Benzocaine enhances and inhibits the K+ current through a human cardiac cloned channel (Kv1.5)

Objective: The aim of this study was to analyze the effects of a neutral lo cal anaesthetic, benzocaine, on a cardiac K+ channel cloned from human vent ricle. Methods: Experiments were performed on hKv1.5 channels stably expres sed on mouse cells using the whole-cell configuration of the patch clamp te chnique. Results: At 10 nM, benzocaine increased the current ampIitude ("ag onist effect") by shifting the activation curve 8.4+/-2.7 mV in the negativ e direction, and slowed the time course of tail current decline. In contras t, benzocaine (100-700 mu M) inhibited hKv1.5 currents (K-D=901+/-81 mu M), modified the voltage-dependence of channel activation, which became biphas ic, and accelerated the channel deactivation. Extracellular K+ concentratio n ([K+](o)) also affected the channel gating. At 140 mM [K+](o), the time c ourse of tail currents deactivation was significantly accelerated, whereas at 0 mM [K+](o), it was slowed. At both [K+](o) the activation curve became biphasic. Benzocaine accelerated the tail current decay at 0 mM but not at 140 mM [K+](o). The reduction in the permeation of K+ through the pore did not modify the blocking effects of micromolar concentrations of benzocaine , but suppressed the agonist effect observed at nanomolar concentrations. C onclusions: All these results suggest that benzocaine blocks and modifies t he voltage- and time-dependent properties of hKv1.5 channels, binding to an extracellular and to an intracellular site at the channel level. Moreover, both sites are related to each other and can also interact with K+. (C) 19 99 Elsevier Science B.V. All rights reserved.