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1.
Proc Natl Acad Sci U S A ; 116(44): 22282-22287, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31619570

RESUMO

Sympathetic activation of ß-adrenoreceptors (ß-AR) represents a hallmark in the development of heart failure (HF). However, little is known about the underlying mechanisms of gene regulation. In human ventricular myocardium from patients with end-stage HF, we found high levels of phosphorylated histone 3 at serine-28 (H3S28p). H3S28p was increased by inhibition of the catecholamine-sensitive protein phosphatase 1 and decreased by ß-blocker pretreatment. By a series of in vitro and in vivo experiments, we show that the ß-AR downstream protein kinase CaM kinase II (CaMKII) directly binds and phosphorylates H3S28. Whereas, in CaMKII-deficient myocytes, acute catecholaminergic stimulation resulted in some degree of H3S28p, sustained catecholaminergic stimulation almost entirely failed to induce H3S28p. Genome-wide analysis of CaMKII-mediated H3S28p in response to chronic ß-AR stress by chromatin immunoprecipitation followed by massive genomic sequencing led to the identification of CaMKII-dependent H3S28p target genes. Forty percent of differentially H3S28p-enriched genomic regions were associated with differential, mostly increased expression of the nearest genes, pointing to CaMKII-dependent H3S28p as an activating histone mark. Remarkably, the adult hemoglobin genes showed an H3S28p enrichment close to their transcriptional start or end sites, which was associated with increased messenger RNA and protein expression. In summary, we demonstrate that chronic ß-AR activation leads to CaMKII-mediated H3S28p in cardiomyocytes. Thus, H3S28p-dependent changes may play an unexpected role for cardiac hemoglobin regulation in the context of sympathetic activation. These data also imply that CaMKII may be a yet unrecognized stress-responsive regulator of hematopoesis.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Insuficiência Cardíaca/metabolismo , Hemoglobinas/genética , Código das Histonas , Histonas/metabolismo , Miocárdio/metabolismo , Sistema Nervoso Simpático/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Animais , Catecolaminas/farmacologia , Células Cultivadas , Feminino , Insuficiência Cardíaca/genética , Hemoglobinas/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação , Ratos , Sistema Nervoso Simpático/efeitos dos fármacos
2.
Inorg Chem ; 58(21): 14626-14634, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31613591

RESUMO

The special linear dioxo cation structure of the uranyl cation, which relegates ligand coordination to an equatorial plane perpendicular to the O═U═O vector, poses an unusual challenge for the rational design of efficient chelating agents. Therefore, the planar hexadentate ligand rational design employed in this work incorporates two bidentate catecholamine (CAM) chelating moieties and a flexible linker with a ß-dicarbonyl chelating moiety (ß-dicarbonyl(CAM)2 ligands). The solution thermodynamics of ß-dicarbonyl(CAM)2 with a uranyl cation was investigated by potentiometric and spectrophotometric titrations. The results demonstrated that the pUO22+ values are significantly higher than for the previously reported TMA(2Li-1,2-HOPO)2, and efficient chelation of the uranyl cation was realized by the planar hexadentate ß-dicarbonyl(CAM)2. The efficient chelating ability of ß-dicarbonyl(CAM)2 was attributed to the presence of the more flexible ß-dicarbonyl chelating linker and planar hexadentate structure, which favors the geometric arrangement between ligand and uranyl coordinative preference. Meanwhile, ß-dicarbonyl(CAM)2 also exhibits higher antiradical efficiency in comparison to butylated hydroxyanisole. These results indicated that ß-dicarbonyl(CAM)2 has potential application prospects as a chelating agent for efficient chelation of a uranyl cation.


Assuntos
Antioxidantes/química , Catecolaminas/química , Quelantes/química , Termodinâmica , Urânio/química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Catecolaminas/síntese química , Catecolaminas/farmacologia , Cátions/química , Quelantes/síntese química , Quelantes/farmacologia , Ligantes , Estrutura Molecular , Picratos/antagonistas & inibidores
3.
Semin Nephrol ; 39(5): 462-472, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31514910

RESUMO

Acute kidney injury (AKI) is common in the setting of shock. Hemodynamic instability is a risk factor for the development of AKI, and pathophysiological mechanisms include loss of renal perfusion pressure and impaired microcirculation. Although restoration of mean arterial pressure (MAP) may mitigate the risk of AKI to some extent, evidence on this is conflicting. Also debatable is the optimal blood pressure needed to minimize the risk of kidney injury. A MAP of 65 mm Hg traditionally has been considered adequate to maintain renal perfusion pressure, and studies have failed to consistently show improved outcomes at higher levels of MAP. Therapeutic options to support renal perfusion consist of catecholamines, vasopressin, and angiotensin II. Although catecholamines are the most studied, they are associated with adverse events at higher doses, including AKI. Vasopressin and angiotensin II are noncatecholamine options to support blood pressure and may improve microcirculatory hemodynamics through unique mechanisms, including differential vasoconstriction of efferent and afferent arterioles within the nephron. Future areas of study include methods by which clinicians can measure renal blood flow in a macrocirculatory and microcirculatory way, a personalized approach to blood pressure management in septic shock using patient-specific measures of perfusion adequacy, and novel agents that may improve the microcirculation within the kidneys without causing adverse microcirculatory effects in other organs.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico , Angiotensina II/farmacologia , Angiotensina II/uso terapêutico , Pesquisa Biomédica , Catecolaminas/farmacologia , Catecolaminas/uso terapêutico , Humanos , Vasopressinas/farmacologia , Vasopressinas/uso terapêutico
4.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207916

RESUMO

Cardiomyocytes and myocardial sleeves dissociated from pulmonary veins (PVs) potentially generate ectopic automaticity in response to noradrenaline (NA), and thereby trigger atrial fibrillation. We developed a mathematical model of rat PV cardiomyocytes (PVC) based on experimental data that incorporates the microscopic framework of the local control theory of Ca2+ release from the sarcoplasmic reticulum (SR), which can generate rhythmic Ca2+ release (limit cycle revealed by the bifurcation analysis) when total Ca2+ within the cell increased. Ca2+ overload in SR increased resting Ca2+ efflux through the type II inositol 1,4,5-trisphosphate (IP3) receptors (InsP3R) as well as ryanodine receptors (RyRs), which finally triggered massive Ca2+ release through activation of RyRs via local Ca2+ accumulation in the vicinity of RyRs. The new PVC model exhibited a resting potential of -68 mV. Under NA effects, repetitive Ca2+ release from SR triggered spontaneous action potentials (APs) by evoking transient depolarizations (TDs) through Na+/Ca2+ exchanger (APTDs). Marked and variable latencies initiating APTDs could be explained by the time courses of the α1- and ß1-adrenergic influence on the regulation of intracellular Ca2+ content and random occurrences of spontaneous TD activating the first APTD. Positive and negative feedback relations were clarified under APTD generation.


Assuntos
Potenciais de Ação , Catecolaminas/farmacologia , Modelos Teóricos , Miócitos Cardíacos/metabolismo , Veias Pulmonares/metabolismo , Animais , Sinalização do Cálcio , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Veias Pulmonares/citologia , Veias Pulmonares/efeitos dos fármacos , Veias Pulmonares/fisiologia , Ratos , Receptores Adrenérgicos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Trocador de Sódio e Cálcio/metabolismo
5.
Crit Care ; 23(Suppl 1): 149, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200777

RESUMO

Catecholamines are used to increase cardiac output and blood pressure, aiming ultimately at restoring/improving tissue perfusion. While intuitive in its concept, this approach nevertheless implies to be effective that regional organ perfusion would increase in parallel to cardiac output or perfusion pressure and that the catecholamine does not have negative effects on the microcirculation. Inotropic agents may be considered in some conditions, but it requires prior optimization of cardiac preload. Alternative approaches would be either to minimize exposure to vasopressors, tolerating hypotension and trying to prioritize perfusion but this may be valid as long as perfusion of the organ is preserved, or to combine moderate doses of vasopressors to vasodilatory agents, especially if these are predominantly acting on the microcirculation. In this review, we will discuss the pros and cons of the use of catecholamines and alternative agents for improving tissue perfusion in septic shock.


Assuntos
Catecolaminas/efeitos adversos , Perfusão/normas , Pressão Arterial/fisiologia , Débito Cardíaco/efeitos dos fármacos , Catecolaminas/farmacologia , Catecolaminas/uso terapêutico , Humanos , Microcirculação/efeitos dos fármacos , Perfusão/métodos , Perfusão/tendências , Ressuscitação/métodos , Ressuscitação/tendências
6.
Microb Pathog ; 131: 270-276, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981718

RESUMO

Stress hormones have been recently suggested to influence the pathogenicity of bacteria significantly. Stress has been identified as part of the factors causing an outbreak of infections in the aquaculture industry. The most studied neuroendocrine hormonal family from a microbial endocrinology perspective is the catecholamine comprising of norepinephrine, epinephrine, and dopamine. It is of importance that catecholamine affects the growth and virulence of bacteria. The influence of stress on bacterial infections is attributed to the ability of catecholamines to suppress the immune system as the mode of action for increased bacterial growth. Catecholamines have increased the growth of bacteria, virulence-associated factors, adhesions, and biofilm formation and consequently influence the outcome of infections by these bacteria in many hosts. The siderophores and the ferric iron transport system plays a vital role in the mechanism by which catecholamines stimulates growth and exposure of genes to stress hormones enhances the expression of genes involved in bacterial virulence. In recent years, it has been discovered that intestinal microflora takes part in bidirectional communication between the gut and brain. The rapidly growing field of microbiome research, understanding the communities of bacteria living within our bodies and the genes they contain is yielding new perspectives. This review reveals catecholamines effects on the growth and virulence of bacteria and the latest trends in microbial endocrinology.


Assuntos
Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas , Catecolaminas/farmacologia , Aquicultura , Bactérias/genética , Bactérias/patogenicidade , Infecções Bacterianas/microbiologia , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Catecolaminas/química , Dopamina/farmacologia , Endocrinologia , Epinefrina/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema Imunitário , Norepinefrina/farmacologia , Percepção de Quorum/efeitos dos fármacos , Virulência/efeitos dos fármacos , Virulência/genética , Fatores de Virulência/genética
7.
J Fish Dis ; 42(4): 477-487, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30694560

RESUMO

In this study, we evaluated the impact of the catecholamines on growth, swimming motility, biofilm formation and some virulence factors activities of pathogenic Yersinia ruckeri. Norepinephrine and dopamine (at 100 µM) significantly increased the growth of Y. ruckeri in culture media containing serum. An increase in swimming motility of the pathogen was found following the exposure to the hormones; however, no effect was seen on caseinase, phospholipase and haemolysin productions. Further, antagonists for the catecholamine receptors were observed to block some of the influences of the catecholamines. Indeed, the effects of catecholamines were inhibited by chlorpromazine (the dopaminergic receptor antagonist) for dopamine, labetalol (α-and ß-adrenergic receptor antagonist) and phenoxybenzamine (the α-adrenergic receptor antagonist) for norepinephrine, but propranolol (the ß-adrenergic receptor antagonist) showed no effect. Pretreatment of Y. ruckeri with the catecholamines resulted in a significant enhancement of its virulence towards rainbow trout and the antagonists could neutralize the effect of the stress hormones in vivo. In summary, our results show that the catecholamines increase the virulence of Y. ruckeri which is pathogenic to trout through increasing the motility, biofilm formation and growth.


Assuntos
Biofilmes/efeitos dos fármacos , Catecolaminas/farmacologia , Oncorhynchus mykiss/microbiologia , Yersinia ruckeri/efeitos dos fármacos , Animais , Dopamina/farmacologia , Doenças dos Peixes/microbiologia , Doenças dos Peixes/prevenção & controle , Locomoção/efeitos dos fármacos , Norepinefrina/farmacologia , Virulência , Fatores de Virulência/metabolismo , Yersinia ruckeri/fisiologia
8.
Gen Comp Endocrinol ; 279: 109-113, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30654022

RESUMO

Interleukin-6 (IL-6) is a pleiotropic cytokine secreted by immune tissues such as monocytes/macrophages and have pro-inflammatory/anti-inflammatory and neuroendocrine actions. In this study, we report the modulatory effects of stress hormones, the cortisol agonist dexamethasone and catecholamines on lipopolysaccharide (LPS) - induced stimulation of head kidney IL-6 in the catfish Heteropneustes fossilis. In the in vivo study, the intraperitoneal administration of LPS stimulated, and dexamethasone time-dependently inhibited IL-6 level. In the in vitro study, the incubation of macrophage cultures with LPS stimulated IL-6 level significantly in all incubation times. Dexamethasone did not alter the basal IL-6 level but inhibited time-dependently the LPS-induced stimulation. Likewise, catecholamines did not alter the basal level of IL-6. Both epinephrine and norepinephrine inhibited the LPS-induced stimulation of IL-6. Dopamine, on the other hand, was ineffective. The results indicate that IL-6 is a useful marker of head kidney macrophage activity for studying endocrine-immune interactions in the catfish.


Assuntos
Catecolaminas/farmacologia , Peixes-Gato/metabolismo , Rim Cefálico/metabolismo , Interleucina-6/biossíntese , Lipopolissacarídeos/farmacologia , Estresse Fisiológico , Animais , Dexametasona/farmacologia , Epinefrina/farmacologia , Rim Cefálico/efeitos dos fármacos , Hidrocortisona/farmacologia , Norepinefrina/farmacologia
9.
Can J Physiol Pharmacol ; 97(6): 570-576, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30557041

RESUMO

An excessive amount of catecholamines produce arrhythmias, but the exact mechanisms of this action are not fully understood. For this purpose, Sprague-Dawley rats were treated with or without atenolol, a ß1-adrenoceptor blocker (20 mg/kg per day), for 15 days followed by injections of epinephrine for cumulative doses of 4 to 128 µg/kg. Another group of animals were pretreated with losartan, an angiotensin receptor (AT1) blocker (20 mg/kg per day), for comparison. Control animals received saline. Varying degrees of ventricular arrhythmias were seen upon increasing the dose of epinephrine, but the incidence and duration of the rhythm abnormalities as well as the number of episodes and severity of arrhythmias were not affected by treating the animals with atenolol or losartan. The levels of both epinephrine and norepinephrine were increased in the atenolol-treated rats but were unchanged in the losartan-treated animals after the last injection of epinephrine; the severity of arrhythmias did not correlate with the circulating catecholamine levels. These results indicate that both ß1-adrenoceptors and AT1 receptors may not be involved in the pathogenesis of catecholamine-induced arrhythmias and support the view that other mechanisms, such as the oxidation products of catecholamines, may play a crucial role in the occurrence of lethal arrhythmias.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/metabolismo , Catecolaminas/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Animais , Arritmias Cardíacas/fisiopatologia , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia
10.
J Exp Zool A Ecol Integr Physiol ; 331(1): 27-37, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30288937

RESUMO

Catecholamines protect the fish heart during hypoxia. However, the humoral adrenergic stress response may only be invoked in extremis. We investigated the hypothesis that endogenous (e.g., neuronal) myocardial catecholamines may also impact cardiac performance during hypoxia in a hypoxia-tolerant tropical fish, the red-bellied piranha (Pygocentrus nattereri). First, we measured endogenous tissue catecholamines and in vitro catecholamine release from piranha myocardium using ultraperformance liquid chromatography. Ventricle homogenates contained detectable levels of both adrenaline (7.27 ng/g) and noradrenaline (14.48 ng/g), but only noradrenaline was released from ventricular tissue incubated in Ringer's solution. Noradrenaline released in this assay was not affected by hypoxia but was promoted by the catecholamine releasing agent tyramine. Our second series of experiments explored cardiac contractile performance in vitro using tyramine, exogenous noradrenaline or adrenaline, and propranolol (a ß-adrenoceptor antagonist). In ventricular strip preparations, ß-adrenergic blockade with propranolol had no effects on twitch force or contraction kinetics in either normoxia or hypoxia, confirming that spontaneous endogenous catecholamine release did not impact cardiac performance. However, in the absence of propranolol, tyramine mimicked the positive inotropic effect of noradrenaline (10 µM) during hypoxia, although adrenaline was capable of generating larger effects. Our results suggest that, although it is not spontaneously released, inducible endogenous noradrenaline release may have a significant ß-adrenoceptor-dependent impact on hypoxic performance in the fish heart.


Assuntos
Caraciformes/fisiologia , Epinefrina/farmacologia , Norepinefrina/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Catecolaminas/farmacologia , Epinefrina/metabolismo , Feminino , Masculino , Contração Miocárdica , Miocárdio , Norepinefrina/metabolismo , Oxigênio , Propranolol/farmacologia , Simpatomiméticos/farmacologia , Tiramina/farmacologia
11.
Plant Cell Environ ; 42(5): 1458-1470, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30556134

RESUMO

Development of adventitious roots (ARs) at the base of the shoot is an important adaptation of plants to waterlogging stress; however, its physiological mechanisms remain unclear. Here, we investigated the regulation of AR formation under waterlogged conditions by hormones and reactive oxygen species (ROS) in Cucumis sativus L., an agriculturally and economically important crop in China. We found that ethylene, auxin, and ROS accumulated in the waterlogged cucumber plants. On the other hand, application of the ethylene receptor inhibitor 1-methylcyclopropene (1-MCP), the auxin transport inhibitor 1-naphthylphthalamic acid (NPA), or the NADPH oxidase inhibitor diphenyleneiodonium (DPI) decreased the number of ARs induced by waterlogging. Auxin enhanced the expression of ethylene biosynthesis genes, which led to ethylene entrapment in waterlogged plants. Both ethylene and auxin induced the generation of ROS. Auxin-induced AR formation was inhibited by 1-MCP, although ethylene-induced AR formation was not inhibited by NPA. Both ethylene- and auxin-induced AR formation were counteracted by DPI. These results indicate that auxin-induced AR formation is dependent on ethylene, whereas ethylene-induced AR formation is independent of auxin. They also show that ROS signals mediate both ethylene- and auxin-induced AR formation in cucumber plants.


Assuntos
Cucumis sativus , Etilenos/metabolismo , Ácidos Indolacéticos/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Espécies Reativas de Oxigênio/metabolismo , Catecolaminas/farmacologia , Cucumis sativus/crescimento & desenvolvimento , Cucumis sativus/metabolismo , Ciclopropanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Imidazolinas/farmacologia , Reguladores de Crescimento de Planta/metabolismo , Proteínas de Plantas/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Receptores de Superfície Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico , Água
12.
ACS Appl Mater Interfaces ; 10(47): 40844-40853, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30403339

RESUMO

The development of a facile and versatile strategy to endow surfaces with synergistically anti-inflammatory, antimicrobial, and anticoagulant functions is of particular significance for blood-contacting biomaterials and medical devices. In this work, we report a simple and environmentally friendly "one-pot" method inspired by byssal cuticle chemistry, namely, [Fe(dopa)3] coordination chemistry for assembly of copper ions (Cu2+) and plant polyphenol (tannic acid)/catecholamine (dopamine or norepinephrine) to form metal-phenolic/catecholamine network-based coatings. This one-pot method enabled us to easily develop a multifunctional surface based on the combination of the characteristic functions of metal ions and plant polyphenol or catecholamine. The residual phenolic hydroxyl groups on the coatings imparted the modified surface with excellent antioxidant and anti-inflammatory functions. The robust chelation of copper ions to the metal-phenolic/catecholamine networks provided not only durable antibacterial property but also glutathione peroxidase like catalytic capability to continuously and controllably produce antithrombotic nitric oxide by catalyzing endogenous S-nitrothiol. The biological functions of such coatings could be well regulated by adjusting the ratios of the feed concentration of Cu2+ ions to plant polyphenol or catecholamine. We envision that our simple, multifunctional, and bioinspired coating strategy can hold great application promise for bioengineering blood-contacting devices.


Assuntos
Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Catecolaminas/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Metais/química , Fenóis/química , Animais , Catálise , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Óxido Nítrico/metabolismo , Coelhos , Ratos Sprague-Dawley , Staphylococcus aureus/efeitos dos fármacos , Trombose/patologia , Fator de Necrose Tumoral alfa/metabolismo
13.
Am J Physiol Endocrinol Metab ; 315(5): E1075-E1085, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253109

RESUMO

Activation of AMP-activated protein kinase (AMPK) is considered an attractive strategy for the treatment of type 2 diabetes. Favorable metabolic effects of AMPK activation are mainly observed in skeletal muscle and liver tissue, whereas the effects in human adipose tissue are only poorly understood. Previous studies, which largely employed the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR), suggest an antilipolytic role of AMPK in adipocytes. The aim of this work was to reinvestigate the role of AMPK in the regulation of lipolysis, using the novel allosteric small-molecule AMPK activators A-769662 and 991, with a focus on human adipocytes. For this purpose, human primary subcutaneous adipocytes were treated with A-769662, 991, or AICAR, as a control, before being stimulated with isoproterenol. AMPK activity status, glycerol release, and the phosphorylation of hormone-sensitive lipase (HSL), a key regulator of lipolysis, were then monitored. Our results show that both A-769662 and 991 activated AMPK to a level that was similar to, or greater than, that induced by AICAR. In contrast to AICAR, which as expected was antilipolytic, neither A-769662 nor 991 affected lipolysis in human adipocytes, although 991 treatment led to altered HSL phosphorylation. Furthermore, we suggest that HSL Ser660 is an important regulator of lipolytic activity in human adipocytes. These data suggest that the antilipolytic effect observed with AICAR in previous studies is, at least to some extent, AMPK independent.


Assuntos
Adenilato Quinase/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Catecolaminas/farmacologia , Lipólise/efeitos dos fármacos , Pironas/farmacologia , Tiofenos/farmacologia , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Feminino , Humanos , Lipólise/fisiologia , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ribonucleotídeos/farmacologia , Esterol Esterase/metabolismo
14.
PLoS One ; 13(9): e0203573, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30199552

RESUMO

Endothelium is the main source of catecholamine release in the electrical-field stimulation (EFS)-induced aortic contractions of the non- venomous snake Panterophis guttatus. However, adrenergic vasomotor control in venomous snakes such as Crotalus durissus terrificus and Bothrops jararaca has not yet been investigated. Crotalus and Bothrops aortic rings were mounted in an organ bath system. EFS-induced aortae contractions were performed in the presence and absence of guanethidine (30 µM), phentolamine (10 µM) or tetrodotoxin (1 µM). Frequency-induced contractions were also performed in aortae with endothelium removed. Immunohistochemical localization of both tyrosine hydroxylase (TH) and S-100 protein in snake aortic rings and brains, as well as in human tissue (paraganglioma tumour) were carried out. EFS (4 to 16 Hz) induced frequency-dependent aortic contractions in both Crotalus and Bothrops. The EFS-induced contractions were significantly reduced in the presence of either guanethidine or phentolamine in both snakes (p<0.05), whereas tetrodotoxin had no effect in either. Removal of the endothelium abolished the EFS-induced contractions in both snakes aortae (p<0.05). Immunohistochemistry revealed TH localization in endothelium of both snake aortae and human vessels. Nerve fibers were not observed in either snake aortae. In contrast, both TH and S100 protein were observed in snake brains and human tissue. Vascular endothelium is the main source of catecholamine release in EFS-induced contractions in Crotalus and Bothrops aortae. Human endothelial cells also expressed TH, indicating that endothelium- derived catecholamines possibly occur in mammalian vessels.


Assuntos
Aorta/efeitos dos fármacos , Bothrops/metabolismo , Catecolaminas/metabolismo , Crotalus/metabolismo , Estimulação Elétrica , Animais , Catecolaminas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Guanetidina/metabolismo , Guanetidina/farmacologia , Técnicas In Vitro , Fentolamina/metabolismo , Fentolamina/farmacologia , Proteínas S100/metabolismo , Tetrodotoxina/metabolismo , Tetrodotoxina/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo
15.
Int Heart J ; 59(4): 837-844, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-29794381

RESUMO

Previous studies have suggested that cellular senescence plays a central role in the progression of pathologic changes in the failing heart. It is well known that the sympathetic nervous system is activated in patients with heart failure, and this change is associated with poor clinical outcomes. Sympathetic activation increases the levels of various catecholamines, such as epinephrine and norepinephrine, but the contribution of these catecholamines to cellular senescence associated with heart failure remains to be determined. We found that catecholamine infusion induced senescence of endothelial cells and bone marrow cells, and promoted cardiac dysfunction in mice. In C57BL/6NCr mice, the continuous infusion of isoproterenol-induced cardiac inflammation and cardiac dysfunction. Expression of p53, a master regulator of cellular senescence, was increased in the cardiac tissue and bone marrow cells of these mice. Suppression of cellular senescence by genetic deletion of p53 in endothelial cells or bone marrow cells led to improvement of isoproterenol-induced cardiac dysfunction. In vitro studies showed that adrenergic signaling increased the expression of p53 and adhesion molecules by endothelial cells and macrophages. Our results indicate that catecholamine-induced senescence of endothelial cells and bone marrow cells plays a pivotal role in the progression of heart failure. Suppression of catecholamine-p53 signaling is crucial for inhibition of remodeling in the failing heart.


Assuntos
Células da Medula Óssea , Catecolaminas , Senescência Celular , Células Endoteliais , Insuficiência Cardíaca , Isoproterenol/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Catecolaminas/metabolismo , Catecolaminas/farmacologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Progressão da Doença , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Expressão Gênica/efeitos dos fármacos , Genes p53/fisiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Simpatomiméticos/farmacologia
16.
Biol Reprod ; 99(3): 611-628, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29668843

RESUMO

Ovine trophectoderm (oTr1) cells were used to investigate effects of epinephrine (EP), norepinephrine (NE), and dopamine (DA) on their proliferation, migration and adhesion, secretion of interferon tau (IFNT), and expression of genes for synthesis of polyamines and apoptosis. Expression of mRNAs for agmatinase (AGMAT), arginine decarboxylase (ADC), ornithine decarboxylase (ODC1), and solute carrier family 7 (SLC7A1) (cationic amino acid transporter, Y + system), member 1 increased (P < 0.05) in oTr1 cells in response to EP and DA. However, expression of SLC7A1 decreased at high doses of EP and expression of ADC mRNA by oTr1 cells decreased in response to 20 and 40 ng/ml NE, and 40 ng/ml DA. Migration of oTr1 cells increased in response to EP, DA, and NE after 48 h of treatment. However, proliferation of oTr1 cells was inhibited by 300 pg/ml EP after 96 h and DA at 20 and 100 ng/ml. EP increased adhesion of oTr1 cells. The secretion of IFNT increased in response to 300 pg/ml EP, 100 ng/ml NE and DA after 48 h and at 96 h, and both DA (40 ng/ml) and NE (100 ng/ml). Expression of mRNAs for apoptotic genes (caspase 3, cathpsin B, BCL2 associated X protein "bax," B-cell lymphoma 2 "bcl2," and proto-oncogene "cmyc") decreased (P < 0.05) in response to catecholamines, but DA did not affect (P < 0.05) expression of cMYC mRNA. These results indicate that catecholamines play important roles in conceptus development during the peri-implantation period of pregnancy through effects on synthesis of polyamines, secretion of IFNT, and expression of apoptotic genes by oTr1 cells.


Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Catecolaminas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon Tipo I/metabolismo , Poliaminas/metabolismo , Proteínas da Gravidez/metabolismo , Carneiro Doméstico/fisiologia , Trofoblastos/metabolismo , Agmatina/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Gravidez , Trofoblastos/efeitos dos fármacos
17.
Int J Mol Sci ; 19(3)2018 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-29495426

RESUMO

Overactivity of the sympathetic nervous system and central endothelins (ETs) are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB) also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Following brain ET receptor type A (ETA) blockade by BQ610 (selective antagonist), transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH) were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ETA blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein) in the right OB of hypertensive animals. However, ETA blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ETA are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/metabolismo , Antagonistas do Receptor de Endotelina A/farmacologia , Hipertensão/etiologia , Hipertensão/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Receptor de Endotelina A/metabolismo , Animais , Catecolaminas/farmacologia , Acetato de Desoxicorticosterona/efeitos adversos , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Expressão Gênica , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Fosforilação , Ratos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Br J Pharmacol ; 175(10): 1669-1690, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29473948

RESUMO

BACKGROUND AND PURPOSE: Antiarrhythmic ß-blockers are used in patients at risk of myocardial ischaemia, but the survival benefit and mechanisms are unclear. We hypothesized that ß-blockers do not prevent ventricular fibrillation (VF) but instead inhibit the ability of catecholamines to facilitate ischaemia-induced VF, limiting the scope of their usefulness. EXPERIMENTAL APPROACH: ECGs were analysed from ischaemic Langendorff-perfused rat hearts perfused with adrenoceptor antagonists and/or exogenous catecholamines (CATs: 313 nM noradrenaline + 75 nM adrenaline) in a blinded and randomized study. Ischaemic zone (IZ) size was deliberately made small or large. KEY RESULTS: In rat hearts with large IZs, ischaemia-induced VF incidence was high in controls. Atenolol, butoxamine and trimazosin did not affect VF at concentrations with ß1 -, ß2 - or α1 - adrenoceptor specificity and selectivity (confirmed in separate rat aortae myography experiments). In hearts with small IZs and low baseline incidence of ischaemia-induced VF, CATs, delivered to the uninvolved zone (UZ), increased ischaemia-induced VF incidence. This effect was not mimicked by atrial pacing, hence, not due to sinus tachycardia. However, the CATs-facilitated increase in ischaemia-induced VF was inhibited by atenolol and butoxamine (but not trimazosin), indicative of ß1 - and ß2 - but not α1 -adrenoceptor involvement (confirmed by immunoblot analysis of downstream phosphoproteins). CATs did not facilitate VF in low-flow globally ischaemic hearts, which have no UZ. CONCLUSIONS AND IMPLICATIONS: Catecholamines facilitated ischaemia-induced VF when risk was low, acting via ß1 - and ß2 - adrenoceptors located in the UZ. There was no scope for facilitation when VF risk was high (large IZ), which may explain why ß-blockers have equivocal effectiveness in humans.


Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Catecolaminas/antagonistas & inibidores , Coração/efeitos dos fármacos , Isquemia/metabolismo , Fibrilação Ventricular/tratamento farmacológico , Animais , Catecolaminas/farmacologia , Masculino , Ratos , Ratos Wistar , Fibrilação Ventricular/metabolismo
19.
Chemphyschem ; 19(10): 1173-1179, 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29356266

RESUMO

General anesthetics are essential in many areas, however, the cellular mechanisms of anesthetic-induced amnesia and unconsciousness are incompletely understood. Exocytosis is the main mechanism of signal transduction and neuronal communication through the release of chemical transmitters from vesicles to the extracellular environment. Here, we use disk electrodes placed on top of PC12 cells to show that treatment with barbiturate induces fewer molecules released during exocytosis and changes the event dynamics perhaps by inducing a less stable fusion pore that is prone to close faster during partial exocytosis. Larger events are essentially abolished. However, use of intracellular vesicle impact electrochemical cytometry using a nano-tip electrode inserted into a cell shows that the distribution of vesicle transmitter content does not change after barbiturate treatment. This indicates that barbiturate selectively alters the pore size of larger events or perhaps differentially between types of vesicles. Alteration of exocytosis in this manner could be linked to the effects of general anesthetics on memory loss.


Assuntos
Anestésicos Gerais/farmacologia , Barbitúricos/farmacologia , Catecolaminas/farmacologia , Modelos Biológicos , Animais , Células Cultivadas , Técnicas Eletroquímicas , Eletrodos , Exocitose/efeitos dos fármacos , Células PC12 , Ratos
20.
Cancer Cell ; 33(1): 75-90.e7, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29249692

RESUMO

Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras+/G12D;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective ß-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.


Assuntos
Catecolaminas/farmacologia , Fatores de Crescimento Neural/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Adrenérgicos/farmacologia , Animais , Carcinoma in Situ/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Camundongos Transgênicos , Neoplasias Pancreáticas/patologia
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