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Bretylium and guanethidine produced a block of neuromuscular transmission in the rat phrenic nerve diaphragm and cat sciatic gastrocnemius preparations, but had a potentiating effect on acetylcholine-induced contracture of the frog rectus. On the sciatic gastrocnemius preparation of the cat the compounds had a twofold action, consisting of an initial transient, and a delayed but more sustained, block of neuromuscular transmission. Bretylium and guanethidine had no immediate effect on the response of the muscle to direct stimulation, though a weak delayed depressant effect was observed. Intravenous injection of these compounds produced a flaccid paralysis in pigeons. Possible mechanisms of the neuromuscular blocking action of bretylium and guanethidine are discussed. Inhibition of acetylcholine release from motor nerve endings resulting from local anaesthesia by these compounds is suggested as a possible mechanism of their neuromuscular blocking action.