title: Antispasmodic effect of shakuyakukanzoto extract on experimental muscle cramps in vivo: role of the active constituents of Glycyrrhizae radix.
abstract: BACKGROUND
  Shakuyakukanzoto (SKT) composed of Glycyrrhizae radix (G. radix) and Paeoniae radix (P. radix) has been traditionally used in Japan, Korea and China as an antispasmodic drug for the treatment of skeletal muscle cramps and intestinal cramps.
  
  
  OBJECTIVE
  To evaluate the antispasmodic activity of SKT and its two components, as well as to identify the key constituents of the components which mediate this effect in skeletal muscles in vivo.
  
  
  METHODS
  An experimental cramp model was constructed to evaluate the effects of peripherally-acting muscle relaxants on electrically-induced cramps under physiological conditions. This was accomplished by surgically isolating the motor supply to the gastrocnemius muscle in an anesthetized rat and delivering electrical stimuli to an isolated tibial nerve to induce tetanic contractions. We first tested dantrolene, a well-known peripherally-acting relaxant, to determine the sensitivity and reliability of our experimental model. We then evaluated the effects of SKT, P. radix, G. radix, and the eight active constituents of G. radix against tetanic contractions.
  
  
  RESULTS
  We found that dantrolene (10 and 30 mg/kg, i.d.) rapidly and significantly inhibited tetanic contractions (P<0.01) irrespective of dose. SKT (0.5, 1.0, and 2.0 g/kg, i.d.) and G. radix (0.5 and 1.0 g/kg, i.d.) also significantly inhibited tetanic contractions (P<0.01) but in a dose-dependent manner owing to the actions of six of the eight active constituents in G. radix (liquiritin apioside, liquiritigenin, isoliquiritin apioside, isoliquiritigenin, glycycoumarin, and glycyrrhetinic acid, 20 μmol/kg, i.v.). These constituents, which include flavonoids, a triterpenoid, and a courmarin derivative, demonstrated temporal variations in their inhibitory activity. In contrast, P. radix (0.5 and 1.0 g/kg, i.d.) did not show a statistically significant antispasmodic effect in our study; however, we previously found that it had a significant antinociceptive effect.
  
  
  CONCLUSIONS
  Our findings show that SKT inhibits tetanic contractions in vivo and that G. radix is the main antispasmodic component due to the actions of its active constituents, thus supporting the traditional use of SKT. We further propose that SKT containing the antispasmodic G. radix and antinociceptive P. radix is a pharmaceutically elegant option for muscle cramps as treatment requires a two-pronged approach, i.e., inhibition of hyperexcitable skeletal tissues and modulation of the pain accompanying cramps.
authors.affiliation: Department of Hospital Administration and Center for Advanced Kampo Medicine and Clinical Research, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. keikokhlee@gmail.com
authors.forename: Keiko K
authors.initials: KK
authors.lastname: Lee
authors.forename: Yuji
authors.initials: Y
authors.lastname: Omiya
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Yuzurihara
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kase
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology; D047188:Chalcones / Q000302:isolation & purification / Q000494:pharmacology; D003374:Coumarins / Q000302:isolation & purification / Q000494:pharmacology; D003620:Dantrolene / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004558:Electric Stimulation / Q000379:methods; D044950:Flavanones / Q000302:isolation & purification / Q000494:pharmacology; D005960:Glucosides / Q000302:isolation & purification / Q000494:pharmacology; D006034:Glycyrrhetinic Acid / Q000302:isolation & purification / Q000494:pharmacology; D006035:Glycyrrhiza / Q000737:chemistry; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009120:Muscle Cramp / Q000188:drug therapy* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D029596:Paeonia / Q000737:chemistry; D010276:Parasympatholytics / Q000737:chemistry / Q000494:pharmacology; D008517:Phytotherapy / Q000379:methods*; D018517:Plant Roots / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test / Q000379:methods; D013979:Tibial Nerve / Q000187:drug effects / Q000502:physiology
chemical_list: D047188:Chalcones; D003374:Coumarins; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D044950:Flavanones; D005960:Glucosides; D010276:Parasympatholytics; C515155:glycycoumarin; C084321:isoliquiritin apioside; C038462:shakuyaku-kanzoh-toh; D002599:Chalcone; C040920:isoliquiritigenin; D003620:Dantrolene; D006034:Glycyrrhetinic Acid; C512196:liquiritin; C083152:liquiritigenin