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Two-step inhibitory effect of kanzo on oxytocin-induced and prostaglandin F-induced uterine myometrial contractions

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Abstract

We previously reported that shakuyaku-kanzo-to, a kampo medicine consisting of shakuyaku and kanzo, has an inhibitory effect on myometrial contractions in pregnant women. In this study, we evaluated the effects of kanzo, glycyrrhizin (a major component of kanzo), glycyrrhetinic acid (GA; a major metabolite of glycyrrhizin), shakuyaku, and paeoniflorin (a major component of shakuyaku) on agonist-induced contractions of the uterus of pregnant humans and rats. We prepared myometrial strips from the uterus of pregnant humans and rats and induced contractions with oxytocin (50 μU/mL) or prostaglandin F (PGF) (10−7 or 10−6 M). Kanzo (250 μg/mL) and GA (5 × 10−6 M) inhibited the oxytocin-induced and PGF-induced contractions in pregnant human and rat myometrium, but shakuyaku (250 μg/mL), paeoniflorin (10−5 M), and glycyrrhizin (10−5 M) did not inhibit contractions in either. Interestingly, kanzo and GA showed an inhibitory effect after temporarily enhancing the PGF-induced contractions in the rat myometrium, but not in the human myometrium. These results suggest that kanzo has at least a two-step inhibitory effect on the myometrial contractions that originate from the kanzo itself and a metabolite of glycyrrhizin in kanzo. Furthermore, kanzo was found to be safe for inhibiting PGF-induced contractions in humans because it did not temporarily enhance PGF-induced contractions.

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References

  1. Hinoshita F, Ogura Y, Suzuki Y, Hara S, Yamada A, Tanaka N, Yamashita A, Marumo F (2003) Effect of orally administered shao-yao-gan-cao-tang (Shakuyaku-kanzo-to) on muscle cramps in maintenance hemodialysis patients: a preliminary study. Am J Chin Med 31:445–453

    Article  PubMed  Google Scholar 

  2. Hyodo T, Taira T, Kumakura M, Yamamoto S, Yoshida K, Uchida T, Sakai T, Endo T, Baba S, Hidai H (2002) The immediate effect of shakuyaku-kanzo-to, traditional Japanese herbal medicine, for muscular cramps during maintenance hemodialysis. Nephron 90:240

    Article  PubMed  Google Scholar 

  3. Hyodo T, Taira T, Takemura T, Yamamoto S, Tsuchida M, Yoshida K, Uchida T, Sakai T, Hidai H, Baba S (2006) Immediate effect of Shakuyaku-kanzo-to on muscle cramp in hemodialysis patients. Nephron Clin Pract 104:c28–c32

    Article  PubMed  Google Scholar 

  4. Tanaka T (2003) A novel anti-dysmenorrhea therapy with cyclic administration of two Japanese herbal medicines. Clin Exp Obstet Gynecol 30:95–98

    Article  CAS  PubMed  Google Scholar 

  5. Katsura T (1995) The remarkable effect of kanzo-to and shakuyakukanzo-to in the treatment of acute abdominal pain. Jpn J Orient Med 4:293–299

    Google Scholar 

  6. Inoue M, Yokoyama M, Ishii A, Watanabe T, Yamato T, Kumon H (2011) The effect of shakuyakukanzoto for renal colic. Jpn J Orient Med 62:359–362

    Google Scholar 

  7. Sakai Y, Tsuyuguchi T, Ishihara T, Kato K, Tsuboi M, Ooka Y, Katsuura K, Ohara T, Takayama S, Kimura M, Kasanuki J, Ai M, Yokosuka O (2009) Confirmation of the antispasmodic effect of shakuyaku-kanzo-to (TJ-68), a Chinese herbal medicine, on the duodenal wall by direct spraying during endoscopic retrograde cholangiopancreatography. J Nat Med 63:200–203

    Article  PubMed  Google Scholar 

  8. Ai M, Yamaguchi T, Odaka T, Mitsuhashi K, Shishido T, Yan J, Seza A, Saisho H (2006) Objective assessment of the antispasmodic effect of shakuyaku-kanzo-to (TJ-68), a Chinese herbal medicine, on the colonic wall by direct spraying during colonoscopy. World J Gastroenterol 12:760–764

    PubMed  Google Scholar 

  9. Hosokawa A, Ogawa K, Ando T, Suzuki N, Ueda A, Kajiura S, Kobayashi Y, Tsukioka Y, Horikawa N, Yabushita K, Fukuoka J, Sugiyama T (2012) Preventive effect of traditional Japanese medicine on neurotoxicity of FOLFOX for metastatic colorectal cancer: a multicenter retrospective study. Anticancer Res 32:2545–2550

    CAS  PubMed  Google Scholar 

  10. Yoshida T, Sawa T, Ishiguro T, Horiba A, Minatoguchi S, Fujiwara H (2009) The efficacy of prophylactic shakuyaku-kanzo-to for myalgia and arthralgia following carboplatin and paclitaxel combination chemotherapy for non-small cell lung cancer. Support Care Cancer 17:315–320

    Article  PubMed  Google Scholar 

  11. Tsuji S, Yasuda K, Sumi G, Cho H, Tsuzuki T, Okada H, Kanzaki H (2012) Shakuyaku-kanzo-to inhibits smooth muscle contractions of human pregnant uterine tissue in vitro. J Obstet Gynaecol Res 38:1004–1010

    Article  PubMed  Google Scholar 

  12. Sato Y, He JX, Nagai H, Tani T, Akao T (2007) Isoliquiritigenin, one of the antispasmodic principles of glycyrrhiza ularensis roots, acts in the lower part of intestine. Biol Pharm Bull 30:145–149

    Article  CAS  PubMed  Google Scholar 

  13. Kim BK, Ozaki H, Hori M, Karaki H (1996) Increased inhibitory effect of phorbol ester on cytosolic Ca2+ level and contraction in rat myometrium after gestation. Jpn J Pharmacol 72:111–118

    Article  CAS  PubMed  Google Scholar 

  14. Morrison JJ, Dearn SR, Smith SK, Ahmed A (1996) Activation of protein kinase C is required for oxytocin-induced contractility in human pregnant myometrium. Hum Reprod 11:2285–2290

    Article  CAS  PubMed  Google Scholar 

  15. Nakamoto T, Yasuda K, Yasuhara M, Nakajima T, Mizokami T, Okada H, Kanzaki H (2006) Cigarette smoke extract enhances oxytocin-induced rhythmic contractions of rat and human preterm myometrium. Reproduction 132:343–353

    Article  CAS  PubMed  Google Scholar 

  16. Hoshimoto K (2007) Combined with shakuyakukanzoto at the time of embryo transfer in is vitro fertilization. Jpn J Orient Med 58:475–479

    Google Scholar 

  17. Imai A, Horibe S, Fuseya S, Iida K, Takagi H, Tamaya T (1995) Possible evidence that the herbal medicine shakuyaku-kanzo-to decreases prostaglandin levels through suppressing arachidonate turnover in endometrium. J Med 26:163–174

    CAS  PubMed  Google Scholar 

  18. Shibata T, Morimoto T, Suzuki A, Saito H, Yanaihara T (1996) The effect of shakuyaku-kanzo-to on prostaglandin production in human uterine myometrium (Article in Japanese). Nihon Sanka Fujinka Gakkai Zasshi 48:321–327

    CAS  PubMed  Google Scholar 

  19. Kimura M, Kimura I, Nojima H (1985) Depolarizing neuromuscular blocking action induced by electro pharmacological coupling in the combined effect of paeoniflorin and glycyrrhizin. Jpn J Pharmacol 37:395–399

    Article  CAS  PubMed  Google Scholar 

  20. Yang Y, Shi Q, Liu Z, Li RJ, Pan PW, Hou YY, Lu WG, Bai G (2010) The synergistic anti-asthmatic effects of glycyrrhizin and salbutamol. Acta Pharmacol Sin 31:443–449

    Article  PubMed  Google Scholar 

  21. Wang CY, Kao TC, Lo WH, Yen GC (2011) Glycyrrhizic acid and 18β-glycyrrhetinic acid modulate lipopolysaccharide-induced inflammatory response by suppression of NF-κB through PI3K p110δ and p110γ inhibitions. J Agric Food Chem 59:7726–7733

    Article  CAS  PubMed  Google Scholar 

  22. Guan X, Wilson S, Schlender KK, Ruch RJ (1996) Gap-junction disassembly and connexin 43 dephosphorylation induced by 18 beta-glycyrrhetinic acid. Mol Carcinog 16:157–164

    Article  CAS  PubMed  Google Scholar 

  23. Davidson JS, Baumarten IM, Harley EH (1986) Reversible inhibition of intercellular junctional communication by glycyrrhetinic acid. Biochem Biophys Res Commun 134:29–36

    Article  CAS  PubMed  Google Scholar 

  24. Doring B, Shynlova O, Tsui P, Eckardt D, Jansen-Bienhold U, Hofmann F, Feil S, Feil R, Lye SJ, Willecke K (2006) Ablation of connexin 43 in uterine smooth muscle cells of the mouse causes delayed parturition. J Cell Sci 119:1715–1722

    Article  PubMed  Google Scholar 

  25. Kim DH, Lew SW, Han MJ (1999) Biotransformation of glycyrrhizin to 18beta-glycyrrhetinic acid-3-O-beta-d-glucuronide by Streptococcus LJ-22, a human intestinal bacterium. Biol Pharm Bull 22:320–322

    Article  CAS  PubMed  Google Scholar 

  26. Bando M, Shibahara N, Shimada Y, Meselhy MR, Akao T, Itoh T, Terasawa K (2000) Pharmacokinetic study of paeoniflorin, paeonimetabolin-1 and glycyrrhetic acid in humans after oral administration of paeony root, glycyrrhiza and shakuyaku-kanzo-to (sha-yao-gan-cao-tang). J Trad Med 17:26–33

    CAS  Google Scholar 

  27. Seitchik J, Amico JA, Castillo M (1985) Oxytocin augmentation of dysfunctional labor. Am J Obstet Gynecol 151:757–761

    Article  CAS  PubMed  Google Scholar 

  28. Kinoshita K, Satoh K, Sakamoto S (1977) Prostaglandin PGF and E1 in plasma and amniotic fluid during human pregnancy and labor. Endocrinol Jpn 24:155–156

    Article  CAS  PubMed  Google Scholar 

  29. Myatt L, Lye SJ (2004) Expression, localization and function of prostaglandin receptors in myometrium. Prostaglandins Leukot Essent Fatty Acids 70:137–148

    Article  CAS  PubMed  Google Scholar 

  30. Farina M, Ribeiro ML, Weissmann C, Estevez A, Billi S, Vercelli C, Franchi A (2004) Biosynthesis and catabolism of prostaglandin F2alpha (PGF) are controlled by progesterone in the rat uterus during pregnancy. J Steroid Biochem Mol Biol 91:211–218

    Article  CAS  PubMed  Google Scholar 

  31. Rask-Madsen J, Bukhave K, Madsen PE, Bekker C (1983) Effect of carbenoxolone on gastric prostaglandin E2 levels in patients with peptic ulcer disease following vagal and pentagastrin stimulation. Eur J Clin Invest 13:351–356

    Article  CAS  PubMed  Google Scholar 

  32. Minuz P, Cavallini G, Angelini GP, Lechi A, Brocco G, Riela A, Scuro LA, Velo GP (1984) Carbenoxolone and prostaglandin E2 and F gastric juice levels in man. Pharmacol Res Commun 16:875–884

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Ms. Miyuki Imai for her excellent technical assistance and Ms. Ayu Yamamoto for her secretarial assistance. This work was supported by a grant from the Japan Smoking Research Foundation.

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The authors declare that there is no conflict of interest regarding the publication of this article.

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Correspondence to Katsuhiko Yasuda.

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Sumi, G., Yasuda, K., Kanamori, C. et al. Two-step inhibitory effect of kanzo on oxytocin-induced and prostaglandin F-induced uterine myometrial contractions. J Nat Med 68, 550–560 (2014). https://doi.org/10.1007/s11418-014-0835-y

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