Dr J. Tack, Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: email@example.com
Background : The role of 5-hydroxytryptamine in the control of gastric fundus tone in humans is still unknown. Selective 5-hydroxytryptamine re-uptake inhibitors act both centrally and peripherally to enhance the availability of physiologically released 5-hydroxytryptamine.
Aim : To study the influence of a selective 5-hydroxytryptamine re-uptake inhibitor, paroxetine, on gastric fundus tone, on the perception to gastric distension and on gastric accommodation to a meal.
Methods : Sixteen healthy volunteers underwent a gastric barostat study on two occasions, after pre-treatment with placebo or paroxetine, 20 mg/day. Graded isobaric and isovolumetric distensions were performed and perception was scored by a questionnaire. Subsequently, the amplitude of the gastric accommodation to a mixed liquid meal was also measured.
Results : Pre-treatment with paroxetine did not alter the thresholds for perception and discomfort during isobaric (4.7 ± 2.3 vs. 4.0 ± 2.0 mmHg and 13.3 ± 3.1 vs. 12.7 ± 2.3 mmHg above the minimum intragastric distending pressure, N.S.) and isovolumetric (307 ± 90 vs. 417 ± 114 mL and 772 ± 74 vs. 750 ± 76 mL, N.S.) distensions. Paroxetine significantly enhanced the amplitude of the meal-induced fundus relaxation (136 ± 51 vs. 255 ± 43 mL, P < 0.05).
Conclusions : Pre-treatment with paroxetine enhances gastric accommodation to a meal. These data suggest that the release of 5-hydroxytryptamine, probably at the level of the enteric nervous system, is involved in the control of the accommodation reflex in humans, and that paroxetine may be beneficial to patients with impaired post-prandial fundus relaxation.
During fasting, muscle fibres of the proximal stomach maintain a vagally mediated tonic contractile activity, which generates gastric fundus tone.1,2 During and after the ingestion of a meal, relaxation of the proximal stomach occurs, which provides the meal with a reservoir and enables the gastric volume to increase without a rise in pressure.2,3
Studies in animals and humans have established that this accommodation reflex is mediated via a vagovagal reflex pathway, which activates nitrergic neurones in the gastric wall.3–7 Recent studies have established that impaired accommodation to a meal is a major pathophysiological mechanism in functional dyspepsia, and restoration of accommodation is considered to be a valid therapeutic target.8–11 However, the control of the accommodation reflex in humans is incompletely understood.
In the mouse and guinea pig, the involvement of 5-hydroxytryptamine (5-HT) receptors on intrinsic neurones in the vagally mediated gastric relaxation has been demonstrated.12 More recently, it has been demonstrated that 5-HT-induced relaxations of the guinea pig stomach are mediated via the release of nitric oxide through the activation of a 5-HT1-like receptor.13 In humans, it is unclear whether 5-HT is involved in the control of the gastric accommodation reflex. Recently, we demonstrated that the 5-HT1 receptor agonist, sumatriptan, is able to induce a relaxation of the proximal stomach in humans through a nitrergic pathway.14,15 In the absence of a suitable antagonist, it is unclear whether activation of the same receptor might be involved in the control of the accommodation reflex in humans.
Selective 5-HT re-uptake inhibitors act both centrally and peripherally to enhance the availability of physiologically released 5-HT.16,17 Using a short-term treatment with the selective 5-HT re-uptake inhibitor, paroxetine, Gorard et al. were able to demonstrate the involvement of 5-HT in the control of small intestinal inter-digestive motility in humans.18 We used the same approach to test the hypothesis that 5-HT is involved in the control of gastric fundus tone in humans.
Materials and methods
Sixteen healthy volunteers (13 males and three females, aged 20–29 years) participated in the study. They underwent a gastric barostat study on two separate occasions at least 2 weeks apart, after pre-treatment for 7 days with placebo or paroxetine, 20 mg/day. None of the subjects had symptoms or a history of gastrointestinal disease or drug allergies, and none were taking any medication. Informed consent was obtained from each participant. The study was a double-blind, randomized, cross-over design. The order of placebo and paroxetine treatment was randomized by drawing cards from a box of cards determining the sequence. A study nurse who was otherwise uninvolved in the study drew the cards, administered the medication and assessed treatment compliance by counting the remaining number of pills at each visit. Half of the subjects received placebo first; the other half received paroxetine first. The Ethics Committee of the University Hospital had previously approved the protocol.
Following an overnight fast of at least 12 h, a double-lumen polyvinyl tube (Salem sump tube 14 Ch., Sherwood Medical, Petit Rechain, Belgium) with an adherent plastic bag (capacity, 1200 mL; maximum diameter, 17 cm), finely folded, was introduced through the mouth and secured to the subject's chin with adhesive tape. The position of the bag in the gastric fundus was checked fluoroscopically.
The polyvinyl tube was then connected to a computer-driven, programmable, volume-displacement barostat device (Synectics Visceral Stimulator, Stockholm, Sweden). The barostat device delivered volume ramps or pressure steps at different rates, whilst simultaneously monitoring the pressure and volume at a sampling rate of 8/s. Pressure was monitored within the inflation device. To unfold the intragastric bag, it was inflated with a fixed volume of 500 mL of air for 2 min with the study subject in a recumbent position, and again deflated completely. After a 10-min equilibration period, the subjects were positioned in a comfortable sitting position with the knees slightly bent (80°) in a bed specifically designed for that purpose.
After a 30-min accommodation period, the intra-bag pressure was increased by 1 mmHg every minute to determine the minimum intragastric distending pressure (MDP), as the lowest pressure level that provided an intra-bag volume of 30 mL or more.19 This pressure level is equal to the intra-abdominal pressure. Subsequently, graded isobaric and isovolumetric distensions were applied in random order, with a 30-min accommodation period between the two series of distensions.
Sequential isobaric distensions were performed in stepwise increments of 2 mmHg, starting from MDP, each lasting for 2 min, and the corresponding intragastric volume was recorded. Subjects were instructed to score their perception of the upper abdominal sensations induced by each distending stimulus at the end of every distending step, using a graphic rating scale that combined verbal descriptors with a numerical scale of 0–6.19 The end-point of each sequence of distensions was established at an intra-bag volume of 1000 mL, or when the subjects reported discomfort or pain (score of five or six). Sequential isovolumetric distensions were performed in stepwise increments of 100 mL, each lasting for 2 min, and the corresponding pressure was recorded. The same perception score and distension end-points were applied.
After another 30-min accommodation period, the pressure level was set at MDP + 2 mmHg. After 30 min, a mixed liquid meal (200 mL; 300 kcal; 13% proteins, 48% carbohydrates, 39% lipids; Nutridrink, Nutricia, Belgium) was administered. Measurement continued until the end of the meal-induced gastric relaxation.
For each 2-min distending period, the dependent variable was calculated by averaging the recording. The thresholds for perception and discomfort were computed after the experiments by analysing the perception score corresponding to each distension step. The perception threshold was defined as the first level of pressure (during isobaric distensions) or the lowest volume (during isovolumetric distensions) that provoked a perception score of one or more. The discomfort threshold was defined as the first level of pressure (during isobaric distensions) or the lowest volume (during isovolumetric distensions) that provoked a perception score of five or more. Gastric compliance was calculated as the slope of the pressure–volume curve obtained by stepwise isobaric distensions. No further distensions were performed when a given subject reached the discomfort threshold. For the analysis of gastric compliance, only those distending steps which were applied in at least 75% of the subjects were used.
To evaluate gastric tone before and after the administration of the meal, the mean intra-balloon volume was calculated over consecutive 5-min intervals. The meal-induced gastric relaxation was quantified by calculating the difference between the average intragastric volume during the 30 min before and the first 60 min after the administration of the meal.10 The maximum post-prandial volume increase and the time needed to reach the maximum post-prandial volume were calculated. In addition, the duration of the meal-induced relaxation (defined as the time needed for the intragastric volume to return to or below the mean pre-prandial volume) was also determined.
All numbers are given as the mean ± S.E.M. MDP, gastric compliance and thresholds to gastric distension during paroxetine and placebo were compared using the paired Student's t-test. Pressure–volume curves and distension–perception score curves after paroxetine or placebo were compared by two-way analysis of variance (anova). The numbers of subjects who reported perception or discomfort at a given intragastric volume or pressure after placebo or paroxetine were compared using a logistic regression procedure with stratification, implying exact conditional inference. The post-prandial gastric relaxation curves were compared by two-way anova. The meal-induced gastric relaxation, maximum post-prandial volume increase, time needed to reach the maximum post-prandial volume and duration of the meal-induced relaxation were compared using the paired Student's t-test. Differences were considered to be significant at the 5% level.
Conduct of the study
All participants completed the trial as planned. There was no significant difference in the occurrence of side-effects during paroxetine or placebo treatment. During paroxetine treatment, two subjects reported mild to moderate nausea and one subject reported mild insomnia. During placebo treatment, one subject reported mild fatigue.
Influence of paroxetine on isobaric gastric distensions
Paroxetine had no significant effect on MDP (6.5 ± 0.6 vs. 6.5 ± 0.6 mmHg, N.S.). After both placebo and paroxetine, distensions of the stomach with progressively higher set pressures produced progressively larger intragastric volumes. Gastric compliance, calculated using the first five distending steps, did not differ significantly between placebo and paroxetine (52.4 ± 5.9 vs. 59.9 ± 7.4 mL/mmHg, N.S.). At the same distending pressures, similar intragastric volumes were obtained after placebo or paroxetine (Figure 1) (anova, N.S.). Also, similar perception scores were obtained for the same distending pressures (Figure 2) (anova, N.S.).
Pre-treatment with paroxetine did not alter the pressures needed to induce first perception (4.4 ± 0.9 vs. 3.5 ± 0.8 mmHg above MDP, N.S.) or discomfort (12.8 ± 1.3 vs. 11.6 ± 1.0 mmHg above MDP, N.S.) during isobaric distensions (Figure 3). The corresponding volumes at the threshold for perception (267 ± 46 vs. 242 ± 45 mL, N.S.) and at the threshold for discomfort (625 ± 51 vs. 686 ± 47 mL, N.S.) were also not significantly altered after paroxetine treatment (Figure 3). Logistic regression analysis of pressure–perception and pressure–discomfort curves revealed no significant shift in thresholds after paroxetine (N.S.).
Influence of paroxetine on isovolumetric gastric distensions
After both placebo and paroxetine, distensions of the stomach with progressively larger volumes produced progressively larger intragastric pressures. At the same distending volumes, intragastric pressures were not significantly altered after pre-treatment with paroxetine (anova, N.S.). In addition, after paroxetine, similar perception scores were obtained for the same distending volumes (anova, N.S.).
Pre-treatment with paroxetine did not alter significantly the perception thresholds (300 ± 51 vs. 281 ± 50 mL, N.S.) and discomfort thresholds (703 ± 47 vs. 727 ± 41 mL, N.S.) during isovolumetric distensions. The corresponding intragastric pressures at the threshold for perception (11.9 ± 1.7 vs. 11.3 ± 1.5 mmHg, N.S.) and at the threshold for discomfort (20.0 ± 1.6 vs. 18.5 ± 1.1 mmHg, N.S.) were also not significantly altered by paroxetine. Logistic regression analysis of volume–perception and volume–discomfort curves revealed no significant shift of the thresholds after paroxetine.
Influence of paroxetine on the gastric accommodation to a meal
Before the meal, the intragastric volumes after placebo or paroxetine were similar (216 ± 24 vs. 217 ± 21 mL, N.S.). After paroxetine pre-treatment, significantly higher intragastric volumes were recorded post-prandially (388 ± 39 vs. 487 ± 36 mL, P < 0.05). Paroxetine significantly enhanced the amplitude of the meal-induced fundus relaxation (mean 1-h post-prandial volume increase: 172 ± 36 vs. 270 ± 37 mL, P < 0.05) (Figure 4). After pre-treatment with paroxetine, the maximum volume increase after the meal tended to be higher (318 ± 34 mL after placebo vs. 403 ± 36 mL after paroxetine, P = 0.05) and occurred earlier (30 ± 3 vs. 21 ± 3 min after the meal, P = 0.04). The duration of the meal-induced gastric relaxation was not significantly altered by paroxetine pre-treatment (101 ± 6 vs. 109 ± 7 min, N.S.).
The control of the gastric accommodation reflex in humans is incompletely understood. Studies in animals have demonstrated the involvement of 5-HT receptors on intrinsic neurones in the regulation of post-prandial gastric tone.12 Although a number of 5-HT receptor agonists are able to alter gastric accommodation to a meal,14,20,21 a physiological role for 5-HT in the control of proximal gastric tone in humans has not been established.
In this study, we used a gastric barostat to examine the influence of pre-treatment with the selective serotonin re-uptake inhibitor, paroxetine, on fasting proximal gastric tone, gastric sensitivity to distension and gastric accommodation to a meal. Pre-treatment with paroxetine had no influence on fasting gastric tone, fasting gastric compliance and the perception of gastric distensions. These data suggest that 5-HT does not play a major role in maintaining the fasting tone of the proximal stomach, or in the perception of gastric distension in healthy subjects. These findings are in agreement with a recent study which found no influence of the selective serotonin re-uptake inhibitor, sertraline, on gastric sensitivity and compliance in healthy volunteers.22
We did, however, observe an enhanced gastric accommodation to a meal after short-term pre-treatment with paroxetine. This observation suggests the involvement of 5-HT in the gastric accommodation reflex in humans: after short-term pre-treatment, selective 5-HT re-uptake inhibitors enhance 5-HT-mediated actions by prolonging the availability of physiologically released 5-HT.16,17 The 5-HT receptor involved and its localization cannot be determined from the present study. Selective serotonin re-uptake inhibitors may act on neurones that are located centrally as well as peripherally.16,17 Previous studies have shown that peripherally acting 5-HT1 agonists or 5-HT4 agonists are also able to enhance gastric accommodation to a meal.14,20 These observations support, but do not prove, the involvement of one or both of these peripheral 5-HT receptors. Unfortunately, the lack of selective antagonists precludes a more detailed pharmacological analysis in humans at the present time.
The effect of paroxetine on gastric accommodation to a meal is of potential therapeutic relevance in functional dyspepsia. Impaired post-prandial relaxation of the proximal stomach is present in a proportion of patients with functional dyspepsia, and is associated with more prevalent symptoms of early satiety and weight loss.10 Enhancement of the gastric accommodation to a meal by paroxetine, as observed after short-term treatment in the present study, might be beneficial in these patients, and clinical studies addressing this question seem to be warranted on the basis of our observations. However, during longer term use, the enhanced availability of physiologically released 5-HT may eventually lead to desensitization, especially of 5-HT inhibitory auto-receptors, which is the presumed mechanism of action in the treatment of depression.17 It is unclear whether this would affect the changes in gastric accommodation observed in short-term treatment.
In conclusion, pre-treatment with the selective 5-HT re-uptake inhibitor, paroxetine, in humans has no influence on inter-digestive gastric tone or the sensitivity to gastric distension. Pre-treatment with paroxetine enhances gastric accommodation to a meal. These data suggest that the release of 5-HT, probably at the level of the enteric nervous system, is involved in the control of the accommodation reflex in humans.