Lidocaine, one of the drugs effective in treating ventricular arrhythmias in acute
myocardial infarction (AMI), sometimes loses its efficacy after prolonged administration, possibly owing to the counteraction of
glycylxylidide, one of the metabolites of
lidocaine, through modulation of binding of
lidocaine to
sodium channels. To determine whether
glycylxylidide interferes with the antiarrhythmic action of
lidocaine, we compared the antifibrillatory effects of
lidocaine,
glycylxylidide, and their combination in 14 anesthetized open-chest dogs. Although
glycylxylidide alone prolonged intraventricular conduction time (CT) and did not affect ventricular effective refractory period (VERP), it had different effects when added to
lidocaine; i.e., it had no effect on intraventricular conduction time but shortened VERP. Although
glycylxylidide alone did not change
ventricular fibrillation threshold (VFT), the increase in VFT induced by
lidocaine was decreased by addition of
glycylxylidide, possibly as a result of competition for the same cardiac
sodium channels between
lidocaine and
glycylxylidide with similar onset but different offset kinetics, which may explain, at least in part, the drug-resistance phenomena that ensue from prolonged
lidocaine administration.