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The effects of edrophonium and choline have been compared with those of the depolarizing substances acetylcholine, decamethonium, and suxamethonium, in both innervated and chronically denervated tibialis anterior muscles of cats under chloralose anaesthesia. Both edrophonium and choline were more potent antagonists to paralysis by tubocurarine than could be accounted for by their ability to stimulate the motor end-plates directly. It appeared likely that direct depolarization of the end-plate played no part in the anti-curare action of edrophonium and only some part in the anti-curare action of choline. A paralysis produced by the neuromuscular blocking agent, benzoquinonium, was more readily antagonized by a tetanus or by acetylcholine, suxamethonium, and decamethonium than a similar paralysis produced by tubocurarine. The tetraethyl ammonium ion was also slightly more effective against a paralysis by benzoquinonium. On the other hand, edrophonium was about 300 times and choline about five times less potent as an antagonist to benzoquinonium than to tubocurarine. Furthermore, the previous administration of benzoquinonium abolished the antagonistic action to tubocurarine of normally effective doses of edrophonium and reduced that of choline. These results were similar to those previously obtained with neostigmine, physostigmine and ethyl pyrophosphate and suggested that there was some similarity in the mechanism of action of all of these substances. Benzoquinonium, therefore, showed promise as a useful pharmacological tool for distinguishing compounds with this particular type of action. These anti-curare compounds did not appear to act by cholinesterase inhibition, not by an increase in the sensitivity of the motor end-plates. In common with other workers, we suggest that there is a pre-synaptic mechanism of action.

1. Cholinomimetics, acetylcholine antagonists and some other compounds of pharmacological interest were administered electrophoretically near neurones within the vermal cerebellar cortex of anaesthetized (pentobarbitone) and unanaesthetized (cerveau isolé) cats.2. The neurones were identified by position within the cortex, spontaneous activity, and the responses to afferent and antidromic stimulation.3. Purkinje cells, but neither granule nor basket cells, were excited by cholinomimetics, and the acetylcholine receptors had muscarinic properties. Excitation was often preceded by depression of the spontaneous firing.4. Intravenously administered atropine and dihydro-beta-erythroidine did not depress the synaptic excitation of cerebellar neurones evoked by impulses in mossy, climbing or parallel fibres.5. Acetylcholine is thus unlikely to be an excitatory transmitter within the feline cerebellum, particularly at mossy fibre-granule cell synapses, despite the presence of relatively high levels of acetylcholinesterase within mossy fibre terminals.

Subthreshold concentrations of the depolarizing agents, acetylcholine and decamethonium, potentiated isotonic contractures of the isolated frog rectus abdominis muscle elicited by effective doses of either of these drugs or by choline in the absence of the anticholinesterases, sarin, or dyflos. Comparable potentiation of the contracture produced by decamethonium or choline could be obtained by alternate stimulation with acetylcholine in the absence of dyflos or sarin. Furthermore, dyflos alone did not effect potentiation in the absence of alternate stimulation with acetylcholine. Finally, the inhibitory action of tubocurarine, as measured by depression of the contracture elicited by decamethonium and acetylcholine, was not antagonized by sarin. It was concluded that the enhancement of the response to acetylcholine produced by dyflos and by sarin was brought about exclusively by their action as inhibitors of cholinesterase. The ability of dyflos and of sarin to potentiate contractures elicited by decamethonium or by choline may be attributed to a facilitation of the action of the depolarizing compounds by subthreshold concentrations of acetylcholine available in the presence of these anticholinesterases.

Bretylium inhibits the contractions of the longitudinal muscle caused by histamine and, to a lesser extent, those by acetylcholine, carbachol and nicotine. It is a very weak antagonist of 5-hydroxytryptamine and in concentrations of up to 190 mug/ml. does not inhibit the actions of bradykinin and substance P on the longitudinal muscle. The inhibitory effect of bretylium on the emptying phase of the peristaltic reflex is similar to that of ganglion blocking agents, while the much less pronounced effect on the contraction of the longitudinal muscle during the preparatory phase is assumed to be due to a weak atropine-like action.

The actions of both reversible and irreversible anticholinesterase drugs on the nerve-free smooth muscle of the chick amnion are described. The tertiary compound physostigmine and the irreversible inhibitor diisopropylfluorophosphonate were found to be active in causing contractions, whereas the quaternary compound neostigmine and the irreversible inhibitor Mipafox were only slightly active in this respect. Manometric studies showed that all four compounds were highly active, however, in inhibiting the cholinesterase found in the chick amnion. The effects produced by these compounds in the organ bath are thought to be due to the accumulation of endogenously produced acetylcholine within the tissue. Evidence for an intracellular action of endogenously produced acetylcholine in the smooth muscle of the chick amnion is discussed.