Effect of lidocaine hydrochloride on membrane conductance in mammalian cardiac purkinje fibers

Abstract

Lidocaine depresses automaticity in cardiac Purkinje fibers by decreasing the slope of slow diastolic depolarization, but the mechanisms of this effect are poorly understood. To test the proposal that the antiautomatic effect of lidocaine might be mediated by an increase in membrane potassium conductance, transmembrane voltage (V_m) was measured in Purkinje fibers perfused with sodium-deficient Tyrode containing choline as the major cation. V_m was varied by altering the external potassium concentration, [K]_o, from 0.5 to 150 mM before and after lidocaine, 2.14 × 10^-5 M, a concentration considered equivalent to clinical plasma antiarrhythmic levels. In Purkinje fibers, resting V_m varies linearly with [K]_o plotted on a logarithmic scale from 4 to 150 mM, approximately as predicted by the Nernst equation. At [K]_o of 0.5-2.7 mM, resting V_m diverges from the predicted potassium equilibrium potential (V_K) resulting in an increased driving force for the outward K⁺ current (V_m — V_K). In choline Tyrode at [K]_o of 2.7 mM or less, lidocaine caused a significant increase in V_m, the change being a positive linear function of (V_m — V_K) with a P < 0.01. This effect was more striking in Purkinje fibers with a V_m reduced by stretch. These findings imply that lidocaine increased membrane chord conductance for the potassium ion (gK). Current-voltage relationships using intracellular current pulses were performed in choline Tyrode at [K]_o of 0.5, 2.0, and 4.0 mM and, at each [K]_o, lidocaine was found to increase membrane slope conductance (GK). The increase in GK was even more apparent when the current-voltage relationships in long Purkinje fibers was corrected for cable complications or when experiments were done in short Purkinje fibers. To minimize complications due to membrane rectifier properties, GK was measured using intracellular application of small hyperpolarizing current pulses as V_m was decreased from -90 to -60 mv by increasing the [K]_o from 3 to 15 mM before and after lidocaine. Lidocaine increased the GK over this range of V_m. These results suggest that lidocaine increases membrane potassium conductance within the range of V_m where the pacemaker potential is seen, an action which can account for its ability to suppress automaticity, and, in part, for its ability to prevent reentrant arrhythmias.