EFFECTS OF THE CLASS-III ANTIARRHYTHMIC DRUG AMBASILIDE ON OUTWARD CURRENTS IN HUMAN ATRIAL MYOCYTES

We have studied the inhibitory influence of the class III antiarrhythm ic drug ambasilide (LU 47110) on the transient outward current I-to1 a nd the sustained current I-so following inactivation of I-to1, in huma n atrial myocytes. The two currents are separated by a mathematical pr ocedure based on the amplitudes and time constants of the biexponentia l inactivation of the total outward current. The frequency dependence, the recovery from inactivation and the kinetics of activation and ina ctivation are described. Ambasilide reversibly and concentration depen dently inhibited I-to1, I-so and the sodium current I-Na. Concentratio n required for half maximal inhibition (IC50) for the effects on I-to1 and I-so were 23.3 mu mol/l and 45.7 mu mol/l respectively, concentra tions shown by others to be effective in terminating and preventing fi brillation in a dog atrial arrhythmia model. Ambasilide not only reduc ed the amplitude of I-to1 and I-so but also accelerated the time cours e of inactivation from 14.22 to 6.69 ms and from 202.3 to 87.9 ms resp ectively. The amplitude of I-to1 showed only a small dependence on sti mulation frequency characteristic for human atrial myocytes, whereas I -so was reduced significantly at higher stimulation frequencies. Ambas ilide did not change these relationships (0.1-4 Hz) and therefore did not show the reverse use-dependence known from other class III antiarr hythmic agents and which is an important property for a prospective an tiarrhythmic drug. The lack of an effect of ambasilide on both steady- state activation and inactivation of I-to1, and the time constant of r ecovery from inactivation, suggests that ambasilide acts by changing c onductance rather than by influencing the gating mechanism. The descri bed characteristics make ambasilide an interesting substance in the gr oup of class III antiarrhythmic drugs.