Effects of RS-2135, a new antiarrhythmic agent, on the kinetics of use-dependent decrease in maximum upstroke...

The use-dependent decrease in maximum upstroke velocity (Vmax) caused by RS-2135, a new antiarrhythmic compound was analyzed in isolated papillary muscles of guinea pigs. RS-2135 3 and 10 microM decreased Vmax of action potential (AP) in a concentration-related manner without affecting resting membrane potential (RMP). Vmax decay in the presence of RS-2135 was exponential at stimulation rates > 0.5 Hz. This use-dependent block of Vmax was enhanced at higher stimulation frequencies. The time constants and onset rates per action potential of the use-dependent block were 10.7-26.9 s and 0.021-0.041 AP-1, respectively. The time constants of recovery from use-dependent block were 57.9 and 63.6 s, respectively, in the presence of 3 and 10 microM RS-2135. The predicted half-time of the recovery process calculated by physicochemical parameters of RS-2135 agreed well with the observed values. These results suggest that RS-2135 is a sodium channel blocking agent with slow kinetics and that the physicochemical properties underlie these characteristics.