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