Key result
Cibenzoline directly inhibits K channels but exerts less potent anticholinergic effects than disopyramide.
Why the study?
Does cibenzoline inhibit muscarinic K channels differently than disopyramide in guinea pig atrial myocytes?
Does cibenzoline inhibit muscarinic K channels differently than disopyramide in guinea pig atrial myocytes?
Absolute Event Rate: 8% vs 3%
Cibenzoline has less potent anticholinergic effects than disopyramide but acts by inhibiting the muscarinic K channel itself or coupled GTP-binding proteins, whereas disopyramide mainly blocks muscarinic receptors.
Suggests mechanistic differences may influence clinical anticholinergic profiles; leaves open translation from guinea pig myocytes to human therapy.
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.
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Wu et al. (1994) studied this question. Cibenzoline vs. Disopyramide was evaluated on Concentration for half-maximal inhibition (EC50) of ACh-induced K current. Cibenzoline suppressed ACh-induced K current with an EC50 of 8 microM compared to 3 microM for disopyramide, indicating less potent anticholinergic effects but direct inhibition of the K channel.
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