Interaction between external Na+ and mexiletine on Na+ channel in guinea-pig ventricular myocytes.

Abstract

To assess the modulation of Na+ channel block with local anaesthetics by the change of external Na+ concentration ([Na+]o), we examined the block by mexiletine at different [Na+]o using the whole-cell and the cell-attached configurations of the patch-clamp technique. Lowering [Na+]o increased the degree of use-dependent block of the whole-cell Na+ current. The external Na+ dependence of the Na+ current block was caused by the interaction of mexiletine with the activated Na+ channel, but not with the inactivated channel. In single-Na+ channel current recordings at a reduced [Na+]o of 70 mM, mexiletine shortened the mean open time of the channels (1.32 +/- 0.06 ms in the control vs. 0.86 +/- 0.12 ms with the drug, P < 0.05) without changes in the unitary current amplitude, whereas the drug did not affect mean open time at a [Na+]o of 140 mM. Moreover, the open time distributions during drug exposure at the reduced [Na+]o were better fitted to a double exponential than to a single exponential in four out of six experiments. These data suggest that mexiletine induces two conductive states: the native open state and a state representing the first step of open channel block. The transition from the former to the latter is dependent on [Na+]o, suggesting an antagonistic interaction of external Na+ with mexiletine.