A voltage-clamp study of the effect of two lidocaine derivatives on the time course of end-plate currents.

1. Voltage-clamped end-plate currents (e.p.c.s) have been studied in the glycerol-treated Rana pipiens sartorius nerve-muscle preparations in normal Ringer solution and in the presence of QX-222 and QX-314. 2. Both QX-222 and QX-314, the trimethyl and triethyl analogues, respectively, of lidocaine, greatly modify end-plate current kinetics. The altered e.p.c.s still show a true reversal potential, which is essentially the same as the reversal potential before drug treatment. The time course of the altered end-plate currents varies with both membrane potential and drug concentration. 3. In the presence of 0-1-1-0 mM QX-222, end-plate currents decay as the sum of three exponentials: I(t) =I1(0)e-k1t+I2(0)e-k2t+I3(0)e-k3t, where the subscipts 1, 2 and 3 refer to the rapidly, intermediately, and slowly decaying components, respectively. Both the amplitudes, Ij(0), and the decay rates, kj, depend upon membrane potential. 4. Hyperpolarization increases the relative size of the first and third components, i.e. I1(0) and I3(0) increase relative to I2(0). Depolarization increases the relative size of the second component. 5. Hyperpolarization causes a decrease in the decay rates k2 and k3 and causes a slight increase in the decay rate k1. Dependence of the three decay rates on membrane potential is well described by: kj=bjeajv. 6. The Q10 of each of the kj is about 3. 7. Raising QX-222 concentration, at any given membrane potential, augments I1(0) and I3(0) at the expense of I2(0). Raising concentration increases k1 and decreases k3; their voltage-dependence is little affected. 8. At all QX-222 concentrations tested the decay rate k2 is nearly the same as the decay rate of a normal e.p.c. recorded at an equivalent holding potential from the same fibre before drug exposure. 9. End-plate currents in the presence of 0-1 mM-QX-314 show a "major" or rapidly decaying phase and a very small, slowly decaying phase or "tail", but no intermediate component. Only the major component is discernible for end-plate currents in 0-5 mM-QX-314. 10. Voltage- and concentration-dependence of the decay rate of the major component in QX-314 is similar to k1 and QX-222. Voltage-dependence of the tails decay rate appears to be similar to k3. It is hypothesized that the second component in QX-222 represents currents of unaltered or normal conductance kinetics, and that the first and third components in QX-222, as well as the major component and tail in QX-314, represent current of "QX-altered conductance kinetics".