Ramosetron, a selective 5-HT3RA, inhibits GI transit. This effect was well demonstrated by its inhibitory effects on accelerated GI transit caused by 5-HT, TRH and MO in this study.
The 5-HT is an important signaling molecule that involves peristaltic, secretory, vagal and nociceptive reflexes.16
This signaling molecule is found in the GI tract in the interneurons that terminate in the myenteric and submucosal plexuses,17
is released from EC cells by vagus nerve stimulation, and induces a release of acetylcholine from excitatory (cholinergic) neurons.18
TRH stimulates the centers of the brain which control the vagal-enteric nervous systems, and involves cholinergic and serotonergic mechanisms.19
The smooth muscle contraction that is elicited is influenced by changes of neurotransmitter release, either positively or negatively.17
TRH also induces release of serotonin, which results in accelerated GI transit and causes diarrhea.13,20
Similarly, MO induces 5-HT release from EC cells in vitro by way of TRPA-1, which is highly expressed in both the intestine and the stomach.10
TRPA-1 agonists are reported to have a contractile effect in isolated mouse intestine in vivo, but the effect of TRPA-1 agonists on GI motility in guinea pigs has not been verified.21
In a previous experiment in rabbits, the contractile responses of allyl isothiocyanate, which is a TRPA-1 agonist, were reduced by ramosetron.22
receptors (the original 5-HT M receptor) are distributed widely in both the GI tract and the central nerve system, and result in increased intestinal secretion and alteration of peristaltic activity.16,23
In animals, 5-HT3
RAs have been found to inhibit stress-induced abnormal defecation in animals.9,12
RAs already have a therapeutic use for IBS-D, and their effectiveness is well-known. 5-HT3
RAs have also been confirmed to have an inhibitory effect on lower GI transit,5,12
but their effects and mechanism on the upper GI tract (stomach and small intestine) have not been verified.
Previously, Doihara et al24
showed that intragastric administration of 1 mg/kg allyl isothiocyanate facilitated phasic contractions in the gastric antrum and jejunum, and that these effects were inhibited by pretreatment with ruthenium red, a TRPA-1 antagonist. However, in another study involving guinea pigs, the selective 5-HT3
RA ondansetron increased the rate of gastric emptying in vivo,25
although the precise mechanisms have not been elucidated.
Ramosetron is a potent and selective 5-HT3
RA. Ohta et al26
have suggested that ramosetron may achieve long-lasting binding to 5-HT3
receptors because ramosetron possesses the distinctive ability to maintain an active 3-dimensional chemical conformation. This drug has already proven to be effective for IBS-D in both animal and clinical studies. Recently, although Hirata et al27
showed that ramosetron significantly inhibited the delayed gastric emptying in a corticotrophin releasing factor and soybean oil-induced rat model, few studies have investigated the effects of ramosetron on altered upper GI transit. Therefore, we hypothesized that ramosetron may affect the motor function of the small bowel as well as the stomach, which was investigated by using charcoal GI transit. Aquiring the data on net effect of the gastric and small intestinal charcoal transit makes our study different from previous studies.
Our study demonstrated that ramosetron inhibits normal GI transit and that it also inhibits the accelerated GI transit induced by 5-HT, TRH and MO in guinea pigs. Along these lines, previous animal and preliminary human studies have indicated that 5-HT3
RAs may facilitate activity dependent on the degree of basal tone.17,23
A few studies have also shown that 5-HT3
RAs accelerated delayed gastric emptying in animal models.28
On the other hand, Talley et al29
reported that ondansetron, a selective 5-HT3
RA, did not significantly alter small intestine transit and oral to cecal transit time in healthy volunteers. Troisetron, a selective 5-HT3
RA, has been found to either modestly increase gastric emptying or reduce it in healthy volunteers.30
The action of 5-HT3
RAs to modify contraction-relaxation responses would be dependent on the relative balance of excitatory-inhibitory tone.17,23
RAs might reduce motor activity in the presence of an abnormally increased basal activity. The transit time at lower doses of TRH and MO is actually slower compared to the control group in this study. Different doses of TRH and MO do affect GI transit. It was shown in higher doses that they accelerated GI transit. Perhaps this is due to a balance of inhibitory and excitatory tone at the neuromuscular junction. It will necessitate further investigation and more studies to explain the odd phenomena that lower doses of TRH and MO causes apparent inhibitory effect on GI transit.
In conclusion, this stuty showed that 5-HT, TRH and MO accelerated GI transit. Ramosetron, which is a 5-HT3RA, inhibited 5-HT, TRH and MO-induced accelerated GI transit. Therefore, we suggest that ramosetron may be therapeutically useful for accelerated upper and lower GI transit.