Vol. 297, Issue 1, 437-445, April 2001

Blockade of Currents by the Antimalarial Drug Chloroquine in Feline Ventricular Myocytes

José A. Sánchez-Chapula, Eduardo Salinas-Stefanon, Julian Torres-Jácome, Dora E. Benavides-Haro and Ricardo A. Navarro-Polanco

Unidad "Carlos Méndez" del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México (J.A.S.-C., D.E.B.-H., R.N.-P.); and Instituto de Fisiología de la Benemérita Universidad Autónoma de Puebla, Puebla, México (E.S.-S., J.T.-J.)

The effects of the antimalarial drug chloroquine on cardiac action potential and membrane currents were studied at clinically relevant concentrations. In cat Purkinje fibers, chloroquine at concentrations of 0.3 to 10 µM increased action potential duration, and reduced maximum upstroke velocity. At concentrations of 3 and 10 µM, chloroquine increased automaticity and reduced maximum diastolic potential, and after 60 min of perfusion with a concentration 10 µM, spontaneous activity was abolished. In isolated cat ventricular myocytes, chloroquine also increased action potential duration in a concentration-dependent manner, and reduced resting membrane potential at 3 and 10 µM. In voltage-clamped cat ventricular myocytes, chloroquine blocked several inward and outward membrane currents. The order of potency was inward rectifying potassium current (I_K1) > rapid delayed rectifying potassium current (I_Kr) > sodium current (I_Na) > L-type calcium current (I_Ca-L). Only tonic block of I_Na and I_Ca-L was observed at a stimulation frequency of 0.1 Hz and no additional blockade was observed during stimulation trains applied at 1 Hz. The effect of chloroquine on I_K1 was voltage-dependent, with less pronounced blockade at negative test potentials. In addition, unblock 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 interval, impaired ventricular conduction, and increased automaticity induced by chloroquine, which have been suggested as responsible for the proarrhythmic effects of the drug.