Effects of alosetron on spontaneous migrating motor complexes
in murine small and large bowel in vitro
Toby G.
Bush,
Nick J.
Spencer,
Niamh
Watters,
Kenton M.
Sanders, and
Terence K.
Smith
Department of Physiology and Cell Biology, University of Nevada
School of Medicine, Reno, Nevada, 89557-0046
 |
ABSTRACT |
Alosetron (Lotronex) is a
serotonin subtype 3 (5-HT3) receptor antagonist that
alleviates symptoms of irritable bowel syndrome (IBS) in female
patients. Alosetron may act centrally, involve the alteration of
ascending pain sensation, or modulate peristaltic, secretory, or
sensory function. To investigate further the mechanisms underlying its
action and gender selectivity we recorded the effect of increasing
concentrations of alosetron or ondansetron on spontaneous migrating
motor complexes (MMCs) from isolated terminal ileum or colon from
C57BL/6 mice. Both antagonists inhibited MMC frequency before affects
on duration or amplitude. The threshold of inhibition for alosetron was
100-fold less in small intestine from females (20 nM) than from males.
The opposite effect of gender was observed with ondansetron in the
colon. All MMCs were abolished by either drug at 10 µM. Our results
demonstrate that alosetron selectively inhibits MMC frequency in
isolated preparations of murine bowel. Because contractile events in
the ileum correlate with symptoms of IBS in humans, the gender
selectivity of alosetron may be caused by a direct action within the
small intestine.
ondansetron; serotonin; enteric nervous system; motility
 |
INTRODUCTION |
IRRITABLE BOWEL
SYNDROME (IBS) is a functional gut disorder characterized by
abdominal pain, discomfort, and altered bowel function
(41). The syndrome affects ~15% of the population
(9, 17) and is characterized by a female predominance of
~70% (35, 47). Although the pathophysiology remains
unclear, it is most likely multifactorial. Dysmotility of both the
large and small bowel of IBS patients has been described (12, 30,
31, 45). Inappropriate secretory activity is also a feature of
IBS (2). Increasingly, however, visceral hypersensitivity
has been implicated in IBS (16, 36, 49). Unfortunately,
current therapies for IBS, including dietary fiber, opioids for
diarrhea, smooth muscle relaxants, and psychotropic and
psychological agents, are not selective and do not give
consistent relief of symptoms (8).
Several lines of evidence support the use of serotonin subtype 3 (5-HT3) receptor antagonists for the treatment of IBS.
Originally developed for suppressing chemotherapy-induced nausea,
5-HT3 receptor antagonists attenuate 5-HT-induced signaling
in visceral afferents (23). Intestinal distension in
animals leads to activation of reflex behavior that is used to model
visceral pain. 5-HT3 antagonists potently suppress these
reflexes (34). These compounds also suppress gut motility
in IBS patients, particularly in the large bowel (26, 38,
46). Additional therapeutic effects of 5-HT3 receptor antagonists may be a consequence of their antianxiolytic properties (14, 28).
Numerous studies have investigated the effects of 5-HT3
receptor antagonists on human bowel function in health and disease. Rectal desensitization by granisetron in IBS patients occurred in the
absence of effect on rectal tone (38). In addition,
postprandial motility was inhibited but distension-induced motility was
unaffected. On the other hand, ondansetron significantly slowed whole
gut transit in healthy men (22) but did not influence any
index of colonic function in five patients with diarrhea-predominant IBS (25). A single intravenous dose of ondansetron failed
to affect rectal or gastric sensitivity in IBS, although compliance of
the colon was increased (51). A gender selectivity of
action for ondansetron has not been reported.
Recent studies demonstrated that alosetron (Lotronex), a novel and
highly potent 5-HT3 antagonist, gives relief of symptoms selectively in female patients with IBS, although in both studies the
number of male patients included was low (1, 10). A larger study, conducted entirely in women, has demonstrated 1 mg b.d. as the
most effective dose for improving abdominal pain and discomfort, urgency, and stool frequency and consistency (11).
Alosetron did not change the perception of colonic distension, yet it
significantly increased the compliance of the colonic wall to
distension in IBS patients (15). In carcinoid diarrhea,
alosetron did not affect gastric emptying or small bowel transit but
significantly slowed proximal colon emptying, the most abnormal
physiological parameter of this disease (43, 48). In both
healthy volunteers and IBS patients, alosetron delayed colonic transit
in the absence of an effect on small bowel transit (26).
To investigate whether alosetron has a direct action on the gut and to
determine whether this is a site of gender selectivity, we examined the
effects of alosetron on spontaneous migrating motor complexes (MMCs) in
the terminal ileum and colon of the C57BL/6 mouse in vitro. These
events recorded from the murine bowel in vitro share
pharmacological characteristics with phase III activity of the human
MMC in vivo (20). Our earlier work (5)
revealed no gender differences in frequency, amplitude, or duration of
MMCs for either tissue. We therefore recorded the effects of alosetron
and ondansetron on spontaneous MMCs in tissue from both males and females.
 |
METHODS |
Measurement of contractile activity.
Nonfasted C57BL/6N mice (Simonsen Labs, Gilroy, CA) of either gender,
7-12 wk of age, were killed by cervical dislocation. The phase of
the ovarian cycle in female mice was not determined. The entire colon
and, separately, the terminal ileum of a comparable length (6-7
cm), were removed into modified Krebs solution. The luminal contents
were flushed gently, a stainless steel rod (1.0-mm diameter) was
inserted into the lumen of the bowel, and the tissue was secured to
mounting posts fixed securely to the bottom of the bath using rubber O
rings. The bath contained prewarmed Krebs solution at 37.0 ± 0.5°C and was gassed (3% CO2-97% O2
vol/vol) throughout the experiment. The Krebs solution was replaced
approximately every hour until activity became coordinated.
Two stainless steel clips (micro-serrefines; Fine Science Tools, Foster
City, CA) were attached to the tissue within 1.5-2 cm of the oral
and anal ends. Suture silk was used to connect each clip to a force
transducer (model TST125C; Biopac Systems, Santa Barbara, CA). Initial
tension was routinely set to <5 mN to minimize local reflex
stimulation of the bowel. Tension was monitored continuously using an
MP100 interface and recorded on a PC running Acqknowledge software
3.2.6 (Biopac Systems).
Solutions and drugs.
The composition of the Krebs solution was (in mM) 120.35 NaCl, 5.9 KCl,
15.5 NaHCO3, 1.2 NaH2PO4, 1.2 MgSO4, 2.5 CaCl2, and 11.5 glucose. The
solution was gassed continuously with a mixture of 3%
CO2-97% O2 (vol/vol) to give a final pH of
7.3-7.4.
Stock solutions of 1 mM alosetron and ondansetron were made up in
distilled water, aliquoted, and stored frozen. Dilution series were
prepared daily and added sequentially to the bath.
Analysis of data and statistical methods.
Contractile activity was analyzed from computer traces. Frequency and
duration of coordinated peaks were assessed from the anal trace using
established experimental parameters (5, 19). The anal
trace was selected because peaks were more uniform and were more stable
with increasing time ex vivo compared with the oral trace (see Figs.
2-4). The duration of each contraction was determined as the time
between the half-maximal amplitude points on the rising and falling
phases. The interval between contractions was determined by the time
between the half-maximal amplitude points on the rising phase of
consecutive contractions (Fig. 1). Amplitude, duration, and frequency were expressed as percentage of
control values for statistical analysis. Control values were obtained
from a minimum of five peaks immediately preceding the application of
antagonist to the bath. Data are presented as means ± SE. Log
IC50 and Hill coefficient values were obtained using GraphPad Prism version 3.00 for Windows (GraphPad Software, San Diego,
CA). Statistical significance was determined using Student's t-test (paired or unpaired as appropriate) or Mann-Whitney
rank correlations.

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Fig. 1.
Migrating motor complex (MMC) parameter analysis. Amplitude was
defined as the difference between precomplex tension and maximum peak
height. Duration was measured between the half-maximum amplitude points
of the rising and falling phases of the complex. Interval was measured
between the half-maximum amplitude points of the rising phase of
consecutive complexes. Measurements were made only in propagated
complexes in anal traces.
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RESULTS |
Stability of MMC activity in large and small bowel.
To demonstrate that stability of MMC activity exceeded the duration of
the antagonist experiments, preparations were monitored continuously in
the absence of any manipulation (Figs.
2A and 3A). Although duration and
frequency remained constant, there was a tendency for the amplitude to
wane. This effect was significant in oral traces but did not reach
significance in anal traces (data not shown). All measurements of
effects of antagonists were measured using recording of activity in
anal traces.

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Fig. 2.
Effect of alosetron on MMC activity in male colon. Once
established, MMC activity was sustained in colonic preparations for >3
h (A). Sequential addition of alosetron caused a pronounced
slowing of MMC frequency (B).
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Fig. 3.
Effect of alosetron on MMC activity in male ileum. MMC activity in
the ileum could be maintained for >4 h (A). Increasing
concentrations of alosetron caused a slowing of MMC frequency
(B).
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Effects of alosetron on spontaneous MMC activity in large and small
bowel.
Alosetron dose-dependently decreased the frequency of MMC activity in
both the large and small bowel (Figs. 2B and 3B).
The effect on frequency occurred before effects on either amplitude or
duration. Although there was no effect of gender on colonic frequency, the small intestine from females showed a significantly greater sensitivity than tissue from males (Fig.
4). There was a 100-fold difference
in threshold concentrations required to slow MMC activity in
females and males (20 nM and 2 µM, respectively). MMC activity
in both tissues was abolished by 10 µM alosetron. In both intestinal
regions, there was a tendency for reduced amplitude in the presence of
2 µM alosetron, but this was only significant in the small bowel
(Fig. 4). With increasing doses of alosetron, the duration of each MMC
appeared to decrease in the male colon. In contrast, there was a
significant increase in the duration of MMCs in female tissue. No
effect of gender on duration of MMC in the small intestine was
observed.

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Fig. 4.
Effect of alosetron on MMC parameters. Alosetron showed a
dose-dependent decrease in frequency of MMC activity in both the small
and large bowel. No effect of gender was observed in the colon.
However, the threshold for slowing of MMCs occurred at a 100-fold lower
dose in female compared with male small intestine (20 nM and 2 µM,
respectively). All MMC activity was abolished by 10 5 M
alosetron. *P < 0.05, **P < 0.01 compared with control activity. SI, small intestine.
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Effects of ondansetron on spontaneous MMC activity in large and
small bowel.
The effects of ondansetron on spontaneous MMC activity in both the
small and large bowel of the mouse were qualitatively indistinguishable from the effects of alosetron (Fig. 5).
As was observed for alosetron, the threshold for effect of ondansetron
on MMC frequency occurred before an effect on either amplitude or
duration. No effect of gender was observed on the decrease in MMC
frequency in the small intestine. At low concentrations of ondansetron
(<5 nM), we observed a small but significant increase in MMC frequency
selectively in male small intestine preparations (Fig.
6). In the colon, however, we observed a
large gender difference in the response to ondansetron. The threshold
for inhibition of MMC frequency was 100-fold lower in the male colon
compared with the female colon (Fig. 6; 20 nM and 2 µM,
respectively).

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Fig. 5.
Effect of ondansetron on MMC activity in male ileum and colon. In
both ileal (A) and colonic (B) preparations
ondansetron decreased MMC frequency in a manner qualitatively
indistinguishable from the effect of alosetron.
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Fig. 6.
Effect of ondansetron on MMC parameters. Ondansetron showed a
dose-dependent decrease in frequency of MMC activity in both the small
and large bowel. No effect of gender was observed in the small
intestine. In the colon, and the reverse of the selectivity of
alosetron, the threshold at which MMC frequency was inhibited in the
male occurred at a 100-fold lower dose then in the female (20 nM and 2 µM, respectively). All MMC activity was abolished by
10 5 M ondansetron. *P < 0.05, **P < 0.01 compared with control activity.
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The effects of ondansetron on amplitude were not affected by gender in
either tissue. In contrast, and similar to the trend observed with
alosetron, ondansetron appeared to reduce the duration of MMC activity
in the colon selectively in male tissue. This effect was not observed
in the small intestine.
Gender selectivity of effect of 5-HT3 antagonists on
MMC activity in large and small bowel.
To determine IC50 values for each drug, the inhibition of
MMC frequency was plotted against drug concentration (Fig.
7). The values ranged from 0.1 to 1.5 µM (Table 1). No gender differences were apparent between any drugs or tissues, with the exception that
ondansetron was significantly more potent in the male compared with the
female colon. Although no differences in IC50 values for
alosetron were observed (Table 1), the inhibitory effect in the female
small intestine was significantly greater than that in male tissue
(Fig. 7). This was reflected in the large difference between the Hill
coefficients for these tissues (Table 2).

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Fig. 7.
Inhibition of MMC frequency by serotonin subtype 3 receptor (5-HT3) antagonists. Although effects of alosetron
were indistinguishable in colonic preparations from both genders, the
threshold for effects of alosetron was lower in small intestine
preparation from female mice compared with males. In contrast, gender
had no effect on the efficacy of ondansetron in the small intestine
preparations from both genders but was significantly move efficacious
in the male colon. *P < 0.05, **P < 0.01 compared with equivalent gender group.
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 |
DISCUSSION |
Recent clinical trials have demonstrated that the
5-HT3 receptor antagonist alosetron (Lotronex) relieves
symptoms of IBS and that this occurs selectively in female patients
(1, 10, 11). However, the sites of action and mechanisms
that underlie both the action and gender selectivity of alosetron
remain uncertain.
In this study, we found that alosetron and ondansetron had a direct,
selective inhibitory effect on the frequency of spontaneous MMC in
isolated small and large intestine from C57BL/6 mice. In addition, with
the exception of human studies, this is the first study to demonstrate
a gender difference in bowel response to 5-HT3 antagonism.
Gender selectivity of action.
Our previous work (5) demonstrated that gender had no
effect on the parameters of MMC activity. We therefore made comparisons between drugs, genders, and bowel regions. A striking and reciprocal effect of gender was observed for the two drugs. The threshold for
effects of alosetron in the female small intestine (20 nM) was 100-fold
lower than for male small intestine. There was no effect of gender in
the colon. Ondansetron, on the other hand, showed no gender effect in
the small intestine, but the threshold in the male colon (20 nM) was
100-fold lower than in the female colon. The threshold for effect and
IC50 values, ranging from 0.1 to 1.5 µM, strongly suggest
that 5-HT3 receptor activation regulates the frequency of
MMCs in the murine bowel.
The therapeutic effect of alosetron in female IBS patients can be
observed at 1 (11) and 2 (1) mg b.d.
Pharmacokinetic studies have demonstrated that the peak plasma
concentration after oral administration of 2 mg is between 10 and 20 ng/ml (approximating 30-60 nM) (24). However, because
the alosetron shows a large first-pass effect and the gastrointestinal
tract may be the site of this effect, the local concentration within
the gastrointestinal tract may be much higher. The pharmacokinetic
profiles of ondansetron and alosetron are similar. Systemic exposure
after oral or intravenous dosing with ondansetron was significantly
higher in women than in men (39). A higher systemic
exposure in women is also observed for alosetron (24).
Three mechanisms may be responsible. First, women cleared the drug more
slowly than men. Second, women showed higher bioavailability,
presumably because of reduced first-pass uptake of drug. Third, the
weight-adjusted volume of distribution was smaller in women. However,
increasing the dose of alosetron in male IBS patients was ineffective
in alleviating symptoms, suggesting that factors other than
bioavailability are responsible for the gender selectivity of alosetron
efficacy (10).
It is therefore currently unclear why alosetron shows efficacy
selectively in female IBS patients. This is the first study to
demonstrate a gender difference in the effects of 5-HT3
antagonists in an animal model of gut physiology. The principal gender
difference in response to alosetron was a 100-fold lower threshold for
decreasing frequency of ileal MMC activity in female mice. Because the
distal small intestine has been implicated as the origin of symptoms in
some patients with IBS (30, 31), it is tempting to
speculate that the gender selectivity of alosetron is based on a direct effect on the female small intestine. Alosetron did not affect ileal
transit in clinical studies, suggesting that effects on ileal motility
are not the mechanism of its therapeutic efficacy (26).
Our data also show that there are gender differences between individual
5-HT3 antagonists in this assay. One explanation for this
effect is a differential distribution of 5-HT3 receptor
subtypes. Recently the pharmacological properties of a shorter splice
variant of the murine 5-HT3 receptor have been reported
(4). Although most drugs exhibited almost identical
properties at the native and variant receptor, ondansetron was more
potent at the shorter splice variant. Whether gender differences in the
expression patterns of the full-length 5-HT3 receptor and
the splice variant exist in either mice or humans is currently unknown.
Extensive preclinical pharmacology has demonstrated the potency and
selectivity of alosetron. The pKi values for the
rat (9.8) and human (9.4) 5-HT3 receptors are very similar,
with no other receptor demonstrating binding with a
pKi >6 (13). The
pKB for alosetron on rat 5-HT3
receptors was 9.8 (13), whereas in the same assay
ondansetron had a pKB of 8.6 (7).
Unfortunately, interspecies comparisons must be interpreted with
caution because large species difference in 5-HT3 receptor
pharmacology have been reported. In particular, binding of antagonists
at the guinea pig 5-HT3 receptor appears to require several
orders of magnitude greater concentrations of drug compared with
binding at the rat receptor (6). Although the binding
affinity for the murine 5-HT3 receptor has not been
assessed directly, in vivo and tissue culture studies have shown that
its pharmacological properties are similar to those of the rat receptor
(4, 32, 50). In vivo studies have shown that ondansetron
(3.2 mg/kg) does not disturb normal colonic transit in the rat
(29). However, lower doses (0.1-1 mg/kg) dose
dependently increased whole gut transit time in male mice
(37). Similarly, the concentrations required to
demonstrate the antianxiolytic effects of ondansetron are similar in
rats and mice (28). Together, these results strongly
suggest that the mouse 5-HT3 receptor more closely
resembles that of the rat than that of the guinea pig.
Possible enteric sites and modes of drug action.
One of the original criteria for diagnosing IBS is abdominal pain
relieved by defecation (33). It has been shown that pain associates temporally with eating but not defecation in IBS
(40). A striking correlation between prolonged propagating
contractions (PPCs) and abdominal pain was observed in IBS patients
(30). Interestingly, this study also reported that PPCs
were also associated with postprandial pain, similar to that regularly
experienced in 44% of IBS patients. Together, these studies suggest
that in some patients the ileum may be the site of origin of symptoms of IBS.
Although 5-HT3 receptors have central, peripheral, and
enteric locations, our data suggest that alosetron and ondansetron have
direct actions on both the small and large intestine. Recent studies
also showed that 5-HT3 receptor antagonists can act
directly on the large intestine, because LY-278584 slows the propulsion of pellets in the isolated guinea pig distal colon (27)
and ondansetron reduces MMC activity in the isolated colon of
nonaffected littermates of the piebald lethal mouse (18).
5-HT3 receptor antagonists could affect neuro-neuronal
transmission down the bowel, because some descending interneurons in the mouse are serotonergic and ligand-gated 5-HT3 receptors
have been demonstrated on different functional classes of enteric
neurons, at least in the guinea pig (42, 44). However,
both alosetron and ondansetron reduced MMC frequency more effectively
than complex amplitude, suggesting that 5-HT3 receptors
were more likely to be involved in the pacemaker responsible for the
generation of the MMC than in the conduction of MMCs down the bowel.
This latter phenomenon is critically dependent on cholinergic
neurotransmission (5, 19). Alosetron and ondansetron could
be blocking 5-HT3 receptors on the mucosal processes of
intrinsic sensory neurons, which are readily activated by mucosally
applied 5-HT (3). The generation of the MMC may therefore
be dependent on spontaneous release of serotonin from enterochromaffin
(EC) cells in the mucosa, which contain over 90% of the body's
serotonin, that excites intrinsic sensory neurons (44). EC
cells themselves express 5-HT3 receptors that appear to
enhance 5-HT release (21). 5-HT3 antagonism at this site would therefore reduce the frequency of 5-HT release and may
in turn reduce MMC frequency.
In conclusion, our results show clear gender differences in the action
of both alosetron and ondansetron on spontaneous migrating motor
activity in the murine bowel. Compared with the male small intestine,
alosetron had a significantly lower threshold for effects in the female
small intestine. The ileum has been identified as a site of origin of
symptoms in IBS in humans. Gender differences in the distribution of
the 5-HT3 receptor or its splice variants have the
potential to contribute to the gender selectivity of action of
alosetron in IBS.
 |
ACKNOWLEDGEMENTS |
Support for this project was provided by the National Institute of
Diabetes and Digestive and Kidney Diseases (DK-10793 to T. K. Smith, PO1-DK-41315 to K. M. Sanders and T. K. Smith) and by
Glaxo Pharmaceuticals (K. M. Sanders and T. K. Smith).
 |
FOOTNOTES |
Preliminary results of this study were presented at the annual meeting
of the American Gastroenterological Society, San Diego, CA, 2000, and
at the International Society for Autonomic Neuroscience, London, UK, 2000.
Address for reprint requests and other correspondence: T. K. Smith, Dept. of Physiology and Cell Biology, Univ. of Nevada, School
of Medicine, Anderson Medical Bldg. MS 352, Reno NV 89557-0046 (E-mail:
tks{at}physio.unr.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 February 2001; accepted in final form 21 May 2001.
 |
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