Possible mechanisms of the effect of physostigmine on the facilitation of acetylcholine release in the guinea pig myenteric plexus.

The automodulation of acetylcholine (ACh) release in the guinea pig myenteric plexus-longitudinal muscle preparation was investigated by studying the electric stimulation-evoked release of radiolabeled ACh. When the release associated with neuronal activity was challenged by the muscarinic antagonist atropine, the release was not significantly enhanced. When the acetylcholinesterase (AChE) blocker physostigmine was present, the well-established muscarinic receptor-mediated autoinhibition was operative, i.e., the release was significantly reduced. However, when both drugs were added together, the release was much higher than under control conditions. Therefore, it seems likely that there is also a facilitatory system. We made an effort to clear up the mechanism of this facilitation by blocking possible nicotinic presynaptic receptors, by excluding the alpha 2-adrenoceptor-mediated masking effect of noradrenergic heteromodulation, by preventing a possible ATP-mediated mechanism, and by attempting to prevent the direct effect of physostigmine. None of these manipulations resulted in a decrease of the surplus release. It is concluded, that when the negative feedback modulation of ACh is inhibited and AChE activity is reduced, high levels of ACh facilitates additional release of ACh from the nerve terminals, possibly through a not yet verified class of receptors.