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.