The effects of luminal nitric oxide on gastro-oesophageal motility

Manning, Jonathan James (2006) The effects of luminal nitric oxide on gastro-oesophageal motility. MD thesis, University of Glasgow.

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Abstract

Over the last few decades, the epidemiology of diseases of the proximal gastrointestinal tract has been changing. The incidence of gastric adenocarcinoma in the United Kingdom has decreased, with squamous carcinoma of the oesophagus remaining relatively static. Adenocarcinoma of both the oesophagus and gastro-oesophageal junction (including the cardia) have increased greatly. The risk of oesophageal adenocarcinoma has been linked with gastro- oesophageal reflux disease. Short-segment reflux at the cardia has also been postulated as a risk factor for cancers at this site. The factors that predispose a particular person to more severe reflux or put them at an increased risk of mucosal damage are poorly understood. Inherent physiological and anatomical parameters will play their roles, with the role of environmental factors often being overlooked. The increase in dietary nitrate consumption, following the post-war intensive farming practices with nitrogenous fertilizers, has been proposed as a risk factor for the increase in several human cancers. The entero-salivary recirculation of dietary nitrate has been examined by several groups. It has demonstrated the generation of high quantities of nitrite in swallowed human saliva. The subsequent luminal chemistry will cause nitrous acid (NA) to be formed in a healthy acid secreting stomach. In the additional presence of ascorbic acid, instantaneous formation of luminal nitric oxide (NO) at the gastric cardia takes place. Nitrous acid is also capable of forming long acting NO-donor compounds, by reacting with ingested dietary thiols. Nitric oxide is a ubiquitous smooth muscle relaxant. It is involved in oesophageal peristalsis, lower oesophageal sphincter (LOS) and gastric relaxation and also the co-ordination of transient lower oesophageal sphincter relaxations (TLOSRs). A series of pilot studies, in healthy volunteers, were designed to investigate the physiological effects on gastro oesophageal motility. A standard water perfused manometry system was adapted, and validated, to deliver a test solution containing NO, whilst also recording pressure data from the proximal gastro-intestinal tract. The profile of distribution of the delivered NO solutions was characterised by a series of silastic tube experiments. A segmented silastic tube was taped to the manometry catheters used for each experiment. The NO was delivered as it would be in each experiment. The segments trapped NO as nitrite, which were then analysed. They showed a pattern of NO distribution similar to the fasting data seen with a luminal NO probe. The post-prandial model showed evidence of NO reflux into the oesophagus and also NO concentrations comparable to those following ingestion of oral nitrate. Smaller amounts of nitrite are present in saliva in the fasting state. In our model of the subsequent formation of NO at the gastric cardia, there was no effect on the resting pressure of the LOS. There was also no effect on the length of the LOS. At high concentrations (>4mM), NO can come out of solution to form gaseous NO. In vitro experiments demonstrated that at the experimental concentrations used, and also at 37°C, no significant quantities of NO gas were formed, excluding the possibility of intra- gastric gaseous distension as a confounding factor in our studies. Post-prandial studies were performed in 15 healthy volunteers. Initially, the manometric effects of a meal on the LOS were observed. Subsequently, double-blinded solutions were perfused into the lumen at the gastro-oesophageal junction. Hydrochloric acid, NA and NO solutions, all at the upper physiological limit, were perfused and recordings made. The effect of a meal on the LOS, was to cause a reduction in the total sphincter length with a preferential loss of the abdominal portion. There also appeared to be a slight elevation of the diaphragm, but no shortening of the oesophagus. Nitric oxide caused an increase in TLOSRs and reflux at the distal oesophagus. Nitrous acid caused a reduction in intra-gastric pressure during the infusion. It caused no alteration to the acid reflux profile. No solutions caused any major alterations to oesophageal peristaltic parameters following 'dry' swallows. These findings support the need for further research into this area. The threshold for effects caused by nitrite chemistry must be addressed. Also, these studies were performed in healthy volunteers. It would be reasonable to examine the effects of this luminal chemistry on those with pre-existing upper gastrointestinal diseases such as hiatus hernias, reflux oesophagitis and Barrett's oesophagus. Repeat studies looking more simply at the effects of swallowed nitrite on oesophageal acid exposure would be enlightening.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Medicine
Date of Award: 2006
Depositing User: Enlighten Team
Unique ID: glathesis:2006-71917
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 May 2019 09:31
Last Modified: 17 May 2019 09:31
URI: http://theses.gla.ac.uk/id/eprint/71917

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