Activation of peripheral 5-HT4 receptors attenuates colonic sensitivity to intraluminal distension

Tegaserod is a 5-HT(4) receptor partial agonist approved for the treatment of irritable bowel syndrome in women with constipation and in both men and women with chronic constipation. The efficacy of tegaserod is based on the importance of 5-HT(4) receptors regulating intestinal peristalsis and secretion, and possibly visceral sensory pathways. Our aim was to investigate the effect of tegaserod on colorectal sensitivity using models of normal and exaggerated responsiveness to colorectal distension (CRD). The visceromotor responses (VMR) to CRD at graded pressures (0-60 mmHg) were measured by the number of reflex abdominal contractions. Acute colorectal hypersensitivity was induced by intracolonic infusion of dilute acetic acid. Chronic hypersensitivity was observed in rats following spontaneous resolution of trinitrobenzenesulfonic acid-induced colitis. Rats with normosensitive colons served as controls. Tegaserod (0.1-10 mg kg(-1)) caused dose-dependent reduction of the VMR to CRD in control rats and in those with colonic hypersensitivity. 5-HT(4) antagonists reversed the effects of tegaserod in rats with normosensitive colons, and partially inhibited effects in rats with colonic hypersensitivity. Central administration of tegaserod had no inhibitory effect. These results support the assumption that colonic hypersensitivity could be normalized by tegaserod acting, at least in part, through peripheral 5-HT(4) receptors.     

Subtypes of Anal Incontinence Associated With Bowel Dysfunction: Clinical,Physiologic, and Psychosocial Characterization

BACKGROUND We hypothesized that functional anal incontinence with no structural explanation comprises distinct pathophysiologic subgroups that could be identified on the basis of the predominant presenting bowel pattern.METHODS Consecutive patients (n = 80) were prospectively grouped by bowel symptoms as 1) incontinence only, 2) incontinence + constipation, 3) incontinence + diarrhea, and 4) incontinence + alternating bowel symptoms. The Hopkins Bowel Symptom Questionnaire, the Symptom Checklist 90-R, and anorectal manometry were completed.RESULTS Significant group differences were found between subcategories of incontinent patients on the basis of symptoms. Abdominal pain was more frequent in patients with altered bowel patterns. Patients with alternating symptoms reported the highest prevalence of abdominal pain, rectal pain, and bloating. Basal anal pressures were significantly higher in alternating patients (P = 0.03). Contractile pressures in the distal anal canal were diminished in the incontinent-only and diarrhea groups (P = 0.004). Constipated patients with incontinence exhibited elevated thresholds for the urge to defecate (P = 0.027). Dyssynergia was significantly more frequent in patients with incontinence and constipation or alternating bowel patterns.CONCLUSIONS Distinct patterns of pelvic floor dysfunction were identified in patient subgroups with anal incontinence, based on the presence or absence of altered bowel patterns. Physiologic assessments suggested different pathophysiologic mechanisms among the subgroups. The evaluation of patients with fecal incontinence should consider altered bowel function.Presented in part at the meeting of the American Gastroenterology Association, San Diego, California, May 21 to 24, 2000.Published in abstract form in Gastroenterology 2000;118:A1166.     

The effects of tegaserod, a 5-HT4 receptor agonist, on gastric emptying in a murine model of diabetes mellitus

The C57BLKS/J db/db transgenic mouse is a model of diabetes mellitus that has been shown to have delayed gastric emptying. We assessed gastric emptying rates in C57BLKS/J mice, and determined the effects of tegaserod, a new selective 5-HT(4) receptor partial agonist, on gastric emptying. METHODS: Gastric emptying rates of a 20% glucose test meal were determined in 12-20-week-old female db/db mice and control littermates. The effects of tegaserod (0.1-2.0 mg kg(-1), i.p.) on gastric transit were tested in a second group of db/db mice. Pretreatment with GR11308, a specific 5-HT(4)antagonist, was used to confirm the mechanism of action of tegaserod on gastric emptying. RESULTS: Gastric emptying of glucose was significantly slower in db/db mice than in control littermates. Tegaserod (0.1 mg kg(-1)) significantly accelerated the gastric emptying rate of glucose in db/db mice, reducing the fraction of the meal remaining in the stomach at 30 min by 80%. GR11308 blocked the gastrokinetic effects of tegaserod. CONCLUSIONS: Gastric emptying was impaired in db/db mice. Low dose tegaserod improved gastric emptying rates in this model of gastroparesis through the activation of 5-HT(4) receptors. These findings suggest that 5-HT(4) receptor agonists may prove useful for improving delayed gastric emptying in gastroparesis.     

Brain–gut connections in functional GI disorders: anatomic and physiologic relationships

Understanding the neural regulation of gut function and sensation makes it easier to understand the interrelatedness of emotionality, symptom-attentive behavior or hypervigilance, gut function and pain. The gut and the brain are highly integrated and communicate in a bidirectional fashion largely through the ANS and HPA axis. Within the CNS, the locus of gut control is chiefly within the limbic system, a region of the mammalian brain responsible for both the internal and external homeostasis of the organism. The limbic system also plays a central role in emotionality, which is a nonverbal system that facilitates survival and threat avoidance, social interaction and learning. The generation of emotion and associated physiologic changes are the work of the limbic system and, from a neuroanatomic perspective, the 'mind-body interaction' may largely arise in this region. Finally, the limbic system is also involved in the 'top down' modulation of visceral pain transmission as well as visceral perception. A better understanding of the interactions of the CNS, ENS and enteric immune system will significantly improve our understanding of 'functional' disorders and allow for a more pathophysiologic definition of categories of patients currently lumped under the broad umbrella of FGID.