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.
- MeSH
- Action Potentials MeSH
- Electric Stimulation MeSH
- Esophagus innervation MeSH
- Motor Neurons physiology MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Vagus Nerve physiology MeSH
- Muscle, Striated innervation MeSH
- Voltage-Gated Sodium Channels genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex.
- MeSH
- Reflex, Abnormal MeSH
- Pneumonia, Aspiration chemically induced physiopathology surgery MeSH
- Esophagus innervation MeSH
- Capillary Permeability MeSH
- Hydrochloric Acid * MeSH
- Medulla Oblongata metabolism physiopathology MeSH
- Guinea Pigs MeSH
- Neurogenic Inflammation chemically induced physiopathology surgery MeSH
- Lung innervation metabolism MeSH
- Proto-Oncogene Proteins c-fos metabolism MeSH
- Substance P metabolism MeSH
- Vagotomy * MeSH
- Animals MeSH
- Check Tag
- Guinea Pigs MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Počas gastroezofágového refluxu (GER) dochádza k výraznému poklesu pH v lumen pažeráka. V úrovniach nervových zakončení sliznice pažeráka je ale vďaka jej bariérovej funkcii pH oveľa vyššie (pH 5,5–6,5). Napriek tomu, že bariérová funkcia sliznice je pri pažerákovej refluxovej chorobe (GERD) čiastočne porušená, dostatočne zabraňuje difúzii kyseliny do tkaniva a nedochádza k následnej deštrukcii buniek. Predpokladá sa, že pažerákové nociceptívne neuróny, ktoré sprostredkujú bolesť a pyrózu, exprimujú receptory vysoko senzitívne na kyselinu, a sú teda stimulované už pri miernom poklese pH. V recentných modelových štúdiách na morčatách sme dokázali, že už slabá kyselina (pH 5,5–6,5) môže masívne stimulovať spinálne nociceptívne C-vlákna. V súlade s týmto pozorovaním sme pomocou génovej analýzy zistili, že pažerákové aferentné nervové vlákna redundantne exprimujú viaceré receptory, ktoré sú vysoko citlivé na kyselinu. Identifikovali sme iónové kanály citlivé na kyselinu (ASICs – acid sensing ion channels), receptory spriahnuté s G-proteínom reagujúce na kyselinu (OGR1 – proton sensing G-protein coupled receptor) a TASK1 zo skupiny drasíkových kanálov zo skupiny K2P. Vysoká vnímavosť nociceptívnych nervov na kyselinu pri oslabenej báriérovej funkcii sliznice (napr. pri GERD) prispieva k vzniku ezofágových senzácií, ako je pyróza a bolesť pažerákového pôvodu. Receptory, ktoré sprostredkúvajú citlivosť na kyselinu, môžu v budúcnosti slúžiť ako nové terapeutické ciele pre aditívnu alebo alternatívnu liečbu k antisekrečnej liečbe.
The pH in the esophageal lumen can be very low (pH 1) during acidic reflux. However, the pH in the esophageal mucosa where the esophageal afferent nerves terminate is predicted to be much higher (pH 5.5–6.5). This is because the esophageal mucosal barrier, even when reduced in gastroesophageal reflux disease, still prevents most acid from diffusing into the esophageal tissue and causing widespread cellular death. It has therefore been predicted that the esophageal nociceptive (pain- and heartburn-mediating) nerves are stimulated by modest acid (pH 5.5–6.5) and express highly sensitive acid receptors. Recent studies in a guinea pig model demonstrated that weak acid (pH 5.5–6.5) robustly stimulates esophageal spinal nociceptive C-fibers. Consistent with this observation, gene expression analysis revealed that esophageal C-fibers redundantly express multiple acid sensing ion channels (ASICs), proton-sensing G-protein coupled receptor OGR1, and the highly acid sensitive two-pore-domain (K2P) TASK1-family potassium channel. The high acid sensitivity of esophageal nociceptive nerves contributes to heartburn and pain in conditions of reduced mucosal barrier function (e. g. GERD), suggesting that the receptors mediating this high acid sensitivity could be targeted by novel drugs as a combinatorial therapy with, or an alternative to acid suppression.
- MeSH
- Afferent Pathways MeSH
- Esophagus * innervation metabolism MeSH
- Gastroesophageal Reflux * physiopathology MeSH
- Acid Sensing Ion Channels * MeSH
- TRPV Cation Channels MeSH
- Hydrogen-Ion Concentration MeSH
- Humans MeSH
- Neurons, Afferent MeSH
- Nociceptors MeSH
- Heartburn physiopathology MeSH
- Esophageal Mucosa innervation MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Tranzientná relaxácia dolného pažerákového zvierača (TLESR – transient lower esophageal sphincter relaxation) je reflexný dej, ktorý umožňuje uvoľnenie prehltnutého vzduchu zo žalúdka. Súčasne je ale aj jedným z mechanizmov vzniku gastroezofágového refluxu. Regulácia TLESR u ľudí je dobre preštudovaná, ale o vplyve pažerákových stimulov na ich vznik nie je veľa informácií. V prípade, že existuje regulácia TLESR stimuláciou pažeráka, je predpoklad, že je sprostredkovaná aferentnými neurónmi pažeráka. Ich stimulácia zložkami refluxátu (napr. kyselinou) sa teda môže podieľať na dysregulácii TLESR. Autori v kontexte nedávno publikovaných vedeckých výsledkov pojednávajú o význame dysregulácie TLESR v patogenéze pažerákovej refluxovej choroby.
Transient lower esophageal sphincter relaxation (TLESR) is a reflexive process allowing swallowed air to be released from the stomach. At the same time, it is also one of the mechanisms participating in the emergence of gastroesophageal reflux. TLESR regulation in humans has been well studied, but there is little information so far on the influence of esophageal stimuli on TLESR development. If TLESR regulation by esophageal stimulation exists, then it is likley to be mediated by afferent esophageal neurons, whose stimulation by refluxate components (e. g. acid) can lead to TLESR dysregulation. The authors are contemplating, within the context of recently published work, the importance of TLESR dysregulation in the pathogenesis of gastroesophageal reflux disease.
- MeSH
- Esophageal Sphincter, Lower * physiology MeSH
- Esophagus physiology innervation MeSH
- Gastroesophageal Reflux * etiology physiopathology MeSH
- Acids * MeSH
- Humans MeSH
- Manometry MeSH
- Postprandial Period MeSH
- Muscle Relaxation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Clinical studies showed that GABA(B) receptor agonists improve symptoms in patients with gastroesophageal reflux disease. One proposed mechanism of this effect is direct inhibition of the gastroesophageal vagal tension mechanosensors by GABA(B) agonists leading to reduction of reflux. In addition to tension mechanosensors, the vagal nodose ganglion supplies the esophagus with nociceptive C-fibers that likely contribute to impairment of esophageal reflex regulation in diseases. We hypothesized that GABA(B) agonists inhibit mechanically-induced activation of vagal esophageal nodose C-fibers in baseline and/or in sensitized state induced by inflammatory mediators. Ex vivo extracellular recordings were made from the esophageal nodose C-fibers in the isolated vagally-innervated guinea pig esophagus. We found that the selective GABA(B) agonist baclofen (100-300 microM) did not inhibit activation of esophageal nodose C-fibers evoked by esophageal distention (10-60 mmHg). The mechanical response of esophageal nodose C-fibers can be sensitized by different pathways including the stimulation of the histamine H(1) receptor and the stimulation the adenosine A(2A) receptor. Baclofen failed to inhibit mechanical sensitization of esophageal nodose C-fibers induced by histamine (100 microM) or the selective adenosine A(2A) receptor agonist CGS21680 (3 nM). Our data suggest that the direct mechanical inhibition of nodose C-fibers in the esophagus is unlikely to contribute to beneficial effects of GABA(B) agonists in patients with esophageal diseases.
- MeSH
- Afferent Pathways drug effects physiology MeSH
- GABA-A Receptor Agonists administration & dosage MeSH
- Baclofen administration & dosage MeSH
- Esophagus drug effects innervation physiology MeSH
- Nodose Ganglion drug effects physiology MeSH
- Guinea Pigs MeSH
- Neural Inhibition drug effects physiology MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Guinea Pigs MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Achalazie jícnu je nejlépe poznaná primární porucha motility. Dle aktuálních literárních údajů se v etiopatogenezi onemocnění uplatňuje zánět myenterického plexu vedoucí k degenerativním změnám na podkladě genetické predispozice a pravděpodobně autoimunitního poškození. Léčba je dosud jen symptomatická, vedoucí ke snížení tlaku v dolním jícnovém svěrači. Samotná aplikace bolulotoxinu by měla být rezervovaná pro pacienty neschopné podstoupit jinou léčbu. Použití a efekt pneumatické dilatace (eventuálně v kombinaci s botulotoxinem) nebo Hellerovy myotomie je většinou individualizováno dle dostupných možností a zkušeností na jednotlivých pracovištích. U mladých nemocných je vhodné vždy zvážit možnost operace.
Achalasia ot the esophagus is the best known primary motility dysfunction. According to recent literary review the inflammation of myenteric plexus leading to degenerative changes on basis of genetic predisposition and probably autoimmune injury is the main step in etiopathogenesis of that disorder. The treatment is only symptomatic which leads to decreasing of esophageal sfincter pressure. Botulotoxin only treatment should be reserved for patients unable to be treated by other methods. The pneumatic dilatation (or with botulotoxin application) or Heller’s myotomy is mostly individualised according to available methods and experience of each units. In young patients the consideration of surgery is necessary.
