title: Molecular mechanism of cibenzoline-induced anticholinergic action in single atrial myocytes: comparison with effect of disopyramide.
abstract: The anticholinergic effects of cibenzoline were examined and compared with those of disopyramide in atrial myocytes isolated from guinea pig heart. The tight-seal whole-cell voltage clamp technique was performed with a patch pipette filled with guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S). In GTP-loaded cells, both acetylcholine (ACh) and adenosine (Ado) induced a specific K channel current through GTP-binding proteins by binding to the muscarinic and Ado receptors, respectively. Both cibenzoline and disopyramide suppressed the ACh-induced K current effectively in a concentration-dependent manner. The concentrations for half-maximal inhibition of the current (EC50) caused by cibenzoline and disopyramide were 8 and 3 microM, respectively. In GTP gamma S-loaded cells, the K current was irreversibly activated because GTP binding proteins were directly elicited by GTP gamma S. Cibenzoline effectively caused a decrease in the GTP gamma S-induced K current, whereas the extent of disopyramide action on the GTP gamma S-induced K current was much less. Cibenzoline also caused significant inhibition of Ado-induced K current in GTP-loaded cells. However, the action of disopyramide was less effective in inhibiting Ado-induced K current. These results indicate that cibenzoline has less potent anticholinergic effects than disopyramide in atrial myocytes. In addition, cibenzoline effectively inhibits the muscarinic K channel itself and/or GTP-binding proteins coupled to the channel, whereas the effect of disopyramide is attributed mainly to blockade of muscarinic receptors. These findings provide novel understanding of the molecular mechanism of anticholinergic action of cibenzoline.
authors.affiliation: 2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: S N
authors.initials: SN
authors.lastname: Wu
authors.forename: T
authors.initials: T
authors.lastname: Nakajima
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: E
authors.initials: E
authors.lastname: Hamada
authors.forename: H
authors.initials: H
authors.lastname: Hazama
authors.forename: K
authors.initials: K
authors.lastname: Iwasawa
authors.forename: M
authors.initials: M
authors.lastname: Omata
authors.forename: Y
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000818:Animals; D004206:Disopyramide / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D010276:Parasympatholytics / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000187:drug effects
chemical_list: D007093:Imidazoles; D010276:Parasympatholytics; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D018047:Receptors, Purinergic P1; D004206:Disopyramide; C032151:cifenline