84 



D. NACHMANSOHN 



VOL. 4 (1950) 



100 



50 



in chemical structure and properties is responsible for the difference in permeability of 

 these two types of compounds. Possibly the lipid membrane, known to surround all 

 axons, whether myelinated or not, may be the structural barrier. 



Acetylcholine like prostigmine is a methylated quaternary ammonium salt. The 

 failure of acetylcholine to affect conduction was explained by the assumption that the 

 axonal surface membrane may be impervious to the choline ester. This assumption has 

 been tested directly in the following way. The axons were exposed to acetylcholine 

 labelled with N^^. High concentrations (20 gram per liter) were used. When the axoplasm 

 was tested for the presence of N^^, only insignificant traces were present. These traces, 

 moreover, were largely accounted for by the contamination of the acetylchoHne used 

 with tertiary amine containing N^^. Tertiary amine labelled similarly with isotopic N 

 penetrated rapidly and an equilibrium between the inside and outside concentration 

 was obtained within 60 minutes*^. Fig. i demonstrates the results obtained. 



The experiments show conclusively that 

 the axonal surface membranes are im- 

 pervious to acetylcholine. They explain why 

 the fibre remains inert when the ester is 

 applied externally, even in high concentra- 

 tions. The fact that the action of the ester is 

 limited to the synaptic junction indicates 

 that the active membrane may be reached 

 at these foci even by those compounds which 

 do not penetrate into the interior of the 

 axon or the muscle fibre. The peculiar abil- 

 ity of the synapse to react to compounds 

 which do not affect axonal conduction ap- 

 pears thus to be due to a difference in ana- 

 tomical structure. This applies also to curare 

 which, as recent observations have shown 



(KlNG*2, WiNTERSTEINER AND DuTCHER*^), 



has as active principle a methylated quater- 

 nary ammonium salt. The observation of 

 Claude Bern.\rd that this compound acts 

 exclusively on the neuromuscular junction 

 and does not affect nerve or muscle fibres 

 was for a century the basis underlying the assumption that the neuromuscular junction 

 has special properties. It seemed to support the view that the fundamental mechanism 

 of transmission may differ from that of conduction. 



On the basis of the investigations described, the schematic presentation of the 

 neuromuscular junction in Fig. 2 may serve as illustration of the situation. Only the 

 compounds on the left side are capable of acting everywhere, because they may penetrate 

 through the structural barriers. In contrast, the compounds on the right side act only 

 upon the post-synaptic membrane which appears to be either less or not at all protected. 

 The nerve ending itself, although not surrounded by myelin, appears also to be protected 

 by a structural barrier since, according to Bronk^*, it is inexcitable even by relatively 

 high concentrations of acetylcholine in the perfusion fluid. 



Recently it was found that tetraeth} 1 pyrophosphate (TEPP) does not affect con- 



References p. 93l95- 



15 



25 



60 

 Min. of exposure 



Fig. I. Rate of penetration of trimethylamine 

 and acetylcholine labelled with N^* into the 

 interior of the giant axon of Squid. The ratio 

 of the concentration of the N of these com- 

 pounds inside (Ci) to th9,t outside (Co) is 

 plotted against the time of exposure in mi- 

 nutes. The dotted line indicates the rate of 

 penetration of N on exposure to trimethyl- 

 amine (286 fig N per ml), the straight line, 

 that of the N found on exposure to acetylchol- 

 ine (1430 /ig N per ml of which 55 /ig were 

 non-quaternary N)*^. 



