Blockade of hERG K+ channel by antimalarial drug, primaquine

Lengthening of the Q-T interval and proarrhythmia are adverse effects associated with antimalarial agents. Also, lengthening of the Q-T interval is a definite outcome when patients are administered with an overdose of primaquine. Inhibition of potassium current I Kr and resultant QT prolongation is suggested as the reason behind drug-induced arrhythmias. The present study investigated the molecular mechanisms of voltage-dependent inhibition of human Ether-a-go-go Related Gene ( h ERG) delayed rectifier K + channels expressed in HEK-293 cells by primaquine. Primaquine inhibited h ERG current in a concentration-dependent manner with the half-maximal inhibitory concentration (IC 50 ) of 21.5 µM. The voltage-dependent inhibition of h ERG current resulted in the activation curve to be shifted to a negative voltage after primaquine exposure in a dose-dependent manner. Blockade of h ERG by primaquine was also found to be time-dependent, occurring rather rapidly. Blockade of wild-type h ERG channel by primaquine was similar to those of both the S6 residue h ERG mutants (F656A and Y652A) and the pore region mutants (T623A). In conclusion, these results indicate that primaquine preferentially inhibits the h ERG potassium channel, but blockade of h ERG channel by primaquine may not be related to the S6 residue or the pore region, but may be induced through other pathways such as binding other region or effect by drug binding receptor which indicates a need for further exploration.