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Keywords:

  • Barostat;
  • gastric hypersensitivity;
  • gastric wall tone;
  • rikkunshito;
  • virtual reality stress

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Competing interests
  9. References
  10. Supporting Information

Background  The herbal medicine rikkunshito is effective for the treatment of gastrointestinal symptoms in patients with functional dyspepsia. Although some basic studies on the effects of rikkunshito have been reported in rats, its effects on human gastric function have not yet been clarified. Psychosocial stress induces visceral hypersensitivity and elements of rikkunshito may reasonably affect or suppress this process. We conducted a study to verify the hypothesis that rikkunshito improves stress-induced gastric hypersensitivity and/or changes in gastric wall tone.

Methods  Nine healthy volunteers (five males, four females) participated in the study. The counterbalanced regimen consisted of a 2-week period of oral administration of 7.5 g day−1 rikkunshito, then a 2-week period without treatment. Fundic sensorimotor function was examined using a gastric barostat twice on the day after each period. Virtual reality stress was imposed during the measurements of gastric tone and electrocardiogram.

Key Results  Stress induced a significant increase in heart rate (= 0.041), gastric volume (= 0.008), and phasic volume events (= 0.049) and a decrease in sensory (= 0.038), discomfort (= 0.011), and pain (= 0.041) thresholds of the stomach. Rikkunshito significantly reduced epigastric fullness (= 0.037) and perceived stress (= 0.034) following stimulation of the pain threshold, regardless of stress without the drug. Stress reduced gastric volume at the sensory threshold and increased anxiety at the discomfort threshold, and these responses were significantly inhibited by rikkunshito (= 0.026, = 0.022, respectively).

Conclusions & Inferences  These findings suggest that rikkunshito may improve symptoms and impaired gastric accommodation under distention stimuli of the proximal stomach superimposed by stress.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Competing interests
  9. References
  10. Supporting Information

There has been an increase in the onset or worsening of medical diseases due to psychosocial stress associated with changes in the social structure.1 This trend is observed in daily clinical practice and is particularly apparent in relation to gastrointestinal (GI) disorders.2 In addition, the importance of examining and treating functional GI disorders is increasing.3 These constitute disorders with GI symptoms and signs that chronically persist without major organic disorders (e.g., cancer or ulcers) by routine clinical examinations.4 They occur in 10–15% of the overall population, and the quality of life of the patients is markedly impaired. Effective treatments are lacking, and the burden due to associated medical costs is huge.4

Functional dyspepsia is a representative functional gastroduodenal disorder with one or more of the following symptoms: postprandial fullness, early satiation, epigastric pain, and/or epigastric burning without evidence of structural disease (including during upper endoscopy). Symptom onset usually occurs at least 6 months prior to diagnosis.5 Although the pathophysiology of functional dyspepsia has not yet been fully elucidated, gastroduodenal dysmotility, impaired gastric accommodation, gastric hypersensitivity, and psychological properties are considered to be related.5–7 Given this background, agents that modify both gastric sensorimotor function and psychological properties are beneficial in the treatment of patients with functional dyspepsia or stress-induced gastroduodenal symptoms.

Rikkunshito is a kampo herbal medicine that improves gastric emptying,8 increases plasma levels of somatostatin9 and ghrelin,10 and shows efficacy in functional dyspepsia.8 Of the herbal components of rikkunshito, Ginseng radix and Pinelliae tuber are associated with gastric emptying and somatostatin.8,9 Takeda et al. found that ghrelin secretion by rikkunshito occurs in response to the representative active ingredients of heptamethoxyflavone, hesperidin, and isoliquiritigenin.10 In addition, rikkunshito contains ginsenoside and oleanolic acid which have anxiolytic activities.11,12 Moreover, the herbal components of rikkunshito, P. tuber and Zingiberis rhizome, have modulatory effects on human plasma adrenocorticotropic hormone (ACTH) and cortisol levels with continual stress exposure.13 Therefore, rikkunshito is a theoretically beneficial drug for the treatment of patients with functional dyspepsia and stress-induced gastroduodenal symptoms. However, little is known about its effects on changes in human gastric function measured using a barostat under stress. Therefore, we conducted this study to verify the hypothesis that rikkunshito may improve stress-induced gastric hypersensitivity and/or changes in gastric wall tone.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Competing interests
  9. References
  10. Supporting Information

Subjects

Nine healthy volunteers participated in this study. These were five males and four females with ages ranging from 19 to 22 years (mean age, 20.3 years). They had no symptoms and no history of organic diseases or psychiatric disorders. This study was conducted in accordance with the Declaration of Helsinki for medical research involving human subjects, and was approved by the Ethics Committee of Tohoku University Graduate School of Medicine, Sendai, Japan prior to its initiation (approval number 2000-42). A detailed explanation of the study was given to all subjects who provided their written informed consent to participate.

Study design

Rikkunshito was obtained from Tsumura & Co. (Tokyo, Japan) in the form of a dried powder extract (TJ43). There are eight different types of crude herbal components in rikkunshito: Ginseng radix, Atractylodis lanceae rhizoma, Hoelen, Glycyrrhizae radix, Aurantii nobilis pericarpium, P. tuber, Z. rhizoma, and Zizyphi fructus.

Subjects were instructed to orally administer 2.5 g of rikkunshito three times daily before each meal with an appropriate volume of water. A daily dose of 7.5 g was thus administered for 2 weeks and gastric function in the presence and absence of rikkunshito treatment was compared. To avoid bias from repetition, subjects were randomly allocated into two groups such that there was an even number of males and females. In group one, the first gastric barostat was carried out. Rikkunshito was then administered for 2 weeks followed by the second barostat on the next day of treatment. In group two, rikkunshito was administered for 2 weeks, then the first gastric barostat was carried out. Observation (and washout) continued for 2 weeks, after which the second barostat was performed on the next day of the observation (Fig. 1A).

image

Figure 1.  (A) Study design of the present study. (B) Protocol of barostat experiments.

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Gastric barostat

In the morning of the day after treatment or observation, a gastric barostat was performed under fasting conditions. A standardized barostat procedure was performed.14 Firstly, a thin polyethylene bag attached to a catheter was orally inserted into the proximal stomach under X-ray observation. The maximum capacity of the bag was 1400 mL. Next, the catheter was connected to a barostat unit (Synectics Visceral Stimulator; Synectics Medical, Stockholm, Sweden) and the intragastric bag pressure was controlled using a computer attached to the barostat unit. The software used was Polygram for Windows SVS module (Synectics Medical). The pressure and volume of the bag were recorded at a frequency of 12 Hz.

In the gastric function test, a preliminary measurement of perception was performed followed by a 5-min interval before the first measurement. After a second 5-min interval, the second measurement of perception was repeated. A 15-min interval was then followed by measurement of the gastric wall tone (narrowly defined barostat). This consisted of a 30-min rest followed by 10-min of virtual reality stress. A 30-min recovery period was followed by a 10-min rest, then re-measurement of perception was performed twice with a 5-min interval in-between. Subjects were scored on an ordinate scale of perception and emotion during the test (Fig. 1B).

In the preliminary measurement of the perception threshold, the intrabag pressure of 0 mmHg was increased by 2 mmHg increments every 10 s (stepwise distention). Subjects were instructed to press the perception input terminal button 1 (first sensation) when they first sensed visceral perception, button 2 (discomfort) when they sensed upper abdominal discomfort, and button 3 (pain) when they sensed upper abdominal pain. Subject reactions were recorded.

In the measurement of perception threshold, intrabag pressure was returned to 0 mmHg and then increased up to a low value of 2 mmHg from the first sensation. From here, pressure was increased in a random order in the period from the first sensation to pain and subjects were instructed to press buttons 1–3 in each case as appropriate (random staircase distention). When there was no perception, subjects pressed button 0. The interval after each stimulus was 30 s. From this measurement, perception based on perception threshold pressure could be interpreted from the button pushing response and reflex gastric motility based on the volume of the intragastric bag. The intrabag volume decreases during gastric contraction and increases during gastric distention.

Measurement of gastric wall tone was performed using a narrowly defined barostat mode.14 The pressure force at the point when the intragastric bag volume became 30 mL was determined from the first pressure wavelength in the preliminary measurement of perception threshold (stepwise distention), and this was used as the minimal distending pressure (MDP). Next, the barostat was computer controlled such that a low fixed pressure of MDP + 2 mmHg was added to the bag. The barostat mode measures gastric wall tone by analyzing changes in the intragastric bag under this fixed low pressure. Specifically, the volume of the bag decreases when the gastric wall tone increases, and increases when the gastric wall tone decreases. Furthermore, the intrabag volume decreases significantly over a short time period, and contraction of the stomach can be detected from the restoring waveform. In the present study, the waveform of the volume modified by 10% or more from baseline that appeared in 1–4 min was taken as the phasic volume event (PVE) according to previous reports14–17 and analyzed values.

Virtual reality stress

During the measurement of gastric wall tone, subjects were asked to view video images wearing a head mounted display (HMD, Mediamask MW601; Olympus, Tokyo, Japan) connected to a video cassette recorder (SLV-RX9; SONY, Tokyo, Japan). During resting and recovery periods, images were of natural surroundings while those during virtual reality stress were three-dimensional (3D) films that gave subjects the feeling of being on a roller coaster ride. Electrocardiograms were recorded to detect stress-induced changes in heart rate and heart rate variability. These methods were the same as those of our previous report.18

Ordinate scale

The ordinate scale is a subjective symptom measure of importance in analyzing the clinical efficacy of a treatment19 and pathophysiological research20 for functional GI disorders. We used an eight-item and seven-step evaluation scale. The eight items were as follows: epigastric fullness, nausea, sense of satiety, epigastric discomfort, epigastric pain, anxiety, drowsiness, and perceived stress. The evaluation scale was as follows: 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = moderately severe, 5 = severe, 6 = very severe. Subjects completed a total of nine ordinate scales: four during measurement of perception threshold, two at 10- and 20-min during the rest period, one during the stress task, and two at 10- and 20-min during the recovery period.

Statistical analysis

To compare and contrast the data obtained in this experiment in the presence [TJ43 (+)] and absence [TJ43 (−)] of rikkunshito treatment, measurement values before and after stress induction were examined statistically. In the measurement of perception threshold, two (first and second) measurements of first sensation, discomfort and pain were averaged. Intrabag pressure (mmHg) and volume (mL) at these thresholds before and after stress were analyzed. In the measurement of gastric wall tone, intrabag volume (mL) and PVE score were determined at 10-min intervals for 30-min during the resting period, 10-min during the stress period, and 30-min during the recovery period. The ordinate scale was averaged at each perception and period. Heart rate and frequency domain analysis values were determined from the ECG recording taken for 30-min during the resting stage, 10-min during the stress task stage, and 30-min during the recovery period while measuring gastric wall tone. All the above measurement values obtained in the presence and absence of rikkunshito (drug) and before and after stress (period) were used as main effects and two-factor (drug × period) interaction to perform a two-way analysis of variance (anova) based on repeated measures. Post hoc tests and/or one-way anova followed as required. spss 11.0 J for Windows was used for statistical analysis and a value of < 0.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Competing interests
  9. References
  10. Supporting Information

Heart rate and heart rate variability

Heart rate was significantly increased by stress with both TJ43 (+) and TJ43 (−) (F = 5.38, = 0.041). One-way anova showed that heart rate was significantly increased in TJ43 (+) (F = 2.53, = 0.033) and in TJ43 (−) (F = 2.41, = 0.043). There was no significant difference between TJ43 (+) and TJ43 (−) regarding changes in heart rate. There was also no statistically significant difference between TJ43 (+) and TJ43 (−) regarding frequency domain analysis, as well as before and after the stress task for both the high frequency (HF) and low frequency (LF) component of heart rate variability.

Gastric function

Pressure threshold of gastric perception  In the comparisons before and after stress, the pressure threshold was significantly changed in both TJ43 (+) and TJ43 (−) (Fig. 2). Stress induced a significant decrease in sensory (first sensation) (F = 6.19, = 0.038) (Fig. 2A), discomfort (F = 10.83, = 0.011) (Fig. 2B), and pain (F = 11.92, = 0.041) (Fig. 2C) thresholds. However, there was no significant difference in pressure threshold between TJ43 (+) and TJ43 (−).

image

Figure 2.  Gastric perception threshold pressure before and after stress, in the presence [TJ43 (+)] and absence [TJ43 (−)] of rikkunshito during measurements of gastric perception. Data are expressed as mean ± standard error. Threshold pressure was significantly decreased in both TJ43 (+) and TJ43 (−) after stress. Asterisk (*) indicates significant difference from the value before stress by post hoc test (< 0.05). (A) Pressure at the first gastric sensation (F = 6.19, = 0.038). (B) Pressure at epigastric discomfort (F = 10.83, = 0.011). (C) Pressure at epigastric pain (F = 11.92, = 0.041).

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Changes in reflex gastric volume toward gastric distention stimulus  The anova of reflex gastric volume at the first sensation threshold detected a significant drug × period interaction (F = 7.50, = 0.026) (Fig. 3). A significant period effect (before and after stress) was also observed (F = 6.85, = 0.031). At the time of the first sensation, the intragastric volume after stress was significantly decreased compared with that before stress in TJ43 (−) (< 0.05). By contrast, the mean intragastric volume after stress was unchanged from that before stress in TJ43 (+). There was no significant difference in reflex gastric volume at the discomfort threshold and pain threshold between TJ43 (+) and TJ43 (−).

image

Figure 3.  Intragastric volume at the first gastric sensation during the measurement of gastric perception. Data are expressed as mean ± standard error. A significant drug (TJ43 + and −) × period (before and after stress) interaction (F = 7.50, = 0.026) and a significant period effect (F = 6.85, = 0.031) were observed. Asterisk (*) indicates significant difference from the value before stress by post hoc test (< 0.05). By contrast, the mean intragastric volume after stress was unchanged from that before stress in TJ43 (+).

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Changes in intragastric volume during the narrowly defined barostat mode  In both TJ43 (+) and TJ43 (−), intragastric volume increased significantly after stress in the recovery period compared with baseline (F = 9.28, = 0.008) (Fig. 4A). In TJ43 (+), intragastric volume was significantly increased during stress and at recovery during 0–10 min, 10–20 min, and 20–30 min after stress compared with the first 10-min of baseline (< 0.05). In TJ43 (−), intragastric volume was also significantly increased at recovery during 10–20 min and 20–30 min after stress compared with the first 10-min of baseline (< 0.05). On the other hand, there was no significant difference between TJ43 (+) and TJ43 (−) both before and after stress.

image

Figure 4.  (A) Changes in intragastric volume during barostat mode. Intragastric volume every 10 min in resting period (baseline), stress task period, and recovery period each following TJ43 (+) or TJ43 (−) is expressed as mean ± standard error. In both TJ43 (+) and TJ43 (−), intragastric volume increased after stress compared with baseline (F = 9.28, = 0.008). Asterisk (*) indicates significant increase from the value of the first baseline (base 10) by post hoc test (< 0.05). (B) Changes in gastric contractile activity during barostat mode. Phasic volume events (PVE) number (wave 10 min −1) every 10 min in resting period (baseline), stress period, and recovery period each following TJ43 (+) or TJ43 (−) are expressed as mean ± SE. In both TJ43 (+) and TJ43 (−), PVE number was increased in the stress and recovery periods compared with baseline (F = 2.71, = 0.049).

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Changes in PVE  In both TJ43 (+) and TJ43 (−), PVE number was significantly increased in the stress and recovery periods compared with baseline (F = 2.71, = 0.049) (Fig. 4B). There was no statistically significant difference between TJ43 (+) and TJ43 (−) regarding PVE number before and after stress. However, looking at the original waveform, three out of nine subjects showed a marked decrease in PVE number with TJ43 (+) compared with TJ43 (−). A representative example of subjects is shown in Fig. 5. The main results of barostat findings are shown in Table S1.

image

Figure 5.  Original waveforms of intragastric volume during barostat mode. Upper panel TJ43 (+), and lower panel TJ43 (−). One of subjects of 21-year-old male was shown.

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Ordinate scale

Both before and after stress, the ordinate scales for epigastric fullness at the pain threshold with TJ43 (+) were significantly lower than those with TJ43 (−) (F = 12.79, = 0.037) (Fig. 6A). Post hoc testing indicated that epigastric fullness at the pain threshold before stress with TJ43 (+) was significantly lower than that with TJ43 (−). Similarly, the ordinate scales for perceived stress at the pain threshold with TJ43 (+) were significantly lower than those with TJ43 (−), independent from stress (F = 13.71, = 0.034) (Fig. 6B). Post hoc testing indicated that perceived stress at the pain threshold before stress with TJ43 (+) was significantly lower than that with TJ43 (−). There was a significant drug × period interaction in the ordinate scales for anxiety at the discomfort threshold (F = 8.00, = 0.022) (Fig. 6C). Anxiety slightly increased following stress in TJ43 (−), and slightly decreased following stress in TJ43 (+).

image

Figure 6.  Ordinate scale during the measurement of gastric perception. Data are expressed as mean ± standard error. Asterisk (*) indicates significant difference from the value of TJ43 (−) by post hoc test (< 0.05). (A) Ordinate scale of epigastric fullness at pain threshold pressure. A significant main effect of TJ43 was observed (F = 12.79, = 0.037). (B) Ordinate scale of perceived stress at pain threshold pressure. A significant main effect of TJ43 was observed (F = 13.71, = 0.034). (C) Ordinate scale of anxiety at discomfort threshold pressure. A significant interaction was observed (F = 8.00, = 0.022).

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The ordinate scale for nausea at the pain threshold stimulus significantly increased after stress compared with before stress in both TJ43 (+) and TJ43 (−) (F = 16.33, = 0.027). The ordinate scale for drowsiness at the first sensation (F = 8.31, = 0.02) and at the discomfort threshold (F = 6.89, = 0.03) decreased significantly after stress compared with before stress regardless of TJ43 (+) or TJ43 (−). There were no significant changes in the other scales before or after stress, or between TJ43 (+) and TJ43 (−). The main results of ordinate scale are shown in Table S2–S4.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Competing interests
  9. References
  10. Supporting Information

This is the first study to report physiological evidence of the effect of rikkunshito on human gastric sensorimotor function using a barostat. The most important finding of this study is that rikkunshito inhibits visceral perception (epigastric fullness) and emotion (perceived stress) triggered by gastric distension, regardless of the presence or absence of virtual reality stress. We also show that rikkunshito appears to inhibit stress-induced decreases in gastric accommodation in response to stimuli at the first sensory threshold, which partially supports our hypothesis that rikkunshito may improve stress-induced gastric hypersensitivity and changes in gastric wall tone.

There are two dimensions in gastric perception.5 One is the level of the stimulus that can be perceived, which is a threshold aspect, and the other is how strong a stimulus is perceived. In patients with functional dyspepsia, the GI perception threshold is decreased5 and this pathological phenomenon is known as allodynia.21 Hyperalgesia21 is defined as an excessive response to noxious stimuli in dyspepsia patients, and measurements regarding this phenomenon make up the ordinate scale. Because administration of rikkunshito inhibited the ordinate scale of epigastric fullness triggered by gastric distension at the pain threshold without altering any threshold levels in this study, it appears to be effective on the hyperalgesic domain of gastric perception.

Recent studies of visceral perception suggested that painful visceral stimulation, including gastric distention,22 is processed in the homeostatic afferent processing networks.23 The anterior cingulate cortex, amygdala, hippocampus, and insula that regulate negative emotion are activated by gastric distention.22 The rationale of high perceived stress during gastric distention in this study is therefore probably due to neural processing in these brain structures. Decreased perceived stress and interaction with anxiety in this study suggest that rikkunshito may be effective through modification of these networks.

In the present study, rikkunshito inhibited stress-induced decreases in gastric accommodation in response to stimuli at the first sensory threshold. The gastric distention stimulus that triggers the first visceral perception in humans is normally a low-pressure stimulus that arises when food is ingested.5,14 Such a low-pressure stimulus triggers a tone reaction in the upper stomach that consists mainly of the fundus and upper area of the stomach to enable it to receive, retain, and digest food. This is called adaptive relaxation or accommodation.14,24 This notion is supported by in vitro experiments showing that rikkunshito enhances gastric accommodation,25,26 while another study reported that rikkunshito ameliorates abnormalities of nitric oxide-mediated gastric function.27 Thus, the reduced gastric volume after stress can be interpreted as a stress-induced impairment in accommodation, which can be reversed by rikkunshito.

Rikkunshito has also been reported to regulate plasma ACTH and cortisol levels under stress.13 However, its effects on accommodation are limited to a relatively narrow range, that is, the gastric distension stimulus that triggers the first visceral perception. Conversely, rikkunshito had no effect on changes in gastric volume during the barostat mode or during discomfort/pain stimuli. The present study and previous reports suggest that the primary effect of rikkunshito might be the inhibition of stress-induced impairment in accommodation in humans.

We found that virtual reality stress with 3D image viewing caused an increase in heart rate. Therefore, this task induced an autonomic (and possibly sympathetic) arousal as part of the stress response.28,29 The usefulness of 3D image with HMD has earlier been reported.30,31 The threshold of gastric perception after stress was found to be lower than that before stress, which is consistent with previous animal and human studies showing that stress causes GI hypersensitivity. An involvement of corticotropin-releasing hormone was also previously shown.32,33 By contrast, few reports have investigated the effect of stress on gastric contraction and accommodation.34–36 Mental stress is reported to reduce antral contraction amplitude measured with real-time ultrasonography.34 Acute stress initiated by a serial subtraction task had no effect on gastric accommodation variables measured with a barostat.35 On the other hand, Geeraerts et al. reported that experimentally induced anxiety reduced gastric compliance, gastric volume, and meal-induced gastric relaxation.36 Our findings cannot be directly compared with these earlier reports because of differences in the stress loading method. However, a similarity between our findings and those of Geeraerts et al.36 suggests that experimental stress mimicking real-life situations may inhibit gastric accommodation induced by low-pressure stimuli.

There were some limitations in this study. Firstly, only nine subjects were examined. This is because of the difficulty in performing barostat examinations twice in the same subjects. However, a single procedure is sufficient to determine physiological or pharmacological phenomena in in vivo human studies depending on the accuracy and parameters of measurement. Furthermore, the present study warrants that studies on rikkunshito that investigate greater numbers of subjects with functional dyspepsia be followed carefully. Secondly, our study design aimed to clarify the effect of rikkunshito but did not depict the more basic effect of stress on gastric sensorimotor function in humans. To solve this problem, the addition of a control observation in the absence of stress would be necessary. The barostat itself may also induce a stress response. However, it should be noted that the baseline-stress-recovery paradigm has long been used to investigate the stress response.20,28,29,31,34,35 Changes in heart rate detected during virtual reality tasks also minimized this limitation. Thirdly, at the time of this experiment, it was extremely difficult to produce a placebo for rikkunshito as it is characterized by a certain taste and smell. Therefore, instead of using a placebo, the TJ43 (−) state was compared with the TJ43 (+) state. Suggestion bias was minimized because we did not inform the subjects of the effects of rikkunshito or administer rikkunshito on the same day as the barostat procedure. Our observation of the response to rikkunshito was different from that of the placebo reported in an earlier study.37 Fourth, animal experiments suggest that one of the mechanisms of rikkunshito on gastric function may be due to the release of the hormone ghrelin.10,38 We did not measure plasma levels of ghrelin in the present study, but this will be investigated in future work.

In conclusion, rikkunshito improves stress-induced gastric wall tone in response to a low-pressure distention stimulus of the proximal stomach. In addition, we demonstrated that the clinical action of rikkunshito is likely to decrease upper abdominal bloating, perceived stress, and anxiety induced by gastric distention stimuli.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Competing interests
  9. References
  10. Supporting Information

Prof. Fukudo designed the research study and wrote the paper; Dr. Shiratori performed the research and analyzed the data and wrote the paper; Dr. Shoji performed the research and analyzed the data; Dr. Kanazawa analyzed the data, and Prof. Hongo set up the study. We appreciate Tsumura & Co for supplying information of rikkunshito. This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology-Japan and Ministry of Health, Labor, and Welfare, Japan.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Competing interests
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Competing interests
  9. References
  10. Supporting Information

Table S1. Barostat findings.

Table S2. Ordinate scale at the pain threshold (point).

Table S3. Ordinate scale at the discomfort threshold (point).

Table S4. Ordinate scale at the sensory (first sensation) threshold (point).

FilenameFormatSizeDescription
NMO_1648_sm_Tables.doc413KSupporting info item

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