An attempt to distinguish between the actions of neuromuscular blocking drugs on the acetylcholine receptor and on its associated ionic channel

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The effects of lobeline and tubocurarine on the voltage-clamped endplates of frog sartorius and cutaneous pectoris muscles were examined at room temperature (20-23°C). Like tubocurarine, lobeline causes nondepolarizing neuromuscular blockade. The half-time of decay (t½) of endplate currents (e.p.c.s) recorded at a holding potential (Vm) of -90 mV was significantly shorter in endplates treated with lobeline (50 μM; mean t½ ± SEM = 0.41 ± 0.02 ms) or tubocurarine (11.4 μM; t½ = 0.64 ± 0.04 ms) than in those treated with Mg2+ (13 mM; t½ = 1.39 ± 0.11 ms) or a low concentration of tubocurarine (3 μM; t½ = 0.87 ± 0.05 ms). Similarly, lobeline (10 μM) shortened the t½ of untreated miniature e.p.c.s by 35%; tubocurarine, however, abolished miniature e.p.c.s at the concentration required to observe its actions on e.p.c. decay kinetics. The t½ of e.p.c.s recorded from preparations treated with Mg2+ (13 mM), tubocurarine at low concentrations (3 μM), or untreated miniature e.p.c.s was logarithmically related to Vm, being slower at more hyperpolarized values. By contrast, the t½s of e.p.c.s recorded in either lobeline (50 μM) or tubocurarine (11.4 μM) were independent of voltage in the range -150 to -80 mV. The ability of lobeline to shorten t½ and to remove the voltage dependence of t½ was partially antagonized by Mg2+ (13 mM). As expected, when lobeline or tubocurarine was removed from the bath or when acetylcholine release from the motor nerve terminals was increased by 4-aminopyridine (20 μM) and Ca2+ (10 mM) (in the presence of lobeline or tubocurarine), the amplitude of e.p.c.s increased as a function of time. However, the t½ of the decay phase of the e.p.c.s remained shortened (i.e., unaltered from the earlier treatment). These results suggest that both tubocurarine and lobeline have at least two distinct postjunctional actions including: (i) a block of the acetylcholine receptor and (ii) a block of the ionic channel associated with the acetylcholine receptor.

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