Lidocaine alters activation gating of cardiac Na channels

The class IB antiarrhythmic drug, lidocaine, interacts strongly with depola rized sodium (Na) channels, an action that is thought to underlie its clini cal efficacy. Previously, we have reported Na channel gating current (I,) e xperiments with a quaternary form of lidocaine, QX-222, which binds prefere ntially to open Na channels and modifies the gating-charge/voltage (Q/V) re lationship of cardiac Na channels by reducing maximal gating, charge (Q(max )) and lessening its voltage dependence. We report here investigations with lidocaine itself on I, of native canine and cloned human cardiac Na channe ls. Although the state dependence of lidocaine binding to Na channels diffe rs from that of quaternary drugs, I measurements demonstrated that lidocain e produced changes in the Q/V relationships similar to those elicited by QX -222, with a reduction in Q(max) by 33% and a corresponding decrease in the slope factor. Concentration/response curves for the reduction in gating ch arge by lidocaine matched those for the block of sodium current (I-Na), as would be expected if modification of Na channel voltage sensors by lidocain e underlied its action. The application of site-3 toxins, which inhibit mov ement of the voltage sensor associated with inactivation, to lidocaine-boun d Na channels elicits an additional reduction in Q(max) suggesting that lid ocaine does not "stabilize" the Na channel in an inactivated state. We conc lude that lidocaine blocks INa by modification of the Na channel's voltage sensors predominately associated with channel activation leading to channel opening.