RESUMEN
In this chapter, we review how ligands, both agonists and antagonists, for the major classes of adrenoreceptors, are utilized in acute care clinical settings. Adrenergic ligands exert their effects by interacting with the three major classes of adrenoceptors. Adrenoceptor agonists and antagonists have important applications, ranging from treatment of hypotension to asthma, and have proven to be extremely useful in a variety of clinical settings of acute care from the operating room to the critical care environment. Continued research interpreting the mechanisms of adrenoreceptors may help the discovery of new drugs with more desirable clinical profiles.
Asunto(s)
Receptores Adrenérgicos , Humanos , Ligandos , Receptores Adrenérgicos/metabolismo , Receptores Adrenérgicos/efectos de los fármacos , Antagonistas Adrenérgicos/farmacología , Antagonistas Adrenérgicos/uso terapéutico , Animales , Cuidados Críticos , Agonistas Adrenérgicos/farmacología , Agonistas Adrenérgicos/uso terapéuticoRESUMEN
The stimulation of fat thermogenesis and modulation of the gut microbiota are promising therapeutic strategies against obesity. Zeaxanthin (ZEA), a carotenoid plant pigment, has been shown to prevent various diseases; however, the therapeutic mechanism for obesity remains unclear. Herein, whether ZEA improves obesity by activating the ß3-adrenergic receptor (ß3-AR) to stimulate white adipose tissue (WAT) thermogenesis and modulating the gut microbiota was investigated. C57BL6/N mice were fed a high-fat diet (HFD) supplemented with ZEA for 22 weeks. ZEA treatment reduced body weight, fat weight, adipocyte hypertrophy, liver weight, and lipid deposition, and improved dyslipidaemia, serum GPT, GOT, leptin, and irisin levels, glucose intolerance, and insulin resistance in HFD-fed mice. Mechanistically, ZEA treatment induced the expression of ß3-AR and thermogenic factors, such as PRDM16, PGC-1α, and UCP1, in inguinal WAT (iWAT) and brown adipose tissue. ZEA treatment stimulated iWAT thermogenesis through the synergistic cooperation of key organelles, which manifested as an increased expression of lipid droplet degradation factors (ATGL, CGI-58 and pHSL), mitochondrial biogenesis factors (Sirt1, Nrf2, Tfam, Nampt and Cyt-C), peroxisomal biogenesis factors (Pex16, Pex19 and Pmp70), and ß-oxidation factors (Cpt1, Cpt2, Acadm and Acox1). The thermogenic effect of ZEA was abolished by ß3-AR antagonist (SR59230A) treatment. Additionally, dietary supplementation with ZEA reversed gut microbiota dysbiosis by regulating the abundance of Firmicutes, Clostridia, Proteobacteria, and Desulfovibrio, which were associated with the thermogenesis- and obesity-associated indices by Spearman's correlation analysis. Functional analysis of the gut microbiota indicated that ZEA treatment significantly enriched the lipid metabolism pathways. These results demonstrate that ZEA is a promising multi-target functional food for the treatment of obesity by activating ß3-AR to stimulate iWAT thermogenesis, and modulating the gut microbiota.
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Tejido Adiposo/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/metabolismo , Receptores Adrenérgicos/metabolismo , Termogénesis/efectos de los fármacos , Zeaxantinas/farmacología , Tejido Adiposo/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Receptores Adrenérgicos/efectos de los fármacos , Transducción de SeñalRESUMEN
We report the first isolation of the alkaloid aaptamine from the Philippine marine sponge Stylissa sp. Aaptamine possessed weak antiproliferative activity against HCT116 colon cancer cells and inhibited the proteasome in vitro at 50 µM. These activities may be functionally linked. Due to its known, more potent activity on certain G-protein coupled receptors (GPCRs), including α-adrenergic and δ-opioid receptors, the compound was profiled more broadly at sub-growth inhibitory concentrations against a panel of 168 GPCRs to potentially reveal additional targets and therapeutic opportunities. GPCRs represent the largest class of drug targets. The primary screen at 20 µM using the ß-arrestin functional assay identified the antagonist, agonist, and potentiators of agonist activity of aaptamine. Dose-response analysis validated the α-adrenoreceptor antagonist activity of aaptamine (ADRA2C, IC50 11.9 µM) and revealed the even more potent antagonism of the ß-adrenoreceptor (ADRB2, IC50 0.20 µM) and dopamine receptor D4 (DRD4, IC50 6.9 µM). Additionally, aaptamine showed agonist activity on selected chemokine receptors, by itself (CXCR7, EC50 6.2 µM; CCR1, EC50 11.8 µM) or as a potentiator of agonist activity (CXCR3, EC50 31.8 µM; CCR3, EC50 16.2 µM). These GPCRs play a critical role in the treatment of cardiovascular disease, diabetes, cancer, and neurological disorders. The results of this study may thus provide novel preventive and therapeutic strategies for noncommunicable diseases (NCDs).
Asunto(s)
Alcaloides/farmacología , Naftiridinas/farmacología , Enfermedades no Transmisibles/tratamiento farmacológico , Poríferos/química , Antagonistas Adrenérgicos/farmacología , Alcaloides/química , Alcaloides/aislamiento & purificación , Regulación Alostérica/efectos de los fármacos , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Humanos , Naftiridinas/química , Naftiridinas/aislamiento & purificación , Filipinas , Receptores Adrenérgicos/efectos de los fármacos , Receptores de Quimiocina/agonistas , Receptores de Quimiocina/efectos de los fármacos , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/efectos de los fármacos , Saccharomyces cerevisiae/efectos de los fármacosRESUMEN
Noradrenaline (NA) in the thalamus has important roles in physiological, pharmacological, and pathological neuromodulation. In this work, a complete characterization of NA axons and Alpha adrenoceptors distributions is provided. NA axons, revealed by immunohistochemistry against the synthesizing enzyme and the NA transporter, are present in all thalamic nuclei. The most densely innervated ones are the midline nuclei, intralaminar nuclei (paracentral and parafascicular), and the medial sector of the mediodorsal nucleus (MDm). The ventral motor nuclei and most somatosensory relay nuclei receive a moderate NA innervation. The pulvinar complex receives a heterogeneous innervation. The lateral geniculate nucleus (GL) has the lowest NA innervation. Alpha adrenoceptors were analyzed by in vitro quantitative autoradiography. Alpha-1 receptor densities are higher than Alpha-2 densities. Overall, axonal densities and Alpha adrenoceptor densities coincide; although some mismatches were identified. The nuclei with the highest Alpha-1 values are MDm, the parvocellular part of the ventral posterior medial nucleus, medial pulvinar, and midline nuclei. The nucleus with the lowest Alpha-1 receptor density is GL. Alpha-2 receptor densities are highest in the lateral dorsal, centromedian, medial and inferior pulvinar, and midline nuclei. These results suggest a role for NA in modulating thalamic involvement in consciousness, limbic, cognitive, and executive functions.
Asunto(s)
Norepinefrina/fisiología , Receptores Adrenérgicos/fisiología , Sistema Nervioso Simpático/fisiología , Tálamo/fisiología , Animales , Autorradiografía , Axones/fisiología , Dopamina beta-Hidroxilasa/metabolismo , Fenómenos Electrofisiológicos , Femenino , Macaca mulatta , Macaca nemestrina , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Receptores Adrenérgicos/efectos de los fármacos , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Sistema Nervioso Simpático/diagnóstico por imagen , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The plant Combretum hypopilinum Diels (Combretaceae) is used in traditional medicine for the treatment of diarrhoea and other diseases in Africa. Previously, the antidiarrhoeal activity of its methanol leaf extract was reported. However, the mechanism(s) responsible for this activity is yet to be evaluated. AIM OF THE STUDY: This study aimed to elucidate the possible mechanism(s) of antidiarrhoeal activity of methanol leaf extract of Combretum hypopilinum (MECH) in mice. MATERIALS AND METHODS: Phytochemical screening and acute toxicity study were conducted according to standard methods. Adult mice were orally (p.o) administered distilled water (10 ml/kg), MECH (1000 mg/kg) and loperamide (5 mg/kg). The probable mechanisms of antidiarrhoeal activity of MECH were investigated following pretreatment with naloxone (2 mg/kg, subcutaneously), prazosin (1 mg/kg, s.c), yohimbine (2 mg/kg, intraperitoneally), propranolol (1 mg/kg, i.p), pilocarpine (1 mg/kg, s.c) and isosorbide dinitrate (150 mg/kg, p.o) 30 min before administration of MECH (1000 mg/kg). The mice were then subjected to castor oil-induced intestinal motility test. RESULTS: The oral median lethal dose (LD50) of MECH was found to be higher than 5000 mg/kg. There were significant (p < 0.05) decrease in the charcoal movement in the mice treated with the MECH (1000 mg/kg) and loperamide (5 mg/kg). The pretreatment of the mice with naloxone, prazosin and propranolol each significantly (p<0.05) reversed the antidiarrhoeal activity produced by MECH. CONCLUSION: The results obtained in this study suggest the probable involvement of opioidergic and (α1 and ß)-adrenergic systems in the antidiarrhoeal activity of the methanol leaf extract of Combretum hypopilinum.
Asunto(s)
Antidiarreicos/farmacología , Combretum/química , Diarrea/tratamiento farmacológico , Extractos Vegetales/farmacología , Receptores Adrenérgicos/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Animales , Antidiarreicos/uso terapéutico , Aceite de Ricino/toxicidad , Diarrea/inducido químicamente , Femenino , Motilidad Gastrointestinal/efectos de los fármacos , Dosificación Letal Mediana , Loperamida/farmacología , Loperamida/uso terapéutico , Masculino , Medicinas Tradicionales Africanas , Metanol/química , Ratones , Óxido Nítrico/metabolismo , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Receptores Colinérgicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Adrenoceptor and calcium channel modulating medications are widely used in clinical practice for acute neurological and systemic conditions. It is generally assumed that the cerebrovascular effects of these drugs mirror that of their systemic effects - and this is reflected in how these medications are currently used in clinical practice. However, recent research suggests that there are distinct cerebrovascular-specific effects of these medications that are related to the unique characteristics of the cerebrovascular anatomy including the regional heterogeneity in density and distribution of adrenoceptor subtypes and calcium channels along the cerebrovasculature. In this review, we critically evaluate existing basic science and clinical research to discuss known and putative interactions between adrenoceptor and calcium channel modulating pharmacotherapies, the neurovascular unit, and cerebrovascular anatomy. In doing so, we provide a rationale for selecting vasoactive medications based on lesion location and lay a foundation for future investigations that will define neuroprotective paradigms of adrenoceptor and calcium channel modulating therapies to improve neurological outcomes in acute neurological and systemic disorders.
Asunto(s)
Adrenérgicos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio/efectos de los fármacos , Trastornos Cerebrovasculares/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Receptores Adrenérgicos/efectos de los fármacos , Animales , Humanos , Vasoconstrictores/farmacología , Vasoconstrictores/uso terapéuticoRESUMEN
Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.
Asunto(s)
Antidepresivos/uso terapéutico , Antipsicóticos/uso terapéutico , Trastornos del Humor/tratamiento farmacológico , Neuronas/efectos de los fármacos , Antidepresivos/farmacología , Antipsicóticos/farmacología , Dopaminérgicos/farmacología , Dopaminérgicos/uso terapéutico , Neuronas Dopaminérgicas/efectos de los fármacos , Histamínicos/farmacología , Histamínicos/uso terapéutico , Humanos , Receptores Adrenérgicos/efectos de los fármacos , Receptores Purinérgicos/efectos de los fármacos , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiologíaRESUMEN
Several biochemical parameters within the brain are altered by antidepressants. However, it is still uncertain which parameters are important for the evaluation of the effectiveness of these drugs. What seems certain is that the response of the nervous system is dynamic. The dynamic nature of the nervous system is still poorly understood, although it has implications in clinical management. Criteria for evaluating treatment resistant depression are based on this temporal variability. The present study was designed to evaluate dynamic alterations in catecholaminergic receptors and calcyon (associated with monoaminergic theory of depression) in the rat brain as well as brain-derived neurotrophic factor (BDNF) and tyrosine kinase beta (TRKB; related to neurotrophin theory) induced by three antidepressant drugs (ADs) with various pharmacological profiles (imipramine, desipramine, and citalopram) administered for 21 days or acutely, followed by various drug-free periods. Receptor autoradiography and in situ hybridization studies allowed us to identify changes in various brain regions simultaneously in each rat. Repeated treatment with ADs induced biochemical alterations, which were in agreement with the results of previous studies. These alterations include the downregulation of ß1, ß2, and α1 adrenergic receptors, upregulation of α2-adrenergic receptors and dopamine D2 receptors, and increased expression of BDNF in the hippocampus. Additionally, we observed dynamic alterations in the measured parameters after acute drug administration, particularly at the level of dopamine receptors, which were extremely sensitive to a single dose of ADs followed by various drug-free periods. All three ADs induced the upregulation of dopamine D2 receptor mRNA levels in the nucleus accumbens. The same effect was induced by single doses of ADs followed by various drug-free periods. The obtained results indicate that alterations in the availability of neurotransmitters at synapses induced by ADs are strong enough to induce immediate and long-lasting adaptive changes in the neuronal network.
Asunto(s)
Antidepresivos/farmacología , Encéfalo/efectos de los fármacos , Receptores de Catecolaminas/metabolismo , Animales , Antidepresivos Tricíclicos/farmacología , Química Encefálica/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Citalopram/farmacología , Desipramina/farmacología , Imipramina/farmacología , Masculino , Proteínas de la Membrana/metabolismo , Ratas , Receptor trkB/metabolismo , Receptores Adrenérgicos/efectos de los fármacos , Receptores de Catecolaminas/efectos de los fármacos , Receptores Dopaminérgicos/efectos de los fármacosRESUMEN
The ability of animals to retrieve memories stored in response to the environment is essential for behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. Here, we developed a novel chemogenetic activation strategy exploiting insect olfactory ionotropic receptors (IRs), termed "IR-mediated neuronal activation," and used it for selective stimulation of NE neurons in the locus coeruleus (LC). Drosophila melanogaster IR84a and IR8a subunits were expressed in LC NE neurons in transgenic mice. Application of phenylacetic acid (a specific ligand for the IR84a/IR8a complex) at appropriate doses induced excitatory responses of NE neurons expressing the receptors in both slice preparations and in vivo electrophysiological conditions, resulting in a marked increase of NE release in the LC nerve terminal regions (male and female). Ligand-induced activation of LC NE neurons enhanced the retrieval process of conditioned taste aversion without affecting taste sensitivity, general arousal state, and locomotor activity. This enhancing effect on taste memory retrieval was mediated, in part, through α1- and ß-adrenergic receptors in the basolateral nucleus of the amygdala (BLA; male). Pharmacological inhibition of LC NE neurons confirmed the facilitative role of these neurons in memory retrieval via adrenergic receptors in the BLA (male). Our findings indicate that the LC NE system, through projections to the BLA, controls the retrieval process of taste associative memory.SIGNIFICANCE STATEMENT Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation, but the role of the NE system in memory retrieval remains unclear. We developed a chemogenetic activation system based on insect olfactory ionotropic receptors and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons enhanced the retrieval of conditioned taste aversion, which was mediated, in part, through adrenoceptors in the basolateral amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdala pathway plays an important role in the recall of taste associative memory.
Asunto(s)
Locus Coeruleus/efectos de los fármacos , Memoria/fisiología , Norepinefrina/fisiología , Receptores Adrenérgicos/fisiología , Células Receptoras Sensoriales/fisiología , Gusto/fisiología , Animales , Nivel de Alerta/fisiología , Drosophila melanogaster , Fenómenos Electrofisiológicos , Humanos , Locus Coeruleus/citología , Memoria/efectos de los fármacos , Recuerdo Mental/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/fisiología , Fenilacetatos/farmacología , Receptores Adrenérgicos/efectos de los fármacos , Receptores Odorantes/fisiología , Células Receptoras Sensoriales/efectos de los fármacos , Gusto/efectos de los fármacos , Gusto/genéticaRESUMEN
Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA's scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.
Asunto(s)
Mitragyna/química , Plantas Medicinales/química , Alcaloides de Triptamina Secologanina/química , Animales , Sitios de Unión , Células HEK293 , Humanos , Técnicas In Vitro , Simulación del Acoplamiento Molecular , Ensayo de Unión Radioligante , Receptores Adrenérgicos/efectos de los fármacos , Receptores Adrenérgicos/metabolismo , Receptores Opioides/efectos de los fármacos , Receptores Opioides/metabolismo , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/metabolismo , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Alcaloides de Triptamina Secologanina/farmacocinética , Alcaloides de Triptamina Secologanina/farmacología , Relación Estructura-ActividadRESUMEN
There is recent evidence that cocaine, nicotine, and their conditioned stimuli have the ability to enhance memory consolidation. The present study compared the effects of post-training heroin and of a heroin contextual conditioned stimulus (CS+) on consolidation of object recognition memory and investigated the roles of opioid and beta-adrenergic receptors in heroin/CS+ memory modulation by co-administering the respective antagonists, naltrexone (NTX) and propranolol (PRO). Three experiments were performed in male Sprague-Dawley rats demonstrating that immediate, but not delayed, post-sample exposure to heroin (0.3, 1 mg/kg), or exposure (30 min) to a contextual CS+ paired with 1 mg/kg heroin (5 pairings, each 120 min), equally enhanced object memory. Importantly, while the memory enhancing effects of 1 mg/kg heroin and of the contextual CS+ were not altered by post-training co-administration of 3 mg/kg naltrexone, they were blocked by post-training co-administration of 10 mg/kg propranolol. Taken together, these data suggest that a context paired with heroin shares the memory enhancing effect of heroin itself and that these unconditioned and conditioned drug stimuli may modulate memory through the activation of beta-noradrenergic receptors.
Asunto(s)
Heroína/farmacología , Consolidación de la Memoria/efectos de los fármacos , Narcóticos/farmacología , Norepinefrina , Receptores Adrenérgicos/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Antagonistas Adrenérgicos beta/farmacología , Animales , Condicionamiento Operante/efectos de los fármacos , Masculino , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacosAsunto(s)
Divertículo del Colon/complicaciones , Hipotensión/terapia , Perforación Intestinal/complicaciones , Complicaciones Posoperatorias/terapia , Sepsis/etiología , Sepsis/terapia , Anestesia/efectos adversos , Humanos , Hipotensión/etiología , Masculino , Persona de Mediana Edad , Norepinefrina/efectos adversos , Norepinefrina/uso terapéutico , Receptores Adrenérgicos/efectos de los fármacos , Simpatomiméticos/efectos adversos , Simpatomiméticos/uso terapéutico , Vasoconstrictores/efectos adversos , Vasoconstrictores/uso terapéutico , Vasopresinas/efectos adversos , Vasopresinas/uso terapéuticoRESUMEN
AIMS: To evaluate the functional and molecular alterations of contractile and relaxant machinery in the bladder and urethra that lead to the underactive bladder (UAB) in old female mice. METHODS: Female young (3-months) and old (18-months) C57BL/6 mice were used. Urodynamic was assessed in awake and anaesthetized mice. Electrical-field stimulation (EFS) and concentration-response curves to contractile and relaxing agents in isolated bladders and urethras were performed. Messenger RNA (mRNA) expressions of muscarinic, adrenergic, and transient receptor potential vanilloid-4 (TRPV4), and of the enzymes tyrosine hydroxylase and neuronal nitric oxide synthase (nNOS) were determined. Bladder cyclic adenosine monophosphate (cAMP) levels were measured. RESULTS: Cystometry in old mice showed incapacity to produce bladder emptying. On filter paper, old mice showed reduced urinary spots. Compared to the young group, bladder contractions induced by EFS and carbachol were lower in old mice. The ß3 -adrenoceptor agonist mirabegron promoted higher bladder relaxation and elevation of cAMP levels in old mice. In old mice urethras, the α1a -adrenoceptor agonist phenylephrine produced higher contractions, but no differences were found for the NO donor sodium nitroprusside-induced relaxations. In old mice, increased mRNA expressions of ß3 - and α1a -adrenoceptors in bladder and urethra were found, respectively, whereas the muscarinic M2 and M3 receptors and ß2 -adrenoceptors did not change between groups. Reduced mRNA expressions of tyrosine hydroxylase and nNOS were found in old mouse urethras. Additionally, TRPV4 expression was reduced in bladder urothelium from old mice. CONCLUSION: Age-associated mouse UAB is the result of autonomic dysfunction at multiple levels leading to the less sensitive and overrelaxed bladder, along with urethral hypercontractility.
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Envejecimiento/patología , Sistema Nervioso Autónomo/fisiopatología , Vejiga Urinaria de Baja Actividad/fisiopatología , Animales , AMP Cíclico/metabolismo , Estimulación Eléctrica , Femenino , Ratones , Ratones Endogámicos C57BL , Contracción Muscular/efectos de los fármacos , Receptores Adrenérgicos/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Uretra/fisiopatología , Vejiga Urinaria/inervación , Vejiga Urinaria/fisiopatología , UrodinámicaRESUMEN
Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.
Asunto(s)
Cardiotónicos/uso terapéutico , Acoplamiento Excitación-Contracción/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Choque Cardiogénico/tratamiento farmacológico , Enfermedad Aguda , Animales , Antioxidantes/efectos adversos , Antioxidantes/uso terapéutico , Calcio/metabolismo , Cardiotónicos/efectos adversos , Estudios de Casos y Controles , Catecolaminas/efectos adversos , Catecolaminas/uso terapéutico , Ensayos Clínicos como Asunto , Diástole/efectos de los fármacos , Dobutamina/efectos adversos , Dobutamina/uso terapéutico , Perros , Metabolismo Energético/efectos de los fármacos , Insuficiencia Cardíaca/mortalidad , Humanos , Mitocondrias/metabolismo , Modelos Animales , Contracción Miocárdica/efectos de los fármacos , Óxidos de Nitrógeno/efectos adversos , Óxidos de Nitrógeno/uso terapéutico , Oxidación-Reducción/efectos de los fármacos , Inhibidores de Fosfodiesterasa/efectos adversos , Inhibidores de Fosfodiesterasa/uso terapéutico , Placebos/administración & dosificación , Receptores Adrenérgicos/efectos de los fármacos , Sarcómeros/efectos de los fármacos , Sarcómeros/metabolismo , Choque Cardiogénico/mortalidad , Simendán/efectos adversos , Simendán/uso terapéutico , Porcinos , Sístole/efectos de los fármacos , Urea/efectos adversos , Urea/análogos & derivados , Urea/uso terapéuticoRESUMEN
Natural products have a long history as a source of psychoactive agents and pharmacological tools for understanding the brain and its circuitry. In the last two decades, marine cyanobacteria have become a standard source of natural product ligands with cytotoxic properties. The study of cyanobacterial metabolites as CNS modulatory agents has remained largely untapped, despite the need for new molecules to treat and understand CNS disorders. We have generated a library of 301 fractions from 37 field collected cyanobacterial samples and screened these fractions against a panel of CNS receptors using radiolabeled ligand competitive-binding assays. Herein we present an analysis of the screening data collected to date, which show that cyanobacteria are prolific producers of compounds which bind to important CNS receptors, including those for 5-HT, DA, monoamine transporters, adrenergic, sigma, and cannabinoid receptors. In addition to the analysis of our screening efforts, we will also present the isolation of five compounds from the same cyanobacterial collection to illustrate how pre-fractionation followed by radioligand screening can lead to rapid identification of selective CNS agents. The systematic screening of natural products sources, specifically filamentous marine cyanobacteria, will yield a number of lead compounds for further development as pharmacological tools and therapeutics.
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Productos Biológicos/química , Proliferación Celular/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Cianobacterias/química , Organismos Acuáticos/química , Autofagia/efectos de los fármacos , Productos Biológicos/farmacología , Sistema Nervioso Central/metabolismo , Humanos , Ligandos , Receptores Adrenérgicos/efectos de los fármacos , Receptores de Cannabinoides/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Proteínas de Transporte Vesicular de Monoaminas/efectos de los fármacosRESUMEN
Rats produce high rates of ultrasonic vocalizations (USVs) in social situations; these vocalizations are influenced by multiple neurotransmitter systems. Norepinephrine (NE) plays a significant role in vocalization biology; however, the contribution of NE to normal, prosocial vocal control has not been well established in the rat. To address this, we used NE adrenoceptor agonists (Cirazoline, Clonidine) and antagonists (Prozasin, Atipamezole, Propranolol) to quantify the contribution of specific alpha-1, alpha-2, and beta NE receptors to USV parameters in male Long Evans rats during seminaturalistic calling. We found that multiple USV acoustic variables (intensity, bandwidth, duration, peak frequency, and call profile) are modified by alterations in NE signaling. Very generally, agents that increased NE neurotransmission (Atipamezole) or activated alpha-1 receptors (Cirazoline), led to an increase in intensity and duration, respectively. Agents that decreased NE neurotransmission (Clonidine) or blocked alpha-1 receptors (Prazosin) reduced call rate, intensity, and bandwidth. However, the beta-receptor antagonist, Propranolol, was associated with increased call rate, duration, and intensity. Limb motor behaviors were largely unaffected by any drug, with the exception of Clonidine. Higher doses of Clonidine significantly reduced gross motor, grooming, and feeding behavior. These results confirm the involvement of NE transmission in vocal control in the rat, and suggest that this USV model is useful for studying the neuropharmacology of behavioral measures that may have implications for disease states, such as Parkinson's disease. (PsycINFO Database Record
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Agonistas alfa-Adrenérgicos/farmacología , Norepinefrina/farmacología , Receptores Adrenérgicos/efectos de los fármacos , Ultrasonido/métodos , Vocalización Animal/efectos de los fármacos , Agonistas alfa-Adrenérgicos/administración & dosificación , Animales , Clonidina/farmacología , Imidazoles/farmacología , Masculino , Modelos Animales , Norepinefrina/administración & dosificación , Propranolol/farmacología , Ratas , Ratas Long-EvansRESUMEN
The nucleus accumbens (NAc), integrating information from the prefrontal cortex and limbic structures, plays a critical role in reward and emotion regulation. Previous studies have reported that the NAc shell receives direct noradrenergic projections, and activation of α2-adrenoceptor (α2-AR) in the NAc shell decreases the fear or anxiety level of rats. However, the underlying mechanism is still little known. Intriguingly, glutamatergic neurotransmission in the NAc shell is closely related to reward and emotion. Here, using brain slice preparations and whole-cell patch clamp recordings, we examined the effect of activation of α2-AR on glutamatergic neurotransmission in the NAc shell. Perfusing slice with α2-AR selective agonist clonidine (CLON) reduced the evoked excitatory postsynaptic currents (EPSCs) on the NAc shell neurons. This inhibitory effect on AMPA-mediated glutamatergic EPSCs was blocked by the α2-AR selective antagonist yohimbine (YOH). Notably, CLON reduced the frequency but not the amplitude of miniature EPSCs. Furthermore, CLON decreased the first EPSC amplitude but increased the paired-pulse facilitation on the NAc shell neurons, and it did not affect postsynaptic AMPA/NMDA ratio, revealing a presynaptic mechanism of α2-AR-mediated inhibition on glutamatergic transmission. In addition, the modulation on glutamatergic transmission by α2-AR was independent of presynaptic NMDA receptor. These results suggest that noradrenergic afferent inputs may suppress glutamatergic synaptic transmission via presynaptic α2-AR in the NAc shell, and actively participate in rewarding and emotional processes via the NAc.
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Potenciales Postsinápticos Excitadores/efectos de los fármacos , Ácido Glutámico/farmacología , Neuronas/efectos de los fármacos , Receptores Adrenérgicos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Núcleo Accumbens/efectos de los fármacos , Técnicas de Placa-Clamp/métodos , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
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.
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Glucemia/metabolismo , Hidrocortisona/farmacología , Hiperglucemia/inducido químicamente , Prazosina/farmacología , Antagonistas Adrenérgicos/metabolismo , Animales , Ayuno , Glucosa/farmacología , Hiperglucemia/metabolismo , Lactatos/sangre , Masculino , Receptores Adrenérgicos/efectos de los fármacos , Receptores Adrenérgicos beta/efectos de los fármacosRESUMEN
Heterodimeric IL-27 (p28/EBV-induced gene 3) is an important member of the IL-6/IL-12 cytokine family. IL-27 is predominantly synthesized by mononuclear phagocytes and exerts immunoregulatory functional activities on lymphocytic and nonlymphocytic cells during infection, autoimmunity or neoplasms. There is a great body of evidence on the bidirectional interplay between the autonomic nervous system and immune responses during inflammatory disorders, but so far IL-27 has not been defined as a part of these multifaceted neuroendocrine networks. In this study, we describe the role of catecholamines (as mediators of the sympathetic nervous system) related to IL-27 production in primary mouse macrophages. Noradrenaline and adrenaline dose-dependently suppressed the release of IL-27p28 in LPS/TLR4-activated macrophages, which was independent of α1 adrenoceptors. Instead, ß2 adrenoceptor activation was responsible for mediating gene silencing of IL-27p28 and EBV-induced gene 3. The ß2 adrenoceptor agonists formoterol and salbutamol mediated suppression of IL-27p28 production, when triggered by zymosan/TLR2, LPS/TLR4, or R848/TLR7/8 activation, but selectively spared the polyinosinic-polycytidylic acid/TLR3 pathway. Mechanistically, ß2 adrenergic signaling reinforced an autocrine feedback loop of macrophage-derived IL-10 and this synergized with inhibition of the JNK pathway for limiting IL-27p28. The JNK inhibitors SP600125 and AEG3482 strongly decreased intracellular IL-27p28 in F4/80+CD11b+ macrophages. In endotoxic shock of C57BL/6J mice, pharmacologic activation of ß2 adrenoceptors improved the severity of shock, including hypothermia and decreased circulating IL-27p28. Conversely, IL-27p28 was 2.7-fold increased by removal of the catecholamine-producing adrenal glands prior to endotoxic shock. These data suggest a novel role of the sympathetic neuroendocrine system for the modulation of IL-27-dependent acute inflammation.
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Epinefrina/farmacología , Interleucinas/inmunología , Interleucinas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Norepinefrina/farmacología , Albuterol/farmacología , Animales , Antracenos/farmacología , Células Cultivadas , Fumarato de Formoterol/farmacología , Inflamación , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Interleucinas/sangre , Interleucinas/genética , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Poli I-C/metabolismo , Receptores Adrenérgicos/efectos de los fármacos , Choque Séptico , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Sistema Nervioso Simpático/inmunología , Sistema Nervioso Simpático/fisiología , Tiadiazoles/farmacología , Receptor Toll-Like 3/metabolismo , Zimosan/farmacologíaRESUMEN
RATIONALE: Noradrenergic system plays a critical role in the hypothalamic-pituitary-adrenal (HPA) axis regulation and the stress response. A dysregulated HPA axis may be indicative of an increased biological vulnerability for depression. In addition, a variety of studies have focused on specific alterations of α2-adrenoceptors as a mechanism involved in the pathogenesis of mood disorders and antidepressant response. OBJECTIVES: This study aimed to evaluate the effect of subchronic corticosterone administration on rat brain α2-adrenoceptor functionality by in vitro [35S]GTPγS binding stimulation assays and in vivo dual-probe microdialysis determination of extracellular noradrenaline concentrations. RESULTS: Implantation of a time release corticosterone pellet during 14 days induced sustained changes in endocrine function. However, there were no differences in α2-adrenoceptor agonist UK14304-induced stimulation of [35S]GTPγS binding in prefrontal cortex (PFC) between corticosterone-treated and control rats. In the same way, the in vivo evaluation of α2-adrenoceptor-mediated noradrenaline release responses to the α2-adrenoceptor agonist clonidine local administration into the locus coeruleus (LC), and the PFC did not show differences between the groups. CONCLUSIONS: The present results show that subchronic corticosterone administration does not induce changes on functionality of α2-adrenoceptors neither in the LC nor in noradrenergic cortical terminal areas.