is markedly depleted in these areas, and is thought to contribute to the neurodegeneration of the subgenual prefrontal cortex and the hippocampus. The PPARg system strongly increases BDNF levels and activity in these brain areas. The PPARg system promotes both neuroplasticity and neurogenesis, both via effects on BDNF, and through other mechanisms. Ample evidence exists that these brain areas transduce many of the cardinal features of depression, directly or through their projections to sites such as the amygdala and nucleus accumbens. Behaviorally, these include feelings of worthlessness, anxiety, dread of the future, and significant reductions in the capacity to anticipate and experience pleasure. Physiologically, these include activation of the CRH and noradrenergic system in brain and the sympathetic nervous system and hypothalamic-pituitary-adrenal axis in the periphery. Patients with depression are also insulin-resistant. The PPARg system influences each of these behavioral and physiological in ways that would ameliorate the manifestations of depressive illness. In addition to the cognitive and behavioral manifestations of depression, depressive illness is associated with the premature onsets of coronary artery disease, stroke, diabetes, and osteoporosis. As a consequence, patients with depressive illness lose approximately seven years of life. Inflammation and insulin resistance are two of the predominant processes that set into motion these somatic manifestations. PPARg agonists significantly ameliorate both pathological processes. In summary, PPARg augmentation can impact positively on multiple significant pathological processes in depression. These include loss of brain tissue, defective neuroplasticity and neurogenesis, widespread inflammation in the central nervous system and periphery, and insulin resistance. Thus, PPARg agonists could potentially have significant antidepressant effects.


Assuntos
Transtorno Depressivo Maior/etiologia , Transtorno Depressivo Maior/metabolismo , Suscetibilidade a Doenças , PPAR gama/genética , PPAR gama/metabolismo , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/parasitologia , Animais , Biomarcadores , Estudos de Casos e Controles , Cognição , Hormônio Liberador da Corticotropina/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Gerenciamento Clínico , Humanos , Inflamação/complicações , Inflamação/etiologia , Inflamação/metabolismo , Norepinefrina/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Estresse Fisiológico , Avaliação de Sintomas
19.
BMC Musculoskelet Disord ; 22(1): 724, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425806

RESUMO

BACKGROUND: The influence of the sympathetic nervous system (SNS) on metabolism of bone and cartilage expressing ß-adrenergic receptors (AR) was suggested. Here, we investigated whether the SNS functions as a modulator of cartilage metabolism induced by interleukin-1beta (IL-1ß). METHODS: Human articular chondrocytes and articular cartilage were collected from patients with osteoarthritis (OA). Chondrocyte monolayer and cartilage explant culture were stimulated with IL-1ß. The activity of ß-ARs was modulated by an agonist, norepinephrine (NE), and antagonists, including propranolol, atenolol, nebivolol, and nadolol. RESULTS: The levels of ß1-, ß2-, and ß3-AR in OA cartilage and IL-1ß-treated chondrocytes were lower than normal cartilage and untreated cells. Treatment of chondrocytes with IL-1ß and ß-blockers, including propranolol, atenolol, nebivolol, and nadolol, for 6 h significantly upregulated IL-1ß-induced expression of MMP-1, -3, and - 13, compared to chondrocytes treated with IL-1ß alone, indicating that antagonism of ß-AR confers catabolic signals. On the other hand, NE antagonized IL-1ß-induced catabolic response. In addition, NE significantly inhibited IL-1ß-induced release of glycosaminoglycan (GAG) from cartilage explant culture. In addition, ß-AR activity significantly affected IL-1ß-stimulated phosphorylation of JNK and ERK. These results indicate that ß-AR signal is associated with cartilage metabolism. CONCLUSIONS: Our findings showed that ß-ARs is a regulator of cartilage catabolism induced with IL-1ß.


Assuntos
Cartilagem Articular , Osteoartrite , Condrócitos , Humanos , Interleucina-1beta , Norepinefrina/farmacologia , Osteoartrite/tratamento farmacológico
20.
Neuroscience ; 473: 13-28, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34418519

RESUMO

The present study was undertaken to identify the noradrenergic receptors underlying the production of hippocampal formation (HPC) type 2 theta rhythm. The experiments were performed on urethanized rats wherein type 2 theta is the only rhythm present. In three independent stages of experiments, the effects of noradrenaline (NE) and selective noradrenergic α and ß agonists and antagonists were tested. We indicate that the selective activation of three HPC noradrenergic receptors, α1, α2 and ß1, induced a similar effect (i.e., inhibition) on type 2 theta rhythm. The remaining HPC ß2 and ß3 noradrenergic receptors do not seem to be directly involved in the pharmacological mechanism responsible for the suppression of theta rhythm in anaesthetized rats. Obtained results provide evidence for the suppressant effect of exogenous NE on HPC type 2 theta rhythm and show the crucial role of α1, α2 and ß1 noradrenergic receptors in the modulation of HPC mechanisms of oscillations and synchrony. This finding is in contrast to the effects of endogenous NE produced by electrical stimulation of the locus coeruleus (LC) and procaine injection into the LC (Broncel et al., 2020).


Assuntos
Hipocampo , Ritmo Teta , Animais , Locus Cerúleo , Norepinefrina , Procaína , Ratos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...