Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor-operated K+ current in guinea-pig atrial cells

Citation
Y. Ohmoto-sekine et al., Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor-operated K+ current in guinea-pig atrial cells, BR J PHARM, 126(3), 1999, pp. 751-761
Citations number
52
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
00071188 → ACNP
Volume
126
Issue
3
Year of publication
1999
Pages
751 - 761
Database
ISI
SICI code
0007-1188(199902)126:3<751:IEOAOT>2.0.ZU;2-6
Abstract
1 In order to clarify the mechanisms by which the class Ib antiarrhythmic d rug aprindine shows efficacy against atrial fibrillation (AF), we examined the effects of the drug on the repolarizing K+ currents in guinea-pig atria l cells by use of patch-clamp techniques. We also evaluated the effects of aprindine on experimental AF in isolated guinea-pig hearts. 2 Aprindine (3 mu M) inhibited the delayed rectifier K+ current (I-K) with little influence on the inward rectifier K+ current (I-K1) Or the Ca2+ curr ent. Electrophysiological analyses including the envelope of tails test rev ealed that aprindine preferentially inhibits I-Kr (rapidly activating compo nent) but not I-Ks (slowly activating component). 3 The muscarinic acetylcholine receptor-operated K+ current (I-K.ACh) was a ctivated by the extracellular application of carbachol (1 mu M) or by the i ntracellular loading of GTP gamma S. Aprindine inhibited the carbachol- and GTP gamma S-induced I-K.ACh With the IC50 values of 0.4 and 2.5 mu M, resp ectively. 4 In atrial cells stimulated at 0.2 Hz, aprindine (3 mu 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. 5 In isolated hearts, perfusion of carbachol (1 mu M) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered a trial fibrillation threshold. Addition of aprindine (3 mu M) inhibited the induction of AF by prolonging MAP and ERP. 6 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.