Coexistence of a retroesophageal right subclavian artery with a left maxillary artery medial to the mandibular nerve.

This case report describes the coexistence of a retroesophageal right subclavian artery and left maxillary artery which passed deep to the mandibular nerve. An 88-year-old woman died of acute heart failure, and the postmortem revealed that the right subclavian artery originated from the aortic arch as the last branch at the level of the fourth thoracic vertebra, then passed between the esophagus and the vertebral column. The artery then ascended right superiorly and passed behind the anterior scalene muscle. The right vertebral artery arose from the retroesophageal right subclavian artery and entered the transverse foramen of the sixth cervical vertebra. The left maxillary artery branched at the common trunk of the posterior deep temporal and the inferior alveolar arteries. The maxillary artery then turned anteromedially and branched to give the middle meningeal artery. The mandibular nerve gave off the buccal nerve, deep temporal nerve and a thick nerve just below the foramen ovale. The auriculotemporal nerve that branched from the thick nerve ran deep to the maxillary artery. The maxillary artery turned anteriorly, passing deep to the branches. The artery then split to give the buccal artery and the anterior deep temporal artery. In the pterygopalatine section, the maxillary artery branched off to form the common trunk of the infraorbital and sphenopalatine arteries and the posterior superior alveolar artery. It may be necessary to pay attention to the course of the maxillary artery and its relationship to the mandibular nerve branches, when a retroesophageal right subclavian artery is seen.

Localization of sensory nerve terminals containing calcitonin gene-related peptide (CGRP) on striated muscle fibers in the rat esophagus: Evidence for triple innervation via motor endplates.

BACKGROUND: Many esophageal striated muscles of mammals are dually innervated by the vagal and enteric nerves. Recently, substance P (SP)-sensory nerve terminals with calcitonin gene-related peptide (CGRP) were found on a few striated muscle fibers in the rat esophagus, implying that these muscle fibers are triply innervated. In this study, we examined the localization and origin of CGRP-nerve endings in striated muscles to consider their possible roles in the esophagus regarding triple innervation. METHODS: Wholemounts of the rat esophagus were immunolabeled to detect CGRP-nerve endings in striated muscles. Also, retrograde tracing was performed by injecting Fast Blue (FB) into the esophagus, and cryostat sections of the medulla oblongata, nodose ganglion (NG), and the tenth thoracic (T10) dorsal root ganglion (DRG) were immunostained to identify the origin of the CGRP-nerve endings. RESULTS: CGRP-fine, varicose nerve endings were localized in motor endplates on a few esophageal striated muscle fibers (4 %), most of which received nitric oxide (NO) synthase nerve terminals, and most of the CGRP nerve endings were SP- and transient receptor potential vanilloid member 1 (TRPV1)-positive. Retrograde tracing showed many FB-labeled CGRP-neurons positive for SP and TRPV1 in the NG and T10 DGR. CONCLUSIONS: This study suggests that the CGRP-varicose nerve endings containing SP and TRPV1 in motor endplates are sensory, and a few esophageal striated muscle fibers are triply innervated. The nerve endings may detect acetylcholine-derived acetic acid from the vagal motor nerve endings and NO from esophageal intrinsic nerve terminals in the motor endplates to regulate esophageal motility.

Prox2 and Runx3 vagal sensory neurons regulate esophageal motility.

Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron subtypes expressing Prox2 and Runx3 in mice. We show that three of these neuronal subtypes innervate the esophagus and stomach in regionalized patterns, where they form intraganglionic laminar endings. Electrophysiological analysis revealed that they are low-threshold mechanoreceptors but possess different adaptation properties. Lastly, genetic ablation of Prox2 and Runx3 neurons demonstrated their essential roles for esophageal peristalsis in freely behaving mice. Our work defines the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain and could lead to better understanding and treatment of esophageal motility disorders.

Neurochemical classification of serotonin-immunoreactive neurons co-innervating motor endplates in the mouse esophagus.

Serotonin immunoreactivity was previously found in myenteric neurons co-innervating motor endplates in the mouse esophagus striated muscle and an involvement in motility control was suggested. However, it is not known if other neuroactive substances are present in these neurons and to what extent they co-localize. First, vasoactive intestinal peptide (VIP) was established as a bona fide marker for putative inhibitory myenteric neurons by evaluating co-localization with neuronal nitric oxide synthase (nNOS) and neuropeptide Y (NPY). Then, co-localization of serotonin and VIP was tested in co-innervating axons on motor endplates, which were visualized with α-bungarotoxin (α-BT) by multilabel immunofluorescence. Myenteric ganglia were also surveyed for co-localization in neuronal perikarya and varicosities. nNOS, NPY, and VIP were completely co-localized in enteric co-innervating nerve terminals on motor endplates. After co-staining with VIP, we found (a) serotonin (5-HT)-positive nerve endings without VIP (44% of 5-HT-positively innervated endplates), (b) 5-HT- and VIP-positive endings without co-localization (35%), and (c) 5-HT- and VIP-positive endings with co-localization (21%). About one-fifth of nerve terminals on motor endplates containing 5-HT originate from putative inhibitory peptidegic nitrergic neurons. However, the majority represents a different population presumably subserving different functions.

Ginger Constituent 6-Shogaol Attenuates Vincristine-Induced Activation of Mouse Gastroesophageal Vagal Afferent C-Fibers.

Chemotherapeutic agent-induced nausea and vomiting are the severe adverse effects that are induced by their stimulations on the peripheral and/or central emetic nerve pathways. Even though ginger has been widely used as an herbal medicine to treat emesis, mechanisms underlying its neuronal actions are still less clear. The present study aimed to determine the chemotherapeutic agent vincristine-induced effect on gastroesophageal vagal afferent nerve endings and the potential inhibitory role of ginger constituent 6-shogaol on such response. Two-photon neuron imaging studies were performed in ex vivo gastroesophageal-vagal preparations from Pirt-GCaMP6 transgenic mice. Vincristine was applied to the gastroesophageal vagal afferent nerve endings, and the evoked calcium influxes in their intact nodose ganglion neuron somas were recorded. The responsive nodose neuron population was first characterized, and the inhibitory effects of 5-HT3 antagonist palonosetron, TRPA1 antagonist HC-030031, and ginger constituent 6-shogaol were then determined. Vincristine application at gastroesophageal vagal afferent nerve endings elicited intensive calcium influxes in a sub-population of vagal ganglion neurons. These neurons were characterized by their positive responses to P2X2/3 receptor agonist α,ß-methylene ATP and TRPA1 agonist cinnamaldehyde, suggesting their nociceptive placodal nodose C-fiber neuron lineages. Pretreatment with TRPA1 selective blocker HC-030031 inhibited vincristine-induced calcium influxes in gastroesophageal nodose C-fiber neurons, indicating that TRPA1 played a functional role in mediating vincristine-induced activation response. Such inhibitory effect was comparable to that from 5-HT3 receptor antagonist palonosetron. Alternatively, pretreatment with ginger constituent 6-shogaol significantly attenuated vincristine-induced activation response. The present study provides new evidence that chemotherapeutic agent vincristine directly activates vagal nodose nociceptive C-fiber neurons at their peripheral nerve endings in the upper gastrointestinal tract. This activation response requires both TRPA1 and 5-HT3 receptors and can be attenuated by ginger constituent 6-shogaol.

Contribution of tetrodotoxin-sensitive, voltage-gated sodium channels (NaV1) to action potential discharge from mouse esophageal tension mechanoreceptors.

Action potentials depend on voltage-gated sodium channels (NaV1s), which have nine α subtypes. NaV1 inhibition is a target for pathologies involving excitable cells such as pain. However, because NaV1 subtypes are widely expressed, inhibitors may inhibit regulatory sensory systems. Here, we investigated specific NaV1s and their inhibition in mouse esophageal mechanoreceptors-non-nociceptive vagal sensory afferents that are stimulated by low threshold mechanical distension, which regulate esophageal motility. Using single fiber electrophysiology, we found mechanoreceptor responses to esophageal distension were abolished by tetrodotoxin. Single-cell RT-PCR revealed that esophageal-labeled TRPV1-negative vagal neurons expressed multiple tetrodotoxin-sensitive NaV1s: NaV1.7 (almost all neurons) and NaV1.1, NaV1.2, and NaV1.6 (in ∼50% of neurons). Inhibition of NaV1.7, using PF-05089771, had a small inhibitory effect on mechanoreceptor responses to distension. Inhibition of NaV1.1 and NaV1.6, using ICA-121341, had a similar small inhibitory effect. The combination of PF-05089771 and ICA-121341 inhibited but did not eliminate mechanoreceptor responses. Inhibition of NaV1.2, NaV1.6, and NaV1.7 using LSN-3049227 inhibited but did not eliminate mechanoreceptor responses. Thus, all four tetrodotoxin-sensitive NaV1s contribute to action potential initiation from esophageal mechanoreceptors terminals. This is different to those NaV1s necessary for vagal action potential conduction, as demonstrated using GCaMP6s imaging of esophageal vagal neurons during electrical stimulation. Tetrodotoxin-sensitive conduction was abolished in many esophageal neurons by PF-05089771 alone, indicating a critical role of NaV1.7. In summary, multiple NaV1 subtypes contribute to electrical signaling in esophageal mechanoreceptors. Thus, inhibition of individual NaV1s would likely have minimal effect on afferent regulation of esophageal motility.

Effect of low-threshold versus high-threshold genitalia stimuli on the cystometry parameters in male rats.

The cross talk between external genitalia and urinary bladder could be used as part of management to certain pathological conditions affecting urinary bladder. Since urinary bladder function is also affected by pathologies of other organs (e.g., colon and esophagus), the effect of genitalia stimuli on parameters of bladder function in normal or under different pathological conditions needs to be characterized. Cystometry recordings in male rats were used to examine the effect of low-threshold (LT) and high-threshold (HT) stimulation of the scrotum and penis on urinary bladder function. These effects were studied in intact, colon irritation (CI), and esophagus irritation (EI) groups. Although HT penile stimulation had a significant inhibitory effect on micturition reflex in all groups, CI hypersensitized the penile-bladder inhibitory reflex. In addition, LT penile stimulation had a significant inhibitory effect on micturition, which was significant in CI group only. On the other hand, HT penile stimulation in CI group significantly increased the timing parameters of cystometry. Whereas LT and HT penile stimuli in EI group had a significantly increasing effect on all pressure parameters of cystometry. The scrotal stimuli had minimal effect on bladder function in all groups except for HT scrotal stimulation in the CI group, where it had a significant inhibitory effect on micturition reflex and significantly increased the maximum pressure and pressure amplitude of micturition cycles. These results show that CI and EI exacerbate the effects of genitalia stimuli, especially penile stimuli, on urinary bladder function.

Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus.

Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.

Deoxycholic acid activates and sensitizes vagal nociceptive afferent C-fibers in guinea pig esophagus.

Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders, where it can induce esophageal pain and heartburn. The present study aimed to determine whether bile acid, deoxycholic acid (DCA), directly activates and sensitizes esophageal vagal nociceptive afferent C-fiber subtypes. DCA-elicited effects on vagal nodose and jugular neurons were studied by calcium imaging. Its effects on esophageal-labeled nodose and jugular neurons were then determined by patch-clamp recording. At nodose and jugular C-fiber nerve endings in the esophagus, DCA-evoked action potentials (APs) were compared by extracellular single-unit recordings in ex vivo esophageal-vagal preparations. DCA application induced calcium influxes in nodose and jugular neurons and elicited inward currents in esophageal-labeled nodose and jugular neurons. In the presence of DCA, the current densities elicited by capsaicin were enhanced in those labeled neurons. Consistently, DCA perfusion at nerve terminals in the esophagus evoked APs in about 50% of esophageal nodose and jugular C-fibers. In DCA-sensitive C-fibers, DCA perfusion also sensitized the fibers such that the subsequent response to capsaicin was amplified. Collectively, these results provide new evidence that DCA directly activates and sensitizes nociceptive nodose and jugular C-fibers in the esophagus. Such activation and sensitization effects may contribute to bile acid-induced esophageal nociceptive symptoms that are refractory to proton-pump inhibitor therapy.NEW & NOTEWORTHY Bile acid reflux in the esophagus can induce pain and heartburn in certain esophageal disorders, but the underlying neuronal mechanism is still unclear. The present study demonstrated that bile acid, deoxycholic acid (DCA), directly activates esophageal vagal afferent nodose and jugular nociceptive C-fibers and sensitizes their response to capsaicin. Such effects may contribute to bile acid-induced esophageal nociceptive symptoms that refractory to proton-pump inhibitors (PPIs) therapy.

Anatomical variation and distribution of the vagus nerve in the esophageal hiatus: a cross-sectional study of post-mortem cases in Uganda.

PURPOSE: Vagus nerve injuries during gastroesophageal surgery may cause significant symptoms due to loss of vagal anti-inflammatory and neuromodulator function. Many previous studies have shown high anatomical variability of the vagus nerve at the esophageal hiatus, but information on its variability in Uganda specifically and Africa in general is scanty. This study provides a reliable and detailed description of the anatomical variation and distribution of the vagus nerve in the esophageal hiatus region of post-mortem cases in Uganda. METHODS: This was an analytical cross-sectional survey of 67 unclaimed post-mortem cases. Data collection used a pretested data collection form. Data were entered into Epi-Info version 6.0 data base then exported into STATA software 13.0 for analysis. RESULTS: The pattern of the anterior vagal trunk structures at the esophageal hiatus was: single trunk [65.7%]; biplexus [20.9%]; triplexus [8.9%] and double-but-not-connected trunks [4.5%]. The pattern of the posterior trunk structures were: single trunk [85.1%]; biplexus 10.4% and triplexus [4.5%]. There was no statistically significant gender difference in the pattern of vagal fibres. There was no major differences in the pattern from comparable British studies. CONCLUSION: The study confirmed high variability in the distribution of the vagus nerve at the esophageal hiatus, unrelated to gender differences. Surgeons must consider and identify variants of vagal innervation when carrying out surgery at the gastroesophageal junction to avoid accidental vagal injuries. Published surgical techniques for preserving vagal function are valid in Uganda.

Mast cell effects on esophageal smooth muscle and their potential role in eosinophilic esophagitis and achalasia.

Mast cells and eosinophils are the key effector cells of allergic disorders. Although most studies on eosinophilic esophagitis (EoE), an allergic disorder of the esophagus, have focused on the role of eosinophils, recent studies suggest a major role for mast cells in causing the clinical manifestations of this disease. Cellular and animal studies have demonstrated that mast cells can cause esophageal muscle cells to proliferate and differentiate into a more contractile phenotype, and that mediators released by degranulating mast cells such as tryptase and histamine can activate smooth muscle contraction pathways. Thus, activated mast cells in the esophageal muscularis propria might cause esophageal motility abnormalities, including the failure of lower esophageal sphincter relaxation typical of achalasia. In addition, mast cells have been implicated in the pathogenesis of a number of neurodegenerative disorders of the central nervous system such as Alzheimer's and Parkinson's diseases, because degranulating mast cells release proinflammatory and cytotoxic mediators capable of damaging neurons. Such mast cell degranulation in the myenteric plexus of the esophagus could cause the loss of enteric neurons that characterizes achalasia. In this report, we review the molecular mechanisms of esophageal smooth muscle contraction, and how mast cells products might affect that muscle and cause neurodegeneration in the esophagus. Based on these data, we present our novel, conceptual model for an allergy-induced form of achalasia mediated by mast cell activation in the esophageal muscularis propria.

Assessment of esophageal body peristaltic work using functional lumen imaging probe panometry.

The goal of this study was to conceptualize and compute measures of "mechanical work" done by the esophagus using data generated during functional lumen imaging probe (FLIP) panometry and compare work done during secondary peristalsis among patients and controls. Eighty-five individuals were evaluated with a 16-cm FLIP during sedated endoscopy, including asymptomatic controls (n = 14) and those with achalasia subtypes I, II, and III (n = 15, each); gastroesophageal reflux disease (GERD; n = 13); eosinophilic esophagitis (EoE; n = 9); and systemic sclerosis (SSc; n = 5). The FLIP catheter was positioned to have its distal segment straddling the esophagogastric junction (EGJ) during stepwise distension. Two metrics of work were assessed: "active work" (during bag volumes ≤ 40 mL where contractility generates substantial changes in lumen area) and "work capacity" (for bag volumes ≥ 60 mL when contractility cannot substantially alter the lumen area). Controls showed median [interquartile range (IQR)] of 7.3 (3.6-9.2) mJ of active work and 268.6 (225.2-332.3) mJ of work capacity. Patients with all achalasia subtypes, GERD, and SSc showed lower active work done than controls (P ≤ 0.003). Patients with achalasia subtypes I and II, GERD, and SSc had lower work capacity compared with controls (P < 0.001, 0.004, 0.04, and 0.001, respectively). Work capacity was similar between controls and patients with achalasia type III and EoE. Mechanical work of the esophagus differs between healthy controls and patient groups with achalasia, EoE, SSc, and GERD. Further studies are needed to fully explore the utility of this approach, but these work metrics would be valuable for device design (artificial esophagus), to measure the efficacy of peristalsis, to gauge the physiological state of the esophagus, and to comment on its pumping effectiveness.NEW & NOTEWORTHY Functional lumen imaging probe (FLIP) panometry assesses esophageal response to distension and provides a simultaneous assessment of pressure and dimension during contractility. This enables an objective assessment of "mechanical work" done by the esophagus. Eighty-five individuals were evaluated, and two work metrics were computed for each subject. Controls showed greater values of work compared with individuals with achalasia, gastroesophageal reflux disease (GERD), and systemic sclerosis (SSc). These values can quantify the mechanical behavior of the distal esophagus and assist in the estimation of muscular integrity.

Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.

We investigated voltage-gated sodium channel (NaV1) subunits that regulate action potential initiation in the nerve terminals of vagal nodose C-fibers innervating the esophagus. Extracellular single fiber recordings were made from the nodose C-fibers, with mechanically sensitive nerve terminals in the isolated innervated guinea pig esophagus. NaV1 inhibitors were selectively delivered to the tissue-containing nerve terminals. Graded esophageal distention was used for mechanical stimulation. The NaV1.7 inhibitor PF-05089771 nearly abolished action potential initiation in response to low levels of esophageal distention but only partially inhibited the response to higher levels of esophageal distention. The PF-05089771-insensitive component of the response progressively increased (up to ≈50%) with increasing esophageal distention and was abolished by tetrodotoxin (TTX). In addition to NaV1.7, nodose C-fiber [transient receptor potential channel-vanilloid subfamily member 1 (TRPV1)-positive] neurons retrogradely labeled from the esophagus expressed mRNA for multiple TTX-sensitive NaV1s. The group NaV1.1, NaV1.2, and NaV1.3 inhibitor ICA-121431 inhibited but did not abolish the PF-05089771-insensitive component of the response to high level of esophageal distention. However, combination of ICA-121431 with compound 801, which also inhibits NaV1.7 and NaV1.6, nearly abolished the response to the high level of esophageal distention. Our data indicate that the action potential initiation in esophageal nodose C-fibers evoked by low (innocuous) levels of esophageal distention is mediated by NaV1.7. However, the response evoked by higher (noxious) levels of esophageal distention has a progressively increasing NaV1.7-independent component that involves multiple TTX-sensitive NaV1s. The stimulus intensity-dependent recruitment of NaV1s may offer novel opportunities for strategic targeting of NaV1 subunits for inhibition of nociceptive signaling in visceral C-fibers.NEW & NOTEWORTHY We report that pharmacologically distinguishable voltage-gated sodium channels (NaV1) mediate action potential initiation at low (innocuous) versus high (noxious) intensity of esophageal distention in nerve terminals of vagal nodose C-fibers. Action potential initiation at low intensity is entirely dependent on NaV1.7; however, additional tetrodotoxin (TTX)-sensitive NaV1s are recruited at higher intensity of distention. This is the first demonstration that NaV1s underlying action potential initiation in visceral C-fibers depend on the intensity of the stimulus.

Changes in specific esophageal neuromechanical wall states are associated with conscious awareness of a solid swallowed bolus in healthy subjects.

Esophageal neuromechanical wall states are the physical manifestations of circular muscle inhibition and contraction resulting from neural inputs and leading to bolus propulsion. A novel method infers esophageal neuromechanical wall states through simultaneous determination of pressure and diameter in vivo using impedance manometry. We hypothesized that changes in esophageal neuromechanical wall states relate to conscious awareness of esophageal bolus passage ("bolus perception"). Seven healthy participants were selected for perception of solid bolus passage and were compared with seven healthy participants with no conscious awareness of solid bolus passage. Participants were studied using impedance manometry (MMS Solar, Unisensor, 20 Hz). Subjects swallowed ten 5-ml liquid and ten 2-cm square saline-soaked bread boluses and rated bolus perception using a visual analog scale. Esophageal neuromechanical wall states were calculated and analyzed. Proportions of time spent in states with and without luminal distension were compared using a two-proportions Z-test. Bolus perception was associated with neuromechanical wall states corresponding to luminal distension more frequently than matching states without distension in the proximal esophagus (P < 0.001) and transition zone (P < 0.001), whereas there were no differences for the distal esophagus. In healthy volunteers, perceived swallows relate to changes in esophageal neuromechanical wall states in the proximal esophagus. We postulate that these changes relate to bolus retention and summation of active and passive wall tension activating intramural tension receptors.NEW & NOTEWORTHY This study explores esophageal neuromechanical wall states derived from changes in pressure and impedance-derived distension in relation to conscious awareness of esophageal solid bolus transit in healthy volunteers. There are increases in neuromechanical wall states indicative of esophageal distension in healthy volunteers with conscious awareness of bolus transit as compared with unaware individuals. Bolus-based esophageal distension is postulated as a mechanism for esophageal symptoms such as dysphagia.

The ventral peptidergic system of the adult ascidian Ciona robusta (Ciona intestinalis Type A) insights from a transgenic animal model.

Ascidians are the sister group of vertebrates and occupy a critical position in explorations of the evolution of the endocrine and nervous systems of chordates. Here, we describe the complete ventral peptidergic system in adult transgenic Ciona robusta (Ciona intestinalis Type A) which expresses the Kaede reporter gene driven by the prohormone convertase 2 (PC2) gene promoter. Numerous PC2 promoter-driven fluorescent (Kaede-positive) non-neural cells were distributed in the blood sinus located at the anterior end of the pharynx, suggesting the acquisition of a peptidergic circulatory system in Ciona. Kaede-positive ciliated columnar cells, rounded cells, and tall ciliated cells were observed in the alimentary organs, including the endostyle, pharynx, esophagus, stomach, and intestine, suggesting that digestive functions are regulated by multiple peptidergic systems. In the heart, Kaede-positive neurons were located in the ring-shaped plexus at both ends of the myocardium. Nerve fiber-like tracts ran along the raphe and appeared to be connected with the plexuses. Such unique structures suggest a role for the peptidergic system in cardiac function. Collectively, the present anatomic analysis revealed the major framework of the ventral peptidergic system of adult Ciona, which could facilitate investigations of peptidergic regulation of the pharynx, endostyle, alimentary tissues, and heart.

Voltage-gated sodium channels mediating conduction in vagal motor fibers innervating the esophageal striated muscle.

The vagal motor fibers innervating the esophageal striated muscle are essential for esophageal motility including swallowing and vomiting. However, it is unknown which subtypes of voltage-gated sodium channels (NaV1s) regulate action potential conduction in these efferent nerve fibers. The information on the NaV1s subtypes is necessary for understanding their potential side effects on upper gut, as novel inhibitors of NaV1s are developed for treatment of pain. We used isolated superfused (35 °C) vagally-innervated mouse esophagus striated muscle preparation (mucosa removed) to measure isometric contractions of circular striated muscle evoked by electrical stimulation of the vagus nerve. NaV1 inhibitors were applied to the de-sheathed segment of the vagus nerve. Tetrodotoxin (TTX) applied to the vagus nerve completely abolished electrically evoked contractions. The selective NaV1.7 inhibitor PF-05089771 alone partially inhibited contractions and caused a >3-fold rightward shift in the TTX concentration-inhibition curve. The NaV1.1, NaV1.2 and NaV1.3 group inhibitor ICA-121431 failed to inhibit contractions, or to alter TTX concentration-inhibition curves in the absence or in the presence of PF-05089771. RT-PCR indicated lack of NaV1.4 expression in nucleus ambiguus and dorsal motor nucleus of the vagus nerve, which contain motor and preganglionic neurons projecting to the esophagus. We conclude that the action potential conduction in the vagal motor fibers to the esophageal striated muscle in the mouse is mediated by TTX-sensitive voltage gated sodium channels including NaV1.7 and most probably NaV1.6. The role of NaV1.6 is supported by ruling out other TTX-sensitive NaV1s (NaV1.1-1.4) in the NaV1.7-independent conduction.

Vagus Nerves Provide a Robust Afferent Innervation of the Mucosa Throughout the Body of the Esophagus in the Mouse.

The vagal afferent nerves regulate swallowing and esophageal motor reflexes. However, there are still gaps in the understanding of vagal afferent innervation of the esophageal mucosa. Anatomical studies found that the vagal afferent mucosal innervation is dense in the upper esophageal sphincter area but rare in more distal segments of the esophagus. In contrast, electrophysiological studies concluded that the vagal afferent nerve fibers also densely innervate mucosa in more distal esophagus. We hypothesized that the transfection of vagal afferent neurons with adeno-associated virus vector encoding green fluorescent protein (AAV-GFP) allows to visualize vagal afferent nerve fibers in the esophageal mucosa in the mouse. AAV-GFP was injected into the vagal jugular/nodose ganglia in vivo to sparsely label vagal afferent nerve fibers. The esophageal tissue was harvested 4-6 weeks later, the GFP signal was amplified by immunostaining, and confocal optical sections of the entire esophagi were obtained. We found numerous GFP-labeled fibers in the mucosa throughout the whole body of the esophagus. The GFP-labeled mucosal fibers were located just beneath the epithelium, branched repeatedly, had mostly longitudinal orientation, and terminated abruptly without forming terminal structures. The GFP-labeled mucosal fibers were concentrated in random areas of various sizes in which many fibers could be traced to a single parental axon. We conclude that the vagus nerves provide a robust afferent innervation of the mucosa throughout the whole body of the esophagus in the mouse. Vagal mucosal fibers may contribute to the sensing of intraluminal content and regulation of swallowing and other reflexes.

Neuronal Control of Esophageal Peristalsis and Its Role in Esophageal Disease.

PURPOSE OF REVIEW: Esophageal peristalsis is a highly sophisticated function that involves the coordinated contraction and relaxation of striated and smooth muscles in a cephalocaudal fashion, under the control of central and peripheral neuronal mechanisms and a number of neurotransmitters. Esophageal peristalsis is determined by the balance of the intrinsic excitatory cholinergic, inhibitory nitrergic and post-inhibitory rebound excitatory output to the esophageal musculature. RECENT FINDINGS: Dissociation of the longitudinal and circular muscle contractions characterizes different major esophageal disorders and leads to esophageal symptoms. Provocative testing during esophageal high-resolution manometry is commonly employed to assess esophageal body peristaltic reserve and underpin clinical diagnosis. Herein, we summarize the main factors that determine esophageal peristalsis and examine their role in major and minor esophageal motility disorders and eosinophilic esophagitis.

Gastroesophageal reflux disease and atrial fibrillation: Insight from autonomic cardiogastric neural interaction.

BACKGROUND: The relationship between gastroesophageal reflux disease (GERD) and atrial fibrillation (AF) has been previously reported. However, the detailed mechanism remains unknown. In this study, we investigated the effects of acid reflux on the intrinsic cardiac autonomic nervous system, atrial/ventricular electrophysiology, and AF inducibility. METHODS: Eighteen rabbits were randomized into three groups: acid reflux (group 1, n = 6), control (group 2, n = 6), and acid reflux with periesophageal vagal blockade (group 3, n = 6). Atrial and ventricular effective refractory periods (ERPs) and AF inducibility were checked at baseline and then hourly until 5 hours after the experiment. RESULTS: Three hours after the experiment, atrial ERP prolongation was noted in groups 2 and 3 (P < .05), whereas shortening of the atrial ERPs was observed in group 1, compared with the baseline. However, no changes were observed in ventricular ERPs in the three groups. The AF inducibility was higher in group 1 than in groups 2 and 3. Pathological examination showed clear esophageal mucosal breaks in groups 1 and 3. CONCLUSIONS: In this study, we found that the antimuscarinic blockade prevents GERD induced changes to atrial electrophysiology and susceptibility to AF-making it highly likely that autonomic activity is important in mediating this effect.

Characterization and mechanism of the esophago-esophageal contractile reflex of the striated muscle esophagus.

An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. The aim of this study was to characterize and determine the mechanisms of the EECR. Cats (n = 35) were decerebrated, electrodes were placed on pharynx and cervical esophagus, and esophageal motility was recorded using manometry. All areas of esophagus were distended to locate and quantify the EECR. The effects of esophageal perfusion of NaCl or HCl, vagus nerve or pharyngoesophageal nerve (PEN) transection, or hexamethonium administration (5 mg/kg iv) were determined. We found that distension of the esophagus at all locations activated EECR rostral to stimulus only. EECR response was greatest when the esophagus 2.5-11.5 cm from cricopharyngeus (CP) was distended. HCl perfusion activated repetitively an EECR-like response of the proximal esophagus only within 2 min, and after ~20 min EECR was inhibited. Transection of PEN blocked or inhibited EECR 1-7 cm from CP, and vagotomy blocked EECR at all locations. Hexamethonium blocked EECR at 13 and 16 cm from CP but sensitized its activation at 1-7 cm from CP. EECR of the entire esophagus exists, which is directed in the orad direction only. EECR of striated muscle esophagus is mediated by vagus nerve and PEN and inhibited by mechanoreceptors of smooth muscle esophagus. EECR of smooth muscle esophagus is mediated by enteric nervous system and vagus nerve. Activation of EECR of the striated muscle esophagus is initially sensitized by HCl exposure, which may have a role in prevention of supraesophageal reflux.NEW & NOTEWORTHY An esophago-esophageal contractile reflex (EECR) exists, which is directed in the orad direction only. EECR of the proximal esophagus can appear similar to and be mistaken for secondary peristalsis. The EECR of the striated muscle is mediated by the vagus nerve and pharyngoesophageal nerve and inhibited by mechanoreceptor input from the smooth muscle esophagus. HCl perfusion initially sensitizes activation of the EECR of the striated muscle esophagus, which may participate in prevention of supraesophageal reflux.