Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes

The effects of the antimalarial drug chloroquine on cardiac action potentia l and membrane currents were studied at clinically relevant concentrations. In cat Purkinje fibers, chloroquine at concentrations of 0.3 to 10 muM inc reased action potential duration, and reduced maximum upstroke velocity. At concentrations of 3 and 10 muM, chloroquine increased automaticity and red uced maximum diastolic potential, and after 60 min of perfusion with a conc entration 10 muM, spontaneous activity was abolished. In isolated cat ventr icular myocytes, chloroquine also increased action potential duration in a concentration- dependent manner, and reduced resting membrane potential at 3 and 10 muM. In voltage-clamped cat ventricular myocytes, chloroquine bloc ked several inward and outward membrane currents. The order of potency was inward rectifying potassium current (I-K1) > rapid delayed rectifying potas sium current (I-Kr). sodium current (I-Na) > L-type calcium current (ICa-L) . Only tonic block of I-Na and ICa-L was observed at a stimulation frequenc y of 0.1 Hz and no additional blockade was observed during stimulation trai ns applied at 1 Hz. The effect of chloroquine on I-K1 was voltage-dependent , with less pronounced blockade at negative test potentials. In addition, u nblock was achieved by hyperpolarizing pulses to potentials negative to the current reversal potential. Chloroquine blocked the rapid component of the delayed rectifying outward current, I-Kr, but not the slow component, I-Ks . These findings provide the cellular mechanisms for the prolonged QT inter val, impaired ventricular conduction, and increased automaticity induced by chloroquine, which have been suggested as responsible for the proarrhythmi c effects of the drug.