TY - JOUR
T1 - Molecular mechanism of cibenzoline-induced anticholinergic action in single atrial myocytes
T2 - Comparison with effect of disopyramide
AU - Wu, S. N.
AU - Nakajima, T.
AU - Yamashita, T.
AU - Hamada, E.
AU - Hazama, H.
AU - Iwasawa, K.
AU - Omata, M.
AU - Kurachi, Y.
PY - 1994
Y1 - 1994
N2 - 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) (GTPγS). 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 μM, respectively. In GTPγS-loaded cells, the K current was irreversibly activated because GTP binding proteins were directly elicited by GTPγS. Cibenzoline effectively caused a decrease in the GTPγS-induced K current, whereas the extent of disopyramide action on the GTPγS-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.
AB - 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) (GTPγS). 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 μM, respectively. In GTPγS-loaded cells, the K current was irreversibly activated because GTP binding proteins were directly elicited by GTPγS. Cibenzoline effectively caused a decrease in the GTPγS-induced K current, whereas the extent of disopyramide action on the GTPγS-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.
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U2 - 10.1097/00005344-199404000-00014
DO - 10.1097/00005344-199404000-00014
M3 - Article
C2 - 7516012
AN - SCOPUS:0028348651
SN - 0160-2446
VL - 23
SP - 618
EP - 623
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 4
ER -