Decreased Motility of the Lower Esophageal Sphincter in a Rat Model of Gastroesophageal Reflux Disease May Be Mediated by Reductions of Serotonin and Acetylcholine Signaling

Abstract

The pathogenesis of gastroesophageal reflux disease (GERD) is multifactorial but the main factor is extended exposure to gastric acid. The extent of esophageal mucosal injury is determined by the degree and duration of esophageal exposure to acid. Patients with GERD have been found to have delayed acid clearance times that are 2-3 times longer than those without GERD. 1) Indeed, the process of esophageal acid clearance is an important factor in the worsening of esophageal mucosal injury. 2) Impaired esophageal clearance can be partly caused by peristaltic dysfunction 2) and lower esophageal sphincter (LES) functioning. 3) Esophageal motility is also regulated by the esophageal vagal nerve at the interneurons of the central subnucleus of the solitary tract complex. 4) A recent study demonstrated the effect of baclofen, a gamma aminobutyric acid B receptor agonist, on esophageal motility and transient LES relaxation in GERD patients. 5) Although esophageal acid clearance is regulated by neurotransmitters both peripherally and centrally, the local responsiveness of the muscle is still unknown.The motor innervations of LES and the proximal stomach are known to be under cholinergic control. [6][7][8] A recent study demonstrated that the serotonin-4 (5-hydroxytryptamine 4; 5-HT 4 ) receptor is localized in LES and regulates LES tone. 9) Thus, we hypothesized that a neurotransmitter-induced LES response in GERD rats may be impaired at the esophagealtissue level, leading to the development of GERD pathology. In the present study, we examined this hypothesis by measuring LES motility in GERD rats and the effects of neurotransmitters on contraction and relaxation using isolated LES strips in an in vitro study. In addition, we investigated the effects of activation of the 5-HT 4 receptor on esophageal erosion in GERD rats. MATERIALS AND METHODSTest Substances Acetylcholine (Ach), atropine, 5-HT, sodium nitroprusside (SNP), a-methylserotonin (a-Me-5-HT: a 5-HT 2 receptor agonist), 5-methoxytryptamine (5-MeOT: a nonspecific 5-HT receptor agonist), 1-(3-chlorophenyl)biguanide HCl (a 5-HT 3 receptor agonist), BW723 C86HCl (a 5-HT 2B receptor agonist), m-chlorophenylpiperazine HCl (mCPP: a 5-HT 2C receptor agonist), or SB204070 (a 5-HT 4 receptor antagonist) were all purchased from Sigma Aldrich Corp. U.S.A. Cisapride and mosapride (5-HT 4 receptor agonists) was purchased from Tocris Bioscience. Ondansetron (a 5-HT 3 receptor antagonist) was purchased from GlaxoSmithKline.Test Animals Male Wistar rats aged 8 weeks (CLEA Japan Inc., Tokyo, Japan) were used for all experiments. During testing, 4-5 animals were housed in each cage and were allowed free access to food and water in a room that was illuminated between 07:00 and 19:00 h. Temperature and humidity were maintained at constant levels. For tests that evaluated the motility of the proximal LES, animals were housed singly in cages and deprived of food for 24 h after surgery, after which they were given free access to food. Animals that Sapporo, Japan: and d Gastroenterol...

Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease

“…However, treatment with prokinetic agents has been shown to improve several symptoms in patients with GERD (16,39), and we have recently demonstrated that cisapride improves the motility proximal to the lower esophageal sphincter in GERD rats (40). These findings suggest that gastrointestinal dysmotility is involved in GERD progression.…”

“…GERD was surgically induced in rats according to the method of Omura et al (36,40). In brief, rats were first anesthetized with ether after 24 h of fasting, and then laparotomy was then performed at the midline.…”

The Non-Neuronal Cholinergic System in Health and Disease

“…Reduced ACh concentrations and signalling can lead to a reduction in lower oesophageal sphincter function and subsequently to gastro-oesophageal reflux disease [85]. Additionally, a recent study on cats revealed that the NNCS could also contribute to gastro-oesophageal reflux disease by e.g.…”

Histomorphology and Immunohistochemistry of the Lower Esophageal Sphincter of the Least Shrew <b><i>(Cryptotis Parva)</i></b>

“…and the clinical importance of this junction have been studied in several species, including dogs [Alsafy and ElGendy, 2012], frogs [Yoshida, 2001], opossums [Seelig and Goyal, 1978], rats [Saegusa et al, 2011], cats [Al-Tikriti et al, 1987], house musk shrews [Takeuchi and Yoshioka, 2004] and humans [Nakanishi et al, 2007]. The closeness of the least shrew to primates including humans provides an excellent research model for functional physiological and pharmacological studies.…”

“…Furthermore, there is considerable interest in the pathophysiology and pharmacology of the LES [Pratschke et al, 2004]. Numerous drugs, neurotransmitters and hormones can act via several different receptors to exert effects on the LES [Barnette et al, 1992;Saegusa et al, 2011]. A better understanding of the LES junction may shed further light on therapeutic approaches for the treatment of gastroesophageal reflux disease and vomiting [Darmani and Ray, 2009;Gershon 2013].…”