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1.
Life Sci ; 241: 117155, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837330

RESUMO

AIMS: ß-Adrenoceptors (ß-ADRs) mediating the relaxation of rat superior mesenteric arteries (SMAs) were pharmacologically identified, and the effects of chemical sympathetic denervation on ß-ADR-mediated relaxation were examined. MAIN METHODS: The tension changes of endothelium-denuded SMAs were isometrically recorded and the mRNA of endothelium-denuded SMA ß-ADR was detected using RT-PCR. KEY FINDINGS: In endothelium-denuded SMAs contracted with ≥10-7 M phenylephrine (an α1-ADR agonist), isoprenaline (a ß-ADR agonist)-induced relaxation was competitively inhibited by 3 × 10-9-10-8 M propranolol (a ß1,2-ADR antagonist), but not further affected by ≥10-8 M propranolol. Although isoprenaline-induced relaxation was not affected by ICI-118,551 (10-9-10-8 M; a ß2-ADR antagonist), it was competitively inhibited by atenolol (10-7-3 × 10-7 M; a ß1-ADR antagonist) in the presence of ICI-118,551. In the presence of 10-7 M propranolol, isoprenaline- and CGP-12177A (a ß3-ADR partial agonist)-induced relaxation was competitively inhibited by high concentrations of bupranolol (a ß1,2,3-ADR antagonist), with pA2 values of 6.49 and 5.76, respectively. We detected the mRNA of ß1- and ß3-ADRs in endothelium-denuded SMAs. Treatment with 6-hydroxydopamine (a catecholaminergic neurotoxin) reduced maximal isoprenaline-induced relaxation in the presence and absence of 10-7 M propranolol, but not CGP-12177A-induced relaxation. SIGNIFICANCE: Isoprenaline-induced relaxation of rat SMAs is mediated by ß1- and ß3-ADRs. ß-ADR-mediated relaxation of rat SMAs is shown to be attenuated by chemical sympathetic denervation. The differences in the effects of bupranolol and chemical sympathetic denervation on the responses to isoprenaline and CGP-12177A in rat SMAs might be explained by the possible presence of multiple ß3-ADRs with different pharmacological properties.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Artéria Mesentérica Superior/fisiologia , Relaxamento Muscular/fisiologia , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/metabolismo , Simpatectomia Química/métodos , Animais , Isoproterenol/farmacologia , Masculino , Artéria Mesentérica Superior/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Propanolaminas/farmacologia , Ratos , Ratos Wistar
2.
Invest Ophthalmol Vis Sci ; 60(14): 4924-4930, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31770432

RESUMO

Purpose: In the dark, photoreceptor outer segments contain high levels of cyclic guanosine 3'-5' monophosphate (cGMP), which binds to ion channels, holding them open and allowing an influx of cations. Ion pumping activity, which balances cation influx, uses considerable amounts of adenosine triphosphate (ATP) and oxygen. Light reduces cation influx and thereby lowers metabolic demand. Blood vessels are compromised in the diabetic retina and may not be able to meet the higher metabolic demand in darkness. Emixustat is a visual cycle modulator (VCM) that reduces chromophore levels and, therefore, may mimic light conditions. We evaluated the effect of emixustat on oxygen consumption and cation influx in dark conditions. Methods: Cation influx was measured in rats using Mn2+-magnetic resonance imaging (MEMRI). Retinal oxygen profiles were recorded to evaluate oxygen consumption. In the MEMRI protocol, animals were treated with either emixustat or vehicle. In the oxygen protocol, animals were untreated or treated with emixustat. Results: In vehicle-treated animals, cation channel activity increased in the dark. Emixustat treatment reduced cation channel activity; activity was comparable to vehicle-treated controls in light conditions. In vehicle-treated animals, minimum retinal oxygen tension decreased as the retina recovered from a photobleach, indicating that more oxygen was being consumed. Emixustat treatment prevented the decrease in oxygen pressure after photobleach. Conclusions: Emixustat reduced the cation influx and retinal oxygen consumption associated with dark conditions. VCMs are a promising potential treatment for ischemic retinal neovascularization, such as that in diabetic retinopathy.


Assuntos
Adaptação à Escuridão/fisiologia , Manganês/metabolismo , Consumo de Oxigênio/fisiologia , Éteres Fenílicos/farmacologia , Propanolaminas/farmacologia , Retina/efeitos dos fármacos , Animais , Imagem por Ressonância Magnética , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Long-Evans , Retina/metabolismo , cis-trans-Isomerases/antagonistas & inibidores
3.
Nat Neurosci ; 22(11): 1771-1781, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636449

RESUMO

Microglia dynamically survey the brain parenchyma. Microglial processes interact with neuronal elements; however, what role neuronal network activity plays in regulating microglial dynamics is not entirely clear. Most studies of microglial dynamics use either slice preparations or in vivo imaging in anesthetized mice. Here we demonstrate that microglia in awake mice have a relatively reduced process area and surveillance territory and that reduced neuronal activity under general anesthesia increases microglial process velocity, extension and territory surveillance. Similarly, reductions in local neuronal activity through sensory deprivation or optogenetic inhibition increase microglial process surveillance. Using pharmacological and chemogenetic approaches, we demonstrate that reduced norepinephrine signaling is necessary for these increases in microglial process surveillance. These findings indicate that under basal physiological conditions, noradrenergic tone in awake mice suppresses microglial process surveillance. Our results emphasize the importance of awake imaging for studying microglia-neuron interactions and demonstrate how neuronal activity influences microglial process dynamics.


Assuntos
Microglia/fisiologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Receptor 1 de Quimiocina CX3C/genética , Clozapina/análogos & derivados , Clozapina/farmacologia , Isoflurano/farmacologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microinjeções , Muscimol/farmacologia , Norepinefrina/farmacologia , Optogenética , Propanolaminas/farmacologia , Propranolol/farmacologia , Receptores Purinérgicos P2Y12/genética , Privação Sensorial/fisiologia , Córtex Somatossensorial/efeitos dos fármacos , Tetrodotoxina/farmacologia , Vigília
4.
Nat Neurosci ; 22(11): 1782-1792, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636451

RESUMO

Microglia are the brain's resident innate immune cells and also have a role in synaptic plasticity. Microglial processes continuously survey the brain parenchyma, interact with synaptic elements and maintain tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals. Here we report that microglial surveillance and injury response are reduced in awake mice as compared to anesthetized mice, suggesting that arousal state modulates microglial function. Pharmacologic stimulation of ß2-adrenergic receptors recapitulated these observations and disrupted experience-dependent plasticity, and these effects required the presence of ß2-adrenergic receptors in microglia. These results indicate that microglial roles in surveillance and synaptic plasticity in the mouse brain are modulated by noradrenergic tone fluctuations between arousal states and emphasize the need to understand the effect of disruptions of adrenergic signaling in neurodevelopment and neuropathology.


Assuntos
Microglia/fisiologia , Plasticidade Neuronal/fisiologia , Norepinefrina/fisiologia , Córtex Visual/fisiologia , Animais , Benzilaminas/farmacologia , Receptor 1 de Quimiocina CX3C/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Ritmo Circadiano/fisiologia , Clembuterol/farmacologia , Dexmedetomidina/farmacologia , Dominância Ocular , Feminino , Fentanila/farmacologia , Locus Cerúleo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Nadolol/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Norepinefrina/metabolismo , Propanolaminas/farmacologia , Restrição Física/fisiologia , Terbutalina/farmacologia , Vigília , Ferimentos e Lesões/fisiopatologia
5.
Oxid Med Cell Longev ; 2019: 6325424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360296

RESUMO

The increased circulation of norepinephrine, found in the diseased heart as a result of sympathetic nervous system overactivation, is responsible for its cardiotoxic effects including pathological hypertrophy, cell death, and oxidative stress. Bucindolol is a third generation adrenergic blocker, which acts on the ß1 and ß2 receptors, and has additional α1 antagonist activity. Thus, the aim of this study was to investigate the action of bucindolol on oxidative stress, hypertrophy, cell survival, and cell death signaling pathways in H9c2 cardiac cells exposed to norepinephrine. H9c2 cells were incubated with 10 µM norepinephrine for 24 h in the presence or absence of bucindolol (10 µM) treatment for 8 h. Western blot was used to determine the expression of proteins for hypertrophy/survival and death signaling pathways. Flow cytometry was used to assess cell death via caspase-3/7 activity and propidium iodide and reactive oxygen species via measuring the fluorescence of CM-H2DCFDA. Norepinephrine exposure resulted in an increase in oxidative stress as well as cell death. This was accompanied by an increased protein expression of LC3B-II/I. The protein kinase B/mammalian target of the rapamycin (Akt/mTOR) pathway which is involved in cardiac remodeling process was activated in response to norepinephrine and was mitigated by bucindolol. In conclusion, bucindolol was able to modulate cardiac remodeling which is mediated by oxidative stress.


Assuntos
Norepinefrina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Propanolaminas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Proteínas Associadas aos Microtúbulos/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
6.
Biomed Res Int ; 2019: 6791971, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139645

RESUMO

The present study aims to investigate whether intravenous dexmedetomidine shows superiority to esmolol for hemodynamic response to tracheal intubation after rapid sequence induction. In the present meta-analysis, PubMed, EMBASE, and the Cochrane Library were searched for trials comparing dexmedetomidine with esmolol for the attenuation of the hemodynamic response to intubation. Ten trials were selected in the present meta-analysis. Compared to esmolol, the use of dexmedetomidine maintains stable heart rates (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) at 1 min, 3 min, and 5 min after tracheal intubation. Dexmedetomidine causes less hemodynamic response to tracheal intubation after rapid sequence induction compared with esmolol.


Assuntos
Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Hemodinâmica/efeitos dos fármacos , Intubação Intratraqueal , Propanolaminas/administração & dosagem , Propanolaminas/farmacologia , Administração Intravenosa , Adulto , Pressão Sanguínea/efeitos dos fármacos , Diástole/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Viés de Publicação , Sístole/efeitos dos fármacos , Adulto Jovem
7.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052299

RESUMO

Ewing Sarcoma (ES) is an aggressive paediatric tumour where oxidative stress and antioxidants play a central role in cancer therapy response. Inhibiting antioxidants expression, while at the same time elevating intracellular reactive oxygen species (ROS) levels, have been proposed as a valid strategy to overcome ES cancer progression. Flavonoid intake can affect free radical and nutritional status in children receiving cancer treatment, but it is not clear if it can arrest cancer progression. In particular, apigenin may enhance the effect of cytotoxic chemotherapy by inducing cell growth arrest, apoptosis, and by altering the redox state of the cells. Little is known about the use of apigenin in paediatric cancer. Recently, ß3-adrenergic receptor (ß3-AR) antagonism has been proposed as a possible strategy in cancer therapy for its ability to induce apoptosis by increasing intracellular levels of ROS. In this study we show that apigenin induces cell death in ES cells by modulating apoptosis, but not increasing ROS content. Since ES cells are susceptible to an increased oxidative stress to reduce cell viability, here we demonstrate that administration of ß3-ARs antagonist, SR59230A, improves the apigenin effect on cell death, identifying ß3-AR as a potential discriminating factor that could address the use of apigenin in ES.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apigenina/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Sarcoma de Ewing/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Propanolaminas/farmacologia
8.
Mol Brain ; 12(1): 31, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943999

RESUMO

Merkel discs, located in skin touch domes and whisker hair follicles, are tactile end organs essential for environmental exploration, social interaction, and tactile discrimination. Recent studies from our group and two others have shown that mechanical stimulation excites Merkel cells via Piezo2 channel activation to subsequently activate sensory neural pathways. We have further shown that mechanical stimulation leads to the release of 5-HT from Merkel cells to synaptically transmit tactile signals to whisker afferent nerves. However, a more recent study using skin touch domes has raised the possibility that Merkel discs are adrenergic synapses. It was proposed that norepinephrine is released from Merkel cells upon mechanical stimulation to subsequently activate ß2 adrenergic receptors on Merkel disc nerve endings leading to nerve impulses. In the present study, we examined effects of norepinephrine and ß2 adrenergic receptor antagonist ICI 118,551 on Merkel disc mechanoreceptors in mouse whisker hair follicles. We show that norepinephrine did not directly induce impulses from Merkel disc mechanoreceptors. Furthermore, we found that ICI 118,551 at 50 µM inhibited voltage-gated Na+ channels and suppressed impulses of Merkel disc mechanoreceptors, but ICI 118,551 at 1 µM had no effects on the impulse. These findings challenge the hypothesis of Merkel discs being adrenergic synapses.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Folículo Piloso/metabolismo , Mecanorreceptores/metabolismo , Células de Merkel/metabolismo , Norepinefrina/farmacologia , Propanolaminas/farmacologia , Sinapses/metabolismo , Vibrissas/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/metabolismo , Animais , Folículo Piloso/efeitos dos fármacos , Células de Merkel/efeitos dos fármacos , Sinapses/efeitos dos fármacos
9.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(2): 193-197, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30827308

RESUMO

OBJECTIVE: To explore whether ß1 receptor blocker could decrease the myocardial inflammation through the Toll-like receptor 4/nuclear factor-ΚB (TLR4/NF-ΚB) signaling pathway in the sepsis adult rats. METHODS: Sixty male Wistar rats (250-300 g) aged 3 months old were allocated to four groups by random number table (n = 15): sham operation group (S group), sepsis model group (CLP group), ß1 receptor blocker esmolol intervention group (ES group), and inhibitor of the TLR4 E5564 intervention group (E5564 group). The rat sepsis model was established by cecal ligation and puncture (CLP); S group of rats underwent only an incision. Rats in S group, CLP group and E5564 group were subcutaneous injected with 0.9% sodium chloride (NaCl) 2.0 mL/kg. Besides, the rats in ES group were injected with esmolol (15 mg×kg-1×h-1) by micro pump through the caudal vein. The rats in E5564 group were injected with E5564 (0.3 mg×kg-1×h-1) by micro pump through the caudal vein 1 hour before the CLP surgery. Samples were collected 6 hours after the modelling in each group. The average arterial pressure (MAP) and cardiac output index (CI) were monitored by PU electrical conduction ECG monitor. The levels of serum cardiac troponin I (cTnI), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were detected by enzyme linked immunosorbent assay (ELISA). The expressions of TLR4, NF-ΚB p65, IL-1ß, TNF-α in myocardial tissue was detected by Western Blot. RESULTS: There was no significant difference in MAP in each group. Compared with the S group, the CI in the CLP group was significantly decreased, the levels of serum cTnI, IL-1ß, TNF-α were significantly increased, the protein expressions of myocardial tissue TLR4, NF-ΚB p65, IL-1ß and TNF-α were significantly increased. Compared with the CLP group, the CI in the ES group and E5564 group were significantly increased (mL×s-1×m-2: 58.6±4.3, 58.9±4.4 vs. 41.2±3.9, both P < 0.01), the levels of serum cTnI, IL-1ß and TNF-α were significantly decreased [cTnI (µg/L): 1 113.81±26.64, 1 115.74±25.90 vs. 1 975.96±42.74; IL-1ß (ng/L): 39.6±4.3, 38.9±4.4 vs. 61.2±3.9; TNF-α (ng/L): 43.1±2.8, 48.7±2.6 vs. 81.3±4.4, all P < 0.01], the protein expressions of myocardial tissue NF-ΚB p65, IL-1ß, TNF-α were significantly decreased (NF-ΚB p65/ß-actin: 0.31±0.03, 0.43±0.04 vs. 0.85±0.08; IL-1ß/ß-actin: 0.28±0.05, 0.32±0.03 vs. 0.71±0.06; TNF-α/ß-actin: 0.18±0.04, 0.28±0.03 vs. 0.78±0.07, all P < 0.01), but there was no significant difference in protein expression of TLR4 (TLR4/ß-actin: 0.89±0.07, 0.87±0.09 vs. 0.95±0.09, both P > 0.05). There was no significant difference in CI, the levels of serum cTnI, IL-1ß, TNF-α, and the protein expressions of myocardial tissue TLR4, NF-ΚB p65, IL-1ß, TNF-α between ES group and E5564 group (all P > 0.05). CONCLUSIONS: ß1 receptor blocker esmolol may inhibit myocardial inflammatory response in sepsis adult rats through TLR4/NF-ΚB signaling pathway, thereby alleviating sepsis-induced myocardial injury.


Assuntos
Inflamação/prevenção & controle , Miocárdio/patologia , NF-kappa B/metabolismo , Propanolaminas/farmacologia , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Interleucina-1beta , Masculino , Ratos , Ratos Wistar , Sepse/complicações , Fator de Necrose Tumoral alfa
10.
Chin Med J (Engl) ; 132(7): 757-764, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30741832

RESUMO

BACKGROUND: Sevoflurane is widely used to anesthetize children because of its rapid action with minimal irritation of the airways. However, there is a high risk of agitation after emergence from anesthesia. Strabismus surgery, in particular, can trigger agitation because patients have their eyes covered in the postoperative period. The aim of this study was to determine whether or not esmolol and lidocaine could decrease emergence agitation in children. METHODS: Eighty-four patients aged 3 to 9 years undergoing strabismus surgery were randomly assigned to a control group (saline only), a group that received intravenous lidocaine 1.5 mg/kg, and a group that received intravenous esmolol 0.5 mg/kg and lidocaine 1.5 mg/kg. Agitation was measured using the objective pain score, Cole 5-point score, and Richmond Agitation Sedation Scale score at the end of surgery, on arrival in the recovery room, and 10 and 30 min after arrival. RESULTS: The group that received the combination of esmolol and lidocaine showed lower OPS and RASS scores than the other two groups when patients awoke from anesthesia (OPS = 0 (0-4), RASS = -4 [(-5)-1]) and were transferred to the recovery room (OPS = 0 (0-8), RASS = -1 [(-5)-3]) (P < 0.05). There was no significant difference in the severity of agitation among the three groups at other time points (P > 0.05). CONCLUSIONS: When pediatric strabismus surgery is accompanied by sevoflurane anesthesia, an intravenous injection of esmolol and lidocaine could alleviate agitation until arrival in the recovery room. TRIAL REGISTRATION: Clinical Research Information Service, No. KCT0002925; https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=11532.


Assuntos
Anestesia/métodos , Lidocaína/farmacologia , Propanolaminas/farmacologia , Sevoflurano/uso terapêutico , Vigília/efeitos dos fármacos , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Injeções Intravenosas , Lidocaína/administração & dosagem , Propanolaminas/administração & dosagem , Estrabismo/cirurgia
11.
Nat Commun ; 10(1): 321, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659174

RESUMO

Context-dependent inhibition of N-methyl-D-aspartate (NMDA) receptors has important therapeutic implications for the treatment of neurological diseases that are associated with altered neuronal firing and signaling. This is especially true in stroke, where the proton concentration in the afflicted area can increase by an order of magnitude. A class of allosteric inhibitors, the 93-series, shows greater potency against GluN1-GluN2B NMDA receptors in such low pH environments, allowing targeted therapy only within the ischemic region. Here we map the 93-series compound binding site in the GluN1-GluN2B NMDA receptor amino terminal domain and show that the interaction of the N-alkyl group with a hydrophobic cage of the binding site is critical for pH-dependent inhibition. Mutation of residues in the hydrophobic cage alters pH-dependent potency, and remarkably, can convert inhibitors into potentiators. Our study provides a foundation for the development of highly specific neuroprotective compounds for the treatment of neurological diseases.


Assuntos
Propanolaminas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Sítios de Ligação , Cristalografia por Raios X , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Mutagênese Sítio-Dirigida , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Oócitos , Técnicas de Patch-Clamp , Propanolaminas/química , Ratos , Receptores de N-Metil-D-Aspartato/química , Xenopus laevis
12.
Biochim Biophys Acta Biomembr ; 1861(2): 504-513, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30528894

RESUMO

N­Acylserinols (NASOHs) exhibit anti-cancer activity by elevating ceramide levels, and/or by activating proapoptotic effectors. In the present work we investigated the thermotropic phase behavior and supramolecular organization of a homologous series of NASOHs (number of C-atoms in the acyl chain, n = 8-18), and the interaction of N-myristoylserinol (NMSOH) with cholesterol, and characterized cationic niosomes made up of NMSOH, cholesterol and cetyltrimethylammonium bromide (CTAB). Differential scanning calorimetric studies revealed that NASOHs exhibit a major chain-melting phase transition in both dry and hydrated states. The thermodynamic parameters, transition enthalpy and entropy show linear dependence on the acyl chain length in the dry state, but exhibit odd-even alternation in the hydrated state. Powder X-ray diffraction studies revealed that NASOHs adopt a tilted bilayer structure, wherein the bilayer repeat distances (d-spacings) also showed odd-even alteration, with even-chainlength compounds exhibiting slightly higher d-spacings. Studies on the interaction between NMSOH and cholesterol revealed that both lipids mix well with up to 55 mol% cholesterol, whereas phase separation was observed at higher cholesterol content. The transition enthalpy corresponding to the NMSOH-cholesterol complex increases up to 55 mol% cholesterol and decreases at higher cholesterol content. Presence of the cationic surfactant CTAB affects the phase behavior, fluidity and size of the NMSOH-cholesterol (45,55, mol/mol) niosomes, with unilamellar vesicles of about 85 (±20) nm in diameter being obtained at 10 mol% CTAB. These results provide a thermodynamic and structural basis for further investigations on these cationic niosomes towards their use in drug delivery applications, especially for anticancer drugs.


Assuntos
Apoptose , Cetrimônio/química , Colesterol/química , Lipossomos/química , Transição de Fase , Propanolaminas/farmacologia , Propilenoglicóis/farmacologia , Temperatura Ambiente , Apoptose/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Cátions , Entropia , Lipossomos/ultraestrutura , Fluidez de Membrana , Propanolaminas/química , Propilenoglicóis/química , Difração de Raios X
13.
Oncol Rep ; 41(1): 341-350, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30542705

RESUMO

The ß2­adrenergic receptor (ß2­AR, encoded by the ADRB2 gene) is a member of the G­protein­coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that ß­blockers (ß­AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single­nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of ß2­AR, which may alter the ß­blocker drug response. The aim of the present study was to investigate the effect of ß­blockers on triple­negative breast cancer cells and determine whether ADRB2 SNPs affect the response to ß­blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA­MB­231 cells, arrested cell cycle progression at G0/G1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular­signal­regulated kinase (ERK)1/2 and the expression levels of cyclo­oxygenase 2 (COX­2) were significantly decreased following ß­blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild­type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX­2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA­MB­231 cells by downregulating the ERK/COX­2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Receptores Adrenérgicos beta 2/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Fosforilação/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Propanolaminas/farmacologia , Propanolaminas/uso terapêutico , Propranolol/farmacologia , Propranolol/uso terapêutico , Receptores Adrenérgicos beta 2/metabolismo , Neoplasias de Mama Triplo Negativas/genética
14.
Oxid Med Cell Longev ; 2018: 6816508, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538804

RESUMO

The early phases of embryonic development and cancer share similar strategies to improve their survival in an inhospitable environment: both proliferate in a hypoxic and catecholamine-rich context, increasing aerobic glycolysis. Recent studies show that ß3-adrenergic receptor (ß3-AR) is involved in tumor progression, playing an important role in metastasis. Among ß-adrenergic receptors, ß3-AR is the last identified member of this family, and it is involved in cancer cell survival and induction of stromal reactivity in the tumor microenvironment. ß3-AR is well known as a strong activator of uncoupling protein 1 (UCP1) in brown fat tissue. Interestingly, ß3-AR is strongly expressed in early embryo development and in many cancer tissues. Induction of uncoupling protein 2 (UCP2) has been related to cancer metabolic switch, leading to accelerated glycolysis and reduced mitochondrial activity. In this study, for the first time, we demonstrate that ß3-AR is able to promote this metabolic shift in both cancer and embryonic stem cells, inducing specific glycolytic cytoplasmic enzymes and a sort of mitochondrial dormancy through the induction of UCP2. The ß3-AR/UCP2 axis induces a strong reduction of mitochondrial activity by reducing ATP synthesis and mitochondrial reactive oxygen species (mtROS) content. These effects are reverted by SR59230A, the specific ß3-AR antagonist, causing an increase in mtROS. The increased level of mtROS is neutralized by a strong antioxidant activity in embryonic stem cells, but not in cancer stem cells, where it causes a dramatic reduction in tumor cell viability. These results lead to the possibility of a selective antitumor therapeutic use of SR59230A. Notably, we demonstrate the presence of ß3-AR within the mitochondrial membrane in both cell lines, leading to the control of mitochondrial dormancy.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Células-Tronco Embrionárias/metabolismo , Melanoma/metabolismo , Mitocôndrias/metabolismo , Propanolaminas/farmacologia , Animais , Linhagem Celular , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/patologia , Humanos , Melanoma/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Receptores Adrenérgicos beta 3/metabolismo
15.
Turk J Med Sci ; 48(5): 1068-1072, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30384577

RESUMO

Background/aim: Esmolol and amiodarone are two most commonly used antiarrhythmic drugs in coronary artery bypass grafting (CABG) surgery. Nevertheless, blockade of beta-2 receptors by increasing doses raise concerns about possible vasospasms. We studied the vasoactive effects of amiodarone and esmolol on left internal mammary artery (LIMA), radial artery (RA), and saphenous vein (SV) grafts. Materials and methods: After determining the presence of functional smooth muscle and endothelial layers, the responses of submaximally preconstricted graft samples were recorded in a tissue bath system. A total of 96 graft samples from 40 patients were used: 16 LIMA, 16 RA, and 16 SV grafts for each drug. Esmolol and amiodarone were added to reservoirs separately, starting from a concentration of 10-8 M until a concentration of 10-4 M. Results: Although both drugs caused vasodilatation, amiodarone exhibited a more potent vasodilatory effect than esmolol (P < 0.0001 for LIMA, P = 0.0128 for RA, and P < 0.0001 for SV). The vasodilatation rates with esmolol were 48.99 ± 2.28% in LIMA, 49.77 ± 3.03% in RA, and 41.90 ± 4.05% in SV grafts and with amiodarone they were 71.65 ± 5.18% in LIMA, 58.61 ± 5.87% in RA, and 65.07 ± 4.09% in SV grafts. Conclusion: This in vitro study revealed that even increasing doses of both drugs induce vasodilatation of CABG grafts, with amiodarone having a more potent vasodilatory effect than esmolol.


Assuntos
Amiodarona/farmacologia , Ponte de Artéria Coronária , Vasos Coronários/efeitos dos fármacos , Propanolaminas/farmacologia , Vasodilatação/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
J Vet Emerg Crit Care (San Antonio) ; 28(5): 447-456, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30074662

RESUMO

OBJECTIVE: To determine the effects of esmolol on hemodynamics and heart rate variability (HRV) in the early stage of sepsis. DESIGN: Prospective, randomized, controlled, parallel trial. SETTINGS: Veterinary research laboratory. ANIMALS: Ten anesthetized piglets. INTERVENTIONS: Septic shock was induced by infusing a suspension of live Pseudomonas aeruginosa IV in 10 anesthetized piglets. The piglets were resuscitated according to a standardized protocol using Ringer's lactate solution, norepinephrine, and milrinone. Once stabilized, the piglets were randomized to receive IV esmolol, titrated to a heart rate <90/min, or control, receiving saline. A pulmonary artery catheter and an arterial catheter were inserted for hemodynamic measurements. The Analgesia/Nociception Index (ANI) and the normalized HRV frequency domain parameters - high-frequency (HF), low frequency (LF), LF/HF ratio - were recorded using a proprietary monitor. MEASUREMENTS AND MAIN RESULTS: A significant decrease in cardiac output and heart rate, and a significant increase in systemic vascular resistance were observed over time in the esmolol group in comparison to the control group. No other differences were observed in hemodynamic parameters. No significant differences were observed in ANI variations or HRV parameters over time between groups. CONCLUSIONS: The administration of esmolol produced significant changes in hemodynamics with no change in ANI values or HRV parameters. Further study is needed to understand the effect of esmolol during sepsis.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Propanolaminas/uso terapêutico , Infecções por Pseudomonas/veterinária , Choque Séptico/veterinária , Doenças dos Suínos/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Animais , Animais Recém-Nascidos , Débito Cardíaco/efeitos dos fármacos , Reanimação Cardiopulmonar/veterinária , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Monitorização Fisiológica/veterinária , Nociceptividade , Propanolaminas/administração & dosagem , Propanolaminas/farmacologia , Estudos Prospectivos , Infecções por Pseudomonas/tratamento farmacológico , Distribuição Aleatória , Choque Séptico/tratamento farmacológico , Suínos
17.
Biomed Pharmacother ; 105: 1192-1204, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30021356

RESUMO

In this study, we tried to demonstrate the effects of adding human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) to carvedilol in improving the doxorubicin- induced cardiotoxicity in rats. Rats were randomly divided into four groups: group 1: control group, group 2: doxorubicin untreated group, group 3: rats injected with doxorubicin and received carvedilol, and group 4: rats injected with doxorubicin and received carvedilol and stem cell-treated. Electrocardiography (ECG) was performed to assess cardiac function after animals were sacrificed. Cardiac muscle sections were examined histologically using H&E, Masson trichrome and immunohistochemically using caspase 3 immunostaining. The morphometric and statistical analysis was performed. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), insulin-like growth factor (IGF-1), and vascular endothelial growth factor (VEGF) were measured. We concluded that combination of hUCB-MSCs and carvedilol markedly improves histological and immunohistochemical structure of cardiac muscle fibers and restores cardiac function in doxorubicin- induced cardiotoxicity in rats.


Assuntos
Carbazóis/farmacologia , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/farmacologia , Sangue Fetal/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Propanolaminas/farmacologia , Animais , Cardiotoxicidade/metabolismo , Carvedilol , Sangue Fetal/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Células-Tronco Mesenquimais/metabolismo , Miocárdio/metabolismo , Ratos , Superóxido Dismutase/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Brain Behav Immun ; 73: 520-532, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29935309

RESUMO

Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral ß2- and ß3-adrenergic receptors (ß2- and ß3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Here, we first sought to investigate the role of ß2- and ß3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15 mg/kg/day) or vehicle for 14 days. The ß2AR antagonist ICI118551 and ß3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35 days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3 weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1ß, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral ß2- and ß3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.


Assuntos
Dor/metabolismo , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Animais , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/metabolismo , Catecóis/farmacologia , Citocinas/metabolismo , Etanercepte/farmacologia , Feminino , Fibromialgia/metabolismo , Fibromialgia/fisiopatologia , Hiperalgesia/metabolismo , Imidazóis/farmacologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Microglia/metabolismo , Proteínas Quinases Ativadas por Mitógeno , Neuroglia/metabolismo , Dor/fisiopatologia , Fosforilação , Propanolaminas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 2/fisiologia , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Receptores Adrenérgicos beta 3/fisiologia , Medula Espinal/metabolismo , Transtornos da Articulação Temporomandibular/metabolismo , Transtornos da Articulação Temporomandibular/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Emerg Med J ; 35(9): 559-563, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29921621

RESUMO

OBJECTIVES: Beta blockers (ß-blockers) remain a standard therapy in the early treatment of acute coronary syndromes. However, ß-blocker therapy in patients with cocaine-associated chest pain (CACP) continues to be an area of debate due to the potential risk of unopposed α-adrenergic stimulation and coronary vasospasm. Therefore, we performed a systematic review and meta-analysis of available studies to compare outcomes of ß-blocker versus no ß-blocker use among patients with CACP. METHODS: We searched the MEDLINE and EMBASE databases through September 2016 using the keywords 'beta blocker', 'cocaine' and commonly used ß-blockers ('atenolol', 'bisoprolol', 'carvedilol', 'esmolol', 'metoprolol' and 'propranolol') to identify studies evaluating ß-blocker use among patients with CACP. We specifically focused on studies comparing outcomes between ß-blocker versus no ß-blocker usage in patients with CACP. Studies without a comparison between ß-blocker and no ß-blocker use were excluded. Outcomes of interest included non-fatal myocardial infarction (MI) and all-cause mortality. Quantitative data synthesis was performed using a random-effects model and heterogeneity was assessed using Q and I2statistics. RESULTS: A total of five studies evaluating 1794 subjects were included. Overall, there was no significant difference on MI in patients with CACP on ß-blocker versus no ß-blocker (OR 1.36, 95% CI 0.68 to 2.75; p=0.39). Similarly, there was no significant difference in all-cause mortality in patients on ß-blocker versus no ß-blocker (OR 0.68, 95% CI 0.26 to 1.79; p=0.43). CONCLUSIONS: In patients presenting with acute chest pain and underlying cocaine, ß-blocker use does not appear to be associated with an increased risk of MI or all-cause mortality.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Cocaína/efeitos adversos , Síndrome Coronariana Aguda/etiologia , Antagonistas Adrenérgicos beta/uso terapêutico , Atenolol/farmacologia , Atenolol/uso terapêutico , Bisoprolol/farmacologia , Bisoprolol/uso terapêutico , Carvedilol/farmacologia , Carvedilol/uso terapêutico , Humanos , Metoprolol/farmacologia , Metoprolol/uso terapêutico , Propanolaminas/farmacologia , Propanolaminas/uso terapêutico , Propranolol/farmacologia , Propranolol/uso terapêutico
20.
Clin Nucl Med ; 43(8): 604-605, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29916915

RESUMO

A 37-year-old woman with pheochromocytoma underwent presurgical FDG PET/CT. Despite her usual antiadrenergic medication consisting in 25 mg of carvedilol, PET/CT demonstrated intense and widespread FDG uptake in brown adipose tissue (BAT). No BAT FDG uptake was detectable on a repeated examination after specific preparation consisting in 40 mg propranolol and 5 mg diazepam. We therefore recommend this propranolol-diazepam preparation in patients with pheochromocytoma referred for PET/CT. Carvedilol-classically prescribed to alleviate effects of adrenergic overstimulation-seems ineffective on BAT. This observation questions the benefit of carvedilol to reduce ß3-adrenoreceptor-mediated effects, not only in BAT, but also in other tissues.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/patologia , Antagonistas Adrenérgicos beta/farmacologia , Carbazóis/farmacologia , Feocromocitoma/tratamento farmacológico , Feocromocitoma/patologia , Propanolaminas/farmacologia , Tecido Adiposo Marrom/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Carbazóis/uso terapêutico , Carvedilol , Feminino , Fluordesoxiglucose F18 , Humanos , Feocromocitoma/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Propanolaminas/uso terapêutico , Falha de Tratamento
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