RESUMEN
INTRODUCTION: Adrenoceptor and endothelin (ET) receptor-mediated vasoconstriction as well as endothelium-dependent vasodilation of human saphenous veins were compared before and after 20 h of cold storage. METHODS: Contractile responses to potassium chloride (KCl), norepinephrine (NE), and ET-1 as well as vasodilator responses to acetylcholine (ACh) were evaluated. RESULTS: Storage in HEPES-supplemented Dulbecco's modified Eagle's medium (HDMEM) diminished KCl induced contractile forces to 71% (p = 0.002) and NE induced contractions to 80% (p = 0.037), in contrast to HEPES-supplemented Krebs-Henseleit solution (HKH) and TiProtec solution. KCl-normalized NE contractions were not affected by storage. NE EC50 values were slightly lower (7.1E-8 vs. 7.5E-8, p = 0.019) after storage in HKH, with no changes after storage in the other solutions. Endothelium-dependent responses to ACh were not affected by storage. ET-1 induced contractions were attenuated after storage in HDMEM (77%, p = 0.002), HKH (75%, p = 0.020), and TiProtec (73%, p = 0.010) with no changes in normalized constrictions. ET-1 EC50 values were not affected by storage. CONCLUSION: Loss of contractility after storage in HDMEM may reflect the lower content of dextrose. There was no specific attenuation of adrenoceptor, ET-receptor, or ACh receptor mediated signal transduction after storage in any of the media. HKH or TiProtec are equally suitable cold storage solutions for ex vivo measurements.
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Endotelio Vascular , Receptores Adrenérgicos , Receptores de Endotelina , Conservación de Tejido , Vasoconstricción , Vasodilatación , Humanos , Acetilcolina/farmacología , Endotelina-1/farmacología , Endotelinas/farmacología , Endotelio , Endotelio Vascular/fisiopatología , Glucosa/farmacología , HEPES/farmacología , Norepinefrina/farmacología , Cloruro de Potasio/farmacología , Receptores Adrenérgicos/fisiología , Receptores de Endotelina/fisiología , Vasoconstricción/fisiología , Vasodilatación/fisiología , Vasodilatadores/farmacología , Contracción Muscular/fisiología , Conservación de Tejido/métodos , Frío/efectos adversos , Receptores Colinérgicos/fisiologíaRESUMEN
The ability to make predictions based on stored information is a general coding strategy. A prediction error (PE) is a mismatch between expected and current events. Our memories, like ourselves, are subject to change. Thus, an acquired memory can become active and update its content or strength by a labilization-reconsolidation process. Within the reconsolidation framework, PE drives the updating of consolidated memories. In the past our lab has made key progresses showing that a blockade in the central cholinergic system during reconsolidation can cause memory impairment, while reinforcement of cholinergic activity enhances it. In the present work we determined that PE is a necessary condition for memory to reconsolidate in an inhibitory avoidance task using both male and female mice. Depending on the intensity of the unconditioned stimulus (US) used during training, a negative (higher US intensity) or positive (lower US intensity/no US) PE on a retrieval session modified the behavioral response on a subsequent testing session. Furthermore, we demonstrated that the cholinergic system modulates memory reconsolidation only when PE is detected. In this scenario administration of oxotremorine, scopolamine or nicotine after memory reactivation either enhanced or impaired memory reconsolidation in a sex-specific manner.
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Neuronas Colinérgicas/fisiología , Consolidación de la Memoria , Animales , Reacción de Prevención/fisiología , Neuronas Colinérgicas/efectos de los fármacos , Condicionamiento Clásico/fisiología , Femenino , Masculino , Consolidación de la Memoria/efectos de los fármacos , Consolidación de la Memoria/fisiología , Ratones , Nicotina/farmacología , Oxotremorina/análogos & derivados , Oxotremorina/farmacología , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiología , Escopolamina/farmacologíaRESUMEN
BACKGROUND: The aim of the current study was to investigate the effects of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) on bladder function via prostate-to-bladder cross-sensitization in a rat model of lipopolysaccharide (LPS)-induced prostate inflammation. METHODS: Male rats were intraprostatically injected with LPS or saline, serving as control. Micturition parameters were examined in a metabolic cage 10 or 14 days later. Subsequently, to evaluate bladder function, cystometry was performed. Micturition cycles were induced by saline infusion and cholinergic and purinergic contractile responses were measured by intravenous injection with methacholine and ATP, respectively. Thereafter, the prostate and bladder were excised and assessed histopathologically for possible inflammatory changes. RESULTS: Metabolic cage experiments showed increased urinary frequency in rats with LPS-induced CP/CPPS. Cystometry showed a significant increase in the number of non-voiding contractions, longer voiding time and lower compliance in CP/CPPS animals compared to controls. Induction of CP/CPPS led to significantly reduced cholinergic and purinergic bladder contractile responses. Histopathological analysis demonstrated prostatic inflammation in CP/CPPS animals. There were no significant differences between the groups regarding the extent or the grade of bladder inflammation. Prostate weight was not significantly different between the groups. CONCLUSIONS: The present study shows that prostate-to-bladder cross-sensitization can be triggered by an infectious focus in the prostate, giving rise to bladder overactivity and alterations in both afferent and efferent signalling. Future studies are required to fully understand the underlying mechanisms.
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Dolor Crónico/fisiopatología , Modelos Animales de Enfermedad , Dolor Pélvico/fisiopatología , Próstata/fisiopatología , Vejiga Urinaria/fisiopatología , Animales , Cistitis/fisiopatología , Lipopolisacáridos , Masculino , Próstata/inervación , Próstata/patología , Prostatitis/fisiopatología , Ratas Sprague-Dawley , Receptores Colinérgicos/fisiología , Receptores Muscarínicos/fisiología , Síndrome , Vejiga Urinaria/inervación , Vejiga Urinaria/patología , Vejiga Urinaria Hiperactiva/etiología , MicciónRESUMEN
Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation. Here, we find that spatially constrained cholinergic stimulation can generate theta-modulated gamma rhythms. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we simulate the effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K+ current. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns emerge in ACh modulated network regions. Stable gamma-modulated firing arises within regions with high ACh signaling, while theta or mixed theta-gamma activity occurs at the peripheries of these regions. High gamma activity also alternates between different high-ACh regions, at theta frequency. Our results are the first to indicate a causal role for spatially heterogenous ACh signaling in the emergence of localized theta-gamma rhythmicity. Our findings also provide novel insights into mechanisms by which ACh signaling supports the brain region-specific attentional processing of sensory information.
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Neuronas Colinérgicas/fisiología , Ritmo Gamma/fisiología , Modelos Neurológicos , Ritmo Teta/fisiología , Acetilcolina/farmacología , Acetilcolina/fisiología , Animales , Colinérgicos/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Biología Computacional , Simulación por Computador , Ritmo Gamma/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Redes Neurales de la Computación , Prosencéfalo/efectos de los fármacos , Prosencéfalo/fisiología , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Ritmo Teta/efectos de los fármacosRESUMEN
Understanding the principles underlying age-related changes in motion perception is paramount for improving the quality of life and health of older adults. However, the mechanisms underlying age-related alterations in this aspect of vision, which is essential for survival in a dynamic world, still remain unclear. Using optomotor responses to drifting gratings, we investigated age-related changes in motion detection of adult zebrafish (wild-type/AB-strain and achesb55/+ mutants with decreased levels of acetylcholinesterase). Our results pointed out negative optomotor responses that significantly depend on the spatial frequency and contrast level of stimulation, providing supporting evidence for the visual motion-driven aspect of this behavior mainly exhibited by adult zebrafish. Although there were no significant main effects of age and genotype, we found a significant three-way interaction between contrast level, age, and genotype. In the contrast domain, the changes in optomotor responses and thus in the detection of motion direction were age- and genotype-specific. Accordingly, these behavioral findings suggest a strong but complicated relationship between visual motion characteristics and the cholinergic system during neural aging.
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Acetilcolina/fisiología , Envejecimiento/fisiología , Conducta Animal/fisiología , Genotipo , Percepción de Movimiento/fisiología , Actividad Motora/fisiología , Visión Ocular/fisiología , Percepción Visual/fisiología , Pez Cebra/genética , Pez Cebra/fisiología , Animales , Femenino , Masculino , Estimulación Luminosa , Receptores Colinérgicos/fisiologíaRESUMEN
Neurons within the spinal cord are sensitive to environmental relations and can bring about a behavioral modification without input from the brain. For example, rats that have undergone a thoracic (T2) transection can learn to maintain a hind leg in a flexed position to minimize exposure to a noxious electrical stimulation (shock). Inactivating neurons within the spinal cord with lidocaine, or cutting communication between the spinal cord and the periphery (sciatic transection), eliminates the capacity to learn, which implies that it depends on spinal neurons. Here we show that these manipulations have no effect on the maintenance of the learned response, which implicates a peripheral process. EMG showed that learning augments the muscular response evoked by motoneuron output and that this effect survives a sciatic transection. Quantitative fluorescent imaging revealed that training brings about an increase in the area and intensity of ACh receptor labeling at the neuromuscular junction (NMJ). It is hypothesized that efferent motoneuron output, in conjunction with electrical stimulation of the tibialis anterior muscle, strengthens the connection at the NMJ in a Hebbian manner. Supporting this, paired stimulation of the efferent nerve and tibialis anterior generated an increase in flexion duration and augmented the evoked electrical response without input from the spinal cord. Evidence is presented that glutamatergic signaling contributes to plasticity at the NMJ. Labeling for vesicular glutamate transporter is evident at the motor endplate. Intramuscular application of an NMDAR antagonist blocked the acquisition/maintenance of the learned response and the strengthening of the evoked electrical response.SIGNIFICANCE STATEMENT The neuromuscular junction (NMJ) is designed to faithfully elicit a muscular contraction in response to neural input. From this perspective, encoding environmental relations (learning) and the maintenance of a behavioral modification over time (memory) are assumed to reflect only modifications upstream from the NMJ, within the CNS. The current results challenge this view. Rats were trained to maintain a hind leg in a flexed position to avoid noxious stimulation. As expected, treatments that inhibit activity within the CNS, or disrupt peripheral communication, prevented learning. These manipulations did not affect the maintenance of the acquired response. The results imply that a peripheral modification at the NMJ contributes to the maintenance of the learned response.
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Conducta Animal/fisiología , Sistema Nervioso Central/fisiología , Unión Neuromuscular/fisiología , Animales , Condicionamiento Clásico , Condicionamiento Operante/fisiología , Vías Eferentes/fisiología , Electromiografía , Miembro Posterior/inervación , Miembro Posterior/fisiología , Aprendizaje/fisiología , Masculino , Placa Motora/fisiología , Neuronas Motoras/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Colinérgicos/fisiología , Nervio Ciático/fisiología , Médula Espinal/fisiologíaRESUMEN
Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus and an increasingly common cause of visual impairment. Blood vessel damage occurs as the disease progresses, leading to ischemia, neovascularization, blood-retina barrier (BRB) failure and eventual blindness. Although detection and treatment strategies have improved considerably over the past years, there is room for a better understanding of the pathophysiology of the diabetic retina. Indeed, it has been increasingly realized that DR is in fact a disease of the retina's neurovascular unit (NVU), the multi-cellular framework underlying functional hyperemia, coupling neuronal computations to blood flow. The accumulating evidence reveals that both neurochemical (synapses) and electrical (gap junctions) means of communications between retinal cells are affected at the onset of hyperglycemia, warranting a global assessment of cellular interactions and their role in DR. This is further supported by the recent data showing down-regulation of connexin 43 gap junctions along the vascular relay from capillary to feeding arteriole as one of the earliest indicators of experimental DR, with rippling consequences to the anatomical and physiological integrity of the retina. Here, recent advancements in our knowledge of mechanisms controlling the retinal neurovascular unit will be assessed, along with their implications for future treatment and diagnosis of DR.
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Retinopatía Diabética/fisiopatología , Pericitos/fisiología , Neuronas Retinianas/fisiología , Animales , Barrera Hematorretinal , Retinopatía Diabética/metabolismo , Humanos , Receptores Colinérgicos/fisiología , Receptores Dopaminérgicos/fisiología , Receptores de Neurotransmisores/fisiología , Flujo Sanguíneo Regional/fisiología , Vasos Retinianos/fisiopatologíaRESUMEN
The Dystrophin Glycoprotein Complex (DGC) is a large multi-protein complex that links cytoskeleton actin to the extracellular matrix. This complex is critical in maintaining the structural integrity of muscle fibers and the stability of the neuromuscular synapse. The DGC consists of dystrophin and its utrophin homolog, as well as dystroglycans, sarcoglycans, sarcospan, syntrophins, and dystrobrevins. Deficiencies in DGC proteins result in several forms of muscular dystrophy with varying symptoms and degrees of severity in addition to structurally abnormal neuromuscular junctions (NMJs). This mini-review highlights current knowledge regarding the role of the DGC on the molecular dynamics of acetylcholine receptors (AChRs) as it relates to the formation and maintenance of the mammalian NMJ.
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Distrofina/fisiología , Glicoproteínas/farmacología , Unión Neuromuscular/fisiología , Receptores Colinérgicos/fisiología , Animales , HumanosRESUMEN
Sleep slow waves are known to participate in memory consolidation, yet slow waves occurring under anesthesia present no positive effects on memory. Here, we shed light onto this paradox, based on a combination of extracellular recordings in vivo, in vitro, and computational models. We find two types of slow waves, based on analyzing the temporal patterns of successive slow-wave events. The first type is consistently observed in natural slow-wave sleep, while the second is shown to be ubiquitous under anesthesia. Network models of spiking neurons predict that the two slow wave types emerge due to a different gain on inhibitory versus excitatory cells and that different levels of spike-frequency adaptation in excitatory cells can account for dynamical distinctions between the two types. This prediction was tested in vitro by varying adaptation strength using an agonist of acetylcholine receptors, which demonstrated a neuromodulatory switch between the two types of slow waves. Finally, we show that the first type of slow-wave dynamics is more sensitive to external stimuli, which can explain how slow waves in sleep and anesthesia differentially affect memory consolidation, as well as provide a link between slow-wave dynamics and memory diseases.
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Corteza Cerebral/fisiología , Neuronas/fisiología , Receptores Colinérgicos/fisiología , Sueño de Onda Lenta/fisiología , Anestesia General , Anestésicos Disociativos/farmacología , Anestésicos Intravenosos/farmacología , Animales , Ondas Encefálicas/efectos de los fármacos , Ondas Encefálicas/fisiología , Gatos , Corteza Cerebral/efectos de los fármacos , Agonistas Colinérgicos/farmacología , Simulación por Computador , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/fisiología , Humanos , Técnicas In Vitro , Ketamina/farmacología , Macaca , Consolidación de la Memoria , Ratones , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiología , Inhibición Neural , Neuronas/efectos de los fármacos , Lóbulo Parietal/efectos de los fármacos , Lóbulo Parietal/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Corteza Visual Primaria/efectos de los fármacos , Corteza Visual Primaria/fisiología , Ratas , Receptores Colinérgicos/efectos de los fármacos , Sueño de Onda Lenta/efectos de los fármacos , Sufentanilo/farmacología , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/fisiologíaRESUMEN
Blood flow patterns and heart rate have rarely been investigated in freely swimming turtles and their regulation during swimming is unknown. In this study, we investigated the blood flow patterns and heart rate in surfacing and during graded, submerged swimming activity in common snapping turtles. We further investigated the effects of beta-adrenergic and cholinergic receptor blockade on blood flow and heart rate during these activities. Our findings illustrate that surfacing is accompanied by an increase in heart rate that is primarily due to beta-adrenergic stimulation. During swimming, this mechanism also increases heart rate while vagal withdrawal facilitates a systemic to pulmonary (left to right) shunt. The results indicate there may be important taxonomic effects on the responses of cardiac function to activity in turtle species.
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Frecuencia Cardíaca , Hemodinámica , Receptores Adrenérgicos beta/fisiología , Receptores Colinérgicos/fisiología , Natación/fisiología , Tortugas/fisiología , Antagonistas Adrenérgicos beta/farmacología , Animales , Antagonistas Colinérgicos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Tortugas/sangreRESUMEN
Mutations in GNB5, encoding the G-protein ß5 subunit (Gß5), have recently been linked to a multisystem disorder that includes severe bradycardia. Here, we investigated the mechanism underlying bradycardia caused by the recessive p.S81L Gß5 variant. Using CRISPR/Cas9-based targeting, we generated an isogenic series of human induced pluripotent stem cell (hiPSC) lines that were either wild type, heterozygous or homozygous for the GNB5 p.S81L variant. These were differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed the acetylcholine-activated potassium channel [I(KACh); also known as IK,ACh]. Baseline electrophysiological properties of the lines did not differ. Upon application of carbachol (CCh), homozygous p.S81L hiPSC-CMs displayed an increased acetylcholine-activated potassium current (IK,ACh) density and a more pronounced decrease of spontaneous activity as compared to wild-type and heterozygous p.S81L hiPSC-CMs, explaining the bradycardia in homozygous carriers. Application of the specific I(KACh) blocker XEN-R0703 resulted in near-complete reversal of the phenotype. Our results provide mechanistic insights and proof of principle for potential therapy in patients carrying GNB5 mutations.This article has an associated First Person interview with the first author of the paper.
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Acetilcolina/farmacología , Bradicardia/genética , Subunidades beta de la Proteína de Unión al GTP/genética , Variación Genética , Canales de Potasio/efectos de los fármacos , Receptores Colinérgicos/fisiología , Animales , Bradicardia/terapia , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación , Técnicas de Placa-Clamp , Canales de Potasio/fisiología , Prueba de Estudio Conceptual , Pez CebraRESUMEN
Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.
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Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Acetilcolinesterasa/genética , Acetilcolinesterasa/fisiología , Corticoesteroides/uso terapéutico , Agrina/genética , Agrina/fisiología , Antiinflamatorios no Esteroideos/uso terapéutico , Autoanticuerpos/análisis , Autoanticuerpos/sangre , Biomarcadores/análisis , Biomarcadores/sangre , Blefaroptosis/etiología , Colágeno/genética , Colágeno/fisiología , Cortactina/genética , Cortactina/fisiología , Electromiografía/métodos , Humanos , Canal de Potasio Kv1.4/genética , Canal de Potasio Kv1.4/fisiología , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas Relacionadas con Receptor de LDL/fisiología , Proteínas Musculares/genética , Proteínas Musculares/fisiología , Miastenia Gravis/fisiopatología , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores Colinérgicos/genética , Receptores Colinérgicos/fisiología , Receptores Nicotínicos/genética , Factores de Riesgo , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/fisiologíaRESUMEN
AIMS: Eslicarbazepine acetate (ESL) is a novel dibenzazepine antiepileptic, that has demonstrated efficacy against trigeminal pain, both in preclinical and clinical studies. However, ESL's mechanism of antinociceptive action remains uncertain. Here, we aimed to examine the contribution of adrenergic/cholinergic/opioid receptors to the antinociceptive effects of ESL in a trigeminal pain model, as these neurotransmitter systems are known to have an important role in the modulation of trigeminal nociception. MAIN METHODS: ESL's effects in the orofacial formalin test were examined following peroral and local peripheral administration (subcutaneous, into the perinasal region). The involvement of adrenergic/cholinergic/opioid receptors was evaluated by intraperitoneally pretreating mice with an appropriate antagonist immediately after peroral application of ESL. We used antagonists of α1adrenergic (prazosin), α2adrenergic (yohimbine), ßadrenergic (non-selective, propranolol and ß1-selective, metoprolol), muscarinic (atropine), nicotinic (mecamylamine) and opioid receptors (naloxone). Additionally, the role of peripheral α2adrenergic, ß1adrenergic, muscarinic and opioid receptors was evaluated by co-injecting ESL with an antagonist into the perinasal area. KEY FINDINGS: ESL dose-dependently reduced formalin-induced nociceptive behavior after systemic and local peripheral application. Systemic administration of yohimbine, propranolol, metoprolol, atropine and naloxone inhibited ESL's antinociceptive effects in a dose-related manner. Prazosin and mecamylamine did not produce inhibitory effects. Local application of yohimbine, atropine and naloxone into the perinasal area also produced a dose-related inhibition of ESL's efficacy, whereas metoprolol failed to inhibit the local antinociceptive effects of ESL. SIGNIFICANCE: This study suggests that ESL's efficacy against trigeminal nociception is mediated by peripheral (and possibly central) α2adrenergic, muscarinic and opioid receptors, as well as central ß1adrenergic receptors.
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Analgésicos/farmacología , Dibenzazepinas/farmacología , Dolor/tratamiento farmacológico , Antagonistas Adrenérgicos/farmacología , Animales , Atropina/farmacología , Antagonistas Colinérgicos/farmacología , Formaldehído/toxicidad , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Receptores Adrenérgicos/fisiología , Receptores Colinérgicos/fisiología , Receptores Opioides/fisiología , Neuralgia del Trigémino/tratamiento farmacológico , Yohimbina/farmacologíaRESUMEN
CONTEXT: Quercetin (QCT) has been known as a potential therapeutic strategy for gastrointestinal diseases because it contributes to the stabilization of mast cells, the prevention of histamine release and modulation of CaCC chloride channel. OBJECTIVE: We investigated the laxative effect and action mechanism of QCT in Lop-induced constipation model. MATERIALS AND METHODS: Constipation of SD rats was induced by subcutaneous injection of loperamide (Lop) (4 mg/kg weight) in 0.5% Tween 20 twice a day for three days. After 24 h, the constipation group was further treated with 1× PBS (Lop + Vehicle treated group), 10 mg/kg of QCT (Lop + LQCT treated group), 20 mg/kg of QCT (Lop + MQCT treated group) or 40 mg/kg QCT (Lop + HQCT treated group) at once. At 24 h after QCT treatment, the constipation phenotypes were measured and the transverse colon was collected from SD rats. RESULTS: The gastrointestinal motility, the number of stools and histological structures were significantly recovered in Lop + QCT treated group compared with the Lop + Vehicle treated group. Also, above activity of epithelial cells and smooth muscle cells were regulated by the mRNA expression of the muscarinic acetylcholine receptors M2 and M3 (mAChR M2 and M3) and some mediators of their downstream signalling pathway. Finally, laxative effects of QCT on mAChR signalling pathway were significantly inhibited by the treatment of mAChR antagonist in primary smooth muscle of rat intestine cells (pRISMCs). CONCLUSIONS: This study provides the first strong evidence that QCT can be considered an important candidate for improving chronic constipation induced by Lop treatment in animal models.
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Estreñimiento/tratamiento farmacológico , Motilidad Gastrointestinal/efectos de los fármacos , Loperamida/toxicidad , Mucinas/metabolismo , Quercetina/uso terapéutico , Receptores Colinérgicos/fisiología , Animales , Antidiarreicos/toxicidad , Células Cultivadas , Antagonistas Colinérgicos/farmacología , Estreñimiento/inducido químicamente , Estreñimiento/metabolismo , Motilidad Gastrointestinal/fisiología , Laxativos/uso terapéutico , Quercetina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The mushroom Amanita muscaria (fly agaric) is widely distributed throughout continental Europe and the UK. Its common name suggests that it had been used to kill flies, until superseded by arsenic. The bioactive compounds occurring in the mushroom remained a mystery for long periods of time, but eventually four hallucinogens were isolated from the fungus: muscarine, muscimol, muscazone and ibotenic acid. The shamans of Eastern Siberia used the mushroom as an inebriant and a hallucinogen. In 1912, Henry Dale suggested that muscarine (or a closely related substance) was the transmitter at the parasympathetic nerve endings, where it would produce lacrimation, salivation, sweating, bronchoconstriction and increased intestinal motility. He and Otto Loewi eventually isolated the transmitter and showed that it was not muscarine but acetylcholine. The receptor is now known variously as cholinergic or muscarinic. From this basic knowledge, drugs such as pilocarpine (cholinergic) and ipratropium (anticholinergic) have been shown to be of value in glaucoma and diseases of the lungs, respectively.
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Acetilcolina/historia , Amanita/química , Muscarina/historia , Acetilcolina/fisiología , Asma/tratamiento farmacológico , Asma/historia , Antagonistas Colinérgicos/historia , Antagonistas Colinérgicos/uso terapéutico , Historia del Siglo XVI , Historia del Siglo XVII , Historia del Siglo XIX , Historia del Siglo XX , Historia Antigua , Muscarina/aislamiento & purificación , Pilocarpina/historia , Pilocarpina/aislamiento & purificación , Pilocarpina/uso terapéutico , Pilocarpus/química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/historia , Receptores Colinérgicos/historia , Receptores Colinérgicos/fisiología , Chamanismo/historiaRESUMEN
Inflammatory bowel disease negatively affects the quality of life of millions of patients around the world. Although the precise etiology of the disease remains elusive, aberrant immune system activation is an underlying cause. As such, therapies that selectively inhibit immune cell activation without broad immunosuppression are desired. Inhibition of immune cell activation preventing pro-inflammatory cytokine production through neural stimulation has emerged as one such treatment. These therapeutics are based on the discovery of the cholinergic anti-inflammatory pathway, a reflex arc that induces efferent vagal nerve signaling to reduce immune cell activation and consequently mortality during septic shock. Despite the success of preclinical and clinical trials, the neural circuitry and mechanisms of action of these immune-regulatory circuits are controversial. At the heart of this controversy is the protective effect of vagal nerve stimulation despite an apparent lack of neuroanatomical connections between the vagus and target organs. Additional studies have further emphasized the importance of sympathetic innervation of these organs, and that alternative neural circuits could be involved in neural regulation of the immune system. Such controversies also extend to the regulation of intestinal inflammation, with the importance of efferent vagus nerve signals in question. Experiments that better characterize these pathways have now been performed by Willemze et al. in this issue of Neurogastroenterology & Motility. These continued efforts will be critical to the development of better neurostimulator based therapeutics for inflammatory bowel disease.
Asunto(s)
Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/terapia , Receptores Colinérgicos/fisiología , Animales , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Transducción de Señal , Estimulación del Nervio VagoRESUMEN
Whereas molecular mechanisms of atrial fibrillation (AF) have been widely investigated, there is limited information regarding interrelation between chronic volume overload and parasympathetic nervous system in the pathophysiology of AF. In this study, we investigated the influence of abdominal aorto-venocaval shunt (AVS)-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria. Interstitial fibrosis, cardiomyocyte hypertrophy and atrial enlargement, known as structural arrhythmogenic substrates for AF, took place after one month of AVS operation. Carbachol at 0.1 and 1 µM shortened the effective refractory period, acting as functional arrhythmogenic substrates, but increased the conduction velocity both in the atria of the sham-operated and AVS rats. The extents of the electrophysiological responses to carbachol in the atria of the AVS rat were greater than those in the sham-operated ones. Also, the higher inducibility and longer duration of carbachol-mediated AF were detected in the AVS atria than those in the sham-operated ones. These results showed that chronic volume overload-induced atrial remodeling promoted electrophysiological responses to cholinergic receptor stimulation in the isolated atria of rats, suggesting possible synergistic actions between structural arrhythmogenic substrate in the remodeled atria and functional arrhythmogenic substrates modulated by parasympathetic nerve activity.
Asunto(s)
Fibrilación Atrial/etiología , Remodelación Atrial/fisiología , Carbacol/farmacología , Fenómenos Electrofisiológicos/fisiología , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiología , Animales , Técnicas In Vitro , Masculino , Sistema Nervioso Parasimpático/fisiología , Ratas WistarRESUMEN
A number of studies in the past 20 years have shown that perturbation of activity of the nervous system leads to compensatory changes in synaptic strength that serve to return network activity to its original level. This response has been termed homeostatic synaptic plasticity. Despite the intense interest in homeostatic synaptic plasticity, little attention has been paid to its role in the prototypic synaptic disease, myasthenia gravis. In this review, we discuss mechanisms that have been shown to mediate homeostatic synaptic plasticity at the mammalian neuromuscular junction. A subset of these mechanisms have been shown to occur in myasthenia gravis. The homeostatic changes occurring in myasthenia gravis appear to involve the presynaptic nerve terminal and may even involve changes in the excitability of motor neurons within the spinal cord. The finding of presynaptic homeostatic synaptic plasticity in myasthenia gravis leads us to propose that changes in the motor unit in myasthenia gravis may be more widespread than previously appreciated.
Asunto(s)
Miastenia Gravis/fisiopatología , Unión Neuromuscular/fisiopatología , Plasticidad Neuronal/fisiología , Acetilcolina/fisiología , Potenciales de Acción/fisiología , Animales , Homeostasis/fisiología , Humanos , Ratones , Modelos Neurológicos , Receptores Colinérgicos/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
The neuromuscular junction (NMJ) forms the synaptic connection between a motor neuron and a skeletal muscle fiber. In order to achieve a sustained muscle contraction, this synapse has to reliably transmit motor neuronal action potentials onto the muscle fiber. To guarantee successful transmission even during intense activation of the NMJ, a safety factor of neuromuscular transmission exists. In the neuromuscular disorder myasthenia gravis (MG), autoantibodies are directed against acetylcholine receptors or, in the rarer variants, against other postsynaptic NMJ proteins. This causes loss of functional acetylcholine receptors, which compromises the safety factor of neuromuscular transmission, leading to the typical fatigable muscle weakness of MG. With intracellular microelectrode measurement of (miniature) endplate potentials at NMJs in ex vivo nerve-muscle preparations from MG animal models, these functional synaptic defects have been determined in much detail. Here, we describe the electrophysiological events at the normal NMJ and the pathoelectrophysiology at NMJs of animal models for MG.