Sites of action of procaine at the motor end‐plate.

Abstract

SUMMARY1. The effects of procaine at pH 7-4 and 9 9 were studied by examining the decay phase of spontaneous miniature end-plate currents (m.e.p.c.s) recorded from toad sartorius muscle fibres.2. Following exposure to procaine (005-01 mM) at pH 7 4, the decay of m.e.p.c.s rapidly became biphasic, and could be described as the sum of two exponential components.3. When the same concentrations of procaine were applied at pH 9 9, the development of biphasic m.e.p.c.s took much longer. Reversal of the effect upon washing out the procaine was much slower at pH 9.9 than at pH 7*4. 4. A rapid change in pH from 7-4 to 9-9 during exposure to a constant concentration of procaine quickly reduced the effect of procaine on m.e.p.c.s. The effect gradually returned after prolonged exposure to procaine at pH 9-9.5. These results suggest that procaine applied at high pH, where it is predominantly in uncharged form, may be diffusing to a site of action which is not directly accessible from the external surface of the membrane.6. The voltage-dependence of procaine action was similar whether it was applied at pH 7*4 or 9-9. 7. Intracellular injection of procaine rapidly produced biphasic m.e.p.c.s, whether the extracellular pH was 7-4 or 9-9. The effect of membrane potential on these m.e.p.c.s was similar to that seen for biphasic m.e.p.c.s produced by extracellular application of procaine.8. The results indicate that procaine can affect end-plate channels when applied to either surface of the muscle membrane, and that the voltage-dependence of procaine action does not arise from the influence of membrane field on the movement of charged procaine molecules into open channels.

Agonist self-inhibitory binding site of the nicotinic acetylcholine receptor

“…Among voltage-sensitive NCIs we can quote drugs such as procaine (Adams, 1977;Gage et al, 1983;Cuevas and Adams, 1994), the quaternary ammonium derivatives of the local anesthetic lidocaine QX-222 and QX-314 (Neher and Steinbach, 1978;Horn et al, 1980;Ruff, 1982;Neher, 1983;Charnet et al, 1992;Cuevas and Adams, 1994), HTX (Masukawa and Alburquerque, 1978), quinacrine (Adams and Feltz, 1980a,b), hexamethonium and decamethonium (Bertrand et al, 1990), ent procaine K, increased linearly with the concentration of suberyldicholine (SubCh) indicated that both drugs might bind at the same site within the AChR ion channel (Forman and Miller, 1989). However, evaluation of the kinetic constants of the ion translocation inhibition elicited by procaine and several agonists evidenced two different inhibitory binding sites: one for ACh and the other one for procaine (Shiono et al, 1984;Takeyasu et al, 1986).…”

Independent control of channel closure and block of open channels by methylxanthines at acetylcholine receptors in frog.

“…These might include alterations in the dielectric constant and fluidity of the lipid environment near the channel in such a way as to make channel closure less probable (see e.g. Gage et al 1983). …”

Effects of pentobarbitone on acetylcholine‐activated channels in mammalian muscle

“…the receptor-channel complex rather than by physically blocking channels. Several other drugs thought to have been simple channel blockers have also been found not to act in this way (Gage & Sah, 1982;Gage et al, 1983;Neher, 1983;Gage & Wachtel, 1984).…”