RESUMEN
This study investigated acute responses and post 24-h recovery to four running sessions performed at different intensity zones by supine heart rate variability, countermovement jump, and a submaximal running test. A total of 24 recreationally endurance-trained male subjects performed 90 min low-intensity (LIT), 30 min moderate-intensity (MOD), 6×3 min high-intensity interval (HIIT) and 10×30 s supramaximal-intensity interval (SMIT) exercises on a treadmill. Heart rate variability decreased acutely after all sessions, and the decrease was greater after MOD compared to LIT and SMIT (p<0.001; p<0.01) and HIIT compared to LIT (p<0.01). Countermovement jump decreased only after LIT (p<0.01) and SMIT (p<0.001), and the relative changes were different compared to MOD (p<0.01) and HIIT (p<0.001). Countermovement jump remained decreased at 24 h after SMIT (p<0.05). Heart rate during the submaximal running test rebounded below the baseline 24 h after all sessions (p<0.05), while the rating of perceived exertion during the running test remained elevated after HIIT (p<0.05) and SMIT (p<0.01). The current results highlight differences in the physiological demands of the running sessions, and distinct recovery patterns of the measured aspects of performance. Based on these results, assessments of performance and recovery from multiple perspectives may provide valuable information for endurance athletes, and help to improve the quality of training monitoring.
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Frecuencia Cardíaca/fisiología , Movimiento/fisiología , Carrera/fisiología , Adulto , Atletas , Sistema Nervioso Autónomo/fisiología , Prueba de Esfuerzo/métodos , Humanos , Ácido Láctico/sangre , Masculino , Fibras Parasimpáticas Posganglionares/fisiología , Resistencia Física/fisiología , Esfuerzo Físico/fisiología , Distribución Aleatoria , Recuperación de la Función , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: It is still unknown whether newborn infant parasympathetic evaluation (NIPE), based on heart rate variability (HRV) as a reflection of parasympathetic nerve tone, can predict the hemodynamic response to a nociception stimulus in children less than 2 years old. METHODS: Fifty-five children undergoing elective surgery were analyzed in this prospective observational study. Noninvasive mean blood pressure (MBP), heart rate (HR) and NIPE values were recorded just before and 1 min after general anesthesia with endotracheal intubation as well as skin incision. The predictive performance of NIPE was evaluated by receiver-operating characteristic (ROC) curve analysis. A significant hemodynamic response was defined by a > 20% increase in HR and/or MBP. RESULTS: Endotracheal intubation and skin incision caused HR increases of 22.2% (95% confidence interval [CI] 17.5-26.9%) and 3.8% (2.1-5.5%), MBP increases of 18.2% (12.0-24.4%) and 10.6% (7.7-13.4%), and conversely, NIPE decreases of 9.9% (5.3-14.4%) and 5.6% (2.1-9.1%), respectively (all P < 0.01 vs. pre-event value). Positive hemodynamic responses were observed in 32 patients (62.7%) during tracheal intubation and 13 patients (23.6%) during skin incision. The area under the ROC curve values for the ability of NIPE to predict positive hemodynamic responses at endotracheal intubation and skin incision were 0.65 (0.50-0.78) and 0.58 (0.44-0.71), respectively. CONCLUSIONS: NIPE reflected nociceptive events as well as anesthestic induction in children less than 2 years undergoing general anaesthetia. Nevertheless, NIPE may not serve as a sensitive and specific predictor to changes in hemodynamics. TRIAL REGISTRATION: This study was registered on May 3, 2018 in the Chinese Clinical Trail Registry; the registration number is ( ChiCTR1800015973 ).
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Anestesia General/métodos , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Hemodinámica/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Anestesia General/efectos adversos , Presión Sanguínea/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Humanos , Lactante , Masculino , Fibras Parasimpáticas Posganglionares/efectos de los fármacos , Proyectos Piloto , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
Little is known about the neuronal voltage-gated sodium channels (NaVs) that control neurotransmission in the parasympathetic nervous system. We evaluated the expression of the α subunits of each of the nine NaVs in human, guinea pig, and mouse airway parasympathetic ganglia. We combined this information with a pharmacological analysis of selective NaV blockers on parasympathetic contractions of isolated airway smooth muscle. As would be expected from previous studies, tetrodotoxin potently blocked the parasympathetic responses in the airways of each species. Gene expression analysis showed that that NaV 1.7 was virtually the only tetrodotoxin-sensitive NaV1 gene expressed in guinea pig and human airway parasympathetic ganglia, where mouse ganglia expressed NaV1.1, 1.3, and 1.7. Using selective pharmacological blockers supported the gene expression results, showing that blocking NaV1.7 alone can abolish the responses in guinea pig and human bronchi, but not in mouse airways. To block the responses in mouse airways requires that NaV1.7 along with NaV1.1 and/or NaV1.3 is blocked. These results may suggest novel indications for NaV1.7-blocking drugs, in which there is an overactive parasympathetic drive, such as in asthma. The data also raise the potential concern of antiparasympathetic side effects for systemic NaV1.7 blockers.
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Ganglios Parasimpáticos/fisiología , Pulmón/fisiología , Canal de Sodio Activado por Voltaje NAV1.7/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Transmisión Sináptica/fisiología , Animales , Relación Dosis-Respuesta a Droga , Ganglios Parasimpáticos/efectos de los fármacos , Cobayas , Células HEK293 , Humanos , Pulmón/efectos de los fármacos , Masculino , Ratones , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Técnicas de Cultivo de Órganos , Fibras Parasimpáticas Posganglionares/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Transmisión Sináptica/efectos de los fármacosRESUMEN
KEY POINTS: The dorsal motor nucleus of the vagus (DMV) in the brainstem consists primarily of vagal preganglionic neurons that innervate postganglionic neurons of the upper gastrointestinal tract. The activity of the vagal preganglionic neurons is predominantly regulated by GABAergic transmission in the DMV. The present findings indicate that the overwhelming GABAergic drive present at the DMV is primarily from somatostatin positive GABA (Sst-GABA) DMV neurons. Activation of both melanocortin and µ-opioid receptors at the DMV inhibits Sst-GABA DMV neurons. Sst-GABA DMV neurons may serve as integrative targets for modulating vagal output activity to the stomach. ABSTRACT: We have previously shown that local GABA signalling in the brainstem is an important determinant of vagally-mediated gastric activity. However, the neural identity of this GABA source is currently unknown. To determine this, we focused on the somatostatin positive GABA (Sst-GABA) interneuron in the dorsal motor nucleus of the vagus (DMV), a nucleus that is intimately involved in regulating gastric activity. Also of particular interest was the effect of melanocortin and µ-opioid agonists on neural activity of Sst-GABA DMV neurons because their in vivo administration in the DMV mimics GABA blockade in the nucleus. Experiments were conducted in brain slice preparation of transgenic adult Sst-IRES-Cre mice expressing tdTomato fluorescence, channelrhodopsin-2, archaerhodopsin or GCaMP3. Electrophysiological recordings were obtained from Sst-GABA DMV neurons or DiI labelled gastric-antrum projecting DMV neurons. Our results show that optogenetic stimulation of Sst-GABA neurons results in a robust inhibition of action potentials of labelled premotor DMV neurons to the gastric-antrum through an increase in inhibitory post-synaptic currents. The activity of the Sst-GABA neurons in the DMV is inhibited by both melanocortin and µ-opioid agonists. These agonists counteract the pronounced inhibitory effect of Sst-GABA neurons on vagal pre-motor neurons in the DMV that control gastric motility. These observations demonstrate that Sst-GABA neurons in the brainstem are crucial for regulating the activity of gastric output neurons in the DMV. Additionally, they suggest that these neurons serve as targets for converging CNS signals to regulate parasympathetic gastric function.
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Neuronas GABAérgicas/fisiología , Optogenética/métodos , Fibras Parasimpáticas Posganglionares/fisiología , Antro Pilórico/inervación , Antro Pilórico/fisiología , Somatostatina/fisiología , Animales , Tronco Encefálico/efectos de los fármacos , Tronco Encefálico/fisiología , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Femenino , Neuronas GABAérgicas/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Motilidad Gastrointestinal/fisiología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Ratones , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Fibras Parasimpáticas Posganglionares/efectos de los fármacos , Antro Pilórico/efectos de los fármacos , Estómago/efectos de los fármacos , Estómago/inervación , Estómago/fisiología , alfa-MSH/farmacologíaRESUMEN
Large-conductance Ca2(+)-activated K+ channels (BK) regulate action potential (AP) properties and excitability in many central neurons. However, the properties and functional roles of BK channels in parasympathetic cardiac motoneurons (PCMNs) in the nucleus ambiguus (NA) have not yet been well characterized. In this study, the tracer X-rhodamine-5 (and 6)-isothiocyanate (XRITC) was injected into the pericardial sac to retrogradely label PCMNs in FVB mice at postnatal 7-9 days. Two days later, XRITC-labeled PCMNs in brain stem slices were identified. Using excised patch single-channel recordings, we identified voltage-gated and Ca(2+)-dependent BK channels in PCMNs. The majority of BK channels exhibited persistent channel opening during voltage holding. These BK channels had a conductance of 237 pS and a 50% opening probability at +27.9 mV, the channel open time constant was 3.37 ms at +20 mV, and dwell time increased exponentially as the membrane potential depolarized. At the +20-mV holding potential, the [Ca2+]50 was 15.2 µM with a P0.5 of 0.4. Occasionally, some BK channels showed a transient channel opening and fast inactivation. Using whole cell voltage clamp, we found that BK channel mediated outward currents and afterhyperpolarization currents (IAHP). Using whole cell current clamp, we found that application of BK channel blocker iberiotoxin (IBTX) increased spike half-width and suppressed fast afterhyperpolarization (fAHP) amplitude following single APs. In addition, IBTX application increased spike half-width and reduced the spike frequency-dependent AP broadening in trains and spike frequency adaption (SFA). Furthermore, BK channel blockade decreased spike frequency. Collectively, these results demonstrate that PCMNs have BK channels that significantly regulate AP repolarization, fAHP, SFA, and spike frequency. We conclude that activation of BK channels underlies one of the mechanisms for facilitation of PCMN excitability.
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Potenciales de Acción/fisiología , Tronco Encefálico/citología , Canales de Potasio de Gran Conductancia Activados por el Calcio/fisiología , Neuronas Motoras/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Pericardio/fisiología , Animales , Animales Recién Nacidos , Tronco Encefálico/fisiología , Músculos Laríngeos/citología , Músculos Laríngeos/fisiología , Masculino , Ratones , Técnicas de Cultivo de Órganos , Faringe/citología , Faringe/inervación , Faringe/fisiologíaRESUMEN
OBJECTIVE: Presentation of a case of perioral Frey syndrome. DESIGN: Case report. SUBJECT: A 72-year-old woman with hyperhidrosis around the mouth and chin. RESULTS: This patient suffered from bilateral perioral gustatory sweating following a mandibular osteotomy; such a case has not previously been described. Possible pathophysiological hypotheses are discussed in relation to the anatomy and innervation of the salivary glands. CONCLUSION: Perioral gustatory sweating is a rare complication of osteotomy.
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Mandíbula/cirugía , Regeneración Nerviosa , Osteotomía/efectos adversos , Fibras Parasimpáticas Posganglionares/fisiología , Sudoración Gustativa/etiología , Traumatismos del Nervio Trigémino/etiología , Anciano , Toxinas Botulínicas Tipo A/administración & dosificación , Toxinas Botulínicas Tipo A/uso terapéutico , Femenino , Humanos , Inyecciones Intradérmicas , Neurotoxinas/administración & dosificación , Neurotoxinas/uso terapéuticoRESUMEN
In the orofacial area, noxious stimulation of the orofacial structure in the trigeminal region evokes parasympathetic reflex vasodilatation, which occurs via the trigeminal spinal nucleus (Vsp) and the inferior/superior salivatory nucleus (ISN/SSN). However, the neurotransmitter involved in the inhibitory synaptic inputs within these nuclei has never been described. This parasympathetic reflex vasodilatation is suppressed by GABAergic action of volatile anesthetics, such as isoflurane, sevoflurane, and halothane, suggesting that medullary GABAergic mechanism exerts its inhibitory effect on the parasympathetic reflex via an activation of GABA receptors. The aim of the present study was to determine the role of GABA(A) and GABA(B) receptors in the Vsp and the ISN in regulating the lingual nerve (LN)-evoked parasympathetic reflex vasodilatation in the lower lip. Under urethane anesthesia (1g/kg), change in lower lip blood flow elicited by electrical stimulation of the LN was recorded in cervically vago-sympathectomized rats. Microinjection of GABA (10 µM; 0.3 µl/site) into the Vsp or the ISN significantly and reversibly attenuated the LN-evoked parasympathetic reflex vasodilatation. Microinjection of the GABA(A) receptor-selective agonist muscimol (100 µM; 0.3 µl/site) or the GABA(B) receptor-selective agonist baclofen (100 µM; 0.3 µl/site) into the Vsp or the ISN significantly and irreversibly reduced this reflex vasodilatation, and these effects were attenuated by pretreatment with microinjection of each receptor-selective antagonists [GABA(A) receptor selective antagonist bicuculline methiodide (1mM; 0.3 µl/site) or GABA(B) receptor selective antagonist CGP-35348 (1mM; 0.3 µl/site)] into the Vsp or the ISN. Microinjection of these antagonists alone into the Vsp or the ISN had no significant effect on this reflex vasodilatation. In addition, microinjection (0.3 µl/site) of the mixture of muscimol (100 µM) and baclofen (100 µM) into the Vsp or the ISN also significantly reduced this reflex vasodilatation. These results suggest that medullary GABA signal transduction inhibits the parasympathetic reflex vasodilatation in the rat lower lip via GABA(A) and GABA(B) receptors in the Vsp and the ISN.
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Labio/fisiología , Bulbo Raquídeo/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Reflejo/fisiología , Vasodilatación/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Nervio Lingual/efectos de los fármacos , Nervio Lingual/fisiología , Labio/efectos de los fármacos , Labio/inervación , Masculino , Bulbo Raquídeo/efectos de los fármacos , Fibras Parasimpáticas Posganglionares/efectos de los fármacos , Ratas , Ratas Wistar , Reflejo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Vasodilatación/efectos de los fármacosRESUMEN
The purpose of this study is to test the role that parasympathetic postganglionic neurons could play on the adaptive electrophysiological changes produced by physical training on intrinsic myocardial automatism, conduction and refractoriness. Trained rabbits were submitted to a physical training protocol on treadmill during 6 weeks. The electrophysiological study was performed in an isolated heart preparation. The investigated myocardial properties were: (a) sinus automatism, (b) atrioventricular and ventriculoatrial conduction, (c) atrial, conduction system and ventricular refractoriness. The parameters to study the refractoriness were obtained by means of extrastimulus test at four different pacing cycle lengths (10% shorter than spontaneous sinus cycle length, 250, 200 and 150 ms) and (d) mean dominant frequency (DF) of the induced ventricular fibrillation (VF), using a spectral method. The electrophysiological protocol was performed before and during continuous atropine administration (1 µM), in order to block cholinergic receptors. Cholinergic receptor blockade did not modify either the increase in sinus cycle length, atrioventricular conduction and refractoriness (left ventricular and atrioventricular conduction system functional refractory periods) or the decrease of DF of VF. These findings reveal that the myocardial electrophysiological modifications produced by physical training are not mediated by intrinsic cardiac parasympathetic activity.
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Automatismo , Corazón/fisiología , Neuronas/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Sistema Nervioso Parasimpático/fisiología , Condicionamiento Físico Animal/fisiología , Periodo Refractario Electrofisiológico/fisiología , Animales , Función Atrial/fisiología , Bloqueo Atrioventricular , Vías Autónomas/fisiología , Antagonistas Colinérgicos/farmacología , Sistema de Conducción Cardíaco/fisiología , Masculino , Miocardio/enzimología , Conejos , Receptores Colinérgicos/metabolismo , Fibrilación Ventricular/fisiopatología , Función Ventricular/fisiologíaRESUMEN
PURPOSE: A striking characteristic of the human meibomian gland is its rich sensory, sympathetic, and parasympathetic innervation, yet the functional relevance of these nerve fibers remains unknown. Acting on the hypothesis that neurotransmitters are released in the vicinity of the gland, act on glandular receptors, and influence the production, secretion, and/or delivery of meibomian gland secretions to the ocular surface, the goal in this study was to begin to determine whether neurotransmitters influence the meibomian gland. METHODS: Immortalized human meibomian gland epithelial (SLHMG) cells were examined for the presence of vasoactive intestinal peptide (VIP) and muscarinic acetylcholine (mACh) receptor transcripts and proteins. Cells were also exposed to VIP, carbachol, forskolin, and/or 3-isobutyl-1-methylxanthine (IBMX) to determine whether these agents, alone or in combination, modulate the adenylyl cyclase pathway, the accumulation of intracellular free calcium ([Ca2+]i), or cell proliferation. RESULTS: Results demonstrate that SLHMG cells transcribe and translate VIP and mACh receptors; VIP, with either IBMX or forskolin, activates the adenylyl cyclase pathway, and the effect of VIP and forskolin together is synergistic; both VIP and carbachol increase intracellular [Ca2+] in SLHMG cells; and VIP with forskolin stimulates SLHMG cell proliferation. CONCLUSIONS: This study shows that parasympathetic neurotransmitters and their agonists influence the function of human meibomian gland epithelial cells. It remains to be determined whether this action alters the production, secretion, and/or delivery of meibum to the ocular surface.
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Células Epiteliales/metabolismo , Glándulas Tarsales/citología , Glándulas Tarsales/inervación , Fibras Parasimpáticas Posganglionares/fisiología , Receptores Muscarínicos/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , 1-Metil-3-Isobutilxantina/farmacología , Adenilil Ciclasas/metabolismo , Calcio/metabolismo , Calcio/farmacología , Carbacol/farmacología , División Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular Transformada , Agonistas Colinérgicos/farmacología , Colforsina/farmacología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Humanos , Inhibidores de Fosfodiesterasa/farmacología , Receptores Muscarínicos/genética , Péptido Intestinal Vasoactivo/genética , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
RATIONALE: Recently, we provided a technique of chronic high-frequency electric stimulation (HFES) of the right inferior ganglionated plexus for ventricular rate control during atrial fibrillation in dogs and humans. In these experiments, we observed a decrease of the intrinsic ventricular rate during the first 4 to 5 months when HFES was intermittently shut off. OBJECTIVE: We thus hypothesized that HFES might elicit trophic effects on cardiac neurons, which in turn increase baseline parasympathetic tone of the atrioventricular node. METHODS AND RESULTS: In mongrel dogs atrial fibrillation was induced by rapid atrial pacing. Endocardial HFES of the right inferior ganglionated plexus, which contains abundant fibers to the atrioventricular node, was performed for 2 years. Sham-operated nonstimulated dogs served as control. In chronic neurostimulated dogs, we found an increased neuronal cell size accompanied by an increase of choline acetyltransferase and unchanged tyrosine hydroxylase protein expression as compared with unstimulated dogs. Moreover, ß-nerve growth factor (NGF) and neurotrophin (NT)-3 were upregulated in chronically neurostimulated dogs. In vitro, HFES of cultured neurons of interatrial ganglionated plexus from adult rats increased neuronal growth accompanied by upregulation of NGF, NT-3, glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) expression. NGF was identified as the main growth-inducing factor, whereas NT-3 did not affect HFES-induced growth. However, NT-3 could be identified as an important acetylcholine-upregulating factor. CONCLUSIONS: HFES of cardiac neurons in vivo and in vitro causes neuronal cellular hypertrophy, which is mediated by NGF and boosters cellular function by NT-3-mediated acetylcholine upregulation. This knowledge may contribute to develop HFES techniques to augment cardiac parasympathetic tone.
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Función del Atrio Derecho/fisiología , Factores de Crecimiento Nervioso/fisiología , Neuronas/fisiología , Neurotrofina 3/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Regulación hacia Arriba/fisiología , Animales , Células Cultivadas , Perros , Estimulación Eléctrica/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
RATIONALE: The parasympathetic reduction in heart rate involves the sequential activation of m2 muscarinic cholinergic receptors (m(2)Rs), pertussis toxin-sensitive (Gi/o) heterotrimeric G proteins, and the atrial potassium channel I(KACh). Molecular mechanisms regulating this critical signal transduction pathway are not fully understood. OBJECTIVE: To determine whether the G protein signaling regulator Rgs6/Gß5 modulates m(2)R-I(KACh) signaling and cardiac physiology. METHODS AND RESULTS: Cardiac expression of Rgs6, and its interaction with Gß5, was demonstrated by immunoblotting and immunoprecipitation. Rgs6(-/-) mice were generated by gene targeting, and the cardiac effects of Rgs6 ablation were analyzed by whole-cell recordings in isolated cardiomyocytes and ECG telemetry. Loss of Rgs6 yielded profound delays in m(2)R-I(KACh) deactivation kinetics in both neonatal atrial myocytes and adult sinoatrial nodal cells. Rgs6(-/-) mice exhibited mild resting bradycardia and altered heart rate responses to pharmacological manipulations that were consistent with enhanced m(2)R-I(KACh) signaling. CONCLUSIONS: The cardiac Rgs6/Gß5 complex modulates the timing of parasympathetic influence on atrial myocytes and heart rate in mice.
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Subunidades beta de la Proteína de Unión al GTP/fisiología , Frecuencia Cardíaca/fisiología , Activación del Canal Iónico/fisiología , Miocitos Cardíacos/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Canales de Potasio con Entrada de Voltaje/fisiología , Proteínas RGS/fisiología , Regulación hacia Arriba/fisiología , Animales , Regulación hacia Abajo/genética , Regulación hacia Abajo/fisiología , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/fisiología , Células HEK293 , Atrios Cardíacos/citología , Atrios Cardíacos/fisiopatología , Frecuencia Cardíaca/genética , Humanos , Activación del Canal Iónico/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Transducción de Señal/genética , Transducción de Señal/fisiología , Regulación hacia Arriba/genéticaRESUMEN
RATIONALE: Parasympathetic regulation of heart rate is mediated by acetylcholine binding to G protein-coupled muscarinic M2 receptors, which activate heterotrimeric G(i/o) proteins to promote G protein-coupled inwardly rectifying K(+) (GIRK) channel activation. Regulator of G protein signaling (RGS) proteins, which function to inactivate G proteins, are indispensable for normal parasympathetic control of the heart. However, it is unclear which of the more than 20 known RGS proteins function to negatively regulate and thereby ensure normal parasympathetic control of the heart. OBJECTIVE: To examine the specific contribution of RGS6 as an essential regulator of parasympathetic signaling in heart. METHODS AND RESULTS: We developed RGS6 knockout mice to determine the functional impact of loss of RGS6 on parasympathetic regulation of cardiac automaticity. RGS6 exhibited a uniquely robust expression in the heart, particularly in sinoatrial and atrioventricular nodal regions. Loss of RGS6 provoked dramatically exaggerated bradycardia in response to carbachol in mice and isolated perfused hearts and significantly enhanced the effect of carbachol on inhibition of spontaneous action potential firing in sinoatrial node cells. Consistent with a role of RGS6 in G protein inactivation, RGS6-deficient atrial myocytes exhibited a significant reduction in the time course of acetylcholine-activated potassium current (I(K)(ACh)) activation and deactivation, as well as the extent of I(K)(ACh) desensitization. CONCLUSIONS: RGS6 is a previously unrecognized, but essential, regulator of parasympathetic activation in heart, functioning to prevent parasympathetic override and severe bradycardia. These effects likely result from actions of RGS6 as a negative regulator of G protein activation of GIRK channels.
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Potenciales de Acción/fisiología , Frecuencia Cardíaca/fisiología , Corazón/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Proteínas RGS/fisiología , Transducción de Señal/fisiología , Potenciales de Acción/genética , Animales , Bradicardia/genética , Bradicardia/metabolismo , Bradicardia/fisiopatología , Células Cultivadas , Frecuencia Cardíaca/genética , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas RGS/deficiencia , Proteínas RGS/genética , Receptor Muscarínico M2/fisiología , Transducción de Señal/genética , Nodo Sinoatrial/fisiologíaRESUMEN
Activation of parasympathetic nerves innervating salivary glands evokes not only salivation but also vascular responses. These parasympathetic nerves may have cardiac and/or respiratory-related activity as well as the cardiovascular sympathetic nerves that control vascular bed of salivary glands. Therefore, we investigated whether preganglionic superior salivatory nucleus (SSN) neurons projecting to the submandibular and intra-lingual ganglia exhibit pulse-related and/or respiratory-related activity, and whether they can be excited by electrical stimulation of the lingual nerve. 25% of SSN neurons were found to have pulse-related and tracheal pressure-related activities, implying that they receive cardiac and respiratory inputs. 44% of neurons exhibited only pulse-related activity, whereas 31% of the neurons had neither pulse-related nor tracheal pressure-related activity. Neurons with pulse and tracheal pressure-related activities, and those only with pulse-related activity, had B and C fibre range axons. 53% of SSN neurons received both cardiac and lingual nerve inputs. 16% of neurons recorded were found to receive only cardiac inputs, and 26% only lingual nerve inputs; whereas 5% received neither cardiac nor lingual nerve inputs. We conclude that the inputs from diverse sources converge on the SSN neurons, and they can cooperate to modulate SSN neuronal activity.
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Fibras Parasimpáticas Posganglionares/fisiología , Glándulas Salivales/fisiología , Potenciales de Acción/fisiología , Animales , Estimulación Eléctrica/métodos , Neuronas/fisiología , Presión , Ratas , Ratas Sprague-Dawley , Glándulas Salivales/inervación , Salivación/fisiologíaRESUMEN
PURPOSE OF REVIEW: The cranial blood vessel is considered an integral player in the pathophysiology of migraine, but its perceived role has been subject to much discussion and controversy over the years. We will discuss the evolution in our scientific understanding of cranial blood vessels (primarily arteries) in migraine. RECENT FINDINGS: Recent developments have clarified the role of cranial blood vessels in the trigemino-vascular system and in cortical spreading depression. An underlying theme is the intimate relation between vascular activity and neural function, and we will emphasize the various roles of the blood vessel that go beyond delivering blood. We conclude that migraine cannot be understood, either from a research or clinical point of view, without an understanding of the vascular derangements that accompany it. SUMMARY: Migraine is accompanied by significant derangements in vascular function that may represent important targets for investigation and treatment.
Asunto(s)
Encéfalo/fisiopatología , Arterias Cerebrales/fisiopatología , Trastornos Migrañosos/fisiopatología , Enfermedades del Nervio Trigémino/fisiopatología , Animales , Encéfalo/irrigación sanguínea , Arterias Cerebrales/inervación , Circulación Cerebrovascular/fisiología , Humanos , Mediadores de Inflamación/fisiología , Trastornos Migrañosos/etiología , Modelos Neurológicos , Fibras Parasimpáticas Posganglionares/fisiología , Células Receptoras Sensoriales/fisiología , Nervio Trigémino/fisiopatología , Enfermedades del Nervio Trigémino/etiologíaAsunto(s)
Fibras Autónomas Posganglionares/fisiología , Endocitosis/fisiología , Exocitosis/fisiología , Atrios Cardíacos/inervación , Vesículas Sinápticas/fisiología , Animales , Axones/fisiología , Estimulación Eléctrica , Colorantes Fluorescentes/metabolismo , Masculino , Microscopía Fluorescente , Neuronas Motoras/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Compuestos de Piridinio/metabolismo , Compuestos de Amonio Cuaternario/metabolismo , Ratas , Ratas Wistar , Simpatectomía , Fibras Simpáticas Posganglionares/fisiología , Vena Cava Superior/inervaciónRESUMEN
The parasympathetic vasodilatory fibres are known to innervate vessels in a rat masseter muscle via both cholinergic and non-cholinergic mechanisms. However, the non-cholinergic mechanisms are still unclear. Recently, vasoactive intestinal polypeptide (VIP) was convincingly shown to be involved in the parasympathetic vasodilatation in orofacial areas, such as submandibular glands and lower lip. However, very little is known about the rat masseter muscle. The present study was designed in the rat masseter muscle to assess (1) whether the parasympathetic nerve innervating vessels have VIP immunoreactivities, (2) whether intravenous administration of VIP induces the vasodilatation, and (3) effects of selective VIP receptor antagonist ([4Cl-d-Phe(6), Leu(17)] VIP) in the presence or absence of atropine on the parasympathetic vasodilatation. The VIP immunoreactivities were found at two sites of the parasympathetic otic ganglion and nerve fibres located around vessels. The intravenous administration of VIP induced the vasodilatation, and [4Cl-d-Phe(6), Leu(17)] VIP markedly decreased the vasodilatation evoked by VIP administration. The parasympathetic vasodilatation was not inhibited by [4Cl-d-Phe(6), Leu(17)] VIP. However, treatment with [4Cl-d-Phe(6), Leu(17)] VIP markedly decreased the parasympathetic vasodilatation when [4Cl-d-Phe(6), Leu(17)] VIP was administered together with atropine. These results suggest that (1) VIP exists in the postganglionic parasympathetic nerve innervating the vessels in the masseter muscle, (2) the intravenous administration of VIP induces the vasodilatation in the masseter muscle, and (3) VIP may be involved in the parasympathetic vasodilatation in the masseter muscle when muscarinic cholinergic receptors are deactivated by either atropine or the suppression of the ACh release.
Asunto(s)
Músculo Masetero/irrigación sanguínea , Músculo Masetero/inervación , Fibras Parasimpáticas Posganglionares/fisiología , Péptido Intestinal Vasoactivo/fisiología , Vasodilatación/fisiología , Animales , Atropina/farmacología , Técnica del Anticuerpo Fluorescente , Ganglios Parasimpáticos/fisiología , Flujometría por Láser-Doppler , Masculino , Fibras Parasimpáticas Posganglionares/efectos de los fármacos , Parasimpatolíticos/farmacología , Ratas , Ratas Wistar , Receptores de Péptido Intestinal Vasoactivo/antagonistas & inhibidores , Péptido Intestinal Vasoactivo/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Proteínas de Transporte Vesicular de Acetilcolina/fisiologíaRESUMEN
The pituitary adenylate cyclase-activating polypeptide (PACAP) increases excitability of guinea pig cardiac neurons, an effect mediated through activation of PAC1 receptors. The signaling cascades that couple activation of the PAC1 receptor to alterations in membrane ionic conductances responsible for the PACAP effect are unknown. Intracellular recordings were made from neurons in kinase inhibitor-treated cardiac ganglia preparations to determine which of the intracellular cascades activated by PAC1 receptor stimulation mediate the PACAP effect. In control cells, long depolarizing-current steps elicited one to three action potentials. In contrast, during the application of 10 nM PACAP, depolarizing-current pulses elicited multiple action potential firing (greater than or equal to five action potentials) in 79% of the neurons. Pretreatment with an adenylyl cyclase inhibitor, SQ 22536 (100 microM), suppressed the PACAP-induced increase in excitability, whereas the presence of U-73122 (10 microM), a potent phospholipase C (PLC) inhibitor, had no effect. Thus, the activation of adenylyl cyclase, but not PLC, was a critical step mediating the PACAP effect. Pretreatment with H-89 (1 microM), a protein kinase A inhibitor, and PD 98059 (50 microM), a MEK kinase inhibitor, also significantly blunted the PACAP-induced increase in excitability. Furthermore, treatment with forskolin (5 microM), an activator of adenylyl cyclase, or exposure to the cell-permeable cyclic adenosine monophosphate (cAMP) analogue, 8-bromo-cAMP (1 mM), partially recapitulated the effect of PACAP on excitability. We conclude that the activation of signaling cascades downstream of cAMP mediate the PACAP-induced increase in cardiac neuron excitability.
Asunto(s)
Miocardio/citología , Neuronas/efectos de los fármacos , Fibras Parasimpáticas Posganglionares/efectos de los fármacos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Transducción de Señal/efectos de los fármacos , Adenina/análogos & derivados , Adenina/metabolismo , Inhibidores de Adenilato Ciclasa , Adenilil Ciclasas/metabolismo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Inhibidores Enzimáticos/metabolismo , Estrenos/metabolismo , Flavonoides/metabolismo , Cobayas , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Miocardio/metabolismo , Neuronas/citología , Neuronas/fisiología , Fibras Parasimpáticas Posganglionares/citología , Fibras Parasimpáticas Posganglionares/fisiología , Pirrolidinonas/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Delta-opioid receptors (DORs) are associated with ischemic preconditioning and vagal transmission in the sinoatrial (SA) node and atria. Although functional studies suggested that DORs are prejunctional on parasympathetic nerve terminals, their precise location remains unconfirmed. DORs were colocalized in tissue slices and synaptosomes from the canine right atrium and SA node along with cholinergic and adrenergic markers, vesicular acetylcholine transporter (VAChT), and tyrosine hydroxylase (TH). Synapsin I immunofluorescence verified the neural character of tissue structures and isolated synaptosomes. Acetylcholine and norepinephrine measurements suggested the presence of both cholinergic and adrenergic synaptosomes. Fluorescent analysis of VAChT and TH signals indicated that >80% of the synapsin-positive synaptosomes were of cholinergic origin and <8% were adrenergic. DORs colocalized 75-85% with synapsin in tissue slices from both atria and SA node. The colocalization was equally strong (85%) for nodal synaptosomes but less so for atrial synaptosomes (57%). Colocalization between DOR and VAChT was 75-85% regardless of the source. Overlap between DOR and TH was uniformly low, ranging from 8% to 17%. Western blots with synaptosomal extracts confirmed two DOR-positive bands at molecular masses corresponding to those reported for DOR monomers and dimers. The abundance of DOR was greater in nodal synaptosomes than in atrial synaptosomes, largely attributable to a greater abundance of monomers in the SA node. The abundant nodal and atrial DORs predominantly associated with cholinergic nerve terminals support the hypothesis that prejunctional DORs regulate vagal transmission locally within the heart.
Asunto(s)
Corazón/fisiología , Sistema Nervioso Parasimpático/fisiología , Receptores Opioides delta/fisiología , Nodo Sinoatrial/fisiología , Acetilcolina/metabolismo , Animales , Western Blotting , Perros , Electroforesis en Gel de Poliacrilamida , Técnica del Anticuerpo Fluorescente , Atrios Cardíacos , Inmunohistoquímica , Microscopía Confocal , Microscopía Fluorescente , Miocardio/metabolismo , Norepinefrina/metabolismo , Fibras Parasimpáticas Posganglionares/fisiología , Sistema Nervioso Simpático/fisiología , Sinaptosomas/metabolismo , Proteínas de Transporte Vesicular de Acetilcolina/metabolismoRESUMEN
Purinergic signaling was first recognized in the guinea pig (Cavia porcellus) taenia coli, where relaxation of smooth muscle by nerve-released ATP may involve the activation of P2Y(1) and P2Y(11) receptors, and where transcripts for both genes have been found. A partial sequence for P2Y(11) protein was identified; the full-length P2Y(1) sequence has already been described. P2Y(1) and P2Y(11) proteins were localized by immunohistochemistry in smooth muscle cells. P2X(2) and P2X(3) proteins were also localized in motoneurons of the myenteric plexus. alphabeta-Methylene-ATP (alphabetameATP) and dibenzoyl-ATP (BzATP) evoked fast relaxations in the taenia, and they were inhibited by the P2Y(1) receptor antagonist 2'-deoxy-N(6)-methyladenosine 3',5'-bisphosphate (MRS2179). However, alphabetameATP and BzATP may stimulate neuronal P2X receptors to release ATP, which then acts on P2Y(1) receptors. In accordance, fast relaxations evoked by alphabetameATP and BzATP were inhibited by the P2X(3) and P2X(2/3) receptor antagonist 5-({[3-phenoxybenzyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl] amino} carbonyl)-1,2,4-benzene-tricarboxylic acid (A317491). When P2Y(1), P2X(3), and P2X(2/3) receptors were blocked and adenosine was removed enzymatically, alphabetameATP and BzATP evoked slow relaxations that were inhibited by Reactive Red. Fast and slow relaxations involve small and large conductance calcium-activated potassium channels; the latter are dependent on intracellular cyclic AMP levels, which altered the duration and amplitude of relaxations. alphabetameATP and BzATP were confirmed as agonists, and Reactive Red as an antagonist, of human P2Y(11) receptors. In summary, G(q)-coupled P2Y(1) receptors are involved mainly in fast relaxations, whereas G(q)and G(s)-coupled P2Y(11) receptors are involved in both fast and slow relaxations. These P2Y receptor subtypes, plus neuronal P2X receptors, may explain the phenomenon of parasympathetic inhibition first described by Langley (1898).
Asunto(s)
Colon/fisiología , Músculo Liso/fisiología , Inhibición Neural/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Receptores Purinérgicos P2/fisiología , Secuencia de Aminoácidos/fisiología , Animales , Línea Celular Tumoral , Colon/efectos de los fármacos , Cobayas , Humanos , Técnicas In Vitro , Datos de Secuencia Molecular , Relajación Muscular/efectos de los fármacos , Relajación Muscular/fisiología , Músculo Liso/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Fibras Parasimpáticas Posganglionares/efectos de los fármacos , Parasimpatolíticos/farmacología , Antagonistas del Receptor Purinérgico P2 , Receptores Purinérgicos P2Y1RESUMEN
Forebrain arteries receive nitroxidergic input from parasympathetic ganglionic fibers that arise from the pterygopalatine ganglia. Previous studies have shown that ganglionic stimulation in some species led to cerebral vasodilatation while interruption of those fibers interfered with vasodilatation seen during acute hypertension. Because the ganglionic fibers are quite delicate and are easily damaged when the ganglia are approached with published techniques we sought to develop a method that allowed clear exposure of the ganglia and permitted demonstration of cerebral vasodilatation with electrical stimulation of the ganglia in the rat. We had found that an orbital approach during which the eye was retracted for visualization of the ganglion precluded eliciting vasodilatation with ganglionic stimulation. In the current study approaching the ganglion through an incision over the zygomatic arch provided clear exposure of the ganglion and stimulation of the ganglion with that approach led to vasodilatation.