title: The traditional herbal medicine, Ge-Gen-Tang, inhibits pacemaker potentials by nitric oxide/cGMP dependent ATP-sensitive K(+) channels in cultured interstitial cells of Cajal from mouse small intestine.
abstract: BACKGROUND
  Ge-Gen-Tang (GGT) is a traditional Chinese medicinal formula composed of Puerariae radix (Pueraria lobata Ohwi), Ephedrae Herba (Ephedra sinica Stapf), Cinnamomi Ramulus (Cinnamomum cassia Blume), Paeoniae Radix (Paeonia lactiflora Pallas), Glycyrrhizae Radix preparata (Glycyrrhiza uralensis Fischer), Zingiberis Rhizoma (Zingiber officinale Roscoe), and Zizyphi Fructus (Ziziphus jujuba Mill. var. inermis Rehder) and is widely used to ameoliorate the symptoms of gastrointestinal (GI) disorders related to diarrhea and intestinal mucosal immunity and for anti-cold, antipyretic and analgesic in Eastern Asia.
  
  
  OBJECTIVE
  Interstitial cells of Cajal (ICCs) are pacemaker cells in the GI tract that generate rhythmic oscillations in membrane potentials known as slow waves. We investigated the effects of GGT on pacemaker potentials in cultured ICCs from the mouse small intestine, and sought to identify the receptors and the action mechanisms involved.
  
  
  METHODS
  Enzymatic digestions were used to dissociate ICCs from mouse small intestine tissues. All experiments on ICCs were performed on within 12h after culture. A whole-cell patch-clamp configuration was used to record potentials (current clamp) from cultured ICCs. Intracellular Ca(2+) ([Ca(2+)]i) increase was studied in cultured ICCs using fura-2AM. All of the experiments were performed at 30-32°C.
  
  
  RESULTS
  Under the current clamping mode, GGT decreased the amplitude and frequency of pacemaker potentials; however, these effects were blocked by intracellular GDPβS, a G-protein inhibitor, and glibenclamide, a specific ATP-sensitive K(+) channels blocker. Prazosin (α1-adrenoceptor antagonist) and butoxamine (β2-adrenoceptor antagonist) did not block the GGT-induced effects, whereas atenolol (β1-adrenoceptor antagonist) blocked the GGT-induced effects. Also, yohimbine (α2-adrenoceptor antagonist) partially blocked the GGT-induced effects. Pretreatment with SQ-22536, an adenylate cyclase inhibitor, did not block the GGT-induced effects, whereas pretreatment with ODQ, a guanylate cyclase inhibitor, or L-NAME, an inhibitor of nitric oxide (NO) synthase, did. Additionally, [Ca(2+)]i analysis showed that GGT decreased [Ca(2+)]i.
  
  
  CONCLUSIONS
  These results suggest that GGT inhibits pacemaker potentials in ICCs in a G protein-, cGMP- and NO-dependent manner through stimulation of α2 and β1-adrenoceptors.
authors.affiliation: Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Soojin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Huijin
authors.initials: H
authors.lastname: Gim
authors.affiliation: Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Ji Hwan
authors.initials: JH
authors.lastname: Shim
authors.affiliation: Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Jung Kim
authors.affiliation: Department of Pharmaceutical Engineering, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors.forename: Jong Rok
authors.initials: JR
authors.lastname: Lee
authors.affiliation: College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors.forename: Sang Chan
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Young Kyu
authors.initials: YK
authors.lastname: Kwon
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Ki-Tae
authors.initials: KT
authors.lastname: Ha
authors.affiliation: Department of Physiology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea.
authors.forename: Insuk
authors.initials: I
authors.lastname: So
authors.affiliation: Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea. Electronic address: vision@pusan.ac.kr.
authors.forename: Byung Joo
authors.initials: BJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005260:Female; D056885:Interstitial Cells of Cajal / Q000187:drug effects* / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D018408:Patch-Clamp Techniques; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D004365:Drugs, Chinese Herbal; D054086:KATP Channels; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; C090831:kakkon-to; D009569:Nitric Oxide; D006152:Cyclic GMP
keywords: Gastrointestinal motility; Ge-Gen-Tang; Interstitial cells of Cajal; Pacemaker potentials