Kinetics of Interaction of the Lidocaine Metabolite Glycylxylidide With the Cardiac Sodium Channel Additive Blockade With Lidocaine

The recovery of the sodium channel from blockade by local anesthetic antiarrhythmic drugs is voltage dependent. Recovery from lidocaine-induced blockade is accelerated by hyperpolarization, whereas that from glycylxylidide (GX) blockade has been reported to be slowed by hyperpolarization. This striking difference occurs despite similarities in chemical structure. The fast recovery from GX block at depolarized potentials may lead to a partial reversal of lidocaine blockade when the two drugs are combined. We have examined the kinetics of interaction of GX with the cardiac sodium channel over a range of membrane potentials by measuring whole-cell currents in isolated rabbit myocytes under voltage clamp at 15°C. In the absence of drug, slow inactivation developed with a time constant of 10.7±5.1 seconds (n=6). During exposure to 74,umolIl GX, block developed with a time constant of 7.0±3 seconds (n =6). Because of the similar time course of slow inactivation and block, we used a high concentration of GX to induce a level of block sufficient for analysis. The onset of block was slower than that induced by lidocaine and was unaffected by variation of external sodium from 20 to 75 mmol/l. Use-dependent blockade of sodium channels was greater when pulse trains were applied from a holding potential of-100 than-140 mV. This suggested that recovery from GX block might be slower at-100 than-140 mV. Direct measurements gave time constants of recovery of 10.3±4.2 seconds at-100 mV (n=6) and 4.1±0.