BLOCKADE OF DELAYED RECTIFIER K+ CURRENTS IN NEUROBLASTOMA X GLIOMA HYBRID (NG-108-15) CELLS BY CLOFILIUM, A CLASS-III ANTIDYSRHYTHMIC AGENT

1 The whole-cell patch-clamp technique was used to examine the effects of the class III antidysrhythmic agent, clofilium, on voltage-activated delayed rectifier K+ currents (IK(v)) in undifferentiated mouse neuroblastoma x rat glioma hybrid (NG 108-15) cells. Ca2+-activated K+ currents also seen in these cells were abolished by bath application of 4 mM Co2+. 2 Bath application of clofilium (0.3 to 70-mu-M) caused dose-dependent, irreversible inhibition of IK(v) in these cells. Under control conditions, activated currents were sustained during 200 ms depolarizing steps, but in the presence of clofilium, or after its wash-out, currents were reduced in amplitude and showed a time-dependent decay. 3 Clofilium blockade of IK(v) was voltage-dependent: the degree of current inhibition increased with increasing depolarizations. The transient nature of IK(v) seen in the presence of clofilium was also more apparent at higher test potentials. 4 The effects of clofilium were use-dependent: when cells were left unstimulated during drug application, and then depolarizations were resumed, several pulses were required for clofilium blockade to reach a steady level. Similar results were obtained post-clofilium, when cells were unstimulated during application and then removal of clofilium, suggesting that although the blocking action of the drug was use-dependent, it bound to the closed, delayed rectifier K+ channel. 5 High concentrations (100 or 300-mu-M) of sotalol, another class III antidysrhythmic agent, were without discernible effects on IK(v) in NG 108-15 cells. 6 The effects of clofilium on a neuronal IK(v) described here, and its possible mechanism of action, are compared with previously reported effects of clofilium on the cardiac IK(v).