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Mechanisms of the anticholinergic effect of SUN 1165 in comparison with flecainide, disopyramide and quinidine in single atrial myocytes isolated from guinea‐pig
Author(s) -
Inomata Norio,
Ishihara Takafumi,
Akaike Norio
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12541.x
Subject(s) - quinidine , disopyramide , flecainide , gtp' , chemistry , muscarinic acetylcholine receptor , pharmacology , acetylcholine , biophysics , medicine , biochemistry , receptor , biology , enzyme , atrial fibrillation
1 The mechanism of the anticholinergic effect of SUN 1165 on the acetylcholine (ACh)‐induced K + current ( I K.ACh ) was examined and compared with those of flecainide, disopyramide and quinidine in single atrial myocytes, in a whole‐cell configuration by use of the concentration‐jump technique. This technique combines an intracellular perfusion and a rapid exchange of external solution surrounding the voltage‐clamped single myocyte within 2 ms. 2 In the cells loaded with guanosine‐5′‐triphosphate (GTP), 100 μ m , the muscarinic ACh response, ( I K.ACh ), was mediated by GTP‐binding proteins. The concentrations of the test drugs that produced a half‐maximal inhibition of ACh (1 μ m )‐induced I K.ACh (IC 50 ) were 29 μ m for SUN 1165, 3.6 μ m for flecainide, 1.7 μ m for disopyramide, and 1.6 μ m for quinidine. The blockade of I K.ACh by SUN 1165 and its recovery from the inhibition occurred within a few seconds. Disopyramide had a similar rapid action, while the effects of flecainide and quinidine occurred much more slowly within a few tens of seconds. 3 In cells loaded with 100 μ m guanosine‐5′‐O‐(3‐thio triphosphate) (GTPγS, a nonhydrolysable GTP analogue), the K + channel was uncoupled from the muscarinic receptors and activated irreversibly due to direct activation of GTP‐binding proteins by GTPγS. SUN 1165 and disopyramide had a weak inhibitory effect (IC 50 > 100 μ m for both), while flecainide and quinidine depressed the GTPγS‐induced K + current with similar potencies to the cases of ACh‐induced currents; IC 50 was 5.3 μ m for flecainide and 4.4 μ m for quinidine. 4 These results suggest that the mechanisms underlying the anticholinergic effects of these antiarrhythmic drugs are different; disopyramide and high concentrations of SUN 1165 mainly block muscarinic ACh receptors in atrial myocytes, while flecainide and quinidine inhibit the K + channel itself and/or GTP‐binding proteins.