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These three compounds also had little effect on direct muscle response to acetylcholine and on the acetylcholinesterase activity of the ileum. From these results, it is suggested that the antagonism to the effect of nicotine shown by mecamyl amine does not appear to he a simple competitive blockade of ganglionic receptors as is the case with hexamethonium and that adenosine may antagonize the effect of nicotine non-competitively. The mechanism by which mecamylamine and adenosine showed anti-nicotinic action is discussed.Stone et al. (1) found that a secondary amine, 3-methylaminoisocamphane hydro chloride (mecamylamine) had a potent ganglion-blocking action with a long duration and suggested the similarity of its action to a quarternary ammonium ion, hexamethonium. On the other hand, Bennet et al. (2) reported that the mode of action of mecamylamine completely differed from that of hexamethonium and pentolinium in that mecamylamine, a substance readily diffusible into cells, was not competitive with acetylcholine at the auto nomic ganglia and neuromuscular junction. In the guinea pig isolated intestine, mecamyla mine reportedly exerts non-competitively or competitively-non-competitive antagonism on the dose-response curves for nicotinic stimulants (3-6).Adenosine, a potent coronary vasodilator, reduces acetylcholine release from post ganglionic nerves and exerts an anti-nicotinic action (7-10). However, the mechanism by which mecamylamine and adenosine show anti-nicotinic action has not been fully characterized.In an attempt to determine the mechanism of the anti-nicotinic action, effects on the contractile responses of the guinea pig isolated ileum to agonists such as nicotine, acetyl choline and 5-hydroxytryptamine, and to transmural stimulation were examined using hexamethonium as the reference compound.

Electrically (30 Hz) induced contractions of guinea‐pig isolated ileal longitudinal muscles were reduced by tetrodotoxin (1 μm), atropine (1 μm), adenosine (30 μm) and morphine (10 μm). When stimulated with 10 or 30 Hz for 10 s at 1 min intervals, a progressive decline of amplitude of the contraction was seen (development of tachyphylaxis). At this time, the contractile response to 1,1‐dimethyl‐4‐phenylpiperazinium iodide (DMPP) (10 μm) was also greatly reduced. The smaller responses to electrical stimulation and DMPP during tachyphylaxis were restored to their initial amplitude by the addition of theophylline (10 μm). The appearance of tachyphylaxis was prevented by pretreatment with theophylline (1 to 10 μm) and was greatly accelerated by pretreat‐ment with dipyridamole (0.1, 1 μm). In [14C]‐choline or [3H]‐adenosine preloaded muscle strips, electrical stimulation (30 Hz) increased the 14C‐ or 3H‐output, the effect being sensitive to tetrodotoxin blockade. The tachyphylaxis to electrical stimulation was accompanied by a considerable and sustained increase in 3H‐output, an effect that was accelerated by dipyridamole (1 μm). The 14C‐output initially increased but fell off gradually with the development of tachyphylaxis at which time theophylline (30 1) reversed the fall. There was a marked increase in the proportion of released [3H]‐adenosine to its derivatives during the development of tachyphylaxis. Approximately 60% of the released total radioactivity after tachyphylaxis was found to be [3H]‐adenosine. These results suggest that the development of tachyphylaxis may be closely associated with the release of endogenous adenosine derivatives (mostly adenosine) which have presynaptic inhibitory actions on the cholinergic elements in guinea‐pig ileum.

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