Pre‐and post‐junctional effects of tubocurarine and other nicotinic antagonists during repetitive stimulation in the rat.

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Abstract
The effects of tubocurarine and trimetaphan were examined at voltage-clamped rat diaphragm neuromuscular junctions during single and repetitive stimulation of the phrenic nerve in cut muscles and repetitive ionophoretic application of acetylcholine (ACh). Tubocurarine (2.5 .times. 10-7-10-6M) produced a concentration-dependent reduction in the amplitude of neurally evoked end-plate currents (e.p.c.). It also reduced their time constant of decay (.tau.e.p.c.) in a manner that was independent of membrane potential and not markedly dependent on the tubocurarine concentration. Likewise the snake .alpha.-neurotoxin, erabutoxin b, reduced the e.p.c. amplitude and produced a voltage-independent shortening of .tau.e.p.c. Estimates of mean channel lifetime (.tau.noise) from ACh-induced e.p.c. fluctuations revealed that .tau.noise was 46.4 .+-. 3.7% shorter than .tau.e.p.c. measured at the same end-plate. At these same end-plates in the presence of tubocurarine (2.5 .times. 10-7 M) .tau.e.p.c. was 32.6 .+-. 1.0% shorter than the control .tau.e.p.c. but tubocurarine did not change .tau.noise. Trimetaphan (2.5 .times. 10-5-2 .times. 10-4 M) produced a concentration-dependent and voltage-dependent reduction of .tau.e.p.c. and a concentration-dependent reduction of peak e.p.c. amplitude. Trimetaphan (2.5 .times. 10-5 M) produced a 50% reduction of .tau.noise. Both tubocurarine and trimetaphan produced concentration-dependent increases in the run-down of trains of neurally evoked e.p.c. (50 Hz, 0.4 s). This effect did not vary with membrane potential in tubocurarine, but was voltage dependent when induced by trimetaphan. Erabutoxin b reduced the e.p.c. amplitude but did not produce any increase in the run-down of trains of neurally evoked e.p.c. During 50 Hz repetitive ionophoretic application of ACh, tubocurarine (2.5 .times. 10-7 M) reduced the amplitude of each current in the train without inducing any run-down of the current amplitudes. This effect was not dependent on the membrane potential. In contrast, trimetaphan (2.5 .times. 10-5 M) induced a voltage-dependent run-down of trains of ionophoretically evoked e.p.c. Tubocurarine and erabutoxin b evidently reduce the e.p.c. amplitude by blocking the post-junctional ACh receptor. Tubocurarine produces tetanic run-down of e.p.c. by a prejunctional mechanism, whereas the effects of trimetaphan during single and repetitive stimulation are at least partly due to block of the open ion channel associated with the ACh receptor.