A Kinetic Model for the Action of Xylocaine on Receptors for Acetylcholine

Abstract

A kinetic scheme postulating the rapid formation of a partially active acetylcholine-receptor-drug complex from Xylocaine (or a derivative) and the active acetylcholine-receptor complex can account for the effects of Xylocaine and its derivatives at the neuromuscular junction. Transmembrane currents generated by an analogue computer programmed according to the scheme can exactly match end plate currents produced by nerve stimulation in the presence of the drugs. The scheme also accounts for the qualitatively different effects of the drugs on the end plate potential and on responses to iontophoretically applied acetylcholine. The analysis presented is consistent with very rapid reactions between acetylcholine and receptors, characterized by rate coefficients in the range 104 to 106 sec-'. It is based on the hypothesis that the activation of receptors by acetylcholine changes the structure of the receptors and thus their affinity for Xylocaine. The analysis does not require pharmacological separability of sodium and potassium conductances during the end plate current.Procaine, Xylocaine, and derivatives of Xylocaine depress and modify the response of the postsynaptic receptors of the neuromuscular junction to acetylcholine (ACh) (22,25). The most striking aspect of the effects of these drugs is the production of a prolonged component of the end plate potential (e.p.p.) that cannot be ascribed to an anticholinesterase action. In this respect, and in many other details, the actions of the drugs differ greatly from that of dtubocurarine (d-TC) and other chemicals that also depress the response of receptors. However, the site of action of Xylocaine and procaine, like that of d-TC, appears to be at the postsynaptic receptors (22,25). This suggests that these drugs modify the kinetics of the receptor response, although they do not produce a response themselves. Thus, an analysis of the effects of Xylocaine and procaine at the neuromuscular junction should offer the opportunity to find out more about the receptors themselves.

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.…”

Drug blockade of open end‐plate channels.

“…However this effect is probably accounted for by the prolongation of the terminal action potential (Adams, 1974a;Thomson & Turkanis, 1973). The observation that the main effect develops only following the onset of receptor activation recalls Steinbach's (1968b) …”

Multiple mechanisms of picrotoxin block of GABA‐induced currents in rat hippocampal neurons.

“…Use dependence of non-competitive blocking agents is one of the characteristics of open channel blockade and is seen with local anaesthetic block of the nicotinic acetylcholine receptor (Steinbach, 1968;Skok, 1990) and with quaternary ammonium ion block of the delayed rectifier potassium channel (Hille, 1967;Armstrong, 1975;Stanfield, 1983). For different reasons both of these phenomena are voltage dependent.…”