1. The output of acetylcholine from the plexus of the guinea‐pig ileum longitudinal strip has been used to study the mechanism of acetylcholine release. From the effects of hexamethonium and tetrodotoxin, it was inferred that 60% of the normal resting output is due to propagated activity in the plexus, and 40% to spontaneous release. Tetrodotoxin virtually abolishes the increase in output in response to electrical stimulation. 2. Resting acetylcholine output is increased when the bathing medium is changed in the following ways: (a) sodium replacement by sucrose, trometamol or lithium; (b) addition of ouabain or p‐hydroxymercuribenzoate (PHMB), or withdrawal of potassium; (c) the combination of PHMB and partial sodium replacement; (d) addition of potassium; this increase in output becomes greater in the absence of sodium. 3. The resting output is virtually abolished by calcium withdrawal, and is restored by barium substitution for calcium. It is also reduced by raising the magnesium concentration. 4. The enhanced resting output in response to sodium withdrawal also occurs in the absence of calcium. 5. Cooling to 5° C greatly reduces both the resting output and the output in response to raised potassium concentration or to electrical stimulation. 6. The increase in resting output due to potassium excess is slight up to 25 m M [K+]o, but increases thereafter with about the fourth power of the potassium concentration; it is resistant to tetrodotoxin. 7. Synthesis of acetylcholine by the longitudinal strip is increased when output is enhanced by electrical stimulation, by potassium excess or by addition of barium, so that the acetylcholine content of the strip is maintained approximately normal. Synthesis is reduced, in relation to output, by potassium lack or by treatment with ouabain, and is virtually abolished by sodium withdrawal. 8. The theory is discussed that acetylcholine release depends on inhibition of the activity of a (Na+ + K+ + Mg2+)‐activated ATPase at the axonal membrane.
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