The action of ganglionic blocking drugs on the synaptic responses of rat submandibular ganglion cells.

1 The effects of tubocurarine, hexamethonium and trimetaphan on the synaptic currents of rat submandibular ganglion cells have been measured at 20 degrees C by means of a two-microelectrode voltage-clamp system. The aim was to distinguish between the receptor-blocking and channel-blocking actions of those drugs, and to test for possible selectivity of action on the ;fast' and ;slow' acetylcholine-operated channels.2 Tubocurarine had no effect on the amplitude of evoked synaptic currents (e.s.cs) or miniature synaptic currents (m.s.cs), except at concentrations exceeding 20 muM. The slow component of the e.s.c. was shortened by tubocurarine, this effect becoming more marked as the cell was hyperpolarized. The timecourse of m.s.cs, which have no slow component, was unaffected.3 Hexamethonium (2-30 muM) caused a voltage-dependent reduction of e.s.c. amplitude, and voltage-dependent shortening of both fast and slow components of the e.s.c. M.s.cs were also shortened.4 Trimetaphan (2-10 muM) reduced the amplitude of e.s.cs and m.s.cs. Neither component of the e.s.c. was shortened by trimetaphan; however, the slow component was reduced in amplitude more than the fast component, so that the overall duration of the e.s.c. appeared to be reduced. At higher concentrations (15-25 muM) trimetaphan clearly shortened the fast component.5 It is concluded that tubocurarine acts selectively on the slow ionic channels, the association rate constant being 2.8 x 10(6) M(-1) s(-1) at -80 mV. Hexamethonium acts on both fast and slow channels, the association rate constants, at -80 mV, being respectively 5.3 x 10(6) M(-1) s(-1) and 1.3 x 10(7) M(-1) s(-1). With both drugs, the association rate constant increases if the cell is hyperpolarized, this effect being more pronounced with hexamethonium than with tubocurarine.6 The marked voltage-dependent reduction of e.s.c. amplitude by hexamethonium cannot be accounted for by open channel block, and requires an additional mechanism, the nature of which is discussed.7 Trimetaphan, at low concentrations, acts in a way consistent with receptor block, and shows a degree of selectivity for the slow component of the e.s.c.8 In an appendix, the effect of temporal dispersion of the time of opening of ionic channels on the amplitude and time-course of the composite synaptic response is analysed. It is concluded that the shortening of the time-constant of the e.s.c. decay by hexamethonium cannot, by itself, account for the drug's effect on e.s.c. amplitude.