Cocaine is a potent cardiac stimulant and its use has been linked to life-threatening arrhythmias in humans. A prominent effect of cocaine in the heart is a suppression of the delayed-rectifier potassium current (I(K)) that is important for cardiac repolarization. In this study, cocaine was found to be an inhibitor of HERG channels that underlie the rapidly activating component of I(K). HERG was expressed in tsA201 cells and the whole-cell currents were measured using the patch-clamp technique. HERG currents are inhibited in a dose-dependent fashion with an IC(50) value of 5.6 +/- 0.4 microM. The cocaine inhibition increases over the range of voltages at which the channels activate, indicating that cocaine preferentially binds to open or inactivated channels. At more depolarized potentials, at which the channels are maximally activated, the cocaine inhibition is constant indicating that the binding of the drug is not directly influenced by voltage. Cocaine reduces both the peak tail currents and the instantaneous currents measured by applying voltage steps under conditions where channels are open. The data are consistent with the inhibition of open channels. Cocaine also accelerates the rapid decay of the current at depolarized voltages suggestive of an interaction with inactivated channels. The data indicates that cocaine inhibits the channels by preferentially binding to a combination of open and inactivated states.