BLOCKADE ON SODIUM, POTASSIUM, AND CALCIUM CHANNELS BY A NEW ANTIARRHYTHMIC AGENT CPU-86017

CPU 86017 is derived from tetrahydroberberine and possesses potent ant i-arrhythmic activities in animal models. Its effects on ion channels were studied by electrophysiological approaches. The action potential duration (APD) of isolated myocytes of guinea-pigs and the mono-phasic action potential duration (MAPD) of intact rabbit hearts were prolong ed. CPU 86017 blocked the delayed outward rectifier current [I-K] by 3 0+/-4% and the I-K tail by 16 to 59% at 3-30 mu M; no effect was shown on I-K1. V-max of the isolated papillary muscle of guinea pigs was su ppressed in a dose-dependent manner by 4 to 48% at 0.3 to 30 mu M CPU 86017. This effect on V-max was reproduced under pathological conditio ns: anoxia and two hypertrophic ventricle models. The rate-dependent b lock (RDB) of V-max at steady state was 22% for CPU 86017, 30% for qui nidine, and 50% for propafenone at 10 mu M stimulated at 3 Hz. The max imal rate of depolarization of sinus pacing cells was markedly reduced by 48-70% at 3-30 mu M. CPU 86017 is probably a complex Class III ant iarrhythmic agent combined with Class I and Class IV properties. (C) 1 997 Wiley-Liss, Inc.