1. A comparison has been made of the effects of three acetylcholine antagonists--hexamethonium, tubocurarine and pancuronium--on maximal tetani of limb muscles of cats under chloralose anaesthesia. In most experiments, the indirectly stimulated soleus muscle was studied, but observations were also made on the tibialis anterior and flexor digitorum longus muscles. 2. When neuromuscular block was produced by intra-arterial injections of the acetylcholine antagonists, tetanic tension, though depressed in amplitude did not wane and there was little or no post-tetanic relief of the block as judged by the amplitude of subsequent twitches. On the other hand, during similar degrees of block produced by intravenous injections, tetanic tension rapidly waned, and, after the tetanus, transmission was temporarily facilitated, as evidenced by an increase in the amplitude of post-tetanic twitches. 3. Intravenously injected hexamethonium caused complete waning of tetanic tension in doses too small to depress twitch amplitude and which caused only a small depression of peak tetanic tension. In contrast, pancuronium caused only partial tetanic fade even in doses that produced pronounced depressions of twitch and tetanic tensions. The effects of tubocurarine fell between these extremes. 4. The results suggest that depression of peak tension and tetanic fade are independent effects of acetylcholine antagonists. It is postulated that the former is a consequence of block of post-junctional cholinoceptors, whereas the latter arises from an action of pre-junctional cholinoceptors. 5. The results obtained, together with those of other workers, led to the suggestion that transmitter acetylcholine, in addition to evoking the endplate potential, acts on the nonmyelinated nerve terminals in a positive feed-back mechanism that mobilizes transmitter to keep pace with release during high frequencies of stimulation.

The potencies of tubocurarine, gallamine, pancuronium, benzoquinonium, hexamethonium and mecamylamine in blocking neuromuscular transmission in the soleus muscle, and in blocking contractions of the nictitating membrane evoked by preganglionic sympathetic stimulation have been compared in cats under chloralose anaesthesia. On a molar basis, pancuronium was about 8 times and benzoquinonium about 2.5 times more potent than tubocurarine in blocking the soleus muscle; gallamine was less than half as potent, mecamylamine about 128 times and hexamethonium about 380 times less potent. In blocking the superior cervical ganglion, mecamylamine was about 17 times more, tubocurarine was about 5 times more and pancuronium about twice as potent as hexamethonium. Benzoquinonium was about half as potent as hexamethonium, and gallamine about 5 times less potent. The results emphasize that the shorter distance between charged centres, as in hexamethonium, reduces affinity for muscle receptors but does not necessarily enhance affinity for ganglion receptors, and from the point of view of deductions concerning the configuration of the ganglionic receptor, the ganglion blocking potencies of some neuromuscular blocking drugs should be taken into account.As a preliminary to experiments in which the abilities of a range of acetylcholineantagonists to block the effects of anticholinesterase drugs at the neuromuscular junction were studied (to be published), a comparison was made of the potencies of these drugs in blocking neuromuscular and ganglionic transmission. Despite an extensive literature on the subject, it was considered necessary to make these comparisons under identical experimental conditions. Accordingly, the abilities of tubocurarine, benzoquinonium, gallamine, pancuronium, hexamethonium and mecamylamine to block transmission through the superior cervical ganglion and to block neuromuscular transmission in the soleus muscle have been compared in cats under chloralose anaesthesia.A study of the literature indicates that this is the first time that these drugs have been compared in this way, and our justification for reporting them is that they have apparently hitherto unrealized implications in relation to cholinoceptive receptors on ganglion cells. METHODSThe experiments were made on 58 adult cats of either sex anaesthetized with chloralose (80 mg/kg) injected intraperitoneally as a l % solution in 0.9 % w/v NaCl solution.

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S U M M A R Y 1. The actions have been compared of the acetylcholine antagonists, hexamethonium, tuborcurarine, pancuronium and gallamine on the effects of neostigmine at the neuromuscular junction of the soleus muscle in cats under chloralose anaesthesia.2. Neostigmine produced augmentation of twitch tension, muscle fasciculat ions, repetitive firing in the muscle and antidromic repetitive firing in the ventral roots: all these effects were blocked by the acetylcholine antagonists. The effective doses of hexamethonium were similar to its ganglion blocking doses, being much smaller than those necessary to block the normal soleus twitch, and it is concluded i.hat the effects of neostigmine arise mainly from the action of preserved transmitter (acetylcholine) on the motor nerve endings.3. In the smallest effective doses, hexamethonium preferentially blocked muscle fasciculations and the associated electrical activity in nerve. Tubocurarine, which has considerable ganglion blocking activity (reflecting its affinity for neuronal cholinoceptors) resembled hexamethonium. In contrast, pancuronium and gallamine, which are considered to have a higher affinity for post-junctional muscle cholinoceptors, depressed muscle fasciculations only in doses that also depressed twitch augmentation and repetitive firing in muscle.4. In slightly larger doses, pancuronium and gallamine also blocked antidromic repetitive firing in nerve indicating that these drugs also combine with prejunctional neuronal cholinoceptors, and suggesting that these cholinoceptors are intermediate in character between ganglionic and muscle cholinoceptors.