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|Title:||New insights in the neural regulation of the lower oesophageal sphincter|
|Citation:||European Review for Medical and Pharmacological Sciences, 2008; 12(5):33-39|
|Publisher:||Verduci Editore srl|
|L. Ashley Blackshaw|
|Abstract:||Gastro-oesophageal reflux disease (GORD) is caused by disordered control of the gastro-oesophageal reflux barrier, comprised internally of the lower oesophageal sphincter (LOS) and externally the crural diaphragm (CD). Both relax briefly to allow bolus passage during oesophageal peristalsis. Brief relaxation also occurs prior to gastro-oesophageal reflux, known as transient LOS relaxation (TLOSR), normally allowing venting of gas. TLOSRs also account for up to 90% of acid reflux episodes. The development of GORD therefore depends upon the rate of TLOSR and the physical and chemical nature of refluxate. We established an animal model of reflux in ferrets, in which similar patterns of TLOSR are seen to humans. TLOSRs are mediated via a vago-vagal pathway initiated by tension receptors in the gastric musculature. They have central terminals in the brainstem which provide input to a central program generator. The program has 3 simultaneous outputs: 1. brief activation of vagal motor neurones to the LOS, which activate inhibitory enteric motorneurones, leading to smooth muscle relaxation: 2. suppression of oesophageal peristalsis: 3. suppression of motor output to the CD. We have investigated several aspects of the TLOSR pathway in ferrets, and determined that the optimal site for therapeutic pharmacological intervention is at gastric vagal tension receptor endings. Their responses to distension are potently inhibited by gamma-aminobutyric acid type B (GABAB) receptor agonists and metabotropic glutamate type 5 receptor (mGluR5) antagonists. These effects translate to inhibition of TLOSR and reflux in animal models and humans. Clinical studies indicate both types of drug may have potential in the treatment of GORD.|
|Keywords:||Esophageal Sphincter, Lower; Neural Pathways; Animals; Humans; Gastroesophageal Reflux; Receptors, Cell Surface|
|Appears in Collections:||Molecular and Biomedical Science publications|
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