The mechanisms of motor end-plate depolarization due to a cholinesterase-inhibiting drug / by W.W. Douglas and W.D.M. Paton.

  • Douglas, W. W.
Date:
[1954?]
Catalogue details

Licence: In copyright

Credit: The mechanisms of motor end-plate depolarization due to a cholinesterase-inhibiting drug / by W.W. Douglas and W.D.M. Paton. Source: Wellcome Collection.

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    that large doses of TEPP could cause depolarization of the muscle even in the absence of motor nerve fibres as local sources of acetylcholine. The absence of any fluctuation in the course of the depolarization in these denervated muscles supported our belief that the fluctuating component with the normally innervated muscle was due to motor nerve activity. There is good reason to believe that any changes at the end-plate due to denervation would favour the demonstration of a direct action by TEPP, since denervation is known to sensitize a muscle to acetylcholine. Neverthe¬ less, we did a further experiment, on a 2-day denervated muscle, in the hope of obtaining a preparation with functionless motor nerve, in which any change in sensitivity produced by denervation would be as small as possible. We found, however, that although no obvious contraction resulted on nerve stimulation, this preparation was not completely denervated, since repetitive stimulation of the motor nerve at 33 shocks per second produced a transient depolarization, which in the presence of TEPP amounted to as much as 4 mV. It seems, therefore, that actions independent of functional motor nerves cannot be obtained much earlier than with the 4-day denervation we have studied. These experiments, then, showed that the effect of smaller doses of TEPP ( < 500 fig/kg) requires the integrity of the motor nerve fibres, but that with larger doses (10-20 mg/kg) an additional process may come into play, detect¬ able with denervated muscle. Since it is in this additional mechanism alone that any direct action of TEPP must reside, it was analysed further. Presence of acetylcholine in the blood after TEPP What was most striking about the response of the denervated muscle was the delay in onset of the depolarization and its slow, smooth, steady rise. This seemed most unlike a direct action; rather it suggested to us the course of events seen if an isolated tissue such as the intestine is exposed to anticholin¬ esterase, when endogenous acetylcholine gradually exerts its effect as it progressively accumulates. Since local sources of acetylcholine could be discounted in the denervated preparation, this acetylcholine could accumulate only from other sources and should therefore appear in the blood. Estimates of the acetylcholine equivalent of the blood after TEPP were made in six experiments. Blood (1 ml.) before injection of TEPP, had no depressor action whatever on the blood pressure of a second cat. But shortly after injection of TEPP, and for some time later, the blood of the poisoned animal possessed considerable depressor activity. This closely resembled that produced by acetylcholine, and was abolished by small doses (0*05 mg) of atropine injected into the assay cat. It could not be ascribed to the presence of TEPP in the blood because at the time when the TEPP concentration would be at its peak, i.e. immediately after the injection,
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