Clinical Science (1998) 94,663-670 (Printed in Great Britain)
663
Concentration-dependent stimulation of intestinal
phase 111 of migrating motor complex by circulating
serotonin in humans
Mikael LORDAL, Hikan WALLEN*, Paul HJEMDAHL*,Olof BECK* and Per M. HELLSTROM
Department of Gastroenterology and Hepatology, Karolinska Hospital, 5-171 76 Stockholm, Sweden, and *Seaion
of
Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Hospital, 5- I7 I 76 Stockholm, Sweden
1. The influence of circulating 5-hydroxytryptamine
(serotonin) on small intestinal motility was investigated
in healthy volunteers.
2. Small intestinal motility was studied by means of a
constantly perfused multi-channel manometry tube,
connected to a computer system.
3. Intravenous infusions of either 5-hydroxytryptamine
at increasing doses or saline were given over a period of
4 h.
4. 5-Hydroxytryptamine infusion dodependently increased plasma 5-hydroxytryptamine from approximately 2 to 10 and 25 nmol/l respectively, as well as
urinary excretions of 5-hydroxytryptamine and 5hydroxyindole acetic acid, a major 5-hydroxytryptamine metabolite.
5. The number of phase 111 of the migrating motor
complex originating in the small intestine was dosedependently increased by 5-hydroxytryptamine, and
found to correlate to the plasma concentration of 5hydroxytryptamine. The fraction of phase III also
increased at the expenseof phase 11 activity. In addition,
5-hydroxytryptamine increased the motility index, propagation velocity of phase III activity and the amplitude
of contractions during phase III.
6. Whereas the low dose of 5-hydroxytryptamine (15
nmol min-' kg-') had no haemodynamic effects, an
increase in heart rate by approximately 20 beats/&,
without change in blood pressure, was observed at the
higher dose (60nmol min-' kg-'). Respiratory parameters did not change during infusion of 5-hydroxytryptamine at either dose.
7. In conclusion, elevation of circulating 5-hydroxytryptamine by intravenous infusion results in more
frequent and faster propagating migrating motor complexes in the human small intestine during the interdigestive period.
-
-
-
-
INTRODUCTION
The biogenic amine 5-hydroxytryptamine (5-HT,
serotonin) is present in the enterochromaffin cells of
the mucosa [l] and in nerve cells of the myenteric
plexus [2,3] in the gastrointestinal tract. Occasionally,
5-HT can also be found together with various neuropeptides such as somatostatin, substance P and vasoactive intestinal peptide in gut neurons [4]. In blood, 5HT is predominantly stored in platelets, and may be
released by activation of these cells. The fate of
intravenously infused 5-HT has not been studied in
humans, but animal experiments have shown that 5HT is rapidly removed from the circulation [5,6],
presumably due to uptake by platelets and endothelial
cells, as well as by metabolism.
5-HT has been shown to stimulate gastrointestinal
motility in man, both in vitro and in vivo [7,8].
However, these studies were carried out before the
recognition of the migrating motor complex (MMC)
in man [9]. Insights into the control of gastrointestinal
motility may be studied through analysis of the MMC,
since this is the only motor pattern that can be
predicted to recur within a certain, though variable,
time interval. The effects of 5-HT on MMC have been
most extensively studied in animals [10-121, while
human studies are few. Serotoninergic mechanisms
may be involved in the regulation of MMC in man, as
suggested by the finding that treatment with a selective
5-HT reuptake inhibitor, paroxetine, shortens the
MMC interval and increases the propagation velocity
of phase I11 of MMC in the proximal jejunum [13].
Furthermore, we have previously found that bolus
injections of 5-HT given intravenously induce phase
111-like activity in the small intestine of healthy
volunteers [14].
5-HT exerts its effects through interactions with
different receptor subtypes on nerves and muscle cells
in the small intestine. A number of 5-HT receptor
subtypes exist. Seven main subgroups are defined (5HT,-,) of which three (5-HT1, 5-HT2and 5-HT6)are
further divided into two or more subtypes (5HTIA,B,D,E,
5-HT2, and 5-HT6,,,) [15]. 5-HT may
inhibit (5-HTJ or facilitate (5-HT2) the release of
acetylcholine from nerves. Similarly, 5-HT may contract or relax smooth muscle directly. For example, 5HT,, receptors, present on human intestinal muscle
cells, mediate contraction of longitudinal muscle [161.
5-HT2, and 5-HT4 receptors, also present on human
Key words: Ihydroxytryptamine, motility. serotonin, small intestine.
Abbreviations: SHIM, Shydroxyindole acetic acid; SHT, Shydroxytryptamine;MMC. migrating motor complex.
Correspondence: Dr Mikael Llirdal.
664
M. Lordal and others
intestinal muscle cells, have opposite effects, the former
mediating contraction and the latter mediating relaxation of smoth muscle cells [17].
The aim of the present study was to investigate the
effect of systematically administered 5-HT on the
MMC in healthy humans. Furthermore, we intended
to study the concentration-effect relationship for 5HT by measurements of its plasma levels and to
analyse the relationship between plasma 5-HT and the
urinary excretion of both 5-HT and its main metabolite, 5-hydroxyindole acetic acid (5-HIAA).
MATERIALS A N D METHODS
Twenty-two healthy volunteers, 12 males and 10
females [mean age 28 (range 2 1-39) years], participated
in the study. Two subjects participated in two different
experiments, with at least 1 month between the
experiments. The study protocol was approved by the
Ethics Committee of the Karolinska Hospital, and
informed consent was obtained from all volunteers.
Experimental protocol
Experiments were undertaken after an overnight
fast during a period of 8 h, with subjects in the
recumbent position. Each experiment consisted of two
consecutive motility registration periods of 4 h each.
The controls (n = 8) received saline (0.9Oh NaC1)
during both 4-h periods for recordings of basal
gastrointestinal motor activity. In the experimental
groups, saline was given during the first 4-h period and
5-HT at doses of either 15 nmol min-' * kg-' (n = 8) or
60 nmol-min-'.kg-' (n = 8) during the second 4-h
period.
Intestinal motility recordings
The motility pattern of the proximal small intestine
was monitored by means of a multichannel polyvinylchloride tube (William Cook, Bjaeverskov, Denmark). The tube was 250 cm in length and 4.7 mm in
outer diameter, and had six channels 0.7 mm in width
ending as side-holes at different levels. The tube had a
set of four side-holes 3 cm apart for recordings of
duodenal motility, and 10 cm further aborally another
two side-holes 10 cm apart for recordings of duodenojejunal motility. The tube was passed through a nostril.
Fluoroscopy was used to position the tube in the small
intestine, with the most distal side-hole 10 cm aboral
to the angle of Treitz. Each channel was continuously
perfused with degassed water from a low-compliance
pneumohydraulic system (Amdorfer Medical Specialities, Greendale, WI, U.S.A.). The channels were
connected to external pressure transducers (Synectics,
Stockholm, Sweden). Digital recordings were attained
by connecting the pressure transducers via a PC
POLYGRAPH HR (Synectics) to a personal computer (486D/66 MHz, Dell Corporation, Austin, TX,
U.S.A.). The software program used was POLYGRAM LOWER GI 6.31C3 (Synectics) with a sampling frequency of 4-16 Hz. The pressure rise velocity
upon sudden occlusion of the recording system
exceeded 200 mmHg/s in each channel.
Analysis of motility recordings
Recordings were inspected by two independent
observers who worked separately and agreed upon the
presence or absence of motor patterns. Contractions
exceedinga cut-off amplitude of 10 mmHg at the angle
of Treitz were included in the analysis. MMCs were
identified according to the criteria of Vantrappen et al.
[9], i.e.: (a) appearance of uninterrupted bursts of
pressure waves with a frequency of 11-12 contractions
per min (phase 111), (b) aboral migration of phase I11
activity passing at least the distal two registration
points, and (c) a period of complete quiescence after
phase 111 activity. Phase I11 of MMC (activity front)
was defined as the presence of uninterrupted phasic
pressure changes for at least 2 min at the maximum
frequency for that locus. The duration of phase I11 at
the angle of Treitz was measured from onset of regular
contractions to quiescence. The propagation velocity
of phase I11 was calculated by dividing the traversed
distance from onset of phase I11 by the time interval
from one registration point to the next. Phase I1 was
defined as having 2 2 phasic contractions per min,
whereas phase I was defined as < 2 phasic contractions
per min.
The fraction of time occupied by either phase I, I1 or
I11 of the MMC cycle was calculated during the
control period and during infusion of either saline
or 5-HT. The number of contractions and their
amplitude, as well as the overall motility index, during
the control and infusion periods were calculated.
Urine samples
Urine was collected during the two infusion periods.
One portion was acidified with hydrochloric acid
(6 mol/l, 0.1-10 ml of urine). A second portion was
frozen without additives. The urine was kept frozen
(- 20 "C) until analysis.
Blood sampling and cell counts
Blood samples were collected after 2 h in the first
4-h period and after 1 and 3 h in the second 4-h period.
Clean venipunctures without stasis were performed
using 21 G needles connected to 10 ml vacutainer
tubes containing 1.0 ml of a platelet stabilizing solution [final concentrations: 9 mmol/l EDTA,
1 mmol/l theophylline and 0.2 pg/ml Iloprost
(Schering AG, Berlin, Germany), a stable prostacyclin
analogue], as previously described and validated [ 181.
All samples were immediately centrifuged at 15000 g
(4 "C, 30 min). Plasma was carefully removed from the
mid-layer and stored at -80 "C for measurements of
5-HT.
Platelet counts in whole blood anticoagulated with
EDTA (final concentration 10 mmol/l) were determined by a semi-automated cell counter (Cellanalyzer
460, Medonic AB, Solna, Sweden).
665
Serotonin and the migrating motor complex
Determination of 5-HT and 5-HIAA
5-HT in plasma and urine, and 5-HIAA in urine,
were analysed by GC-MS as previously described and
validated [18,19]. Urine creatinine was measured by
the Jaffk reaction using a Hitachi 717 instrument
(Boehringer Mannheim GmbH, Mannheim, Germany).
changes were observed with regard to either the
frequency of phase I11 of the MMC or the duration,
propagation velocity, contraction frequency or motility index of phase I11 during the two periods (Tables
1 and 2, Figures 1 and 2).
The time fraction of MMC occupied by phase I, I1
and I11did not differ during the two periods (Figure 3).
Effects of 5-HT on motility of small intestine
Chemicals
5-HT (serotonin hydrochloride) was purchased
from Fluka Chemie AG (Neu-Ulm, Germany). The
compound was dissolved and diluted in sterile 0.9 YO
NaCl and the solution was filtered (Millex-Micropore,
pore size 0.22 pm) to sterility by the Karolinska
Hospital Pharmacy. Ten-millilitre vials were prepared
containing sterile stock solution (100 pmol/ml) and
ascorbic acid (17.6 pg) was added as antioxidant.
Saline (NaCl, 154 mmol/l) for intravenous infusion
was purchased from Kabi-Pharmacia (Uppsala,
Sweden).
Vital signs
Measurements of haemodynamic and respiratory
parameters started 2 h before commencing 5-HT
infusions and continued throughout the experiments.
Heart rate, as well as systolic and diastolic blood
pressures, was monitored every 15 min, while respiratory frequency and peak expiratory flow were
monitored every 30 min.
Statistics
Results are presented as medians and interquartile
range, except for haemodynamic data which are
presented as mean and 95% confidence interval.
Kruskal-Wallis one-way analysis of variance, MannWhitney's U-test or Wilcoxon's signed-rank test were
used where appropriate. P < 0.05 was considered
significant.
RESULTS
Baseline motility of small intestine
In control studies with saline, the MMC pattern did
not differ between the two recording periods. No
Infusion of 5-HT increased the number of phase I11
of MMC in a dose-dependent manner. However, at
the dose of 60 nmol .min-' * kg-' some MMC started in
the proximal jejunum instead of in the proximal
duodenum (Figure 1 and Table 1).
The interval between phase I11 decreased dosedependently during infusion of 5-HT as the number of
MMC increased (Figure 2).
The time fraction of MMC occupied by phase I did
not change during infusion of 5-HT, whereas phase I11
increased dose-dependently, and phase I1 decreased to
a corresponding extent during infusion of 5-HT
(Figure 3).
5-HT dose-dependently increased the propagation
velocity of phase I11 as well as the amplitude of
contractions belonging to phase 111. However, the
contraction frequency, motility index and duration of
phase I11 did not change during infusion of 5-HT
(Table 2).
Effect on vital functions and side effects of 5-HT
Although 5-HT infusion did not influence systolic
or diastolic blood pressures at either dose level, an
increase in heart rate was observed at the high-dose
level from 60.5 (57.5-66.0) beats/min at baseline to a
maximum of 72 (72-72) beats/min after 30min of
infusion. Respiratory rate and peak expiratory flow
were not altered during infusion of 5-HT at either
dose. Platelet counts in peripheral venous blood
decreased slightly over time during infusion of both 5HT and saline.
All subjects receiving 5-HT experienced smarting
pain in the arm where the infusion was given. In the
group receiving 5-HT at a dose of 60 nmol ernin-' * kg-'
abdominal cramps were noted in four subjects, nausea
in three, mental discomfort in three and vomiting in
Tabla I Number of phase 111 ofthe MMC during control period and infusion of 5-HT at different doses
respectively
Values are medians and interquartile ranges. *P < 0.05 compared with control period.
yoPhase 111
Total no. of phase 111
No. of phase 111
originating in duodenum
originating in
duodenum
Control period
NaCl
2.0 (I 0-3.0)
2.0 (2.0-3.5)
1.5 (1-2.5)
2.0 (I .cL3.5)
loo (71-loo)
loo (loo-loo)
Control period
5-HT. IS nmol.min-'.kg-'
2.0 ( I .0-2.0)
6.0 (4.0-6.5)*
2.0 (cL2.0)
5.0 (3.0-6.5)*
loo (loo-loo)
loo (75-loo)
Control period
EHT. 60 nmol min-' kg-'
I .5 (0.5-2.0)
13.5 (9.5-21.5)*
I .o (0.5-2.0)
10.5 (8.0-17.0)*
loo (loo-loo)
t~ p.5-90.2)
.
.
M. Lordal and others
666
Table2 Characteristicsof phase 111of the MMC during control period and infusiono f L H T a t different
dorespectively
Values are medians and interquartile ranges. *P < 0.05 compared with control period.
Duration
(min)
Velocity
(cmlmin)
Contraction
frequencylmin
Amplitude
(mmHg)
Motility index
Control period
NaCl
5.5(4.7-6.6)
5.2 (3.9-7.2)
10.1 (6.7-14.1)
9.1 (5.619.9)
11.7(ii.5-12.0)
I I.6 (I1.04 1.9)
22.3(19.6-26.6)
24.4 (21 .6-32.8)
6.8(6.4-6.9)
6.8 (6.67.0)
Control period
5-HT. 15 nmol.min-'.kg-'
6.6(5.47.I)
4.6 (3.2-7.1)
12.0(8.&19.8)
18.5 (12.3-33.3)
I1.8(11.612.1)
11.5 (I 1.2-1 1.8)
23.8(19.6-29.8)
27.3 (24.1-33.8)
6.7(6.>7.2)
7.1 (6.6-7.2)
Control period
EHT. 60 nmol. min-' .kg-'
6.2(4.47.l)
3.6 (2.5-5.2)
15.8(13.9-21.5)
28.8 (I2.&50.0)*
12.0(1 1.7-12.2)
I I.4 (I I.1-1 I.8)
U.S(l9.9-25.4)
26.6 (21.7-36.2)*
6.7(6.6-6.9)
7. I (6.7-7.5)
5-HT 15 nmol kg.' min'
~2
J
,.A .rl~cbw,
pmln,
5-HT 60 nmol kg-' min-I
B
- -
D
Figure I Manometry recordingsfrom the duodenum and upper jejunum
D,-D,: recordings from duodenum. JI and J2: recordings from jejunum. Infusion of 5-HT induced propagating MMC with short interval in the
upper small intestine. (A) Recording from a test subject in the control group, receiving infusion of NaCI. (8) Recording from a test subject
receiving infusion of 5-HT at a dose of 15 nmol.min-'.kg-'. (C) Recording from a test subject receiving 5-HTat a dose of 60 nmol.min-'.kg-'.
(D) Recording from the same subject as (C), but with higher resolution on the x-axis (time).
one. In the group receiving 5-HT at a dose of 15
nmol .min-' kg-' nausea and vomiting were noted in
one test subject only.
Plasma concentration of 5-HT
Data from several experiments were omitted due to
technically inadequate sampling, as this causes arti-
factual elevation of 5-HT in plasma [19]. In five
subjectsreceiving saline plasma 5-HTlevels were stable
around 1.5-2 nmol/l. During infusion of 5-HT, the
plasma concentrations of 5-HT appeared to increase
dose-dependently, but the number of observations
were few. When pooled, the plasma concentrations of
5-HT increased significantly-duringinfusion of 5-HT
(Table 3). A strong correlation between the plasma
667
Serotonin and the migrating motor complex
'7
I?'
I
4
20
0
A
T
SdIlW
SHTI ~'nmo~kplm~n WIT 80 n m w m i n
'3r
Figure 2 Interval between activity fronts (phase 111 of the
MMC) during infusion of saline or 5-HT
Infusionof 5-HT dose-dependently decreasedthe interval between
the activity fronts. * P < 0.05 compared with the control group
(NaCI). **P < 0.05 compared with the control period (NaCI).
concentration of 5-HT and the stimulatory effect on
phase I11 of MMC was demonstrated, with a correlation coefficient of 0.79 (Figure 4).
I
A
Urinary excretion of 5-HT and 5-HIAA
The urinary excretions of 5-HT and 5-HIAA did not
change during infusion of saline, but both parameters
increased dose-dependently during infusion of 5-HT
(Table 4).
C
DISCUSSION
The present study shows that the interdigestive
rhythm of the small intestine in man is dose-dependently stimulated by circulating 5-HT, as verified by an
increased number of phase I11 of MMC, and an
increased propagation velocity and amplitude of contractions during phase 111. The effect was shown to
positively correlate to the plasma concentration of 5HT. The present results confirm and extend our
previous findings with bolus injections of 5-HT [14]
and studies in which 5-HT has been shown to stimulate
the contractile activity of the small intestine in man [8].
The phase I11 activity induced by 5-HT in this study
meets all the criteria of phase I11 postulated by
Vantrappen et al. [9], namely contraction frequency,
aboral migration of phase I11 activity passing at least
the distal two registration points, and a period of
complete quiescence after phase I11 activity.
The 5-HT-induced phase I11 activity originated in
the small intestine. This is in accordance with the
effects of sumatriptan, a 5-HT, receptor agonist, which
induces premature intestinal phase I11 activity and
increases the proportion of phase I11 originating in the
jejunum instead of in the stomach [20]. Both 5-HT
(present data) and sumatriptan [20] increase the
fraction of time occupied by phase I11at the expense of
phase 11. Furthermore, treatment with the selective 5HT uptake inhibitor, paroxetine, enhances intestinal
motility in humans [13]. Thus, the present data are
Figure 3 Distribution of phase 1-111 of MMC during
infusion of saline or 5-HT at different doses
During infusion of 5-HT the fraction of phase 111 increases at the
expense of phase II. A, Control group, infusion of NaCI; B. infusion
of 5-HT at a dose of I 5 nmol .m i d .kg-' ; C. infusion of 5-HT at a
dose of 60nmol.min-l.kg-'. *P<O.O5 compared with the respective control period.
supported by pharmacological data indicating that 5HT is involved in the initiation and control of MMC in
humans.
A role for 5-HT in the regulation of MMC has also
been proposed in other species such as pigs, opossums,
rats and guinea pigs. 5-HT has been shown to increase
both the cycling frequency and propagation velocity of
MMC in pigs [21] and opossums [22]. Animal studies
have also shown that the MMC cycling frequency is
668
M. Lordal and others
Table 3 Plasma concentration (nmol/l) of LHT during infusion of LHT at different doses and during
control conditions
Values are medians and interquartile ranges. *P < 0.05 compared with control period.
~
~~
Infusion of E H T
Group
Control period
Control group
I .9 (0.6-8.7)
i .7 ( I .2-3.8)
E H T , I5 nmol.min-'.kg-'
(n = 5)
3h
2.0 ( I 8-3. I )
I .5 (0.a3.4)
8.7 (7.2-i3.0)*
10.8 (9.0-14.0)*
5-HT. 60 nmol .min-' . kg-'
(n = 4)
2.2 (2.0-5. i)
24.4 (21.8-26.9)*
27.6 (21.0-61.6)*
EHT. all subjects
(n = 9)
2. I (i .63.8)
18.4 (8.4-23.4)*
21 .O (10.624.8)*
/*.,
0
Ih
0
70
5
15
20
25
30
35
Plasma concentration (nmoIA)
Figure 4 Relationship between the plasma concentration
ofLHT and the number of MMC induced by infusion of 5HT
The number of MMC increases with increasing plasma concentration of 5-HT. N = 13. r' = 0.79. P = 0.0003 (Spearman
correlation test).
increased by the 5-HT precursor 5-hydroxytryptophan
[23], and decreased by neuronal depletion of 5-HT
[24], or by selective destruction of 5-HT neurons in the
myenteric plexus using 5,6- and 5,7-dihydroxytryptamine [25].
The net effect of 5-HT on small intestinal motility is
a stimulatory one, but we can only speculate on the 5HT receptor subtypes involved. As noted above, 5HT,-receptor stimulation by sumatriptan induces premature intestinal phase I11 in humans [20]. Stimulation
of 5-HT2 receptors contracts human small intestinal
muscle cell strips [161, but possible influences on the
basal interdigestive rhythm are not known. Blockade
of 5-HT3receptors by ondansetron does not influence
duodeno-jejunal phase 111 activity [26], and the role of
5-HT4 receptors in the modulation of small bowel
motility in humans has not been studied, as potent and
selective 5-HT4 antagonists are not available for
clinical use. Animal studies with different 5-HT4
receptor agonists have given conflicting results regarding the role of 5-HT4receptors in the generation
of propagated motor activity. In dogs, renzapride, a 5HT,-receptor agonist, induces phase 111-like activity in
the small bowel [27], while cisapride, also a 5-HT4receptor agonist, given orally or parenterally to
healthy volunteers, did not induce phase I11 activity or
increase its propagation velocity [28,29]. Possible
explanations for the disparate results obtained in dogs
and man are species differences as well as differences
between the two compounds renzapride and cisapride.
Thus, the available evidence suggests that stimulation of 5-HT1 receptors on myenteric cells changes
the basal rhythm, i.e. increases the number of phase 111
and their propagation velocity, and that stimulation of
Table 4 Urinary excretion of LHT (nmol/mmol creatinine) and S H I M (pmol/mmol creatinine)
during infusion of LHT at different doses and during control conditions
Values are medians and interquartile ranges. *P < 0.05 compared with control period, **P < 0.05 compared with
control period and 5-HT. I5 nmol min-' .kg-'.
.
Infusion of 5-HT
Control period
Group
5-HT
5-HIAA
5-HT
5-HIAA
Control group
52 (39-60)
I .3 (0.62.6)
45 (43-66)
l.o(l.o-l.7)
5-HT. I5 nmol.rnin-'.kg-'
(n = 6)
59 (43-62)
I .2 ( I .&I .6)
108(85-121)*
36.6 (34.7-43.6)*
5-HT. 60 nmol 'min-' .kg-'
57 (36-62)
1.4 (1.1-1.6)
331 (228-953)**
(n = 7)
(n = 7)
106.9 (14.4-134.7)**
Serotonin and the migrating motor complex
5-HT2receptors on smooth muscle cells may increase
their contractile force.
The plasma concentration of 5-HT, as well as the
urinary excretion of 5-HT and 5-HIAA, increased
dose-dependently during infusion of 5-HT. The
plasma concentration of 5-HT, however, increased by
less than expected with the doses given, indicating a
very rapid clearance from plasma. Pharmacokinetic
parameters for 5-HT were not calculated in the present
study, but a comparison with the turnover of other
biogenic amines, such as catecholamines, is relevant.
Thus infusion of noradrenaline, which has a half-life
of approximately 1 min in plasma, elevated arterial
plasma noradrenaline levels almost 20-fold, from basal
levels of approximately 1 nmol/l, at an infusion rate of
0.5 nmol.min-'.kg-' [5]. In the present study, 5-HT
infusion at the rate of 60 nmol.min-'-kg-', i.e. 120
times higher than the dose of noradrenaline used by
Hjemdahl and Linde [5], elevated venous plasma 5-HT
only 10-fold,demonstrating a still more rapid turnover
of 5-HT in plasma. Early animal studies indicated an
extremely short half-life for 5-HT in plasma [6,30], and
our present data are compatible with these observations.
It can be speculated that 5-HT is rapidly cleared
from plasma via uptake by platelets and endothelial
cells together with extensive metabolism in the liver
and lungs. The rapid clearance of 5-HT from plasma
suggests that 5-HT exerts its stimulatory action locally,
after release from enteric neurons, enterochromaffin
cells or platelets.
In the present study 5-HT, at doses resulting in a 5to 12-fold increase of the plasma concentration of 5HT, stimulated the motility of the small intestine and
caused abdominal symptoms. In this connection, a
comparison can be made to the carcinoid syndrome
which is characterized by attacks of, among other
things, cutaneous flushing and diarrhoea. The diarrhoea can be explained by either intestinal hypersecretion or intestinal hypermotility, or both. In a
study by Ahlman et al. [31], attacks of carcinoid
syndrome were provoked by intravenous pentagastrin.
They found an increase in the whole-blood concentration of 5-HT accompanied by cutaneous flushing
and abdominal symptoms such as borborrhygmi,
urgency and colicky cramps. The abdominal symptoms were prevented or relieved by pretreatment with
the 5-HT,-receptor antagonist ketanserin. Against this
background, our findings indicate that 5-HT is involved in the pathophysiology of diarrhoea in the
carcinoid syndrome in part by stimulating motility of
the small intestine.
5-HIAA is normally the predominant metabolite of
5-HT [32]. It has been shown that over 90% of total
body 5-HT turnover is reflected by the urinary excretion of 5-HIAA [33]. In the present study, the
urinary excretion of 5-HT increased approximately 6fold while the urinary excretion of 5-HIAA increased
75-fold during infusion of 5-HT at the highest dose
level.
The side effects of 5-HT in our study differ somewhat
669
from earlier human studies. In the study by Hendrix et
al. [S], intravenous bolus injections of 5-HT, at doses
approximately three times higher than in our study,
caused a transitory burning sensation in the throat,
tongue, lips and cheeks together with transient tachypnoea and occasionally difficulties in breathing. A
possible explanation for the difference in side effects is
the doses used and the mode of administration of 5HT. A higher dose and a rapid injection should result
in higher peak concentrations in plasma and a greater
risk of side effects.
Our finding that 5-HT increases heart rate is in
accordance with the demonstration of 5-HT4receptors
in the human right atrium, mediating positive inotropic and chronotropic effects [34].
In conclusion, this study shows that 5-HT infusion
stimulates the fasting motility with more frequent and
rapidly propagating phase I11 of MMC. It is therefore
suggested that 5-HT released locally, from neurons or
enterochromaffin cells, may participate in the control
of small intestinal interdigestive motility.
ACKNOWLEDGMENTS
We gratefully acknowledge the technical assistance
of Lena Hojvall. This study was supported by grants
from the Ruth and Richard Juhlins Fund, Swedish
Society of Medicine (grant 629.0), Swedish Medical
Research Council (no. 5930 and 7916), The Swedish
Heart-Lung Foundation, Professor Nanna Svartz's
Fund and funds of the Karolinska Institute and Orion
Pharma Ltd.
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