Alteration by Xylocaine (Lidocaine) and Its Derivatives of the Time Course of the End Plate Potential

Abstract

A BSTRACT Xylocaine and its derivatives act specifically at the neuromuscular junction within the concentration range 0.05 to 2.0 m. The charged form is the active form of the drugs. There is no correlation between "local anesthetic" activity and effect at the junction. Like d-tubocurarine, these drugs have little or no effect on quantum content, acetylcholinesterase activity, or the passive impedance of the muscle fiber. Yet they produce end plate potentials characterized by a brief, early component and a late, greatly prolonged component, as does procaine. Analysis of these changes in time course suggests that the drugs have little or no effect before receptors are activated by acetylcholine, but cause a decreased and often greatly prolonged response. Clear structure-activity relations indicate that the receptor to which the drugs bind to produce the prolonged response can be the receptor for acetylcholine. Comparison of the effects of the drugs on the end plate potential and on the response to iontophoretically applied acetylcholine also shows that the effects of Xylocaine depend on the time course of receptor activation and are quite different from the effects of dtubocurarine.The experiments reported here were prompted by previous studies on the effects of the local anesthetic procaine at the neuromuscular junction of frog skeletal muscle (4,10,20,21). Procaine has been found to depress the amplitude of the response of the postsynaptic receptors to acetylcholine (ACh) (4). But unlike d-tubocurarine (d-TC), which depresses the amplitude of the end plate potential (e.p.p.) without greatly altering its time course (rise time of 1-2 msec and half-time of fall 2-8 msec [9]) procaine produces e.p.p.'s that have an initial rapid transient (rise time 0.5-1 msec, half-time of fall 1 msec or less) followed by a greatly prolonged late falling phase (10). Maeno (20,21) has shown that this prolonged phase arises from a prolonged flow '44

A quantitative analysis of local anaesthetic alteration of miniature end‐plate currents and end‐plate current fluctuations.

“…Athird mechanism by which local anaesthetics could interact with the ACh receptor is by perturbing the electric field in its vicinity. Steinbach (1968 a) demonstrated that the charged form of the local anaesthetics are responsible for altering e.p.c.s. The charged local anaesthetic molecules appear to bind to acidic phospholipids (Skou, 1954;Shanes & Gershfield, 1960;Ohki, 1970;Papahadjopoulos, 1970;Muller & Finkelstein, 1972;Seeman, 1972, Papahadjopoulos, Jacobsen, Poste & Shepard 1975, and thereby change the membrane surface electrical potential (Muller & Finkelstein, 1972).…”

Recovery of Some Functional Properties of the Detergent-Extracted Cholinergic Receptor Protein from Torpedo marmorata after Reintegration into a Membrane Environment

“…The site to which local anaesthetics (quinacrine included) bind on the receptor-rich membrane fragments is distinct from the receptor site for agonists [19]. It is probably functionally related to and possibly located on the ion-translocating device, or ionophore [28,29]. The failure to recover both the effect of local anesthetics on the affinity increase caused by agonists and the slow response monitored by quinacrine may explain the variable success of the attempts to 'reconstitute' the permeability response to cholinergic agonists.…”

Presynaptic and Postsynaptic Depressant Effects of Phenytoin Sodium at the Neuromuscular Junction

“…1974;Seyama & *Narahashi, 1975;Torda & Gage, 1976) and to increase the quantal content of end plate potentials (e.p.ps) (Thompson & Turkanis, 1973). In its cardiac antiarrhythmic effect, it resembles lignocaine which also affects the time course of endplate currents (Steinbach, 1968;Ruff, 1976). We have therefore investigated the effect of phenytoin sodium on synaptic transmission at the mammalian endplate.…”