Traditional view holds that gastroesophageal reflux is the consequence of a persistently weak lower esophageal sphincter. Several investigators over the last decade have found that most reflux events, during brief intermittent LES relaxations (TLESR), rather than because of persistently defective LES tone. TLESR is a neural reflex with its afferent and efferent limbs in the vagus nerve and control center in the brain stem. A number of observations from the PI's laboratory show that pharynx is a source of important afferent stimulus that triggers LES relaxation. Studies from the PI's laboratory have also revealed that inhibition of crural diaphragm during TLESR accompanies the occurrence of GER. Esophageal distension in cats causes simultaneous inhibition of LES and crural diaphragm. Preliminary studies from the PI's laboratory show that the crural diaphragm inhibitory mechanism is present in the crural diaphragm at the level of neuromuscular junction and is mediated through nitric oxide. Another interesting observation is that atropine reduces the frequency of reflux through its inhibitory effect on the frequency of TLESR.
The specific aims of the proposal are to determine: 1). Sensitivity of pharyngeal receptors mediated LES relaxation in patients with GER disease. 2). Effect of low frequency, long and short train electrical stimulation of the superior laryngeal nerve, and the effects of gastric distension on-LES relaxation. 3 and 4). Identification of the inhibitory mechanism at the level of neuromuscular junction, particularly the role of nitric oxide as the inhibitory neurotransmitter at neuromuscular junction. 5). Effect of atropine on the gastric distension and pharyngeal stimulus mediated LES relaxation. 6). Effect of atropine on TLESR and GER: Is it mediated through a central versus peripheral mechanism of action of atropine in the inhibition of TLESR? 7). Effects of atropine on the frequency of TLESR and GER in patients with reflux esophagitis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Hamilton, Frank A
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Veterans Medical Research Fdn/San Diego
San Diego
United States
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