Neurotensin (NT) is a brain-gut peptide, localised to mucosal endocrine N-cells in the gastrointestinal tract. The most potent stimuli for NT release are ingested fats. NT, in vivo, inhibits the migrating myoelectric complex and stimulates colonic motility. The aim of this thesis was to investigate NT and its receptors in human isolated intestine, focusing on motility aspects. ???Normal??? colon and ileum were obtained from patients undergoing resection for carcinoma, and ???disease??? colon was obtained from patients undergoing resection for ulcerative colitis (UC), Crohn???s disease (CD), diverticular disease (DD) and slow transit constipation (STC). In functional experiments with ???normal??? ascending and sigmoid colon, NT contracted taenia coli strips by direct mechanisms (EC50 ??? 100 nM). In circular muscle (CM) strips, contractions were mediated by NT-induced release of enteric mediators (indirect actions), which were regionally specific, as well as by direct actions on the smooth muscle. In contrast, in ???normal??? terminal ileum, the predominant action of NT was a potent (EC50 ??? 3 nM), directly mediated inhibition of spontaneous contractions in longitudinal muscle strips. NT receptors were characterised using radioligand binding with [125I]-NT and [3H]-NT, and localised using autoradiography and immunohistochemistry and confocal microscopy. In the sigmoid colon, binding sites corresponded to NTS1 receptors and could be visualised on the smooth muscle and the enteric ganglia, supporting both direct and neuronal actions for NT, respectively. In the ileum, a similar distribution of binding sites could be visualised. In gastrointestinal disease, NT contractile responses were reduced in UC, DD and STC colon CM strips, but were unchanged in CD. In contrast, NT responses in all diseases were largely unchanged in TC strips, suggesting disease/treatment-induced alterations in NT mechanisms. In UC, cholinergic mechanisms appeared to be altered, whereas in DD disease, prostaglandin mechanisms were affected. In STC, there was an apparent loss of a normally predominant component in NT-mechanisms, but contractile mechanisms appeared to be retained. In summary, these studies demonstrated regional and muscle layer specific actions and mechanisms of action for NT, and support alterations in enteric signaling in disease.
| Identifer | oai:union.ndltd.org:ADTP/258581 |
| Date | January 2005 |
| Creators | Azriel, Yael, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. School of Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Yael Azriel, http://unsworks.unsw.edu.au/copyright |
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