ATTENUATION OF ANTIFIBRILLATORY EFFECTS OF LIDOCAINE BY ITS METABOLITE, GLYCYLXYLIDIDE - APPLICATION OF MODULATED RECEPTOR HYPOTHESIS

Lidocaine, one of the drugs effective in treating ventricular arrhythm ias in acute myocardial infarction (AMI), sometimes loses its efficacy after prolonged administration, possibly owing to the counteraction o f glycylxylidide, one of the metabolites of lidocaine, through modulat ion of binding of lidocaine to sodium channels. To determine whether g lycylxylidide 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 gl ycylxylidide 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 glycylxy lidide 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 cardi ac sodium channels between lidocaine and glycylxylidide with similar o nset but different offset kinetics, which may explain, at least in par t, the drug-resistance phenomena that ensue from prolonged lidocaine a dministration.