Therapeutic Research

Abstract

Electrophysiological effects of flecainide acetate, a potent class Ic antiarrhythmic agent,on spontaneous action potentials and membrane currents were studied using small preparation（s 0.2×0.2×0.1 mm）of rabbit sinoatria（l SA）node. Flecainide（1, 3, 10μM）progressively decreased maximal diastolic potential, rate of diastolic depolarization and maximal rate of depolarization, and prolonged action potential duration and diastolic interval in a concentration− dependent manner. At 10μM, the spontaneous activity ceased in 3 of the 6 preparations. In voltage clamp experiments using double microelectrode techniques, 10μM flecainide reduced the L−type Ca2＋ current（ICa,L）obtained on step depolarization from −40 to 0mV by 25±6％（p＜0.05, n＝5）, the delayed rectifying K＋ current （IK）tail obtained on repolarization from ＋10 to −60mV by 50±7％（p＜0.05, n＝4）, and the hyperpolarization− activated inward current（Ih）at −90mV by 9±1％（p＜0.05, n＝4）, respectively. The steady−state inactivation curve for ICa,L was shifted toward more negative potentials by 3.7± 0.5mV（p＜0.05, n＝4）without causing a significant change in the slope factor by 10μM flecainide. 10μM flecainide caused a marked use− or frequency−dependent block of ICa,L in a frequency−dependent manner. Recovery of ICa,L from inactivation was retarded（time constant＝1536±299ms）at a holding potential of −40mV in the presence of 10μM flecainide（n＝5）. The steady−state activation curve for IK was shifted toward more negative potentials by 5.0±1.6mV（p＜0.05, n＝4）without causing a significant change in the slope factor by 10μM flecainide. These results suggest that （1）flecainide exerts a negative chronotropic action by decreasing ICa,L, IK and Ih in rabbit SA node（, 2）the drug has a higher affinity both to the inactivated state of the L−type Ca2＋ channel and to the activated state of the delayed rectifying K＋ channel than to the resting state of these channels, and（3）recovery Therapeutic Research vol. 28 no. 11 2007 2267 Key words：Flecainide, Class Ic antiarrhythmic agent, Action potential, Ionic currents, Sinoatrial node Correspondence：Tomoaki Saeki. Department of Cardio−Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho−cho, Mizuho−ku, Nagoya, 467−8601, Japan, Fax 052−852−3796 Original Paper Electrophysiological Effects of Flecainide Acetate on the Spontaneous Action Potentials and Membrane Currents in Isolated Rabbit Sinoatrial Node Tomoaki Saeki Nobuyuki Ohte Genjiro Kimura Department of Cardio−Renal Medicine and Hypertension,Nagoya City University Graduate School of Medical Sciences kinetics of flecainide from L−type Ca2＋ channel inactivation was slow and therefore the drug showed a marked use− or frequency−dependent block of ICa,L.