Effects of class III antiarrhythmic drugs on transient outward and ultra-rapid delayed rectifier currents in human atrial myocytes.

A variety of class III antiarrhythmic agents have been shown to block the delayed rectifier current, but their effects on other K+ currents, particularly in human tissues, are less clear. We studied the concentration-dependent actions of the class III compounds d-sotalol, E-4031 and ambasilide on the transient outward current (I(to)) and the ultra-rapid delayed rectifier current (I(Kur)) in human atrial myocytes. d-Sotalol and E-4031 failed to alter I(to) or I(Kur) at concentrations up to 500 and 50 microM, respectively. In contrast, ambasilide produced a concentration-dependent inhibition of I(to) and I(Kur), with statistically significant effects at 10 microM and maximum effects at 100 microM. The 50% inhibitory concentration of ambasilide averaged 23 +/- 2 microM and 34 +/- 3 microM for I(to) and I(Kur) respectively. Ambasilide did not alter the voltage-dependence of activation or inactivation of I(to), or the voltage-dependence of I(Kur), and it did not affect I(to) recovery from inactivation. On the other hand, ambasilide accelerated I(to) inactivation, by introducing a more rapid component that accelerated with increasing drug concentration. Furthermore, block of both I(to) and I(Kur) developed over time after the onset of depolarization, with time constants of 5.8 +/- 0.8 msec and 2.5 +/- 0.4 msec at concentrations of 10 and 50 microM for I(to) and 6.1 +/- 0.8 msec and 2.1 +/- 0.3 msec at 10 and 50 microM for I(Kur). We conclude that neither d-sotalol nor E-4031 affects I(to) or I(Kur), whereas ambasilide produces efficacious open-channel block of both currents, in human atrial myocytes.