AN ANALYSIS OF LIDOCAINE BLOCK OF SODIUM CURRENT IN ISOLATED HUMAN ATRIAL AND VENTRICULAR MYOCYTES

Lidocaine is a Na+ channel blocker that is highly effective for the tr eatment of ventricular tachyarrhythmias, but is largely ineffective ag ainst atrial arrhythmias. It is not known if this differential efficac y is the result of differences in lidocaine inhibition of atrial v ven tricular Na+ channels. The purpose of the present study was to charact erize lidocaine block of Na+ channels in human atrium and ventricle. W e used the whole cell voltage clamp technique with low external and in ternal Na+ concentrations (5 mM) to study the Na+ current (I-Na) in si ngle human atrial and ventricular cells isolated enzymatically from sp ecimens obtained during surgery. We found that tonic block of peak I-N a by lidocaine (200 mu M, holding potential = -140 mV, 0.1 Hz, at 1.7 degrees C) was not voltage dependent in either cell type. Reduction of maximal peak Na+ conductance in 41 atrial cells (19.8 +/- 2.7%) and n ine ventricular cells (22.6 +/- 1.7%) was virtually identical. The rat e of onset of block development was determined during depolarization t o either -80 mV or -20 mV. The time course of onset of block was descr ibed by a single exponential at -80 mV and by a double exponential at -20 mV. When the rate of block onset during a single conditioning depo larization was compared to that which developed during conditioning by a train of brief pulses (3 ms, 30 Hz), onset was faster during the pu lse train, The results were nearly identical for atrial and ventricula r I-Na. The time constants of recovery from block following either sin gle pulse or multiple-pulse conditioning did not differ. These data su ggest that lidocaine binds to both the activated and inactivated state s of the human cardiac Na+ channel. Using an analytical method based u pon the Guarded Receptor Hypothesis, we calculated apparent rate const ants describing lidocaine's interaction with the three primary states of the human Na+ channel (resting, activated and inactivated). Rate co nstants were similar to those reported for other mammalian species. Ou r results demonstrate that lidocaine block of I-Na is virtually identi cal for human atrial and ventricular cells; thus additional mechanisms must be invoked to explain the differential efficacy of lidocaine aga inst ventricular as compared to atrial dysrhythmias.