The effects of a novel anti-arrhythmic drug, acehytisine hydrochloride, on the human ether-a-go-go related gene K channel and its trafficking.

Many drugs cause severe side-effects such as long QT syndromes by blocking the human ether-a-go-go related gene (HERG) K(+) channels and/or disrupting HERG protein trafficking. Acehytisine hydrochloride is an anti-arrhythmic drug in phase IV clinical trial. To study whether acehytisine hydrochloride affects HERG channel activity and protein trafficking, we expressed HERG in human embryonic kidney 293 (HEK293) cells and recorded HERG channel currents with a whole-cell patch clamp technique. We also measured the protein levels by Western blot analysis. We found that acehytisine hydrochloride inhibited HERG step current (I(HERG)) in a concentration-dependent manner. However, it had little effect on the tail current (I(tail)). In addition, acehytisine hydrochloride accelerated channel inactivation and slowed recovery from inactivation. In contrast, it did not inhibit HERG protein (135 and 155 kD) trafficking, although it reduced the 155 kD band density at 2500 microM. Moreover, the F656C mutation in the S6 domain abolished acehytisine hydrochloride inhibition on the I(HERG) and enhanced the inhibitive effects on the trafficking of the 155 kD band. Acehytisine hydrochloride interrupted HERG protein trafficking at 1000 and 2500 microM. Our data showed that acehytisine hydrochloride could inhibit I(HERG), but had no effects on I(tail) until the concentration was above 1000 microM. Therefore, acehytisine hydrochloride may not induce QT interval prolongation and could be a promising anti-arrhythmic drug without severe side-effects.