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 (IKv) in undifferentiated mouse neuroblastoma x rat glioma hybrid (NG 108-15) cells. Ca(2+)-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 microM) caused dose-dependent, irreversible inhibition of IKv 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 IKv was voltage-dependent; the degree of current inhibition increased with increasing depolarizations. The transient nature of IKv 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 microM) of sotalol, another class III antidysrhythmic agent, were without discernible effects on IKv in NG 108-15 cells. 6. The effects of clofilium on a neuronal IKv described here, and its possible mechanism of action, are compared with previously reported effects of clofilium on the cardiac IKv.
Reeve
H L
HL
Department of Pharmacology, Leeds University.
Peers
C
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D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005910:Glioma / Q000378:metabolism*; D006822:Hybrid Cells / Q000187:drug effects; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D013015:Sotalol / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; C022799:clofilium; D013015:Sotalol