INTRODUCTION
5-HT4 receptors (5-HT4R) have long been among the most compelling targets for prokinetic agents. Oral doses of 5-HT4R agonists have been used clinically to treat dysmotility; clinical trials have provided evidence that the 5-HT4R agonist prucalopride, given orally, increases transit in humans and can be effective in managing constipation (3, 5, 8). Corroborating live animal studies have shown that oral or intravenous prucalopride result in enhancement of peristaltic activity in the dog colon (6). Studies on whole rat colon by our team provided further insights into actions of 5-HT on colonic motor patterns (51, 52). Furthermore, using high-resolution colonic manometry (HRCM), we observed that oral intake of prucalopride can initiate peristaltic activity within 10 minutes in human healthy volunteers (37) likely through a gastro-colonic reflex mediated by gastric 5-HT4Rs. However, despite the clinical success of 5-HT4R agonists, concerns about their adverse cardiovascular side effects and inconsistent efficacy has limited their use. Several mechanisms of action may underly 5-HT4R agonists because of the fact that within the GI tract, 5-HT4Rs are widespread among various types of enteric neurons, 5-HT containing enterochromaffin cells, smooth muscle cells and interstitial cells of Cajal (ICC). Moreover, 5-HT4R expression is different between anatomical regions and among different species (22).
Animal models have demonstrated that luminal application of 5-HT4R agonists promotes propulsive motility in the gastrointestinal tract (26) (49) (19) (36). For instance, mucosal application of the 5-HT4R partial agonist tegaserod promoted peristalsis in rat and guinea pig colonic segments (21). Moreover, pellet propulsion studies showed that administration of intraluminal 5-HT4R agonists tegaserod, prucalopride and naronapride increased the velocity of pellet propulsion significantly more than their serosal application in guinea pig distal colon. This suggests that intraluminal administration of 5-HT4R agonists may be more effective than their oral application in regulating propulsive activity (26) (36) (21) (27). Mucosal application of tegaserod activated 5-HT release from enterochromaffin cells, mucus discharge from goblet cells and Cl secretion from enterocytes in mouse and guinea pig colonic tissue segments as well as human biopsies (26). Such responses were generated in a TTX insensitive and antagonist sensitive manner indicating that 5-HT4R agonists stimulated 5-HT release from within the lumen by directly activating EC cells rather than via a neural mechanism (26) (45) (22).
Altered 5-HT signaling has been associated with chronic constipation and irritable bowel syndrome (IBS). El-Salhy and colleagues reported that the number of 5-HT-immunoreactive cells per unit area of epithelial cells is lower in colons of patients with slow transit constipation compared to healthy controls (17), suggesting a role for 5-HT signaling in gut homeostasis (2) (47, 48) (32). Consistent with animal studies mentioned above, we have recently shown that intraluminal perfusion of the highly selective 5-HT4R agonist prucalopride significantly increases propulsive motor activities in the whole proximal and mid rabbit colon (45). This likely occurs via 5-HT release from enterochromaffin cells into the lamina propria to activate intestinal primary afferent neurons (IPANs) and subsequently the myenteric motor neurons (22).
Propulsive activity in the rabbit colon takes the form of the Colonic Motor Complexes (CMCs) (15, 24, 33, 39, 45). The development of the CMC occurs in a dose-dependent and antagonist sensitive manner, manifested in various levels of excitation beginning with clusters of fast propagating contractions followed by long distance contractions (LDCs) as the most forceful representation of the CMC in the rabbit. Additionally, intraluminal prucalopride and intraluminal exogenous 5-HT significantly increased contraction amplitude, intraluminal pressure amplitude, frequency, velocity and degree of propagation of the CMC along the colon (45).
In this case study, we show that intraluminal prucalopride enhances propulsive motor activities in the human colon.