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Pflugers Arch. 2000 Apr;439(6):814-21.

Lidocaine alters activation gating of cardiac Na channels.

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Department of Medicine and Neurobiology, University of Chicago, IL 60637, USA.


The class IB antiarrhythmic drug, lidocaine, interacts strongly with depolarized sodium (Na) channels, an action that is thought to underlie its clinical efficacy. Previously, we have reported Na channel gating current (Ig) experiments with a quaternary form of lidocaine, QX-222, which binds preferentially to open Na channels and modifies the gating-charge/voltage (Q/V) relationship of cardiac Na channels by reducing maximal gating charge (Qmax) and lessening its voltage dependence. We report here investigations with lidocaine itself on Ig of native canine and cloned human cardiac Na channels. Although the state dependence of lidocaine binding to Na channels differs from that of quaternary drugs, Ig measurements demonstrated that lidocaine produced changes in the Q/V relationships similar to those elicited by QX-222, with a reduction in Qmax by 33% and a corresponding decrease in the slope factor. Concentration/response curves for the reduction in gating charge by lidocaine matched those for the block of sodium current (I(Na)), as would be expected if modification of Na channel voltage sensors by lidocaine underlied its action. The application of site-3 toxins, which inhibit movement of the voltage sensor associated with inactivation, to lidocaine-bound Na channels elicits an additional reduction in Qmax suggesting that lidocaine does not "stabilize" the Na channel in an inactivated state. We conclude that lidocaine blocks I(Na) by modification of the Na channel's voltage sensors predominately associated with channel activation leading to channel opening.

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