Open channel block of the fast transient outward K+ current by primaquine and chloroquine in rat left ventricular cardiomyocytes.

Anti-malarial drugs may have severe adverse cardiac effects as a result of their ion channel blocking properties. Here we investigate the effect of the aminoquinolines primaquine and chloroquine on the fast transient outward K(+) current (I(to)) of single epicardial myocytes isolated from the left ventricular free wall of female Wistar rats. The ruptured-patch whole-cell configuration of the patch-clamp technique was used to investigate I(to). At +60 mV, primaquine blocked I(to) amplitude (defined as the current inactivating during a test pulse of 600 ms duration) with an IC(50) of 118±8 μM. I(to) charge was blocked with an IC(50) of 33±2 μM (n=42), indicating open channel block. Chloroquine blocked I(to) amplitude with an IC(50) of 4.6±0.9 mM, while the IC(50) for I(to) charge was 439±63 μM (n=23). The kinetic analysis of the onset of block revealed K(d) values of 52±8 μM (n=18) and 520±60μM (n=11) for primaquine and chloroquine, respectively. Both drugs significantly accelerated the apparent inactivation time constant of I(to). Steady-state inactivation of I(to) was not altered by 30 μM primaquine. In contrast, I(to) recovery from inactivation was prolonged with the appearance of an additional long time constant without a change of the short time constant. Exposure to 1mM chloroquine resulted in a right shift of steady-state inactivation, whereas recovery from inactivation was only mildly affected. Both substances exhibited considerable use dependence. In X. laevis oocytes heterologously expressing hKv4.2+hKChIP2b channels the block by the aminoquinolines was voltage dependent. We conclude that primaquine and chloroquine are open-channel blockers of I(to).