Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels

Aim： This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels. Methods： Human ether-a-go-go related gene （hERG）, KCNQ and Kvl.2 channels were expressed in CHO cells. The delayed rectifier potassium current （IK） was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-IO0 Rapid Solution Changer. Results： Both DC031050 and dofetilide potently inhibited hERG currents with IC5o values of 2.3＋1.0 and 17.9±1.2 nmol/L, respectively DC031050 inhibited the IK current with an IC50 value of 2.7±1.5 pmol/L, which was 〉1000 times the concentration required to inhibit hERG current. DC031050 at 3 pmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of IK, or the rate of IK from inactivation. Intracellular application of DC031050 （5 pmol/L） was insufficient to inhibit IK. DC031050 up to 10 pmol/L had no effects on KCNQ2 and Kvl.2 channel currents. Conclusion： DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.