Center for Gastroenterological Research, University Hospital Gasthuisberg, Catholic University of Leuven, B-3000 Louvain, Belgium
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ABSTRACT |
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Fasting gastric fundus tone is maintained by
continuous cholinergic input. 5-Hydroxytryptamine-1
(5-HT1) receptor activation decreases gastric fundus tone in humans. Whether this fundus-relaxing effect is mediated via inhibition of cholinergic input or via activation of a nitrergic pathway is unknown. The aim of the present study was to determine the effect of nitrergic inhibition on feline gastric fundus tone and on 5-HT1
receptor-mediated relaxation of the fundus. Administration of
N-nitro-L-arginine methyl ester
(L-NAME) alone caused a
significant decrease of the mean baseline volume
(P < 0.005), which was restored completely by addition of
L-arginine. Sumatriptan caused a
dose-dependent relaxation of the gastric fundus
(P < 0.0005). This relaxation was
inhibited by L-NAME
(P < 0.02) and was restored by prior
administration of L-arginine.
Buspirone did not cause any change in mean baseline volume, whereas the
sumatriptan-induced relaxation was not affected by prior administration
of NAN-190. Our data indicate that fasting fundus tone relies not only
on continuous cholinergic input but also on continuous nitrergic input,
implying that fasting fundus tone is maintained by the balance of a
cholinergic and nitrergic drive. Furthermore, fundus relaxation via
5-HT1 receptor activation is
mediated through activation of a nitrergic pathway.
sumatriptan; feline gastric fundus; nonadrenergic, noncholinergic; serotonin
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INTRODUCTION |
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GASTRIC FUNDUS TONE in the fasted state is maintained by a vagally mediated cholinergic input (5). Gastric accommodation occurs during and after a meal, and this relaxation is mediated by a vagovagal reflex pathway, involving activation of nonadrenergic noncholinergic (NANC) neurons in the gastric wall (4, 20, 24). It is not known whether activation of NANC input to the stomach is solely involved in triggering postprandial fundus relaxation or whether it also contributes to resting gastric tone by counterbalancing excitatory cholinergic input.
5-Hydroxytryptamine (5-HT) is one of the neurotransmitters shown to be involved in vagally mediated gastric relaxation in both guinea pig and mouse (10). More recently, it was demonstrated that 5-HT-induced relaxations of the guinea pig stomach are mediated via the release of nitric oxide (NO) through activation of a 5-HT1-like receptor (31).
5-HT1 receptor activation using the 5-HT1 receptor agonists sumatriptan and buspirone (13, 36) results in an immediate and profound relaxation of the gastric fundus in humans. The neural pathway involved in the inhibitory action of 5-HT1 receptor activation on fundus tone is unknown. The actions of sumatriptan on the fundus must be mediated via an intrinsic pathway because sumatriptan poorly penetrates the blood-brain barrier (19). Moreover, sumatriptan relaxes the isolated guinea pig stomach, which argues against a central action (30). The acute relaxatory effect of sumatriptan on the gastric fundus suggests activation of an inhibitory pathway. However, it is possible that other mechanisms or pathways may be involved because sumatriptan may act via activation of presynaptic 5-HT1 receptor on cholinergic motoneurons causing inhibition of ACh release at the neuromuscular junction.
The present study was undertaken to test the hypothesis that resting gastric fundus tone relies not only on excitatory cholinergic but also on inhibitory nitrergic input and that 5-HT1 receptor activation by sumatriptan induces a relaxation of the gastric fundus via activation of a nitrergic pathway. Therefore, we developed an in vivo animal model that allowed us to study neural control and pharmacological modulation of gastric fundus tone using an electronic barostat in cats.
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MATERIALS AND METHODS |
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Study subjects. Experiments were performed on seven cats of either sex, with a weight between 3 and 5 kg. The animals were fasted for at least 12 h before the start of the experiment, and light anesthesia was induced with ketamine chloride (Parke-Davis, Warner-Lambert, Zaventem, Belgium) 10-15 mg/kg intramuscularly for induction and 10 mg/kg intramuscularly every 30-45 min for maintenance. The ketamine anesthesia allowed the cats to tolerate intubation by a double-lumen polyvinyl tube with an intragastric plastic bag attached, while spontaneous breathing was preserved. Throughout the experiments a heating pad was used to maintain body temperature of the animal at 37°C.
Gastric barostat.
A computer-driven programmable volume-displacement barostat (Synectics
Visceral Stimulator, Stockholm, Sweden) was used in these studies to
distend the gastric fundus. The barostat device can deliver pressure
steps at different rates, while simultaneously monitoring intraballoon
pressure and volume at a sampling rate of 8 s1. Pressure is monitored
within the inflation device. Both a pressure recording port and an air
inflation port are independently connected by a double-lumen polyvinyl
tube (Salem sump tube, 3.3 mm diam, Sherwood Medical, Petit Rechain,
Belgium) to an intragastric plastic bag (60 ml capacity; 6.5 cm maximal
diam). The bag was tested before and after each experiment to ensure
that there was no leak. In the present study the barostat produced
gastric distensions at fixed pressures (isobaric). To produce
fixed-pressure distensions, the barostat maintains a constant pressure
level by an electronic feedback regulation of the air volume within the
intragastric bag. The desired pressure level is set by means of a
pressure selector dial, and the intragastric volume is recorded.
Study design. After an overnight fast of at least 12 h the polyvinyl tube with the adherent bag finely folded was introduced through the mouth. The position of the bag in the gastric fundus was secured by pulling back the inflated balloon once it was introduced into the stomach until a resistance was noted, indicating that the balloon was just distal to the lower esophageal sphincter. The position of tube and adherent bag was secured with a screw within a bite block. The polyvinyl tube was then connected to the barostat device. To unfold the intragastric bag it was inflated with a fixed pressure of 15 mmHg of air for 2 min.
The minimal distension pressure was defined as the pressure that resulted in a corresponding volume of >10 ml. During the experiment intragastric pressure was set at minimal distension pressure plus 2 mmHg. A stable baseline was recorded for at least 10 min before any drugs were administered. During the experiment the following pharmacological agents were applied: sumatriptan (100, 200, 400, and 800 µg/kg and 1.5 mg/kg; Imitrex; Glaxo-Welcome, Brussels, Belgium), the NO synthase (NOS) inhibitor NData analysis. To evaluate the effect of sumatriptan on basal intragastric volume, the mean volume over a 10-min period before administration of the drug and over a 10-min period starting from maximal relaxation was calculated using a computerized algorithm that was developed in our laboratory. The algorithm allowed us to reconstruct a baseline on the recorded tracing by excluding phasic contractions and by filtering artifacts due to breathing. The calculated mean volumes were compared using the paired Student's t-test. Values of P < 0.05 were considered to be statistically different. Results are given as means ± SE.
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RESULTS |
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Effect of inhibition of nitrergic pathway on resting gastric fundus
tone.
The effect of inhibition of the nitrergic pathway was tested in six
cats. Administration of the NOS inhibitor
L-NAME provoked an increase of
the fundus tone expressed as a decrease of mean basal intraballoon
volume (14.6 ± 3.4 vs. 24.9 ± 3.5 ml,
P < 0.005; Fig.
1). The reversibility of the effect of
L-NAME on resting fundus tone
was tested by administration of the NO-precursor
L-arginine in three cats.
L-Arginine completely reversed
the L-NAME-induced decrease of
baseline volume (25.1 ± 3.2 vs. 16.1 ± 2.7 ml;
P = 0.005).
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Effect of sumatriptan on resting gastric fundus tone.
Subcutaneous administration of sumatriptan in doses of 100 and 200 µg/kg did not provoke any change in baseline intragastric volume
(n = 2, Fig.
2). A dose of 400 µg/kg resulted in a
mean baseline volume increase of 11.8 ± 8.3 ml
(n = 2, Fig. 2). Administration of 800 µg/kg sumatriptan resulted in all animals studied
(n = 7) in an immediate increase of
intragastric volume from a mean baseline volume of 14.6 ± 2 to 40.9 ± 4 ml (P < 0.0005), reflecting a profound relaxation of the gastric fundus (Figs. 1 and 2). Maximal volume was reached after 2.5 ± 0.3 min. Sumatriptan, 1.5 mg/kg, resulted in all animals studied in an immediate increase of
intragastric volume from a mean baseline volume of 17.3 ± 1.6 to
42.1 ± 4.8 ml (P < 0.001, Fig.
2). Maximal volume was reached after 3.5 ± 0.6 min. Because 800 µg/kg sumatriptan elicited maximal relaxatory response, this dose was
used in subsequent experiments.
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Effect of L-NAME on
sumatriptan-induced gastric fundus relaxation.
The NOS inhibitor L-NAME was
administered 10 min before administration of sumatriptan in six cats in
which the effect of 800 µg/kg sumatriptan had already been tested on
a separate day. After administration of
L-NAME the sumatriptan-induced
increase of intraballoon volume was significantly inhibited (V 11.1 ± 5.7 vs. 26.3 ± 2.9 ml, P < 0.02; Fig. 1).
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DISCUSSION |
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Our data show that inhibition of nitrergic input by L-NAME results in an increase in basal fundus tone reflecting contraction of the fundus. This suggests that resting gastric fundus tone is not only dependent on excitatory cholinergic input but that it also depends on a continuous inhibitory nitrergic drive.
Our observations also confirm earlier findings in humans that activation of 5-HT1 receptors by sumatriptan profoundly alters gastric fundus tone. Sumatriptan causes a significant increase in mean basal intragastric volume, reflecting a relaxation of the fundus. This relaxation is reversibly blocked by inhibition of NOS, suggesting activation of a nitrergic pathway.
Gastric fundus tone is the result of tonic contraction of muscle fibers of the proximal stomach (3, 32). During fasting the proximal stomach is in a continuous state of tonic contraction that is maintained by vagally mediated cholinergic input (5, 35).
It is unknown whether the cholinergic drive is counterbalanced by an inhibitory drive. We observed that administration of L-NAME results in an increase of the resting fundus tone, an effect that is reversed by L-arginine. These data demonstrate that resting fundus tone is also subject to a continuous nitrergic input. Therefore, fasting fundus tone in the cat seems to be maintained by the balance of a cholinergic and a nitrergic drive.
Variations in gastric tone are instrumental in achieving the reservoir function of the stomach by regulating both gastric accommodation and gastric emptying (4, 16). The fundus functions primarily to receive and store food by receptive relaxation and accommodation (1). The neural pathway initiating the postprandial receptive relaxation is not entirely understood. Gastric relaxation induced by nutrient perfusion into the intestine is mediated through a vagovagally driven NANC mechanism (4). Receptive relaxation of the isolated guinea pig stomach is mediated through activation of a nitrergic pathway (20). Vagal stimulation results in a marked relaxation of the fundus, a phenomenon that is mediated by the release of a NANC neurotransmitter (2, 24, 25, 33). Efferent vagal preganglionic fibers synapse both on cholinergic excitatory and NANC inhibitory intrinsic neurons within the myenteric plexus of the fundus wall. The precise nature of the specific neurotransmitter released by the NANC neurons responsible for gastric relaxation is still debated. Both in vivo and in vitro studies suggest that the two main candidates are NO and vasoactive intestinal peptide (VIP) (6, 7, 17, 18, 20-22, 27-29, 38). Depending on the species studied, both inhibitory neurotransmitters can act concurrently in mediating NANC relaxation of the fundus (6, 28, 38) or NO can be the only mediator of the NANC relaxation (20, 29, 31).
Data on the effect of 5-HT and the 5-HT receptor subtypes involved in the control of gastric fundus tone are very scarce. Bülbring and Gershon (10) demonstrated that 5-HT acts as a neurotransmitter of intrinsic neurons in the vagally mediated gastric relaxation in mouse and guinea pig. More recent data demonstrated that 5-HT-induced relaxations of the guinea pig stomach are mediated via NO or a NO-related substance (31). These relaxations are not mediated via interaction with 5-HT2, 5-HT3, or 5-HT4 receptors but probably via receptors that most resemble the 5-HT1 receptor subtype (26, 31). Ondansetron does not affect gastric fundus tone in humans, confirming that 5-HT3 receptors are less likely to be involved in the control of fundus tone (40, 41).
Sumatriptan displays weak affinity for the 5-HT1A receptor (23), which is within the myenteric plexus mainly located presynaptically on cholinergic nerve endings (37). Activation of this receptor mediates inhibition of fast synaptic cholinergic transmission by 5-HT and thus could account for the inhibitory effect of sumatriptan by decreasing cholinergic excitatory input to the gastric fundus. In isolated guinea pig stomach, sumatriptan causes a relaxation that is atropine sensitive and that is blocked by the 5-HT1A receptor antagonist NAN-190, suggesting that at least in the guinea pig the mode of action of sumatriptan on gastric tone is via interaction with a 5-HT1A receptor on cholinergic motor neurons, blocking ACh release (30). In our experiments, however, the selective 5-HT1A receptor agonist buspirone did not mimic the sumatriptan-induced fundus relaxation in cats. Moreover, prior administration of NAN-190 did not affect the fundus relaxatory effect of sumatriptan. This suggests that the mechanism underlying the effect of sumatriptan on the gastric fundus and the 5-HT receptor subtype involved are species specific.
The observed inhibitory effect of NOS blockade on gastric relaxation by sumatriptan is not complete. This suggests that the fundus relaxation may only be partially mediated through activation of a nitrergic pathway and that other nonnitrergic mechanisms are involved. Neurally mediated fundus relaxation can also be produced by adrenergic stimulation or by other nonnitrergic inhibitory mechanisms.
Activation of adrenergic input to the gastric fundus cannot be entirely excluded. However, the relaxatory effect of 5-HT on the canine fundus and in other parts of the gastrointestinal tract is not affected by adrenoreceptor blockade or the sympathetic ganglion blocker guanethidine, making it rather unlikely that norepinephrine is involved as an inhibitory neurotransmitter (9, 11, 31).
In addition to NO, VIP has also been shown to act as a NANC neurotransmitter in the gastric fundus (18, 21, 22). Because VIP and NOS are colocalized in a subpopulation of gastric myenteric neurons (15, 34), stimulation of these neurons by vagal input is likely to result in the corelease of both transmitters. It is conceivable that when sumatriptan activates nitrergic-VIPergic intrinsic neurons, release of both transmitters occurs, resulting in inhibition of fundus tone. Hence, fundus relaxation will still occur when only one of the two components of the inhibitory pathway is blocked, although the kinetics of it may be affected.
In conclusion, our data demonstrate that resting tone of the gastric fundus is the result of a precisely regulated balance between excitatory (cholinergic) and inhibitory (partially nitrergic) neural inputs to the fundus.
From our observations both in humans and in cats, it is clear that activation of the 5-HT1 receptor by sumatriptan results in an inhibition of fasting gastric fundus tone. This effect is partially mediated through activation of a NANC mechanism, involving NO as the inhibitory neurotransmitter. In cats the specific 5-HT1 receptor subtype involved does not seem to be a 5-HT1A receptor. Further studies are warranted to characterize the receptor subtype using selective ligands for in vivo use, which are currently not available. Although it was initially thought that 5-HT1 receptors were not critically involved in the regulation of gut motility (12), recent observations provide evidence for a role of all the 5-HT receptor subtypes present in the gut, including the 5-HT1 receptor, in the control of gastric motility (14, 39). Our observations certainly demonstrate that stimulation of 5-HT1 receptors has a major impact on gastric fundus tone in vivo.
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ACKNOWLEDGEMENTS |
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Portions of this study were presented at the American Gastroenterological Association Meeting, 1997, and was printed in abstract form (13).
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests: J. Tack, Dept. of Internal Medicine, Div. of Gastroenterology, Univ. Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Received 3 April 1998; accepted in final form 26 October 1998.
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