Back
 CM  Vol.2 No.2 , June 2011
Pharmacological Modulation by Shakuyakukanzoto (Shao-Yao-Gan-Cao-Tang) and the Ingredients in Rat Intestinal Smooth Muscle
Abstract: Shakuyakukanzoto (Shao-Yao-Gan-Cao-Tang), a formulation of Japanese herbal (Kampo) medicines, is composed of Paeoniae Radix and Glycyrrhizae Radix. Effects of Shakuyakukanzoto and the ingredients on rat intestinal tract were examined. Shakuyakukanzoto (0.01 - 0.3 mg/ml) relaxed a carbachol (CCh, 0.3 μM) - induced contraction in a concentration-dependent manner. Both components (Paeoniae radix and Glycyrrhizae radix) also relaxed the CCh-induced contraction. At 0.1 to 1 mM, their constituents (paeoniflorin and glycyrrhetic acid) and the metabolic products (18-α- and 18-β-glycyrrhetinic acids) exerted almost the same actions. The relaxations induced by Shakuyakukanzoto were not modified by 1 μM nicardipine, 10 μM suramin (ATP receptor inhibitor) and several K+ channel inhibitors, but was attenuated by 20 μM IBMX (a phosphodiesterase inhibitor). Also, IBMX inhibited the relaxations induced by paeoniflorin and glycyrrhetic acid, but not by other ingredients. Nicardipine decreased the relaxation of just 18-α-glycyrrhetinic acid. Even in non-treatment with CCh, Shakuyakukanzoto relaxed the intestinal tract. CCh (0.3 μM) elicited spontaneous contractions in 23% specimens, depressed by application of Shakuyakukanzoto. These results indicate that Shakuyakukanzoto causes a remarkable relaxation by the anti-cholinergic and the PDE inhibitory actions, but by minor contribution of Ca2+ channel inhibition. Thus, Shakuyakukanzoto exerts an anti-spasmodic action due to the interaction with pharmacological effects of its ingredients.
Cite this paper: nullH. Satoh and K. Tsuro, "Pharmacological Modulation by Shakuyakukanzoto (Shao-Yao-Gan-Cao-Tang) and the Ingredients in Rat Intestinal Smooth Muscle," Chinese Medicine, Vol. 2 No. 2, 2011, pp. 62-70. doi: 10.4236/cm.2011.22012.
References

[1]   M. Kimura, I. Kimura, K. Takahashi, M. Muroi, M. Yoshizaki, M. Kanaoka and I. Kitagawa, “Blocking Effects of Blended Paeoniflorin or Its Related Compounds with Glycyrrhizin on Neuromuscular Junctions in Frog and Mouse,” Japanese Journal of Pharmacology, Vol. 36, No. 3, 1984, pp. 275-282. doi:10.1254/jjp.36.275

[2]   M. Kimura, I. Kimura and H. Nojima, “Depolarizing Neuromuscular Blocking Action Induced by Electropharmacological Coupling in the Combined Effect of Paeoniflorin and Glycyrrhizin,” Japanese Journal of Pharmacology, Vol. 37, No. 4, April 1985, pp. 395-399. doi:10.1254/jjp.37.395

[3]   M. Kimura, I. Kimura and M. Kimura, “Decreasing Effects by Glycyrrhizin and Paeoniflorin on Intracellular Ca2+- Aequorin Luminescence Transients with or without Caffeine in Directly Stimulated-Diaphragm Muscle of Mouse,” Japanese Journal of Pharmacology, Vol. 39, No. 3, November 1985, pp. 387-390. doi:10.1254/jjp.39.387

[4]   J. X. He, E. Goto, T. Akao and T. Tani, “Interaction between Shaoyao-Gancao-Tang and a laxative with respect to alteration of paeoniflorin metabolism by intestinal bacteria in rats,” Phytomedicine, Vol. 14, No. 7-8, August 2007, pp. 454-459. doi:10.1016/j.phymed.2006.09.014

[5]   Y. Saegusa, A. Sugiyama, A. Takahara, Y. Nagasawa and K. Hashimoto, “Relationship between Phoshpodiesterase Inhibition Induced by Several Kampo Medicines and Smooth Muscle Relaxation of Gastrointestinal Tract Tissues of Rats,” Journal of Pharmacology, Vol. 93, No. 1, 2003, pp. 62-68.

[6]   Y. Takeda, S. M. Ward, K. M. Sanders and S. D. Koh, “Effects of the Gap Junction Blocker Glycyrrhetinic Acid on Gastrointestinal Smooth Muscle Cells,” American Journal of Physiology, Gastrointestinal Liver Physiology, Vol. 289, No.4, April 2005, pp.G832-G841. doi:10.1152/ajpgi.00389.2004

[7]   Z. Gajda, E. Hermesz, E. Gyengesi, Z. Szupera and M. Szente, “The Functional Significance of Gap Junction Channels in the Epileptogenicity and Seizure Susceptibility of Juvenile Rats,” Epilepsia, Vol. 47, No. 6, 2006, pp. 1009-1022. doi:10.1111/j.1528-1167.2006.00573.x

[8]   E. E. Daniel, A. F. EI-Yazbi, M. Mannarino, G. Galante, G. Boddy, J. Livergant and T. E. Oskouei, “Do Gap Junctions Play a Role in Nerve Transmissions as well as Pacing in Mouse Intestine,” American Journal of Physiology, Gastrointestinal Liver Physiology, Vol. 292, No. 3, 2007, pp. G734-G745. doi:10.1152/ajpgi.00428.2006

[9]   A. Sugaya, H. Okita, Y. Takazu and E. Sugaya, “Nerupharmacological Study of Saiko-keisito,” Shoyaku, Vol. 29, 1975, pp. 160-165.

[10]   K. Tabata, K. Matsumoto and H. Watanabe, “Paeoniflorin, a Major Constituent of Peony Root, Reverses Muscarinic M1-Receptor Antagonist-Induced Suppression of Long- Term Potentiation in the Rat Hippocampal Slice,” Japanese Journal of Pharmacology, Vol. 83, 2000, pp. 25-30. doi:10.1254/jjp.83.25

[11]   J. Liu, D. Z. Jin, L. Xiao and X. Z. Zhu, “Paeoniflorin Attenuates Chronic Cerebral Hypoperfusion-Induced Learning Dysfunction and Brain Damage in Rat,” Brain Research, Vol. 1089, No. 1, May 2006, pp. 162-170. doi:10.1016/j.brainres.2006.02.115

[12]   G. Q. Zhang, X. M. Hao, S. Z. Chen, P. A. Zhou, H. P. Cheng and C. H. Wu, “Blockade of Paeoniflorin on Sodium Current in Mouse Hippocampal CA1 Neurons,” Acta Pharmacologica Sinica, Vol. 24, No. 12, December 2003, pp. 1248-1252.

[13]   T. Y. Tsai, S. N. Wu, Y. C. Liu, A. Z. Wu and Y. C. Tsai, “Inhibitory action of L-type Ca2+ current by paeoniflorin, a major constituent of peony root, in NG108-15 neuronal cells,” European. Journal of Pharmacology, Vol. 523, No. 1-3, October 2005, pp. 16-24. doi:10.1016/j.ejphar.2005.08.042

[14]   K. S. Murthy, Y. S. Yee, J. R. Grider and G. M. Makhlouf, “Phorbol-Stimulated Ca2+ Mobilization and Contraction in Dispersed Intestinal Smooth Muscle Cells,” Journal of Pharmacology and Experimental Therapeutics, Vol. 294, No. 3, 2000, pp. 991-996.

[15]   K. S. Murthy, J. R. Grider, J. F. Kuemmerle and G. M. Makhlouf, “Sustained Muscle Contraction Induced by Agonists, Growth Factors, and Ca2+ Mediated by Distinct PKC Isozymes,” American Journal of Physiology, Gastrointestinal Liver Physiology, Vol. 279, No. 1, July 2000, pp. G201-G210.

[16]   F. Nakao, S. Kobayashi, K. Mogami, Y. Mizukami, S. Shirao, S. Miwa, N. Todoroki-Ikeda, M. Ito and M. Matsuzaki, “Involvement of Src Family Protein Tyrosine Kinase in Ca2+ Sensitization of Coronary Artery Contraction Mediated by a Sphingosylphosphorylcholin-Rho-Kinase Pathway,” Circulation Research, Vol. 91, 2002, pp. 952-960. doi:10.1161/01.RES.0000042702.04920.BF

[17]   S-K. Ryu, D. S. Ahn, Y-E. Cho, S-K. Choi, Y-H. Kim, K, G. Morgan and Y-H. Lee, “Augmented-Induced Ca2+-Sensitization of Mesenteric Artery Contraction in Spontaneous Hypertensive Rat,” Naunyn-Schmiedeberg Archive of Pharmacology, Vol. 373, No. 1, 2006, pp. 30-36. doi:10.1007/s00210-006-0036-7

[18]   H. Satoh, “Sino-Atrial Nodal Cells of Mammalian Hearts: Ionic Currents and Gene Expression of Pacemaker Ionic Channels,” Journal of Smooth Muscle Research, Vol. 39, No. 5, 2003, pp.175-193. doi:10.1540/jsmr.39.175

[19]   H. Satoh, “Identification of Hyperpolarization-Activated Inward Current in Uterine Smooth Muscle Cell during Pregnancy,” General Pharmacology, Vol. 26, No. 6, October 1995, pp. 1335-1338. doi:10.1016/0306-3623(95)00006-M

[20]   L. Thomsen, T. L. Robinson, J. C. F. Lee, L. A. Farraway, M. J. G. Hughes, S. W. Andrews and J. D. Huizinga, “Interstitial Cells of Cajal Generate a Rhythmic Pacemaker Current,” Nature Medicine, Vol. 4, No. 7, July 1998, pp. 848-851. doi:10.1038/nm0798-848

[21]   M. T. Nelson, H. Cheng, M. Rubart, L. F. Santana, A. D. Bonev, H. J. Knot and W. J. Lederer, “Relaxation of Arterial Smooth Muscle by Calcium Sparks,” Science, Vol. 270, No. 5236, October 1995, pp. 633-637. doi:10.1126/science.270.5236.633

[22]   R. ZhuGe, S. M. Sims, R. A. Tuft, K. E. Fogarty and J. V. Jr. Walsh, “Ca2+ Sparks Activate K+ and Cl- Channels Resulting in Spontaneous Transient Currents in Guinea-Pig Tracheal Myocytes,” Journal of Physiology (London) , Vol. 513, No. 3, December 1998, pp. 711-718. doi:10.1111/j.1469-7793.1998.711ba.x

[23]   Y. Himeno, F. Toyoda, H. Satoh, A. Amano, C. Y. Cha, H. Matsumura and A. Noma, ”Minor Contribution to Pacemaking in Guinea Pig SA Node,” American Journal of Physiology, Heart Circulation Physiology, Vol. 300, 2011, pp. H251-H261. doi:10.1152/ajpheart.00764.2010

[24]   H. Satoh, “Modulation of Ca2+-Activated K+ Current by Isoprenaline, Carbachol, and pHorbol Ester in Cultured (and Fresh) Rat Aortic Vascular Smooth Muscle Cells,” General Pharmacology, Vol. 27, No. 2, March 1996, pp. 319-324. doi:10.1016/0306-3623(95)02005-5

[25]   P. Kojodjojo, P. Kanagaratnam, O. R. Segal, W. Hussain and N. S. Peters, “The effects of carbenoxolone on human myocardial conduction: a tool to investigate the role of gap junction uncoupling in human arrhythmogenesis,” Journal of the American College of Cardiology, Vol. 48, No. 6, September 2006, pp. 1242-1249. doi:10.1016/j.jacc.2006.04.093

[26]   L. C. Chen, M. H. Chou, M. F. Lin and L. L. Yang, “Pharmacokinetics of Paeoniflorin after Oral Administration of Dshao-yao Gan-chao Tang in Mice,” Japanese Journal of Pharmacology, Vol. 88, No. 3, 2002, pp. 250-255. doi:10.1254/jjp.88.250

[27]   H. Hosseinzadeh, Asl. M. Nassiri and S. Parvardeh, “The Effects of Carbenoxolone, a Semisynthetic Derivative of Glycyrrhizinic Acid, on Peripheral and Central Ischemia- Reperfusion Injuries in the Skeletal Muscle and Hippocampus of Rats,” Phytomedicine, Vol. 12, No. 9, September 2005, pp. 632-637. doi:10.1016/j.phymed.2004.07.007

[28]   I. G. Sava, V. Battaglia, C. A. Rossi, M. Salvi and A. Toninello, “Free Radical Scavenging Action of the Natual Polyamine Spermine in Rat Liver Mitochondria,” Free Radical Biology and Medicine, Vol. 41, No. 8, October 2006, pp. 1272-1281. doi:10.1016/j.freeradbiomed.2006.07.008

[29]   H. Y. Park, S. H. Park, H. K. Yoon, M. J. Han and D. H. Kim, “Anti-Allergic Activity of 18-β-Glycyrrhetinic Acid-3-O-β-D-Glucuronide,” Archives of Pharmacal Research, Vol. 27, 2004, pp. 57-60. doi:10.1007/BF02980047

[30]   O. H. Kang, J. A. Kim, Y. A. Choi, H. J. Park, D. K. Kim, Y. H. An, S. C. Choi, K. J. Yun, Y. H. Nah, X. F. Cai, Y. H. Kim, K. H. Bae and Y. M. Lee, “Inhibition OH Interleukin-8 Production in the Human Colonic Epithelial Cell Line HT-29 by 18-β-Glycyrrhetinic Acid,” International Journal of Molecular Medicine, Vol. 15, 2005, pp. 981-985.

[31]   H. Kato, M. Kanaoka, S. Yano and M. Kobayashi, “3-Monoglucuronyl-Glycyrrehetic Acid is a Major Metabolite That Causes Licorice-Induced Pseudoaldosteronism,” Journal of Clinical Endocrinology and Metabolism, Vol. 80, No. 6, June 1995, pp. 1929-1933.

 
 
Top