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 microM) inhibited the delayed rectifier K+ current (IK) with little influence on the inward rectifier K+ current (IK1) or the Ca2+ current. Electrophysiological analyses including the envelope of tails test revealed that
aprindine preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component). The
muscarinic acetylcholine receptor-operated K+ current (IK.ACh) was activated by the extracellular application of
carbachol (1 microM) or by the intracellular loading of
GTPgammaS.
Aprindine inhibited the
carbachol- and
GTPgammaS-induced IK.ACh with the IC50 values of 0.4 and 2.5 microM, respectively. In atrial cells stimulated at 0.2 Hz,
aprindine (3 microM) 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 microM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered
atrial fibrillation threshold. Addition of
aprindine (3 microM) 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 IKr and IK.ACh.