Skip to main content

Advertisement

Log in

Intragastric administration of rikkunshito stimulates upper gastrointestinal motility and gastric emptying in conscious dogs

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Traditional Japanese medicine, known as Kampo medicine, consists of mixtures of several medicinal herbs widely used to treat upper gastrointestinal disorders in Japan. Rikkunshito, one of these medicines, has not been evaluated with respect to its influence on gastrointestinal motor activity. We investigated the effect of rikkunshito on upper gastrointestinal motility and plasma ghrelin concentrations in conscious dogs.

Methods

Contractile response to intragastric administration of rikkunshito was studied via surgically implanted force transducers. A powdered extract of rikkunshito (1.3, 2.7, and 4.0 g) dissolved in water was administered into the stomachs of normal and vagotomized dogs before feeding and gastric emptying was evaluated. Several inhibitors of gastrointestinal motility (atropine, hexamethonium, and ondansetron) were injected intravenously before intragastric administration of rikkunshito. Plasma acylated ghrelin levels after intragastric administration of rikkunshito were measured.

Results

In a fasting state, intragastric administration of rikkunshito induced phasic contractions in the duodenum and jejunum in normal dogs. Rikkunshito-induced contractions were inhibited by atropine, hexamethonium and ondansetron. In vagotomized dogs, rikkunshito induced phasic contractions, similar to normal dogs. Gastric emptying was accelerated by intragastric administration of rikkunshito in a dose-dependent manner. The plasma acylated ghrelin level 150 min after intragastric administration of 4.0 g of rikkunshito was significantly higher than the control value.

Conclusions

Intragastric administration of rikkunshito stimulates gastrointestinal contractions in the interdigestive state through cholinergic neurons and 5-HT type 3 receptors. Moreover, rikkunshito increases plasma acylated ghrelin levels. Rikkunshito may alleviate gastrointestinal disorders through its prokinetic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Tatsuta M, Iishi H. Effect of treatment with liu-jun-zi-tang (TJ-43) on gastric emptying and gastrointestinal symptoms in dyspeptic patients. Aliment Pharmacol Ther. 1993;7:459–62.

    Article  PubMed  CAS  Google Scholar 

  2. Kusunoki H, Haruma K, Hata J, Ishii M, Kamada T, Yamashita N, et al. Efficacy of Rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. Intern Med. 2010;49:2195–202.

    Article  PubMed  Google Scholar 

  3. Tominaga K, Iwakiri R, Fujimoto K, Fujiwara Y, Tanaka M, Shimoyama Y, et al. Rikkunshito improves symptoms in PPI-refractory GERD patients: a prospective, randomized, multicenter trial in Japan. J Gastroenterol. 2012;47(3):284–92.

    Article  PubMed  CAS  Google Scholar 

  4. Kawahara H, Kubota A, Hasegawa T, Okuyama H, Ueno T, Ida S, et al. Effects of rikkunshito on the clinical symptoms and esophageal acid exposure in children with symptomatic gastroesophageal reflux. Pediatr Surg Int. 2007;23:1001–5.

    Article  PubMed  Google Scholar 

  5. Kawahara H, Mitani Y, Nomura M, Nose K, Yoneda A, Hasegawa T, et al. Impact of rikkunshito, an herbal medicine, on delayed gastric emptying in profoundly handicapped patients. Pediatr Surg Int. 2009;25:987–90.

    Article  PubMed  Google Scholar 

  6. Yagi M, Homma S, Kubota M, Iinuma Y, Kanada S, Kinoshita Y, et al. The herbal medicine Rikkunshi-to stimulates and coordinates the gastric myoelectric activity in post-operative dyspeptic children after gastrointestinal surgery. Pediatr Surg Int. 2004;19:760–5.

    Article  PubMed  CAS  Google Scholar 

  7. Takahashi T, Endo S, Nakajima K, Souma Y, Nishida T. Effect of rikkunshito, a Chinese herbal medicine, on stasis in patients after pylorus-preserving gastrectomy. World J Surg. 2009;33:296–302.

    Article  PubMed  Google Scholar 

  8. Tomono H, Ito Y, Watanabe T. Successful antiemetic treatment of TSUMURA Rikkunshi-to Extract Granules for ethical use in addition to other antiemetic agents in neoadjuvant chemotherapy for an advanced breast cancer patient. Gan To Kagaku Ryoho. 2006;33:1129–31.

    PubMed  Google Scholar 

  9. Hayakawa T, Arakawa T, Kase Y, Akiyama S, Ishige A, Takeda S, et al. Liu-Jun-Zi-Tang, a kampo medicine, promotes adaptive relaxation in isolated guinea pig stomachs. Drugs Exp Clin Res. 1999;25:211–8.

    PubMed  CAS  Google Scholar 

  10. Kito Y, Suzuki H. Properties of Rikkunshi-to (TJ-43)-induced relaxation of rat gastric fundus smooth muscles. Am J Physiol Gastrointest Liver Physiol. 2010;298:G755–63.

    Article  PubMed  CAS  Google Scholar 

  11. Kido T, Nakai Y, Kase Y, Sakakibara I, Nomura M, Takeda S, et al. Effects of rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying induced by N(G)-nitro-l-arginine. J Pharmacol Sci. 2005;98:161–7.

    Article  PubMed  CAS  Google Scholar 

  12. Tominaga K, Kido T, Ochi M, Sadakane C, Mase A, Okazaki H, et al. The traditional Japanese medicine rikkunshito promotes gastric emptying via the antagonistic action of the 5-HT3 receptor pathway in rats. Evid Based Complement Altern Med. 2011;2011:248481.

    Article  CAS  Google Scholar 

  13. Arakawa T, Higuchi K, Fujiwara Y, Watanabe T, Tominaga K, Hayakawa T, et al. Gastroprotection by Liu-Jun-Zi-Tang (TJ-43): possible mediation of nitric oxide but not prostaglandins or sulfhydryls. Drugs Exp Clin Res. 1999;25:207–10.

    PubMed  CAS  Google Scholar 

  14. Goso Y, Ogata Y, Ishihara K, Hotta K. Effects of traditional herbal medicine on gastric mucin against ethanol-induced gastric injury in rats. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1996;113:17–21.

    Article  PubMed  CAS  Google Scholar 

  15. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194–8.

    Article  PubMed  CAS  Google Scholar 

  16. Tack J, Depoortere I, Bisschops R, Delporte C, Coulie B, Meulemans A, et al. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut. 2006;55:327–33.

    Article  PubMed  CAS  Google Scholar 

  17. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86:5992.

    Article  PubMed  CAS  Google Scholar 

  18. Shinomiya T, Fukunaga M, Akamizu T, Irako T, Yokode M, Kangawa K, et al. Plasma acylated ghrelin levels correlate with subjective symptoms of functional dyspepsia in female patients. Scand J Gastroenterol. 2005;40:648–53.

    Article  PubMed  CAS  Google Scholar 

  19. Isomoto H, Ueno H, Nishi Y, Yasutake T, Tanaka K, Kawano N, et al. Circulating ghrelin levels in patients with various upper gastrointestinal diseases. Dig Dis Sci. 2005;50:833–8.

    Article  PubMed  CAS  Google Scholar 

  20. Shindo T, Futagami S, Hiratsuka T, Horie A, Hamamoto T, Ueki N, et al. Comparison of gastric emptying and plasma ghrelin levels in patients with functional dyspepsia and non-erosive reflux disease. Digestion. 2009;79:65–72.

    Article  PubMed  CAS  Google Scholar 

  21. Takeda H, Muto S, Hattori T, Sadakane C, Tsuchiya K, Katsurada T, et al. Rikkunshito ameliorates the aging-associated decrease in ghrelin receptor reactivity via phosphodiesterase III inhibition. Endocrinology. 2010;151:244–52.

    Article  PubMed  CAS  Google Scholar 

  22. Matsumura T, Arai M, Yonemitsu Y, Maruoka D, Tanaka T, Suzuki T, et al. The traditional Japanese medicine Rikkunshito increases the plasma level of ghrelin in humans and mice. J Gastroenterol. 2010;45:300–7.

    Article  PubMed  Google Scholar 

  23. Itoh Z, Honda R, Takeuchi S, Aizawa I, Takayanagi R. An extraluminal force transducer for recording contractile activity of the gastrointestinal smooth muscle in the conscious dogs: its construction and implantation. Gastroenterol Jpn. 1977;12:275–83.

    PubMed  CAS  Google Scholar 

  24. Inatomi N, Satoh H, Maki Y, Hashimoto N, Itoh Z, Omura S. An erythromycin derivative, EM-523, induces motilin-like gastrointestinal motility in dogs. J Pharmacol Exp Ther. 1989;251:707–12.

    PubMed  CAS  Google Scholar 

  25. Itoh Z, Mizumoto A, Iwanaga Y, Yoshida N, Torii K, Wakabayashi K. Involvement of 5-hydroxytryptamine 3 receptors in regulation of interdigestive gastric contractions by motilin in the dog. Gastroenterology. 1991;100:901–8.

    PubMed  CAS  Google Scholar 

  26. Shiba Y, Mizumoto A, Inatomi N, Haga N, Yamamoto O, Itoh Z. Stimulatory mechanism of EM523-induced contractions in postprandial stomach of conscious dogs. Gastroenterology. 1995;109:1513–21.

    Article  PubMed  CAS  Google Scholar 

  27. Park HJ, Jung JK, Song KS, Lee SI, Itoh Z, Park IS. Effect of erythromycin on gastric emptying in healthy individuals assessed by radio-opaque markers and plasma acetaminophen levels. J Gastroenterol. 1997;32:734–9.

    Article  PubMed  CAS  Google Scholar 

  28. Sato F, Marui S, Inatomi N, Itoh Z, Omura S. EM574, an erythromycin derivative, improves delayed gastric emptying of semi-solid meals in conscious dogs. Eur J Pharmacol. 2000;395:165–72.

    Article  PubMed  CAS  Google Scholar 

  29. Yokoyama M, Murakami N, Naganobu K, Hosoda H, Kangawa K, Nakahara K. Relationship between growth and plasma concentrations of ghrelin and growth hormone in juvenile beagle dogs. J Vet Med Sci. 2005;67:1189–92.

    Article  PubMed  CAS  Google Scholar 

  30. Shiratori M, Shoji T, Kanazawa M, Hongo M, Fukudo S. Effect of rikkunshito on gastric sensorimotor function under distention. Neurogastroenterol Motil. 2011;23(323–9):e155–6.

    Google Scholar 

  31. Hasegawa T, Yamaki K, Nadai M, Muraoka I, Wang L, Takagi K, et al. Lack of effect of Chinese medicines on bioavailability of ofloxacin in healthy volunteers. Int J Clin Pharmacol Ther. 1994;32:57–61.

    PubMed  CAS  Google Scholar 

  32. Yoshida N, Mizumoto A, Iwanaga Y, Itoh Z. Effects of 5-hydroxytryptamine 3 receptor antagonists on gastrointestinal motor activity in conscious dogs. J Pharmacol Exp Ther. 1991;256:272–8.

    PubMed  CAS  Google Scholar 

  33. Kawasaki N, Nakada K, Nakayoshi T, Furukawa Y, Suzuki Y, Hanyu N, et al. Effect of Dai-kenchu-to on gastrointestinal motility based on differences in the site and timing of administration. Dig Dis Sci. 2007;52:2684–94.

    Article  PubMed  Google Scholar 

  34. Shibata C, Sasaki I, Naito H, Ueno T, Matsuno S. The herbal medicine Dai-Kenchu-Tou stimulates upper gut motility through cholinergic and 5-hydroxytryptamine 3 receptors in conscious dogs. Surgery. 1999;126:918–24.

    Article  PubMed  CAS  Google Scholar 

  35. Hashimoto K, Kase Y, Murata P, Kido T, Nakai Y, Sakakibara I, et al. Pharmacological evaluation of Shokyo and Kankyo (1). Biol Pharm Bull. 2002;25:1183–7.

    Article  PubMed  CAS  Google Scholar 

  36. Nakai Y, Kido T, Hashimoto K, Kase Y, Sakakibara I, Higuchi M, et al. Effect of the rhizomes of Atractylodes lancea and its constituents on the delay of gastric emptying. J Ethnopharmacol. 2003;84:51–5.

    Article  PubMed  Google Scholar 

  37. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun. 2000;276:905–8.

    Article  PubMed  CAS  Google Scholar 

  38. Fujino K, Inui A, Asakawa A, Kihara N, Fujimura M, Fujimiya M. Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J Physiol. 2003;550:227–40.

    Article  PubMed  CAS  Google Scholar 

  39. Ohno T, Kamiyama Y, Aihara R, Nakabayashi T, Mochiki E, Asao T, et al. Ghrelin does not stimulate gastrointestinal motility and gastric emptying: an experimental study of conscious dogs. Neurogastroenterol Motil. 2006;18:129–35.

    Article  PubMed  CAS  Google Scholar 

  40. Takeda H, Sadakane C, Hattori T, Katsurada T, Ohkawara T, Nagai K, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology. 2008;134:2004–13.

    Article  PubMed  Google Scholar 

  41. Sadakane C, Muto S, Nakagawa K, Ohnishi S, Saegusa Y, Nahata M, et al. 10-Gingerol, a component of rikkunshito, improves cisplatin-induced anorexia by inhibiting acylated ghrelin degradation. Biochem Biophys Res Commun. 2011;412:506–11.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The study was supported by a Grant from Tsumura and Company (Tokyo, Japan).

Conflict of interest

The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mitsuhiro Yanai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yanai, M., Mochiki, E., Ogawa, A. et al. Intragastric administration of rikkunshito stimulates upper gastrointestinal motility and gastric emptying in conscious dogs. J Gastroenterol 48, 611–619 (2013). https://doi.org/10.1007/s00535-012-0687-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-012-0687-8

Keywords

Navigation