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

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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 ± 60 μM (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 1 mM 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.