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Inhibitory effects of aprindine on the delayed rectifier K + current and the muscarinic acetylcholine receptor‐operated K + current in guinea‐pig atrial cells
Author(s) -
OhmotoSekine Yuki,
Uemura Hiroko,
Tamagawa Masaji,
Nakaya Haruaki
Publication year - 1999
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 - 10.1038/sj.bjp.0702334
Subject(s) - carbachol , muscarinic acetylcholine receptor , chemistry , pharmacology , inward rectifier potassium ion channel , acetylcholine , patch clamp , medicine , endocrinology , electrophysiology , biophysics , receptor , biology , biochemistry , ion channel
In order to clarify the mechanisms by which the class Ib antiarrhythmic drug aprindine shows efficacy against atrial fibrillation (AF), we examined the effects of the drug on the repolarizing K + currents in guinea‐pig atrial cells by use of patch‐clamp techniques. We also evaluated the effects of aprindine on experimental AF in isolated guinea‐pig hearts. Aprindine (3 μ M ) inhibited the delayed rectifier K + current (I K ) with little influence on the inward rectifier K + current (I K1 ) or the Ca 2+ current. Electrophysiological analyses including the envelope of tails test revealed that aprindine preferentially inhibits I Kr (rapidly activating component) but not I Ks (slowly activating component). The muscarinic acetylcholine receptor‐operated K + current (I K.ACh ) was activated by the extracellular application of carbachol (1 μ M ) or by the intracellular loading of GTPγS. Aprindine inhibited the carbachol‐ and GTPγS‐induced I K.ACh with the IC 50 values of 0.4 and 2.5 μ M , respectively. In atrial cells stimulated at 0.2 Hz, aprindine (3 μ M ) per se prolonged the action potential duration (APD) by 50±4%. The drug also reversed the carbachol‐induced action potential shortening in a concentration‐dependent manner. In isolated hearts, perfusion of carbachol (1 μ M ) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold. Addition of aprindine (3 μ M ) inhibited the induction of AF by prolonging MAP and ERP. We conclude the efficacy of aprindine against AF may be at least in part explained by its inhibitory effects on I Kr and I K.ACh .British Journal of Pharmacology (1999) 126 , 751–761; doi: 10.1038/sj.bjp.0702334