Quinidine preferentially blocks the slow delayed rectifier potassium channel in the rested state.

We examined the effects of quinidine on a slow delayed rectifier K current induced by a human IsK cDNA (hlsK) in Xenopus oocytes. The apparent blocking potency of quinidine was lowered by membrane depolarization but enhanced by membrane hyperpolarization. After block had been established at a negative membrane voltage, depolarization induced unblock. A quaternary analog of quinidine (Q+1C) was not effective when applied extracellularly, but induced prominent and sustained hlsK suppression when injected intracellularly. The voltage dependence of hlsK suppression by intracellular Q+1C was similar to that seen with extracellular quinidine. Therefore, the quinidine binding site was accessible only from the intracellular side of the membrane. Our data can be explained by proposing that quinidine binds to an intracellular domain of the hisK or an associated subunit preferentially in the rested state, and that conformational changes associated with channel activation induce drug dissociation. Such a mechanism of action predicts that hlsK suppression by quinidine will display a "reverse use dependence" (less current suppression at more frequent depolarizations), and it can at least partly explain the rate dependence in the degree of action potential prolongation induced by quinidine.