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1.
Invest Ophthalmol Vis Sci ; 60(15): 5059-5069, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31800964

RESUMO

Purpose: Beta-adrenergic receptor (AR) antagonists, like propranolol, inhibit angiogenesis in multiple ocular conditions through an unknown mechanism. We previously showed that propranolol reduces choroidal neovascularization (CNV) by decreasing interleukin-6 levels. Since macrophages are one of the central producers of interleukin-6, we examined whether macrophages are required for propranolol-driven inhibition of choroidal angiogenesis. Methods: We tested the anti-angiogenic properties of propranolol in the choroidal sprouting assay and the laser-induced CNV model. Bone marrow-derived monocytes (BMDMs) were added to the choroidal sprouting assay and Ccr2-/- mice were subjected to laser-induced CNV. Multi-parameter flow cytometry was performed to characterize the ocular mononuclear phagocyte populations after laser injury and during propranolol treatment. Results: Propranolol reduced choroidal angiogenesis by 41% (P < 0.001) in the choroidal sprouting assay. Similarly, propranolol decreased laser-induced CNV by 50% (P < 0.05) in female mice, with no change in males. BMDMs increased choroidal sprouting by 146% (P < 0.0001), and this effect was ablated by propranolol. Beta-AR inhibition had no effect upon laser-induced CNV area in female Ccr2-/- mice. MHCII+ and MHCII- macrophages increased 20-fold following laser treatment in wildtype mice as compared to untreated mice, and this effect was completely attenuated in lasered Ccr2-/- mice. Moreover, propranolol increased the numbers of MHCII+ and MHCII- macrophages by 1.9 (P = 0.07) and 3.1 (P < 0.05) fold in lasered female mice with no change in macrophage numbers in males. Conclusions: Our data suggest that propranolol inhibits angiogenesis through recruitment of monocyte-derived macrophages in female mice only. These data show the anti-angiogenic nature of beta-AR blocker-recruited monocyte-derived macrophages in CNV.


Assuntos
Neovascularização de Coroide/tratamento farmacológico , Angiofluoresceinografia/métodos , Macrófagos/patologia , Monócitos/patologia , Propranolol/farmacologia , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Corioide/metabolismo , Corioide/patologia , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Fundo de Olho , Imagem Tridimensional , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Receptores Adrenérgicos beta/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia
2.
Acta Cir Bras ; 34(5): e201900505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166461

RESUMO

PURPOSE: To evaluate the cardioprotective response of the pharmacological modulation of ß-adrenergic receptors (ß-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. METHODS: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with ß-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with ß-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. RESULTS: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of ß-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of ß-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). CONCLUSION: The pharmacological modulation of ß-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Atenolol/farmacologia , Cardiotônicos/farmacologia , Isoproterenol/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Creatina Quinase Forma MB/sangue , Testes de Função Cardíaca , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos Endogâmicos SHR , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
3.
Rev Esp Cardiol (Engl Ed) ; 72(10): 853-862, 2019 Oct.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31178382

RESUMO

Beta-blockers are widely used molecules that are able to antagonize ß-adrenergic receptors (ARs), which belong to the G protein-coupled receptor family and receive their stimulus from endogenous catecholamines. Upon ß-AR stimulation, numerous intracellular cascades are activated, ultimately leading to cardiac contraction or vascular dilation, depending on the relevant subtype and their location. Three subtypes have been described that are differentially expressed in the body (ß1-, ß2- and ß3-ARs), ß1 being the most abundant subtype in the heart. Since their discovery, ß-ARs have become an important target to fight cardiovascular disease. In fact, since their discovery by James Black in the late 1950s, ß-blockers have revolutionized the field of cardiovascular therapies. To date, 3 generations of drugs have been released: nonselective ß-blockers, cardioselective ß-blockers (selective ß1-antagonists), and a third generation of these drugs able to block ß1 together with extra vasodilation activity (also called vasodilating ß-blockers) either by blocking α1- or by activating ß3-AR. More than 50 years after propranolol was introduced to the market due to its ability to reduce heart rate and consequently myocardial oxygen demand in the event of an angina attack, ß-blockers are still widely used in clinics.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Coração/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animais , Doenças Cardiovasculares/fisiopatologia , Humanos , Receptores Adrenérgicos beta/efeitos dos fármacos
4.
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
5.
Curr Hypertens Rev ; 15(1): 22-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30227820

RESUMO

BACKGROUND: Beta-adrenergic receptors are expressed in cardiomyocytes and activated by either noradrenaline released from sympathetic synapses or circulating catecholamines. Their corresponding receptors have three subtypes, namely, ß1, ß2 and ß3, which are members of the G protein-coupled receptors (GPCRs) family. Activation of ß1-adrenergic receptors causes various physiological reactions including cardiac contraction and renin secretion from juxtaglomerular cells of the kidney. Antagonists of ß-adrenergic receptors, known as ß-blockers, have been used effectively for over four decades and have beneficial effects in the treatment of cardiovascular diseases. There are three generations of ß-blockers according to their pharmacological properties. Firstgeneration ß-blockers are non-selective, blocking both ß1- and ß2-receptors; second-generation ß- blockers are more cardioselective in that they are more selective for ß1-receptors; and thirdgeneration ß-blockers are highly selective drugs for ß1-receptors. The latter also display vasodilator actions by blocking α1-adrenoreceptors and activating ß3-adrenergic receptors. In addition, thirdgeneration ß-blockers exhibit angiogenic, antioxidant, anti-proliferative, anti-hypertrophic and antiapoptotic activities among other effects that are still under investigation. CONCLUSION: The objective of this review is to describe the evolution observed during the development of the three distinctive generations, thereby highlighting the advantages of third-generation ß- blockers over the other two drug classes.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Cardiopatias/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/classificação , Animais , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/classificação , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Receptores Adrenérgicos beta/classificação , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
6.
Toxicol Lett ; 302: 18-27, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503853

RESUMO

Exposure to diesel exhaust particles (DEP) may contribute to endothelial dysfunction and cardiovascular disease. DEP, extractable organic material from DEP (DEP-EOM) and certain PAHs seem to trigger [Ca2+]i increase as well as inflammation via GPCRs like ßARs and PAR-2. In the present study we explored the involvement of ßARs and PAR-2 in effects of DEP-EOM on [Ca2+]i and expression of inflammation-associated genes in the endothelial cell-line HMEC-1. We exposed the human microvascular endothelial cell line HMEC-1 to DEP-EOM fractionated by sequential extraction with solvents of increasing polarity: n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol (Methanol-EOM) and water (Water-EOM). While Methanol-EOM and Water-EOM had no marked effects, n-Hex-EOM and DCM-EOM enhanced [Ca2+]i (2-3 times baseline) and expression of inflammation-associated genes (IL-1α, IL-1ß, COX-2 and CXCL8; 2-15 times baseline) in HMEC-1. The expression of ßARs (60-80% of baseline) and ßAR-inhibitor carazolol suppressed the increase in [Ca2+]i induced by both n-Hex- and DCM-EOM. Carazolol as well as the Ca2+-channel inhibitor SKF-96365 reduced the DCM-EOM-induced pro-inflammatory gene-expression. Overexpression of ßARs increased DCM-EOM-induced [Ca2+]i responses in HEK293 cells, while ßAR-overexpression suppressed [Ca2+]i responses from n-Hex-EOM. Furthermore, the PAR-2-inhibitor ENMD-1068 attenuated [Ca2+]i responses to DCM-EOM, but not n-Hex-EOM in HMEC-1. The results suggest that ßAR and PAR-2 are partially involved in effects of complex mixtures of chemicals extracted from DEP on calcium signalling and inflammation-associated genes in the HMEC-1 endothelial cell-line.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Células Endoteliais/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Compostos Orgânicos/toxicidade , Receptores Adrenérgicos beta/efeitos dos fármacos , Emissões de Veículos/toxicidade , Linhagem Celular , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica , Humanos , Receptor PAR-2/efeitos dos fármacos , Receptor PAR-2/metabolismo , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo
7.
Anasthesiol Intensivmed Notfallmed Schmerzther ; 53(11-12): 787-792, 2018 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-30458576

RESUMO

The therapy of patients suffering from sepsis and septic shock is one of the greatest challenges in critical care medicine. In the initial phase of septic shock patients often present with hyperdynamic circulatory conditions with elevated cardiac index, tachycardia and progressive hemodynamic instability. The type of tachycardia differs from atrial fibrillation or flatter to sinus tachycardia. The latter might be persistent even in case of adequate volume therapy according to the surviving sepsis campaign recommendations and may represent an independent pathology due to adrenergic overstimulation. Despite predominantly ß2-mediated immunomodulatory effects the administration of a selective ß1-adrenergic blocker may be beneficial in some cases. On the other hand, incautious administration of beta-blockers especially in case of insufficient volume replacement may result in direct negative inotropic effects rapidly aggravating hypotension and shock. This review focused on pharmacology of the ß-adrenergic system, the pathophysiological rationale and current literature on clinical practice of the use of beta-blockers in sepsis and septic shock.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Choque Séptico/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Humanos , Assistência Perioperatória , Receptores Adrenérgicos beta/efeitos dos fármacos , Choque Séptico/fisiopatologia
8.
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
9.
J Cardiovasc Pharmacol ; 72(5): 242-251, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30403389

RESUMO

BACKGROUND: Hypertension is a major cause of left ventricular (LV) diastolic dysfunction. Although ß-adrenergic receptor (ß-AR) blockers are often used to manage hypertension, the impact of ß-AR activation on LV lusitropic effects and hence filling pressures in the hypertensive heart with LV diastolic dysfunction is uncertain. METHODS: Using tissue Doppler imaging and Speckle tracking software, we assessed LV function in isoflurane anesthetised spontaneously hypertensive (SHR) and Dahl salt-sensitive (DSS) rats before and after ß-AR activation [isoproterenol (ISO) administration]. RESULTS: As compared to normotensive Wistar Kyoto control rats, or DSS rats not receiving NaCl in the drinking water, SHR and DSS rats receiving NaCl in the drinking water had a reduced myocardial relaxation as indexed by lateral wall e' (early diastolic tissue velocity at the level of the mitral annulus) and an increased LV filling pressure as indexed by E/e'. However, LV ejection fraction and deformation and motion were preserved in both SHR and DSS rats. The administration of ISO resulted in a marked increase in ejection fraction and decrease in LV filling volumes in all groups, and an increase in e' in SHR, but not DSS rats. However, after ISO administration, although E/e' decreased in DSS rats in association with a reduced filling volume, E/e' in SHR remained unchanged and SHR retained greater values than Wistar Kyoto control. CONCLUSIONS: The hypertensive heart is characterized by reductions in myocardial relaxation and increases in filling pressures, but ß-AR activation may fail to improve myocardial relaxation and when this occurs, it does not reduce LV filling pressures.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Hipertensão/complicações , Isoproterenol/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Diástole , Modelos Animais de Doenças , Ecocardiografia Doppler de Pulso , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Ratos Endogâmicos Dahl , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Adrenérgicos beta/metabolismo , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Pressão Ventricular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
10.
Heart Rhythm ; 15(6): 895-904, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29410121

RESUMO

BACKGROUND: Sustained ß-adrenergic receptor (ß-AR) stimulation causes pathophysiological changes during heart failure (HF), including inhibition of the slow component of the delayed rectifier potassium current (IKs). Aberrant calcium handling, including increased activation of calcium/calmodulin-dependent protein kinase II (CaMKII), contributes to arrhythmia development during HF. OBJECTIVE: The purpose of this study was to investigate CaMKII regulation of KCNQ1 (pore-forming subunit of IKs) during sustained ß-AR stimulation and associated functional implications on IKs. METHODS: KCNQ1 phosphorylation was assessed using liquid chromatography-tandem mass spectrometry after sustained ß-AR stimulation with isoproterenol (ISO). Peptide fragments corresponding to KCNQ1 residues were synthesized to identify CaMKII phosphorylation at the identified sites. Dephosphorylated (alanine) and phosphorylated (aspartic acid) mimics were introduced at identified residues. Whole-cell, voltage-clamp experiments were performed in human endothelial kidney 293 cells coexpressing wild-type or mutant KCNQ1 and KCNE1 (auxiliary subunit) during ISO treatment or lentiviral δCaMKII overexpression. RESULTS: Novel KCNQ1 carboxy-terminal sites were identified with enhanced phosphorylation during sustained ß-AR stimulation at T482 and S484. S484 peptides demonstrated the strongest δCaMKII phosphorylation. Sustained ß-AR stimulation reduced IKs activation (P = .02 vs control) similar to the phosphorylated mimic (P = .62 vs sustained ß-AR). Individual phosphorylated mimics at S484 (P = .04) but not at T482 (P = .17) reduced IKs function. Treatment with CN21 (CaMKII inhibitor) reversed the reductions in IKs vs CN21-Alanine control (P < .01). δCaMKII overexpression reduced IKs similar to ISO treatment in wild type (P < .01) but not in the dephosphorylated S484 mimic (P = .99). CONCLUSION: CaMKII regulates KCNQ1 at S484 during sustained ß-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , DNA/genética , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Isoproterenol/farmacologia , Miócitos Cardíacos/metabolismo , Receptores Adrenérgicos beta/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Células Cultivadas , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Immunoblotting , Miócitos Cardíacos/patologia , Técnicas de Patch-Clamp , Transdução de Sinais
11.
Life Sci ; 196: 84-92, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29366747

RESUMO

Prior evidence indicates that ghrelin is involved in the integration of cardiovascular functions and behavioral responses. Ghrelin actions are mediated by the growth hormone secretagogue receptor subtype 1a (GHS-R1a), which is expressed in peripheral tissues and central areas involved in the control of cardiovascular responses to stress. AIMS: In the present study, we assessed the role of ghrelin - GHS-R1a axis in the cardiovascular reactivity to acute emotional stress in rats. MAIN METHODS AND KEY FINDINGS: Ghrelin potentiated the tachycardia evoked by restraint and air jet stresses, which was reverted by GHS-R1a blockade. Evaluation of the autonomic balance revealed that the sympathetic branch modulates the ghrelin-evoked positive chronotropy. In isolated hearts, the perfusion with ghrelin potentiated the contractile responses caused by stimulation of the beta-adrenergic receptor, without altering the amplitude of the responses evoked by acetylcholine. Experiments in isolated cardiomyocytes revealed that ghrelin amplified the increases in calcium transient changes evoked by isoproterenol. SIGNIFICANCE: Taken together, our results indicate that the Ghrelin-GHS-R1a axis potentiates the magnitude of stress-evoked tachycardia by modulating the autonomic nervous system and peripheral mechanisms, strongly relying on the activation of cardiac calcium transient and beta-adrenergic receptors.


Assuntos
Grelina/farmacologia , Coração/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Canais de Cálcio/efeitos dos fármacos , Coração/inervação , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Agonistas Muscarínicos/farmacologia , Ratos , Ratos Wistar , Receptores de Grelina/efeitos dos fármacos , Restrição Física , Taquicardia/induzido quimicamente , Taquicardia/fisiopatologia
12.
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
13.
Exp Hematol ; 57: 30-41.e1, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29030083

RESUMO

Granulocyte colony-stimulating factor (G-CSF) is a well-known hematopoietic stem cell (HSC)-mobilizing agent used in both allogeneic and autologous transplantation. However, a proportion of patients or healthy donors fail to mobilize a sufficient number of cells. New mobilization agents are therefore needed. Endocannabinoids (eCBs) are endogenous lipid mediators generated in the brain and peripheral tissues and activate the cannabinoid receptors CB1 and CB2. We suggest that eCBs may act as mobilizers of HSCs from the bone marrow (BM) under stress conditions as beta-adrenergic receptors (Adrß). This study demonstrates that BM mesenchymal stem cells (MSCs) secrete anandamide (AEA) and 2-arachidonylglycerol (2-AG) and the peripheral blood (PB) and BM microenvironment contain AEA and 2-AG. 2-AG levels are significantly higher in PB of the G-CSF-treated group compared with BM plasma. BM mononuclear cells (MNCs) and CD34+ HSCs express CB1, CB2, and Adrß subtypes. CD34+ HSCs had higher CB1 and CB2 receptor expression in G-CSF-untreated and G-CSF-treated groups compared with MSCs. MNCs but not MSCs expressed CB1 and CB2 receptors based on qRT-PCR and flow cytometry. AEA- and 2-AG-stimulated HSC migration was blocked by eCB receptor antagonists in an in vitro migration assay. In conclusion, components of the eCB system and their interaction with Adrß subtypes were demonstrated on HSCs and MSCs of G-CSF-treated and G-CSF-untreated healthy donors in vitro, revealing that eCBs might be potential candidates to enhance or facilitate G-CSF-mediated HSC migration under stress conditions in a clinical setting.


Assuntos
Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Adolescente , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Ácidos Araquidônicos/análise , Ácidos Araquidônicos/farmacologia , Medula Óssea/química , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Microambiente Celular , Endocanabinoides/análise , Endocanabinoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicerídeos/análise , Glicerídeos/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Células-Tronco Hematopoéticas/citologia , Humanos , Plasma , Alcamidas Poli-Insaturadas/análise , Alcamidas Poli-Insaturadas/farmacologia , Receptor CB1 de Canabinoide/biossíntese , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/biossíntese , Receptor CB2 de Canabinoide/efeitos dos fármacos , Receptor CB2 de Canabinoide/genética , Receptores Adrenérgicos beta/biossíntese , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/genética , Estresse Fisiológico/genética , Adulto Jovem
14.
Psychosom Med ; 80(2): 208-215, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29206724

RESUMO

OBJECTIVE: Racial discrimination is increasingly recognized as a contributor to increased cardiovascular disease (CVD) risk among African Americans. Previous research has shown significant overlap between racial discrimination and hostility, an established predictor of CVD risk including alterations in adrenergic receptor functioning. The present study examined the associations of racial discrimination and hostility with adrenergic receptor responsiveness. METHODS: In a sample (N = 57) of young to middle-aged African American adults (51% female) with normal and mildly elevated blood pressure, a standardized isoproterenol sensitivity test (CD25) was used to evaluate ß-AR responsiveness, whereas the dose of phenylephrine required to increase mean arterial pressure by 25 mm Hg (PD25) was used to assess α1-AR responsiveness. Racial discrimination was measured using the Perceived Racism Scale and hostility was assessed using the Cook-Medley Hostility Scale. RESULTS: In hierarchical regression models, greater racial discrimination, but not hostility, emerged as a significant predictor of decreased ß-adrenergic receptor responsiveness (ß = .38, p = .004). However, moderation analysis revealed that the association between racial discrimination and blunted ß-adrenergic receptor responsiveness was strongest among those with higher hostility (ß = .49, 95% confidence interval = .17-.82, p = .004). In addition, hostility, but not racial discrimination, significantly predicted α1-AR responsiveness. CONCLUSIONS: These findings suggest racial discrimination was associated with blunted ß-adrenergic receptor responsiveness, providing further evidence of the potential contribution of racial discrimination to increased CVD risk among African Americans. The adverse effects of discrimination on cardiovascular health may be enhanced in individuals with higher levels of hostility.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Afro-Americanos/etnologia , Hostilidade , Racismo/etnologia , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Adulto , Doenças Cardiovasculares/etnologia , Feminino , Humanos , Isoproterenol/farmacologia , Masculino , Pessoa de Meia-Idade , Fenilefrina/farmacologia , Adulto Jovem
15.
Niger J Physiol Sci ; 32(1): 21-25, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-29134973

RESUMO

Previous studies in man have shown that cortisol induces hyperglycemia through gluconeogenesis. However,the metabolic substrates involved in cortisol-induced hyperglycemia and the role of adrenergic receptors in lactate productionin toads have not been well studied. This study investigated the effects of adrenergic receptor blockers in cortisol-inducedhyperglycemia and blood lactate levels in the common African toad (Bufo regularis). Each toad was fasted and anaesthetizedwith sodium thiopentone given intraperitoneally (50mg/kg/i.p). The animals (control) received 0.7% amphibian saline whileanimals (untreated) received cortisol intravenously (50µg/kg/i.v). In pre-treatment groups, animals received propanolol (0.5mg/kg/i.v), prazosin (0.2 mg/kg/i.v) and combination of propanolol (0.5mg/kg/i.v) and prazosin (0.2 mg/kg/i.v) respectivelyfollowed by administration of cortisol 50µg/kg/i.v. Thereafter, blood samples were collected for estimation of glucose andlactate using the modified glucose oxidase method and colorimetric method respectively. Cortisol caused significant increase in blood glucose level ((p<0.05) and reduction in blood lactate levels. Pre-treatment with Prazosin (0.2 mg/kg/i.v) causedsignificant (p<0.05) increase in blood glucose level and significant reduction in blood lactate levels while pre-treatment withPropanolol (0.5mg/kg/i.v) abolished cortisol-induced hyperglycemia and caused increase in blood lactate levels comparedwith the untreated group. The combination of both blockers abolished the hyperglycemic effect of cortisol and causedincrease in the blood lactate levels. The results of this study show that cortisol-induced hyperglycemia is a consequent ofgluconeogenesis and mediated through the beta-adrenergic receptors. The results also show that lactate is produced andused as a gluconeogenic substrate to induce cortisol hyperglycemia in the Common African toad bufo regularis. The betaadrenergic receptors are involved in the use of lactate to induce cortisol hyperglycemia in the Common African toad Buforegularis.


Assuntos
Glicemia/metabolismo , Hidrocortisona/farmacologia , Hiperglicemia/induzido quimicamente , Prazosina/farmacologia , Antagonistas Adrenérgicos/metabolismo , Animais , Jejum , Glucose/farmacologia , Hiperglicemia/metabolismo , Lactatos/sangue , Masculino , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos
16.
Isr Med Assoc J ; 19(9): 570-575, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28971642

RESUMO

BACKGROUND: Systemic CD11b+ cells have been associated with several cardiac diseases, such as chronic heart failure. OBJECTIVES: To assess the levels of circulating CD11b+ cells and pro-inflammatory cytokines in cardiomyopathy induced by chronic adrenergic stimulation. METHODS: Male Lewis rats were injected with low doses of isoproterenol (isoprel) for 3 months. Cardiac parameters were tested by echocardiography. The percentage of CD11b+ cells was tested by flow cytometry. The levels of inflammatory cytokines in the sera were determined by an inflammation array, and the expression levels of cardiac interleukin-1 (IL-1) receptors were analyzed by real-time polymerase chain reactions. Cardiac fibrosis and inflammation were determined by histological analysis. RESULTS: Chronic isoprel administration resulted in increased heart rate, cardiac hypertrophy, elevated cardiac peri-vascular fibrosis, reduced fractional shortening, and increased heart weight per body weight ratio compared to control animals. This clinical presentation was associated with accumulation of CD11b+ cells in the spleen with no concomitant cardiac inflammation. Cardiac dysfunction was also associated with elevated sera levels of IL-1 alpha and over expression of cardiac IL-1 receptor type 2. CONCLUSIONS: CD11b+ systemic levels and IL-1 signaling are associated with cardiomyopathy induced by chronic adrenergic stimulation. Further studies are needed to define the role of systemic immunomodulation in this cardiomyopathy.


Assuntos
Antígeno CD11b , Cardiomiopatias/sangue , Interleucina-1alfa/sangue , Baço/citologia , Agonistas Adrenérgicos beta/administração & dosagem , Animais , Cardiomegalia/induzido quimicamente , Cardiomiopatias/induzido quimicamente , Isoproterenol/administração & dosagem , Masculino , Ratos , Ratos Endogâmicos Lew , Receptores Adrenérgicos beta/efeitos dos fármacos
17.
J Healthc Eng ; 2017: 4204085, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29065600

RESUMO

In a model of murine ventricular cardiac tissue in vitro, we have studied the inotropic effects of electromagnetic stimulation (frequency, 75 Hz), isoproterenol administration (10 µM), and their combination. In particular, we have performed an image processing analysis to evaluate the kinematics and the dynamics of beating cardiac syncytia starting from the video registration of their contraction movement. We have found that the electromagnetic stimulation is able to counteract the ß-adrenergic effect of isoproterenol and to elicit an antihypertrophic response.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Isoproterenol/farmacologia , Contração Miocárdica/efeitos dos fármacos , Animais , Radiação Eletromagnética , Camundongos , Camundongos Endogâmicos , Modelos Animais , Receptores Adrenérgicos beta/efeitos dos fármacos , Técnicas de Cultura de Tecidos
18.
Surgery ; 162(4): 901-916, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28716301

RESUMO

BACKGROUND: Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by ß1/ß2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of ß1/ß2, ß-2, or ß-3 blockade in burn mediated erythropoietin-resistant anemia. METHODS: Burn mice were randomized to receive daily injections of propranolol (nonselective ß1/ß2 antagonist), nadolol (long-acting ß1/ß2 antagonist), butoxamine (selective ß2 antagonist), or SR59230A (selective ß3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells. RESULTS: Although propranolol improved early and late erythroblasts, only butoxamine and selective ß3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, ß1/ß2 antagonism increased the early erythroblasts through commitment stages via ß2 specific MafB regulation. ß3 antagonism was more effective in improving overall red blood cells through late maturation stages. CONCLUSION: The study unfolds novel ß2 and ß3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively.


Assuntos
Anemia/etiologia , Queimaduras/complicações , Eritropoese , Receptores Adrenérgicos beta/fisiologia , Antagonistas Adrenérgicos/farmacologia , Animais , Butoxamina/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Nadolol/farmacologia , Propanolaminas/farmacologia , Propranolol/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos
19.
Behav Pharmacol ; 28(6): 441-449, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28562459

RESUMO

Emotional memory deficit is a well-known complication in early Parkinson's disease. However, its molecular mechanism is still not well known. To address this issue, we examined the cue-related fear-conditioning task and long-term potentiation (LTP) of the thalamus to the lateral amygdala in rats treated with low doses of reserpine (Res). We found that low-dose Res treatment impaired emotional memory and LTP. We also found that exogenous upregulation of norepinephrine (NE) ameliorated the impairment of LTP by facilitating ß-adrenergic receptors. Finally, acute treatment with NE or desipramine rescued the impaired emotional memory induced by a low-dose of Res. These results imply a pivotal role for NE in synaptic plasticity and associative fear memory in rats treated with low doses of Res and suggest that desipramine is a potential candidate for treating Parkinson's disease-related emotional memory deficit.


Assuntos
Desipramina/farmacologia , Transtornos da Memória/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Sinais (Psicologia) , Desipramina/metabolismo , Emoções , Medo , Potenciação de Longa Duração , Masculino , Memória/fisiologia , Transtornos da Memória/metabolismo , Plasticidade Neuronal/fisiologia , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Reserpina/metabolismo , Reserpina/farmacologia , Tálamo/efeitos dos fármacos , Tálamo/fisiologia
20.
Metabolism ; 70: 125-132, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28403937

RESUMO

INTRODUCTION: Brown adipose tissue (BAT) is a thermogenic organ with substantial metabolic capacity and has important roles in the maintenance of body weight and metabolism. Regulation of BAT is primarily mediated through the ß-adrenoceptor (ß-AR) pathway. The in vivo endocrine regulation of this pathway in humans is unknown. The objective of our study was to assess the in vivo BAT temperature responses to acute glucocorticoid administration. METHODS: We studied 8 healthy male volunteers, not pre-selected for BAT presence or activity and without prior BAT cold-activation, on two occasions, following an infusion with hydrocortisone (0.2mg.kg-1.min-1 for 14h) and saline, respectively. Infusions were given in a randomized double-blind order. They underwent assessment of supraclavicular BAT temperature using infrared thermography following a mixed meal, and during ß-AR stimulation with isoprenaline (25ng.kg fat-free mass-1.min-1 for 60min) in the fasting state. RESULTS: During hydrocortisone infusion, BAT temperature increased both under fasting basal conditions and during ß-AR stimulation. We observed a BAT temperature threshold, which was not exceeded despite maximal ß-AR activation. We conclude that BAT thermogenesis is present in humans under near-normal conditions. Glucocorticoids modulate BAT function, representing important physiological endocrine regulation of body temperature at times of acute stress.


Assuntos
Tecido Adiposo Marrom/fisiologia , Glucocorticoides/administração & dosagem , Termogênese/efeitos dos fármacos , Adolescente , Adulto , Animais , Temperatura Corporal/efeitos dos fármacos , Método Duplo-Cego , Glucocorticoides/fisiologia , Humanos , Isoproterenol/farmacologia , Masculino , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Termografia , Adulto Jovem
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