REVERSAL OF THE ELECTROCARDIOGRAPHIC EFFECTS OF COCAINE BY LIDOCAINE .2. CONCENTRATION-EFFECT RELATIONSHIPS

Ventricular arrhythmias due to cocaine may be related to its ability t o slow ventricular conduction or prolong repolarization. We previously showed that lidocaine reversed QRS prolongation due to cocaine. The p urposes of these experiments were to characterize cocaine's concentrat ion-effect relationship on both ventricular conduction and repolarizat ion, and to determine the effects of lidocaine on these relationships. The effects of lidocaine on cocaine-induced electrocardiographic chan ges were studied in 20 isolated, Tyrode-perfused guinea pig hearts. Va riables at cocaine concentrations ranging from 3-195 muM were measured and repeated in the presence of a fixed concentration of lidocaine 30 muM. Using nonlinear regression analysis, the sigmoid E(max) and simp le E(max) models were fit to cocaine concentration versus percentage c hange in QRS plots. Measures of best fit indicated that this relations hip was best described by the sigmoid E(max) model. Compared with coca ine alone, the curve for cocaine with lidocaine showed a greater EC50 (concentration at 50% of maximum effect) (59 vs 100 muM) but similar E (max) (371 vs 367%), consistent with competition. Similar values were obtained from the linear transformation of the data. Cocaine concentra tion versus percentage change in the JT(c) interval showed a biphasic effect: concentrations below 65 muM prolonged JT(c), but those above 6 5 muM had no effect or decreased JT(c). In contrast to changes in QRS, addition of lidocaine increased the effects of cocaine on JT(c): area under the concentration-effect curve for cocaine alone was 720 versus 859 muM% for cocaine with lidocaine. Lidocaine reverses cocaine-induc ed slowed ventricular conduction through competition for binding, but it appeared to increase cocaine-induced prolongation of repolarization . These findings can be explained by the different effects on sodium a nd potassium currents depending on cocaine concentration, and may have important implications regarding mechanisms and therapy of cocaine-in duced arrhythmias.