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569 Effect of Neurotensin on Colorectal Motor and Sensory Function in Humans [2004년 2월 DCR] 2011-12-23 1836
 
Patrick P. J. van der Veek, M.D., Elleke D. C. M. Schots, M.D., Ad A. M. Masclee, M.D., Ph.D.
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
 
PURPOSE: Animal studies have shown that neurotensin stimulates colonic motility, but little is known on the effectn on rectocolonic function in humans. This study was designed to investigate the effect of neurotensin on rectal and colonic motor and sensory function and colonic reflexes in humans.
METHODS: Motor and sensory function of the descending colon and rectum were studied in eight healthy volunteers (5 females; age range, 20–58 years) by using a dual, computerized, rectocolonic, barostat assembly. Measurements were performed during placebo and neurotensin infusion (5 pmol/kg per minute), respectively. Compliance and reflex mechanisms were assessed in both rectum and
descending colon. Symptom perception (urge and pain) was scored using Visual Analog Scales (0–10 cm).
RESULTS: Neurotensin significantly (P < 0.05) increased rectal compliance (from 9 ± 1.1 to 10.1 ± 1.1 ml/mmHg) and colonic compliance (from 7.9 ± 0.4 to 9 ± 0.7 ml/mmHg) during stepwise distensions. Intensity of urge and pain perception during rectal distension was increased by neurotensin (P <
0.05). Sensations during colonic distensions were not altered by neurotensin. For colonic reflexes, during rectal distension the colonic bag volume increased significantly (P < 0.05), whereas during colonic distension rectal bag volume decreased significantly (P < 0.05). Neurotensin delayed the occurrence of these reflexes: they were present at significantly higher pressures compared to placebo (P < 0.05).
CONCLUSIONS: We demonstrated the presence of both a rectocolonic inhibitory and a colorectal stimulatory reflex in healthy volunteers. Neurotensin increases compliance and modulates rectal but not colonic sensitivity. Colorectal and rectocolonic reflexes are impaired during infusion of neurotensin.
 
Neurotensin (NT) is a 13-amino-acid-peptide that was first detected in bovine hypothalamus in 1973. Later, it was isolated from the human brain and gut. It is found throughout the gastrointestinal tract,
with increasing concentrations going from duodenum to the terminal ileum. Neurotensin is released from
the mucosal endocrine N cells that are present in jejunal and ileal epithelium, whereas NT concentrations in the human colon are below levels of detection
. Plasma levels of NT increase in response to nutrient ingestion, with intraduodenal fat being the most potent stimulus. Apart from vasoactive effects, NT influences proximal gastrointestinal motility and secretion. For instance, during intravenous NT infusion in humans lower esophageal sphincter pressure decreases, gastric emptying becomes delayed, meal-induced and gastrin-induced gastric acid secretion decrease, and exocrine pancreatic secretion increases. In contrast, data on the effect of NT on human colon are contradictory and unclear.
 
In functional bowel disorders, such as irritable bowel syndrome (IBS), alterations in motility and visceral
sensitivity are well documented. Visceral sensory information is transmitted through vagal afferent
fibers and the spinal cord, and is centrally modulated. Furthermore, information is transferred to other parts of the colon directly through enteric neurons via intestino-intestinal reflex mechanisms. Several
gastrointestinal peptides modulate these mechanisms both centrally and peripherally. For instance,
octreotide, a somatostatin analog, alters visceral perception by increasing thresholds in IBS patients, whereas cholecystokinin increases rectal perception in both healthy controls and IBS patients. However,
the effect of NT on colonic motility, intestinointestinal reflexes and visceral perception is not clear.
Knowledge of the effects of NT on colorectal motor and sensory function may lead to a better insight in
colorectal physiology and pathophysiology. This study was designed to investigate the effect of NT on
colorectal motility and on visceroperception and intestino-intestinal reflexes.
 
DISCUSSION
In this study, we demonstrated that neurotensin (NT) affects rectocolonic tone and motility, intestinointestinal reflexes, and visceroperception. We found that intravenous infusion of NT, at a rate that yields plasma concentrations comparable with postprandial levels, increases rectal and colonic compliance. It could be argued that direct stimulation of the colonic wall (e.g., by balloon distension) may lead to release of NT. It has been shown, however, that the most potent stimulus for local (ileal) NT release is intraduodenal fat. Furthermore, concentrations of NT in the wall of the human colon are below levels of detection, which makes it unlikely that local colonic stimulation leads to NT release and subsequent modulation of rectocolonic compliance. No studies have reported on the effect of NT on rectal and colonic compliance by means of barostat measurements. Thor and Rosell found that a high dose of intravenous NT (12 pmol/kg per minute) stimulated motor activity of the proximal colon and the rectosigmoid area, but not of the splenic flexure. However, in that study motility was measured by means of water perfusion manometry. This method records phasic colonic activity by means of pressures changes in the colonic lumen but does not assess colonic tone and, thus, compliance.
Hellström and Rosell found that in anesthetized cats, a high dose of NT administered intravenously (14
pmol/kg per minute) increases basal smooth muscle tone of the descending colon, but others have shown that the effect of NT on colonic smooth muscle is concentration-dependent and can be inhibitory or excitatory.
 
In our experiment, we noted a significant increase in colonic intrabag volumes during rectal distensions,
whereas bag volumes returned to basal on cessation of the distension. These observations confirm measurements previously done in our department and by others in both animals and humans. Furthermore, the higher rectal pressure required to increase colonic bag volume during NT infusion compared with placebo (whereas basal colonic volumes were equal between both experiments) suggests that NT impairs the rectocolonic inhibitory reflex. Recent evidence has shown that NT can act directly on smooth muscle of the human transverse and descending colon by inducing contractions in muscle strips in vitro. Consequently, in our experiment, motor function of the descending colon during NT infusion is not only affected by a rectal pressure distension (enteroenteric reflex pathways), but also by smooth muscle contractions induced by NT. Therefore, NT might not directly influence enteroenteric neural pathways involved in the rectocolonic inhibitory reflex, but NT may affect this reflex indirectly by reducing the ability of the descending colon to relax in response to rectal distensions. This may explain our observation that during NT infusion higher rectal pressures were needed to demonstrate a rectocolonic reflex compared with placebo. However, because our study was not designed to investigate the mechanisms by which NT acts on rectocolonic motor function, the precise physiologic role of NT in this mechanism remains to be elucidated.
 
In response to pressure distensions in the descending colon, rectal volumes were significantly reduced,
but they returned to basal as soon as the colonic bag was deflated. These data are supported by others,
who found that in response to intraluminal colonic distensions or on the arrival of food in the proximal
colon, rectal motor activity increased. Furthermore, we found that in the placebo experiment, rectal volumes significantly decreased during all colonic distensions (i.e., 15, 20, 25, and 30 mmHg), whereas
infusion of NT resulted in a significant decrease only from 20 mmHg. In analogy with the inhibition of the
rectocolonic reflex as seen during NT infusion, these data show that infusion of NT delays the colorectal
stimulatory reflex. It has been suggested that the role of NT is to enhance colonic motility and induce defecation after a meal. In their study, Calam et al.found that NT stimulates defecation. However, patients did not report bowel movements during infusion. Borborygmi and passage of stools occurred only after the infusion had stopped. These observations suggest that abdominal sensations and bowel movements are provoked by changes in plasma NT levels rather than high plasma concentrations. Our volunteers reported increased abdominal sensations like borborygmi and bloating after the experiment had ended. None of the patients reported an urge to defecate during NT infusion, an observation that is in agreement with the observed delay in colorectal stimulatory reflex.
 
Data on the effect of neurotensin on rectal smooth muscle cells are contradictory. In one study, the authors found that the contractile effect of NT on smooth muscle in chick rectum was antagonized by
an experimental NT antagonist, whereas NT did not seem to play a role in the excitation of smooth muscle of the avian rectum. Studies in humans are lacking. NT might impair the colorectal stimulatory reflex by an equivalent mechanism as proposed earlier for the rectocolonic inhibitory reflex, i.e., by reducing rectal responsiveness to colonic balloon distensions. Further investigations on the specific effect of NT on rectal smooth muscle contractility in vitro in humans may help us to understand its effects in vivo.
 
NT did not significantly alter phasic motility. The number of PVEs seemed to be higher during NT infusion compared with placebo, but this difference did not reach statistical significance. It has been reported that intravenous infusion of NT causes an increase in rectosigmoid motility. This increase was even more pronounced after infusion, which could provide an explanation for postinfusion bowel movements. Furthermore, in our study, rectal distensions induced a (nonsignificant) decrease in colonic phasic motility, which is in line with the previously described rectocolonic inhibitory reflex. Similarly, the increased number of rectal PVEs during colonic distensions is in agreement with the observed colorectal stimulatory reflex.
 
An important finding in our study is that NT increased the intensity of urge and pain sensations in
response to rectal, but not colonic, distensions. It has been shown that visceral perception is more closely related to wall tension than to intraballoon pressure
. Wall tension is calculated from the radius of the balloon and balloon pressure and increases as intraballoon pressure or volume rises. Our data show that the increase in colonic perception can be attributed to an increase in wall tension and that NT does not modify this increase. This finding supports our observation that the infusion of NT does not alter colonic sensations. In contrast, equal wall tensions in the rectum yield more intense sensations during NT infusion compared with placebo. These data indicate that rectal visceroperception is not only dependent on wall tension but that NT has an additional effect on perception by intensifying rectal sensation. NT can modify visceral sensory information in the enteric nervous system of the gut, but also at the level of the spinal cord. Furthermore, it has been reported that NT modulates nociception centrally in the brain and both antinociceptive and hyperalgesic responses to NT have been described in animals. However, our observation that NT acts on rectal but not colonic sensation does not support the hypothesis of a central modulation of perception but points at local actions of NT.
 
In human descending colon, the presence of NT receptors and the effects of NT are well documented.
It has been shown, for instance, that NT mainly affects smooth circular muscle and myenteric and submucosal ganglia. However, the extent to which NT receptors are present in the human rectum and the effects of NT on rectal visceromotor function are not known. A possible explanation for our findings is that the sensitivity of colon, rectum, and anal canal increases toward the anus, probably caused by a decreased density of receptors when going more proximal in the colon. This may be correlated with differences in function between colon and rectum (i.e., propulsion vs. storage and continence of feces, respectively). Thus, discrimination between different levels of sensation may be more developed in the rectum compared with the colon, which could account for the difference we observed. However, Petersen et al. showed that for a given wall tension, sensibility in the rectum and sigmoid colon is equal. This supports our hypothesis that it is the infusion of NT (and not mechanical factors such as pressure distensions) that increases rectal sensitivity, without affecting colonic visceroperception. In theory, NT might do so by affecting certain (mechano)receptors that are present only in the rectum and not in the colon, but this is currently unknown. Future research should focus on 1) the presence of NT receptors in the rectum, and 2) the effects of NT in vitro and in vivo on the human rectum in particular (but also on the colon) to clarify the findings presented in this study.
 
Finally, the effects that bowel preparation, colonoscopy, and the residual air after colonoscopy might
have on rectocolonic motility and sensations should be kept in mind when interpreting these data. As
mentioned before, our subjects tolerated bowel preparation and colonoscopy well and none reported
serious side effects or complications that might result from these procedures. Herve et al. have shown that polyethylene glycol 4,000, which is an osmotic laxative like KleanPrep®, does not alter left colonic or rectosigmoid motor activity when measured by 24-hour manometry. We believe that we measured true rectocolonic motility, not affected by bowel preparation. Furthermore, because all participants had bowel preparation and sigmoidoscopy, we believe that the difference in rectal pain perception that we observed is not caused by altered rating of bowel sensations caused by colonoscopy or residual air after the procedure but that it is attributable to NT infusion.