Blockade of delayed rectifier K⁺ currents in neuroblastoma × glioma hybrid (NG 108–15) cells by clofilium, a class III antidysrhythmic agent

Abstract

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,) 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 usedependent, it bound to the closed, delayed rectifier K + channel. 5 High concentrations (100 or 300pM) 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.

The pharmacological properties of K+ currents from rabbit isolated aortic smooth muscle cells

“…However, as previously found (Reeve & Peers, 1992), the blocking action of this drug was on closer inspection clearly use-dependent, implying that it interacted with channels only after they were activated by depolarization ( Figure 5). (Malayev et al, 1995).…”

“…The drugs used were previously found to be specific blockers of particular K+ channels in other preparations (Carmeliet, 1985;Arena & Cass, 1988;Delpon et al, 1992;Reeve & Peers, 1992). In general however, these proved to be of little value in the characterization of K+ channels in rabbit aorta.…”

Inhibition of Ca2+‐sensitive K+ currents in NG 108‐15 cells by substance P and related tachykinins

“…These currents begin to activate at approximately -30 to -20 mV, and thereafter increase in amplitude linearly with increasing depolarization, as has been previously described (Reeve & Peers, 1992 Ca2+ channels (Reeve & Peers, 1992). Bath application of substance P (30 jM) for 1-2 min reversibly inhibited K+ currents in NG 108-15 cells (Figure la), and the degree of inhibition was similar at all activating test potentials studied (Figurelb).…”

A novel enhancing effect of clofilium on transient outward‐type cloned cardiac K+ channel currents

“…Each point represents the mean ± s.e.mean. (Castle, 1991) or on IK of NG 108-15 cells (Reeve & Peers, 1992). Since this effect is not accompanied by modulation of the activation rate, clofilium acts on the activated state of channels and blocks the channel, or it accelerates conversion to the inactivated state from the open state.…”

“…This compound blocks the delayed rectifier (IK) (Arena & Kass, 1988;Reeve & Peers, 1992), the ATPsensitive K+ channels (Sakuta et al, 1993) and Ik (Folander et al, 1990). The drug has also been reported to block the transient outward current (Ito) in isolated ventricular myocytes, but a long exposure time was required for its action (Castle, 1991).…”