Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Achalasia is a motility disorder of the esophagus characterized by the loss of inhibitory neurons in the distal esophagus. Although idiopathic in nature, autoimmune mechanisms have been proposed, and we set out to determine the presence of myenteric neuronal antibodies. We prospectively studied 18 patients with well-characterized achalasia (by clinical, x-ray, and manometric evidence), nine with gastroesophageal reflux disease, and analyzed the sera from 22 disease-free controls. Using double-label, indirect immunofluorescence techniques, rat esophageal and intestinal sections were double-labeled with sera (dilutions of 1:50 to 1:400) from the three groups and with neurofilament antibody to localize neurons. Seven of 18 achalasia patients had sera that stained the majority of neurons within plexi in the esophageal and intestinal sections, including both NADPH diaphorase (nitric oxide synthase) -positive and -negative neurons. None of the gastroesophageal reflux patients or the controls showed staining. Neuronal antibodies in achalasia provide an attractive hypothesis to explain this diffuse, possibly immune-based disorder.
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PMID:Anti-myenteric neuronal antibodies in patients with achalasia. A prospective study. 905 11

The lower esophageal sphincter is innervated by both parasympathetic (vagus) and sympathetic (primarily splanchnic) nerves; however, the vagal pathways are the ones that are essential for reflex relaxation of the lower esophageal sphincter (LES), such as that which occurs during transient LES relaxations. Vagal afferent sensory endings from the distal esophagus and LES terminate in the hindbrain nucleus tractus solitarius. The preganglionic motor innervation of the LES arises from the dorsal motor nucleus of the vagus. Together these nuclei comprise the dorsal vagal complex within which there is a neural network coordinating reflex control of the sphincter. Vagal efferent preganglionic neurons to the gastrointestinal tract are organized viscerotopically in the dorsal motor nucleus of the vagus. Stimulation of the dorsal motor nucleus of the vagus caudal to the opening of the fourth ventricle results in relaxations, whereas stimulation in the rostral portion of the nucleus evokes contractions of the LES. Few details are known about the neural circuitry that links sensory information from the stomach and esophagus within the nucleus tractus solitarius to these separate populations of neurons within the dorsal motor nucleus of the vagus. The motor vagal preganglionic output is primarily cholinergic, which ultimately stimulates excitatory or inhibitory motor neurons that control the smooth muscle tone. Excitatory neurons evoke muscarinic receptor-mediated muscle contraction. Inhibitory neurons evoke nitric oxide or vasoactive intestinal polypeptide-mediated relaxation of the lower esophageal sphincter. However, other neurotransmitters are found in vagal preganglionic neurons, including norepinephrine/dopamine and nitric oxide. A subpopulation of nitric oxide synthase-containing vagal preganglionic neurons innervate the upper gastrointestinal tract and mediate relaxation. The neurotransmitters and circuitry controlling lower esophageal sphincter pressure are important to characterize, because part of the dorsal vagal complex is outside of the blood-brain barrier and is a potential target for pharmacologic intervention in the treatment of such disorders as gastroesophageal reflux disease.
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PMID:Central control of lower esophageal sphincter relaxation. 1071 59

The motor control of the lower esophageal sphincter (LES) is critical for normal swallowing and emesis, as well as for the prevention of gastroesophageal reflux. However, there are surprisingly few data on the central organization and neurochemistry of LES-projecting preganglionic neurons. There are no such data in ferrets, which are increasingly being used to study LES relaxation. Therefore, we determined the location of preganglionic neurons innervating the ferret LES, with special attention to their relationship with gastric fundus-projecting neurons. The neurochemistry of LES-projecting neurons was also investigated using two markers of "nontraditional" neurotransmitters in vagal preganglionic neurons, nitric oxide synthase (NOS), and dopamine (tyrosine hydroxylase: TH). Injection of cholera toxin B subunit (CTB)-horseradish peroxidase (HRP) into the muscular wall of the LES-labeled profiles throughout the rostrocaudal extent of the dorsal motor nucleus of the vagus (DMN) The relative numbers of profiles in three regions of the DMN from caudal to rostral are, 43 +/- 5, 67 +/- 11, and 113 +/- 30). A similar rostrocaudal distribution occurred after injection into the gastric fundus. When CTB conjugated with different fluorescent tags was injected into the LES and fundus both labels were noted in 56 +/- 3% of LES-labeled profiles overall. This finding suggests an extensive coinnervation of both regions by vagal motor neurons. There were significantly fewer LES-labeled profiles that innervated the antrum (16 +/- 9%). In the rostral DMN, 15 +/- 4% of LES-projecting neurons also contained NADPH-diaphorase activity; however, TH immunoreactivity was never identified in LES-projecting neurons. This finding suggests that NO, but not catecholamine (probably dopamine), is synthesized by a population of LES-projecting neurons. We conclude that there are striking similarities between LES- and fundic-projecting preganglionic neurons in terms of their organization in the DMN, presence of NOS activity and absence of TH immunoreactivity. Coinnervation of the LES and gastric fundus is logical, because the LES has similar functions to the fundus, which relaxes to accommodate food during ingestion and preceding emesis, but has quite different functions from the antrum, which provides mixing and propulsion of contents for gastric emptying. The presence of NOS in some LES-projecting neurons may contribute to LES relaxation, as it does in the case of fundic relaxation. The neurologic linkage of vagal fundic and LES relaxation may have clinical relevance, because it helps explain why motor disorders of the LES and fundus frequently occur together.
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PMID:Organization and neurochemistry of vagal preganglionic neurons innervating the lower esophageal sphincter in ferrets. 1113 58

Transient lower esophageal sphincter relaxations (TLESRs) are the major mechanism of reflux in patients with gastroesophageal reflux disease. They are therefore attractive targets for pharmacotherapy. During the past 5 years, there has been a burgeoning interest in the neural pathways that control these events and in the pharmacologic receptors involved in these pathways. Several agents have been shown to reduce the rate of TLESRs, including cholecystokinin-A antagonists, anticholinergic agents, nitric oxide synthase inhibitors, morphine, somatostatin, serotonin type 3-receptor antagonists, and gamma-aminobutyric acid-B (GABA(B)) agonists. Their predominant site of action appears to be on either the afferent pathways and/or the central integrative mechanisms within the dorsal vagal complex in the brainstem. Most of the agents tested are unsuitable for clinical use either because of side effects or because of the lack of an orally effective formulation. The most promising agents identified to date are the GABA(B) agonists. Baclofen, the prototype GABA(B) agonist, inhibits the rate of TLESRs by more than 50%. Control of TLESRs is a major new approach to the treatment of reflux disease. It is likely to be applicable to the majority of patients, particularly those without macroscopic mucosal lesions or only mild erosive disease. Further development of more effective agents will depend both on a better understanding of the neural pathways and receptors involved in the control of TLESRs, as well as on investigation of other novel agents. At present, inhibition of TLESRs is at the threshold of transition from concept to practical use. Whether it makes the final leap into the mainstream of therapy will depend on the development of new, novel, and well-targeted pharmacologic agents.
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PMID:Systemic pharmacomodulation of transient lower esophageal sphincter relaxations. 1174 47

Proximal gastric relaxation is a vago-vagal reflex upon food intake. The efferent neurons involved at the level of the stomach are nonadrenergic noncholinergic. Deficient proximal gastric relaxation is observed in a portion of patients with functional dyspepsia, while exaggerated relaxation might contribute to the development of gastroesophageal reflux disease via triggering of transient lower esophageal sphincter relaxations. Nitric oxide (NO) is mediating, together with vasoactive intestinal polypeptide (VIP) as parallel cotransmitter, the nonadrenergic noncholinergic neurotransmission of the proximal stomach. Evidence for a sequential link between VIP as neurotransmitter and muscular NO generation was obtained when studied in isolated gastric smooth muscle cells; inducible NO synthase seems expressed. The endogenous gastric nitrergic neurotransmitter is not sensitive to superoxide anion generators and NO scavengers, that reduce the relaxation to exogenous NO. This is not due to the release of a nerve-derived hyperpolarizing factor in addition of NO, nor to binding to thiols, but Cu/Zn superoxide dismutase is involved in the protection of endogenous NO versus superoxide anions and scavenging. The release of NO from gastric nitrergic neurons is not sensitive to negative feedback but is inhibited via presynaptic alpha 2-adrenoceptors. Nitric oxide functionally antagonizes acetylcholine in the smooth muscle cells but does not influence the release of acetylcholine at the cholinergic varicosities. Stimulating or inhibiting the gastric nitrergic neurons might be a target for drug therapy in functional dyspepsia or gastro-esophageal reflux, respectively.
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PMID:Pharmacological characterization of the nitrergic innervation of the stomach. 1223 40

Gastro-oesophageal reflux disease (GORD) is a chronic disorder characterised by an increased exposure of the oesophagus to intragastric contents. Currently, GORD symptoms are maintained under control with antisecretory agents, mainly gastric proton pump inhibitors (PPIs). Although impaired oesophageal motility may partly underlie the pathophysiology of GORD, the use of prokinetic agents has been found to be unsatisfactory. To date, novel pharmacological approaches for GORD are mainly related to the control of transient lower oesophageal sphincter (LOS) relaxations (TLOSRs). The majority of patients with GORD have reflux episodes during TLOSRs, which are evoked by gastric distension, mainly occurring after ingestion of a meal. Patients with reflux disease with normal peristalsis and without or with mild erosive disease could potentially benefit from anti-TLOSR therapy. This therapy might also be of value to treat some severe forms of esophagitis in combination with PPIs. GABA-B-receptor agonists are the most promising class of agents identified so far for TLOSR control. The GABA-B-receptor agonist, baclofen, is the most effective compound in inhibiting TLOSRs in humans. Since baclofen has several CNS adverse effects, novel orally available GABA-B agonists are needed for effective and well tolerated treatment of GORD. Endogenous or exogenous cholecystokinin (CCK) causes a reduction in LOS pressure, an increase in TLOSR frequency and a reduction in gastric emptying. In healthy volunteers and patients with GORD, loxiglumide, a selective CCK1-receptor antagonist, was found to reduce the rate of TLOSRs, although its effect on postprandial acid reflux may be modest. Orally effective CCK antagonists are not marketed to date. The anticholinergic agent atropine, given to healthy volunteers and patients with GORD, markedly reduced the rate of TLOSRs. Because of severe gastrointestinal (and other) adverse effects of anticholinergics, including worsening of supine acid clearance and constipation, it is unlikely that this class of drugs will have a future as anti-TLOSR agents on a routine basis. In spite of their effectiveness in reducing TLOSR rate, untoward adverse effects, such as addiction and severe constipation, currently limit the use of morphine and other opioid mu-receptor agonists. The same applies to nitric oxide synthase inhibitors, which are associated with marked gastrointestinal, cardiovascular, urinary and respiratory adverse effects. Animal studies provide promising evidence for the use of cannabinoid receptor 1 agonists, by showing potent inhibition of TLOSRs in the dog, thus opening a new route for clinical investigation in humans. A better understanding of TLOSR pathophysiology is a necessary step for the further development of novel drugs effective for anti-reflux therapy.
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PMID:Progress with novel pharmacological strategies for gastro-oesophageal reflux disease. 1496 71

To evaluate the effect of esophageal acid exposure on epithelial function, transmucosal potential, histopathological markers of acute tissue damage, and local nitric oxide production were examined in healthy volunteers treated with proton pump inhibitors (group I), patients with treated reflux disease (group II), and patients with untreated erosive reflux disease (group III). The participants were randomized to esophageal perfusion with either saline or HCl. Denominators of acute acid exposure were balloon cells in superficial layers and superficial densification. The nitric oxide concentrations in groups I to III increased from < 1, 10.0+/-10.0, and 20.6+/-19.9 ppb, respectively, to 300+/-80, 1360+/-1080, and 920+/-700 ppb after HCl infusion (P < 0.001). Inducible nitric oxide synthase was consistently expressed in the epithelium. Blood flow was lower among reflux patients but did not correlate with acid exposure or nitric oxide. Nitric oxide is formed following acid perfusion and predominantly in gastroesophageal reflux disease.
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PMID:Acid challenge to the esophageal mucosa: effects on local nitric oxide formation and its relation to epithelial functions. 1584 95

We hypothesized that differences among individuals in reflux-induced oxidant production by esophageal squamous epithelial cells might contribute to the development of Barrett's esophagus. We studied the effects of acid and bile acids on the production of reactive oxygen species (ROS) in esophageal squamous cell lines derived from gastroesophageal reflux disease patients with (NES-B3T) and without (NES-G2T) Barrett's esophagus and in a Barrett's epithelial cell line (BAR-T). Cells were incubated with an ROS-sensitive probe and exposed to acidic medium, neutral bile acid medium, or acidic bile acid medium. ROS were quantified in the presence and absence of diphenyleneiodonium chloride (DPI, an NADPH oxidase inhibitor), N(G)-monomethyl-l-arginine (l-NMMA, a nitric oxide synthase inhibitor), and rotenone (a mitochondrial electron transport chain inhibitor). Acidic bile acid medium induced ROS production in both squamous cell lines; however, only DPI blocked ROS production by NES-B3T cells, whereas both DPI and l-NMMA blocked ROS production by NES-G2T cells. In BAR-T cells, acidic medium and acidic bile acid medium induced the production of ROS; l-NMMA prevented ROS production after exposure to acidic medium, whereas ROS production induced by acidic bile acid medium was blocked by DPI. These studies demonstrate that there are differences between esophageal squamous cells and Barrett's epithelial cells and between esophageal squamous cells from gastroesophageal reflux disease patients with and without Barrett's esophagus in the mechanisms of oxidant production induced by exposure to acid and bile acids.
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PMID:Mechanisms of oxidant production in esophageal squamous cell and Barrett's cell lines. 1806 6

Patients with chronic gastro-oesophageal reflux disease experience the reflux of acid and bile into the distal oesophagus. The secondary bile salt sodium deoxycholate (NDC) is implicated in the induction of mucosal injury during reflux episodes. This study hypothesized that NDC damages DNA in oesophageal cells by an oxidative mechanism. In the oesophageal cell line HET1-A, increased production of nitric oxide (NO) was measured in NDC-treated cells. Protection from DNA strand breaks induced by NDC (10 microm) was observed in cells coincubated with the nitric oxide scavenger C-PTIO (p<0.012) or pre-incubated with the NO synthase inhibitor L-NAME (p<0.009) or the NFkappaB inhibitor, TPCK (p<0.036). Collectively these data implicate the involvement of NFkappaB and nitric oxide synthase in the DNA damage induced by NDC in oesophageal cells. In conclusion, NDC-driven NO production may play an important role in inducing DNA damage during episodes of gastro-oesophageal reflux and thereby contribute to reflux-related carcinogenesis.
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PMID:Sodium deoxycholate causes nitric oxide mediated DNA damage in oesophageal cells. 1915 54

Gastroesophageal reflux combined with functional constipation prevented bythe introduction of nitric oxide synthase blocker. Gastroesophageal reflux simulated by the administration of nitric oxide donor - methylene blue at fundal department of the stomach and constipation - by free ligation overlaid on the terminal division sigmoid colon of rats. The protective effect of nitric oxide synthase blocker on the gastroesophageal reflux development was demonstrated.
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PMID:[Model of gastroesophageal reflux concomitant with functional constipation in conditions of nitric oxide synthase inhibition]. 2046 81


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