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1.
Neurobiol Learn Mem ; 161: 72-82, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30930287

RESUMO

Beta-adrenergic receptor (b-AR) activation by noradrenaline (NA) enhances memory formation and long-term potentiation (LTP), a form of synaptic plasticity characterized by an activity-dependent increase in synaptic strength. LTP is believed to be a cellular mechanism for contextual learning and memory. In the mammalian hippocampus, LTP can be observed at multiple synaptic pathways after strong stimulation of a single synaptic pathway. This heterosynaptic LTP is believed to involve synaptic tagging of active synapses and capture of plasticity-related proteins that enable heterosynaptic transfer of persistent potentiation. These processes may permit distinct neural pathways to associate information transmitted by separate, but convergent, synaptic inputs. We had previously shown that transcription and epigenetic modifications were necessary for stabilization of homosynaptic LTP. However, it is unclear whether transfer of LTP to a second, heterosynaptic pathway involves b-ARs signalling to the nucleus. Using electrophysiologic recordings in area CA1 of murine hippocampal slices, we show here that pharmacologically inhibiting b-AR activation, transcription, DNA methyltransferase or histone acetyltransferase activation, prevents stabilization of heterosynaptic LTP. Our data suggest that noradrenergic stabilization of heterosynaptic ("tagged") LTP requires not only transcription, but specifically, DNA methylation and histone acetylation. NA promotes stable heterosynaptic plasticity through engagement of nuclear processes that may contribute to prompt consolidation of short-term memories into resilient long-term memories under conditions when the brain's noradrenergic system is recruited.


Assuntos
Região CA1 Hipocampal/fisiologia , Epigênese Genética/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciação de Longa Duração/fisiologia , Norepinefrina/fisiologia , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Citidina/análogos & derivados , Citidina/farmacologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Histona Acetiltransferases/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propranolol/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
2.
Can J Cardiol ; 35(4): 511-522, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30935642

RESUMO

The slow delayed rectifier potassium current (IKs) significantly contributes to cardiac repolarization under specific conditions, particularly at stimulation by the protein kinase A (PKA) during increased sympathetic tone. Impaired PKA-mediated stimulation of IKs channels may considerably aggravate dysfunction of the channels induced by mutations in the KCNQ1 gene that encodes the structure of the α-subunit of IKs channels. These mutations are associated with several subtypes of inherited arrhythmias, mainly long QT syndrome type 1, less commonly short QT syndrome type 2, and atrial fibrillation. The impaired PKA reactivity of IKs channels may significantly increase the risk of arrhythmia in these patients. Unfortunately, only approximately 2.7% of the KCNQ1 variants identified as putatively clinically significant have been studied with respect to this problem. This review summarizes the current knowledge in the field to stress the importance of the PKA-mediated regulation of IKs channels, and to appeal for further analysis of this regulation in KCNQ1 mutations associated with inherited arrhythmogenic syndromes. On the basis of the facts summarized in our review, we suggest several new regions of the α-subunit of the IKs channels as potential contributors to PKA stimulation, namely the S4 and S5 segments, and the S2-S3 and S4-S5 linkers. Deeper knowledge of mechanisms of the impaired PKA response in mutated IKs channels may help to better understand this regulation, and may improve risk stratification and management of patients suffering from related pathologies.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Canais de Potássio de Retificação Tardia/fisiologia , Síndrome do QT Longo/fisiopatologia , Receptores Adrenérgicos beta/fisiologia , Sistema de Condução Cardíaco/fisiologia , Humanos , Canal de Potássio KCNQ1/genética , Síndrome do QT Longo/genética , Mutação , Fosforilação
3.
Cell Immunol ; 336: 48-57, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30600100

RESUMO

Males exhibit stronger sympathetic nervous system (SNS) activity, but weaker primary CD4+ T-cell (auto)immune responses. To test the role of catecholamines, major end-point SNS mediators, in this dimorphism, influence of propranolol (ß-adrenoceptor blocker) on mitogen/neuroantigen-stimulated CD4+ T cells from female and male EAE rat draining lymph node (dLN) cell cultures was examined. Male rat dLNs exhibited higher noradrenaline concentration and frequency of ß2-adrenoceptor-expressing CD4+ T lymphocytes and antigen presenting cells. Propranolol, irrespective of exogenous noradrenaline presence, more prominently augmented IL-2 production and proliferation of CD4+ lymphocytes in male than female rat dLN cell cultures. In neuroantigen-stimulated dLN cells of both sexes propranolol increased IL-1ß and IL-23/p19 expression and IL-17+ CD4+ cell frequency, but enhanced IL-17 production only in male rat CD4+ lymphocytes, thereby abrogating sexual dimorphism in IL-17 concentration observed in propranolol-free cultures. Thus, ß-adrenoceptor-mediated signalling may contribute to sex bias in rat IL-17-producing cell secretory capacity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Norepinefrina/fisiologia , Receptores Adrenérgicos beta/fisiologia , Caracteres Sexuais , Antagonistas Adrenérgicos beta/farmacologia , Animais , Feminino , Interleucina-17/análise , Ativação Linfocitária , Masculino , Proteína Básica da Mielina/farmacologia , Ratos
4.
Eur J Pharmacol ; 844: 110-117, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30529196

RESUMO

Sustained ventricular arrhythmias (SVAs) lead to sudden cardiac death, for which ß- adrenoreceptor blockers are effective. We hypothesized that electrophysiological changes and arrhythmias by ß- adrenoreceptor stimulation are crucially related to activation of small-conductance calcium-activated potassium (SK) channels via the increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs). The latter served as a model of left ventricular hypertrophy. We performed dual optical mapping of action potentials and Ca2+ transients, and the effects of isoproterenol and apamin, an SK channel blocker, were evaluated in the Langendorff-perfused hearts. Action potential duration was abbreviated by isoproterenol (100 nM) in both WKY rats and SHRs. In contrast, the CaMKII activity was increased by isoproterenol only in SHRs. In the presence of isoproterenol, apamin prolonged the action potential duration only in SHRs (n = 10, from 116.6 ±â€¯5.05 ms to 125.4 ±â€¯3.80 ms, P = 0.011), which was prevented by KN-93, a CaMKII inhibitor. Increase in Ca2+ transients and shortening of Ca2+ transient duration by isoproterenol were similarly observed in both animals, which was not affected by apamin. Apamin reduced the isoproterenol-induced SVAs and maximal slope of action potential duration restitution curve specifically in SHRs. In conclusion, ß- adrenoreceptor stimulation creates arrhythmogenic substrates via the CaMKII-dependent activation of SK channels in cardiac hypertrophy.


Assuntos
Arritmias Cardíacas/fisiopatologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Cardiomegalia/fisiopatologia , Hipertensão/fisiopatologia , Receptores Adrenérgicos beta/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/fisiologia , Animais , Coração/fisiologia , Masculino , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
5.
Ann Palliat Med ; 8(1): 13-23, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30525767

RESUMO

Cancer cachexia, characterized by losses in muscle and adipose tissue (AT), is associated with poor quality of life and prognosis, and lacks effective therapies. Both tumor- and host- derived factors disrupt normal metabolism and are vital to the catabolic drive in cancer cachexia. While muscle loss has long dominated cachexia research, recent work conducted predominantly in rodent models has begun to recognize the significance of AT lipid metabolism alterations in the development and progression of cancer cachexia. AT losses are mainly attributed to the activation of lipolytic pathways. An important recent discovery has been in the demonstration of white AT (WAT) "browning" conferring thermogenic properties to adipocytes that results in wasteful energy expenditure. Collectively, both elevated lipolysis and WAT thermogenesis play an important role in AT depletion in cancer. The purpose of this review is to highlight current knowledge related to the regulation of AT function in cancer cachexia.


Assuntos
Caquexia/metabolismo , Metabolismo dos Lipídeos/fisiologia , Neoplasias/metabolismo , Adipócitos/patologia , Adipogenia/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular , Citocinas/fisiologia , Modelos Animais de Doenças , Hormônios/fisiologia , Humanos , Lipogênese/fisiologia , Camundongos , Músculo Esquelético/metabolismo , Receptores Adrenérgicos beta/fisiologia , Termogênese/fisiologia
6.
J Ethnopharmacol ; 232: 135-144, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30543913

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Citrus reticulatae Pericarpium (Chen pi) was widely used as an important ingredient in the prescription of TCM to treat phlegm fluid retention type hypertension. Since Chen pi is involved in treatment as antihypertensive TCM formula, we have reasonable expectation in believing that it might possess vasorelaxant activity. AIM OF THE STUDY: This study is designed to investigate the vasorelaxant effect of Chen pi and to study its pharmacology effects. MATERIALS AND METHODS: The vasorelaxant effect of water extract of Chen pi (CRW) were evaluated on thoracic aortic rings isolated from Sprague Dawley rats. The fingerprint of Chen pi and the extracts were developed with quantification of hesperidin content by HPTLC. RESULTS: CRW exhibited the strongest vasorelaxant activity. CRW caused the relaxation of the phenylephrine pre-contracted aortic rings in the presence and absence of endothelium as well as in potassium chloride pre-contracted endothelium-intact aortic ring. The incubation of propranolol (ß-adrenergic receptor blocker), atropine (muscarinic receptor blocker), Nω-nitro-L-arginine methyl ester (NO synthase inhibitor), ODQ (sGC inhibitor), indomethacin (COX inhibitor), 4-aminopyridine (KV blocker), barium chloride (Kir blocker), and glibenclamide (KATP blocker) significantly reduced the vasorelaxant effects of CRW. CRW was also found to be active in reducing Ca2+ releases from the sarcoplasmic reticulum and suppressing the voltage-operated calcium channels. CONCLUSION: The vasorelaxant effect of CRW on rat aorta involves NO/sGC, calcium and potassium channels, muscarinic and ß-adrenergic receptors.


Assuntos
Aorta Torácica/efeitos dos fármacos , Citrus , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Canais de Cálcio/fisiologia , Citrus/química , Técnicas In Vitro , Masculino , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Canais de Potássio/fisiologia , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/fisiologia , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/fisiologia , Vasodilatadores/química
7.
Braz J Med Biol Res ; 51(12): e7526, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30462770

RESUMO

It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and ß-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and ß-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of ß-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between ß-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.


Assuntos
Glucose/metabolismo , Hipertensão Portal/metabolismo , Fígado/metabolismo , Receptor Tipo 1 de Angiotensina/fisiologia , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos beta/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Fígado/efeitos dos fármacos , Losartan/farmacologia , Masculino , Prazosina/farmacologia , Propranolol/farmacologia , Ratos Wistar , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Fatores de Tempo
8.
J Surg Res ; 232: 171-178, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30463715

RESUMO

BACKGROUND: Myocardial infarction (MI) is a major etiology for the development of heart failure. We have previously shown that high molecular weight polyethylene glycol (PEG) can protect cardiac myocytes from hypoxia-reoxygenation injury in vitro. In this study, we investigated the potential protective effects of 15-20 kD PEG postinfarction without reperfusion. METHODS: One milliliter of PEG 15-20 was delivered intravenously following permanent left anterior descending ligation in adult male rats with phosphate buffer saline (PBS) as control (n = 9 in each group). Echocardiography was performed at baseline and at 8 wk post-MI. Left ventricles (LVs) were harvested to quantify fibrosis, apoptosis, cell survival signaling, regulation of ß-adrenergic signaling, and caveolin (Cav) expression. RESULTS: The PEG group had significant recovery of LV function at 8 wk compared with the PBS group. There was less LV fibrosis in both the infarct and remote territory. Cell survival signaling was upregulated in the PEG group with increased Akt and ERK phosphorylation. PEG inhibited apoptosis as measured by terminal deoxynucleotidyl transferase [TdT]-mediated dUTP nick-end labeling positive nuclei and caspase-3 activity. There was maintenance of Cav-1, Cav-2, and Cav-3 expression following PEG treatment versus a decline in the PBS group. Negative regulators of ß-adrenergic signaling, G protein-coupled receptor kinase-2, and ß-arrestin 1 and 2 were all upregulated in PBS-treated samples compared to normal control; however, PEG treatment led to decreased expression. CONCLUSIONS: These data suggest that PEG 15-20 may have significant protective effects post-MI even in the setting of no acute reperfusion. Upregulation of Cav expression appears to be a key mechanism for the beneficial effects of PEG on ventricular remodeling and function.


Assuntos
Infarto do Miocárdio/fisiopatologia , Polietilenoglicóis/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caveolina 1/análise , Caveolina 1/fisiologia , Masculino , Peso Molecular , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais/efeitos dos fármacos , Função Ventricular Esquerda
9.
J Neurogenet ; 32(3): 171-182, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30175650

RESUMO

Altered synaptic strength underlies information storage in neural circuits. Neuromodulatory transmitters such as norepinephrine (NE) facilitate long-lasting synaptic plasticity by recruiting and modifying multiple molecular elements of synaptic signaling, including specific transmitter receptors, intracellular protein kinases, and translation initiation. NE regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express ß-adrenergic receptors (ß-ARs), which bind NE and are critical for gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in neural circuits. In this article, in honor of Prof. Harold Atwood, we review the contributions of ß-ARs towards gating the expression of protein synthesis-dependent, long-lasting hippocampal LTP. We focus on the roles of ß-ARs in modifying ion channels, glutamatergic AMPA receptors, and translation initiation factors during LTP. We discuss prospective research strategies that may lead to increased understanding of the roles of NE in regulating neural circuit physiology; these may uncover novel therapies for treatment of specific neurological disorders linked to aberrant circuit activity and dysfunctional noradrenergic synaptic transmission.


Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores Adrenérgicos beta/fisiologia , Animais , Humanos
11.
Neurobiol Learn Mem ; 151: 71-84, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29653257

RESUMO

The hippocampus is a functionally heterogeneous structure with the cognitive and emotional signal processing ascribed to the dorsal (DH) and the ventral hippocampus (VH) respectively. However, the underlying mechanisms are poorly understood. Noradrenaline is released in hippocampus during emotional arousal modulating synaptic plasticity and memory consolidation through activation of ß adrenergic receptors (ß-ARs). Using recordings of field excitatory postsynaptic potentials from the CA1 field of adult rat hippocampal slices we demonstrate that long-term potentiation (LTP) induced either by theta-burst stimulation (TBS) that mimics a physiological firing pattern of hippocampal neurons or by high-frequency stimulation is remarkably more sensitive to ß-AR activation in VH than in DH. Thus, pairing of subthreshold primed burst stimulation with activation of ß-ARs by their agonist isoproterenol (1 µM) resulted in a reliable induction of NMDA receptor-dependent LTP in the VH without affecting LTP in the DH. Activation of ß-ARs by isoproterenol during application of intense TBS increased the magnitude of LTP in both hippocampal segments but facilitated voltage-gated calcium channel-dependent LTP in VH only. Endogenous ß-AR activation contributed to the stabilization and the magnitude of LTP in VH but not DH as demonstrated by the effects of the ß-ARs antagonist propranolol (10 µM). Exogenous (but not endogenous) ß-AR activation strongly increased TBS-induced facilitation of postsynaptic excitability in VH. In DH, isoproterenol only produced a moderate and GABAergic inhibition-dependent enhancement in the facilitation of synaptic burst responses. Paired-pulse facilitation did not change with LTP at any experimental condition suggesting that expression of LTP does not involve presynaptic mechanisms. These findings suggest that ß-AR may act as a switch that selectively promotes synaptic plasticity in VH through multiple ways and provide thus a first clue to mechanisms that underlie VH involvement in emotionality.


Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração , Receptores Adrenérgicos beta/fisiologia , Agonistas Adrenérgicos beta/administração & dosagem , Animais , Estimulação Elétrica , Hipocampo/efeitos dos fármacos , Isoproterenol/administração & dosagem , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos Wistar , Receptores de N-Metil-D-Aspartato/fisiologia
12.
Neurobiol Learn Mem ; 151: 59-70, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29649583

RESUMO

A critical barrier to recovery from alcohol addiction is relapse propensity. Alcohol cues can trigger relapse, and pharmacologically facilitating processes such as extinction, which decreases cue associations, may help prevent relapse. The noradrenergic system mediates extinction learning for alcohol; however, the neural locus of this effect is unknown. This study sought to determine whether the basolateral amygdala (BLA), a region critical for fear extinction, also mediates extinction of alcohol seeking. Hooded Wistar rats (N = 12-15 per experiment) were implanted with bilateral cannula targeting the BLA and trained to lever press for 10% ethanol during auditory or visual cues. Infusions of the ß-receptor antagonist propranolol (2 µg/side) were administered prior to extinction (Experiment 1), and rats assessed for relapse-like behaviour two weeks later, thus allowing for spontaneous recovery. We expected intra-BLA propranolol to impair extinction learning; however, propranolol-treated rats exhibited reduced responding in the test of spontaneous recovery, suggesting enhanced extinction. We investigated this unexpected result by determining if propranolol treatment affected memory processes other than extinction. In a subsequent experiment, rats were infused with propranolol immediately after extinction to target consolidation of extinction (Experiment 2a), and assessed for spontaneous recovery. Propranolol was also infused after self-administration to target reconsolidation of the original learning (Experiment 2b). Propranolol treatment had no effect on consolidation of extinction learning, but impaired reconsolidation of self-administration. Propranolol administered prior to a self-administration session did not affect reinforced responding (Experiment 2c). Extinction and reconsolidation are opposing processes triggered by specific test conditions. We suggest our test conditions induced reconsolidation of self-administration memory by propranolol, rather than modulation of extinction. Thus, our data implicates intra-BLA noradrenergic ß-receptors in reconsolidation of alcohol self-administration memory.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Complexo Nuclear Basolateral da Amígdala/fisiologia , Etanol/administração & dosagem , Extinção Psicológica/fisiologia , Consolidação da Memória/fisiologia , Propranolol/administração & dosagem , Receptores Adrenérgicos beta/fisiologia , Alcoolismo/fisiopatologia , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Operante , Sinais (Psicologia) , Extinção Psicológica/efeitos dos fármacos , Masculino , Consolidação da Memória/efeitos dos fármacos , Ratos Wistar , Recidiva
13.
Anesthesiology ; 128(6): 1175-1186, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29547406

RESUMO

BACKGROUND: Systemic toxicity of local anesthetics is predominantly complicated by their myocardial toxicity. Especially long-acting local anesthetics exert a negative inotropic effect that has been described at lower concentrations than defined for blockade of myocardial ion channels. We evaluated the negative inotropic effect of bupivacaine at a concentration described for clinical toxicity testing the hypothesis that negative inotropy is a result of reduced Ca sensitivity rather than blockade of ion channels. METHODS: We simultaneously measured force development and action potentials in guinea pig right papillary muscles (n = 5 to 7). L-type Ca currents (n = 8 to 16) and Ca transients (n = 10 to 11) were measured in isolated cardiomyocytes. Sensitivity of myofilaments to Ca was assessed in skinned fibers (n = 10). Potential effects of bupivacaine on 3',5'-cyclic adenosine monophosphate concentrations were measured using Förster Resonance Energy Transfer (n = 12 to 14) microscopy. RESULTS: Bupivacaine reduced force in a concentration-dependent manner from 173 ± 119 µN at baseline to 28 ± 13 µN at 300 µM (mean ± SD). At concentrations giving half-maximum negative inotropic effects (5 µM), the maximum upstroke velocity of action potentials, as a surrogate of sodium channel activity, was unaffected. Maximum positive inotropic effects of isoprenaline were also reduced to 50%. Neither basal nor isoprenaline-induced 3',5'-cyclic adenosine monophosphate accumulation, L-type Ca currents, or Ca transients were affected by 5 µM bupivacaine, but this concentration significantly decreased Ca sensitivity of myofilaments, changing the negative logarithm of the half-maximum effective Ca concentrations from 5.66 to 5.56 -log[M]. CONCLUSIONS: We provide evidence that the negative inotropic effect of bupivacaine may be caused mainly by a reduction in myofilament sensitivity to Ca.


Assuntos
Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Cálcio/metabolismo , Contração Miocárdica/fisiologia , Receptores Adrenérgicos beta/fisiologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Cobaias , Masculino , Camundongos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Técnicas de Cultura de Órgãos
14.
J Neurophysiol ; 119(5): 1658-1664, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29361666

RESUMO

Noradrenergic signaling in the amygdala is important for processing threats and other emotionally salient stimuli, and ß-adrenergic receptor activation is known to enhance neuronal spiking in the lateral amygdala (LA) of juvenile animals. Nevertheless, intracellular recordings have not yet been conducted to determine the effect of ß-adrenergic receptor activation on spike properties in the adult LA, despite the potential significance of developmental changes between adolescence and adulthood. Here we demonstrate that the ß-adrenergic agonist isoproterenol (15 µM) enhances spike frequency in dorsal LA principal neurons of juvenile male C57BL/6 mice and fails to do so in strain- and sex-matched adults. Furthermore, we find that the age-dependent effect of isoproterenol on spike frequency is occluded by the GABAA receptor blocker picrotoxin (75 µM), suggesting that ß-adrenergic receptors downregulate tonic inhibition specifically in juvenile animals. These findings indicate a significant shift during adolescence in the cellular mechanisms of ß-adrenergic modulation in the amygdala. NEW & NOTEWORTHY ß-Adrenergic receptors (ß-ARs) in amygdala are important in processing emotionally salient stimuli. Most cellular recordings have examined juvenile animals, while behavioral data are often obtained from adults. We replicate findings showing that ß-ARs enhance spiking of principal cells in the lateral amygdala of juveniles, but we fail to find this in adults. These findings have notable scientific and clinical implications regarding the noradrenergic modulation of threat processing, alterations of which underlie fear and anxiety disorders.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Fenômenos Eletrofisiológicos/fisiologia , Antagonistas de Receptores de GABA-A/farmacologia , Receptores Adrenérgicos beta/fisiologia , Fatores Etários , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Isoproterenol/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos
15.
Life Sci ; 193: 257-269, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29107793

RESUMO

Paracrine factors, including growth factors and cytokines, released from cardiac myocytes following ß-adrenergic receptor (ß-AR) stimulation regulate cardiac fibroblasts. Activated cardiac fibroblasts have the ability to increase collagen synthesis, cell proliferation and myofibroblast differentiation, leading to cardiac fibrosis. However, it is unknown which ß-AR subtypes and signaling pathways mediate the upregulation of paracrine factors in cardiac myocytes. In this study, we demonstrated that sustained stimulation of ß-ARs significantly induced synthesis and secretion of growth factors, including connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF), via the cAMP-dependent and protein kinase A (PKA)-dependent pathways. In addition, isoproterenol (ISO)-mediated synthesis and secretion of CTGF and VEGF through the ß1-AR and ß2-AR subtypes. Paracrine factors released by cardiac myocytes following sustained ß-AR stimulation are necessary for the induction of cell proliferation and synthesis of collagen I, collagen III and α-smooth muscle actin (α-SMA) in cardiac fibroblasts, confirming that ß-AR overstimulation of cardiac myocytes induces cardiac fibrosis by releasing several paracrine factors. These effects can be antagonized by ß-blockers, including atenolol, metoprolol, and propranolol. Thus, the use of ß-blockers may have beneficial effects on the treatment of myocardial fibrosis in patients with heart failure.


Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Coração/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Isoproterenol/farmacologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/fisiologia , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Exp Gerontol ; 109: 90-98, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28408160

RESUMO

We investigated the effects of angiotensin-converting enzyme (ACE) inhibition and aerobic physical training on the heart of old female rats (82-wk-old) submitted to premature ovarian failure (10-wk.-old). We used different approaches: morphology and function by echocardiography, reactivity of the coronary bed and left ventricular contractibility (Langendorff Technique). Female Wistar ovariectomized (OVX) rats (n=42) were assigned to one of four groups: OVX, vehicle treated only; OVX-EM, Enalapril Maleate only (EM, 10mg·kg-1·d-1); OVX-T, aerobic trained only; and OVX-EMT, treated with Enalapril Maleate and aerobic trained. Both Enalapril Maleate treatment and aerobic training were done in the last 20weeks of the experimental protocol. When compared to the OVX group, the OVX-EM group showed lower values of wall thickness and left ventricular (LV) mass, lower values of coronary bed reactivity and reduced maximum response of LV contractility to dobutamine, while the OVX-T group showed lower values of LV wall thickness, increase in end-systolic volume, reduced maximum response of LV contractility to dobutamine, and left intraventricular pressure due to increased flow. The combination of treatments (EM and aerobic physical training) did not promote additional important effects on the parameters evaluated. Our results suggest similar beneficial effects of physical training and EM treatment on the morphology and cardiac function in old female rats submitted to premature ovarian failure. Although the causes of these benefits are still unknown, both treatments have promoted a decrease in cardiac contractility, and the reduced ß1-adrenergic sensitivity suggests that both treatments may attenuate the sympathetic effect on the heart.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalapril/farmacologia , Coração/efeitos dos fármacos , Condicionamento Físico Animal , Insuficiência Ovariana Primária/fisiopatologia , Animais , Feminino , Coração/fisiologia , Contração Miocárdica/efeitos dos fármacos , Miocárdio/patologia , Ovariectomia , Insuficiência Ovariana Primária/patologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/fisiologia , Função Ventricular Esquerda
17.
Br J Dermatol ; 178(6): 1246-1256, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28714085

RESUMO

BACKGROUND: Humans have 4 million exocrine sweat glands, which can be classified into two types: eccrine and apocrine glands. Sweat secretion, a constitutive feature, is directly involved in thermoregulation and metabolism, and is regulated by both the central nervous system (CNS) and autonomic nervous system (ANS). OBJECTIVES: To explore how sweat secretion is controlled by both the CNS and the ANS and the mechanisms behind the neural control of sweat secretion. METHODS: We conducted a literature search on PubMed for reports in English from 1 January 1950 to 31 December 2016. RESULTS AND CONCLUSIONS: Acetylcholine acts as a potent stimulator for sweat secretion, which is released by sympathetic nerves. ß-adrenoceptors are found in adipocytes as well as apocrine glands, and these receptors may mediate lipid secretion from apocrine glands for sweat secretion. The activation of ß-adrenoceptors could increase sweat secretion through opening of Ca2+ channels to elevate intracellular Ca2+ concentration. Ca2+ and cyclic adenosine monophosphate play a part in the secretion of lipids and proteins from apocrine glands for sweat secretion. The translocation of aquaporin 5 plays an important role in sweat secretion from eccrine glands. Dysfunction of the ANS, especially the sympathetic nervous system, may cause sweating disorders, such as hypohidrosis and hyperhidrosis.


Assuntos
Glândulas Apócrinas/metabolismo , Sistema Nervoso Autônomo/fisiologia , Sistema Nervoso Central/fisiologia , Glândulas Écrinas/metabolismo , Suor/metabolismo , Acetilcolina/fisiologia , Glândulas Apócrinas/inervação , Regulação da Temperatura Corporal/fisiologia , Canais de Cálcio/fisiologia , AMP Cíclico/fisiologia , Glândulas Écrinas/inervação , Humanos , Sistema Límbico/fisiologia , Norepinefrina/fisiologia , Receptores Adrenérgicos beta/fisiologia , Receptores Acoplados a Proteínas-G/fisiologia , Via Secretória/fisiologia , Doenças das Glândulas Sudoríparas/fisiopatologia
18.
Cell Mol Neurobiol ; 38(1): 109-120, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29063982

RESUMO

In the heart, catecholamine effects occur by activation of beta-adrenergic receptors (ß-ARs), mainly the beta 1 (ß1-AR) and beta 2 (ß2-AR) subtypes, both of which couple to the Gs protein that activates the adenylyl cyclase signaling pathway. The ß2-ARs can also couple to the Gi protein that counterbalances the effect of the Gs protein on cyclic adenosine monophosphate production and activates the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In several cardiovascular disorders, including heart failure, as well as in aging and in animal models of environmental stress, a reduction in the ß1/ß2-AR ratio and activation of the ß2-AR-Gi-PI3K-Akt signaling pathway have been observed. Recent studies have shown that sirtuins modulate certain organic processes, including the cellular stress response, through activation of the PI3K-Akt signaling pathway and of downstream molecules such as p53, Akt, HIF1-α, and nuclear factor-kappa B. In the heart, SIRT1, SIRT3, and ß2-ARs are crucial to the regulation of the cardiomyocyte energy metabolism, oxidative stress, reactive oxygen species production, and autophagy. SIRT1 and the ß2-AR-Gi complex also control signaling pathways of cell survival and death. Here, we review the role played by ß2-ARs and sirtuins during aging, heart failure, and adaptation to stress, focusing on the putative interplay between the two. That relationship, if proven, merits further investigation in the context of cardiac function and dysfunction.


Assuntos
Envelhecimento/metabolismo , Insuficiência Cardíaca/metabolismo , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais/fisiologia , Sirtuínas/metabolismo , Estresse Psicológico/metabolismo , Adaptação Fisiológica/fisiologia , Adaptação Psicológica/fisiologia , Envelhecimento/psicologia , Animais , Insuficiência Cardíaca/psicologia , Humanos , Miócitos Cardíacos/metabolismo , Estresse Psicológico/psicologia
19.
Microcirculation ; 25(1)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29072364

RESUMO

Voltage-gated K+ (Kv ) channels are major determinants of membrane potential in vascular smooth muscle cells (VSMCs) and regulate the diameter of small cerebral arteries and arterioles. However, the intracellular structures that govern the expression and function of vascular Kv channels are poorly understood. Scaffolding proteins including postsynaptic density 95 (PSD95) recently were identified in rat cerebral VSMCs. Primarily characterized in neurons, the PSD95 scaffold has more than 50 known binding partners, and it can mediate macromolecular signaling between cell-surface receptors and ion channels. In cerebral arteries, Shaker-type Kv 1 channels appear to associate with the PSD95 molecular scaffold, and PSD95 is required for the normal expression and vasodilator influence of members of this K+ channel gene family. Furthermore, recent findings suggest that the ß1-subtype adrenergic receptor is expressed in cerebral VSMCs and forms a functional vasodilator complex with Kv 1 channels on the PSD95 scaffold. Activation of ß1-subtype adrenergic receptors in VSMCs enables protein kinase A-dependent phosphorylation and opening of Kv 1 channels in the PSD95 complex; the subsequent K+ efflux mediates membrane hyperpolarization and vasodilation of small cerebral arteries. Early evidence from other studies suggests that other families of Kv channels and scaffolding proteins are expressed in VSMCs. Future investigations into these macromolecular complexes that modulate the expression and function of Kv channels may reveal unknown signaling cascades that regulate VSMC excitability and provide novel targets for ion channel-based medications to optimize vascular tone.


Assuntos
Circulação Cerebrovascular , Proteína 4 Homóloga a Disks-Large/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Receptores Adrenérgicos beta/fisiologia , Animais , Proteína 4 Homóloga a Disks-Large/metabolismo , Humanos , Músculo Liso Vascular/química , Músculo Liso Vascular/citologia , Ratos , Receptores Adrenérgicos beta/metabolismo
20.
Cell Mol Neurobiol ; 38(2): 441-457, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28353187

RESUMO

Rapid eye movement sleep deprivation-associated elevated noradrenaline increases and decreases neuronal and glial Na-K ATPase activity, respectively. In this study, using C6 cell-line as a model, we investigated the possible intracellular molecular mechanism of noradrenaline-induced decreased glial Na-K ATPase activity. The cells were treated with noradrenaline in the presence or absence of adrenoceptor antagonists, modulators of extra- and intracellular Ca++ and modulators of intracellular signalling pathways. We observed that noradrenaline acting on ß-adrenoceptor decreased Na-K ATPase activity and mRNA expression of the catalytic α2-Na-K ATPase subunit in the C6 cells. Further, cAMP and protein kinase-A mediated release of intracellular Ca++ played a critical role in such decreased α2-Na-K ATPase expression. In contrast, noradrenaline acting on ß-adrenoceptor up-regulated the expression of regulatory ß2-Na-K ATPase subunit, which although was cAMP and Ca++ dependent, was independent of protein kinase-A and protein kinase-C. Combining these with previous findings (including ours) we have proposed a working model for noradrenaline-induced suppression of glial Na-K ATPase activity and alteration in its subunit expression. The findings help understanding noradrenaline-associated maintenance of brain excitability during health and altered states, particularly in relation to rapid eye movement sleep and its deprivation when the noradrenaline level is naturally altered.


Assuntos
Regulação Enzimológica da Expressão Gênica , Líquido Intracelular/enzimologia , Receptores Adrenérgicos beta/fisiologia , ATPase Trocadora de Sódio-Potássio/biossíntese , ATPase Trocadora de Sódio-Potássio/genética , Animais , Carbazóis/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Líquido Intracelular/efeitos dos fármacos , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/biossíntese , Subunidades Proteicas/genética , Pirróis/farmacologia , Ratos , Sódio/farmacologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores
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