Papaverine,[1][2][3]methyl]-6,-7-dimethoxyisoquinoline, has been used as a vasodilator agent and a therapeutic agent for cerebral vasospasm, renal colic, and penile impotence. We examined the effects of papaverine on a rapidly activating delayed rectifier K ϩ channel (hKv1.5) cloned from human heart and stably expressed in Ltk Ϫ cells as well as a corresponding K ϩ current (the ultrarapid delayed rectifier, I Kur ) in human atrial myocytes. Using the whole cell configuration of the patch-clamp technique, we found that papaverine inhibited hKv1.5 current in a time-and voltage-dependent manner with an IC 50 value of 43.4 M at ϩ60 mV. Papaverine accelerated the kinetics of the channel inactivation, suggesting the blockade of open channels. Papaverine (100 M) also blocked I Kur in human atrial myocytes. These results indicate that papaverine blocks hKv1.5 channels and native hKv1.5 channels in a concentration-, voltage-, state-, and time-dependent manner. This interaction suggests that papaverine could alter cardiac excitability in vivo.

KCB-328 [1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride] is a newly synthesized class III antiarrhythmic drug and is known to be highly effective against various types of arrhythmias induced by coronary artery ligation, reperfusion, and programmed electrical stimulation. To understand the potential ionic mechanisms, we examined the effects of KCB-328, which encodes the rapidly activating delayed rectifier K ϩ current in cardiac tissues, on human ether-a-go-gorelated gene (HERG) channels expressed in Xenopus oocytes. The amplitudes of steady-state currents and tail currents of HERG were decreased by KCB-328 dose dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by KCB-328 is voltage-dependent. IC 50 values at Ϫ30, Ϫ20, Ϫ10, 0, ϩ10, ϩ20, ϩ30, and ϩ40 mV were 7.6 Ϯ 0.5, 4.8 Ϯ 0.4, 3.2 Ϯ 0.3, 2.1 Ϯ 0.3, 1.7 Ϯ 0.2, 1.4 Ϯ 0.2, 1.3 Ϯ 0.1, and 1.2 Ϯ 0.1 M, respectively. Induction of block depended on depolarization beyond the threshold for channel opening. In addition, time-dependent block developed slowly, with ϭ 1.7 Ϯ 0.3 s (100 M) at 0 mV, and was delayed by a stronger depolarization to ϩ80 mV, at which HERG channel is inactivated. We can conclude that KCB-328 preferentially blocks open (or activated) HERG channels. The block of HERG current might in part explain the underlying ionic mechanism for the antiarrhythmic and proarrhythmic effect of KCB-328.