Possible ways in which local anaesthetics may act to produce their characteristic alterations of end-plate current (e.p.c.s) are considered. 2. Following Magleby & Stevens (1972b), it is proposed that when acetylcholine (ACh) binds to its end-plate receptor it induces a conformational change which causes an increased ionic permeability and, thus, the measured e.p.c.; the reverse conformational change which returns the permeability to its resting state is postulated to be the rate-limiting event for e.p.c. decay whether or not local anaesthetics are present. Moreover, it is proposed that the ACh receptor had multiple binding sites and the local anaesthetics can bind to one or more of these sites thereby altering the conformational changes induced when ACh binds to remaining sites. 3. Equations based on this proposal are developed and are shown to provide an accurate description of the entire e.p.c. time couse as modified by eith QX-222 or QX-314. 4. Other models are also discussed; models in which local anaesthetic molecules bind only after receptor activation appear to be ruled out.
