Abstract
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.