Effects of BW A256C, a novel class 1 antiarrhythmic agent, on maximum rate of depolarisation of cardiac action potentials in vitro: frequency, use, and voltage dependence

The frequency, use, and voltage-dependence of the effects of a novel antiarrhythmic agent, BW A256C, on the maximum rate of depolarization (Vmax) of action potentials in guinea-pig right ventricle were studied using standard microelectrode recording techniques in vitro. BW A256C (10(-6) M) reduced Vmax in a frequency-dependent way in the range 0.33-3.3 Hz; the maximum reduction was at the highest frequency. BW A256C did not cause resting block of Vmax. The onset of use-dependent Vmax reduction at 3.3 Hz followed a monoexponential function with a very slow rate constant, 0.019 +/- 0.003 AP-1. The recovery from use-dependent reduction, studied by applying single extra stimuli at various times after trains of stimuli at 3.3 Hz, was also very slow; half-life (t 1/2) for recovery was 119.0 +/- 19.2 s, and the time constant tre was 171.7 +/- 27.7 s. For comparison, the values for Flecainide (10(-5) M), obtained under identical conditions, were: rateon, 0.106 +/- 0.010 AP-1; t 1/2, 7.68 +/- 0.20 s; tre 11.07 +/- 0.29 s (means +/- SEM). In the presence of BW A256C (10(-6) M), the normalised diastolic membrane potential-Vmax curve was significantly shifted in the hyperpolarizing direction. The mean shift was 5.5 +/- 1.1 mV, measured at the 50% reduction of Vmax level. BW A256C is therefore classified as a novel "slow" class 1C antiarrhythmic agent.