DAVID NACHMANSOHN 



method is applied. Only in a relatively few cases are the effects com- 

 parable. This variety is due to the fact that all pharmacological action 

 depends on a great number of unknown factors. The limitation of an 

 interpretation of drug effects has been well formulated by Clark (2) : 

 "Even in the most favorable cases, where quantitative relations have 

 been established for the action of drugs on cells, there probably remain 

 dozens of unknown variables, and there is usually a considerable range 

 of alternative explanations." The contrast between the effects of eser- 

 ine and prostigmine on the nerve action potential and, more generally 

 speaking, the great variety of effects obtained with drugs which are 

 strong inhibitors of choline esterase is an excellent illustration of the 

 truth of Clark's statement. The affinity for the enzyme is just one fac- 

 tor since the action depends on many others, like permeability, circu- 

 lation, concentration, interaction with other cell constituents and 

 enzymes, and so on. Changes in the chemical constitution of the 

 molecule are known to influence profoundly the effect of a drug. 

 Eserine acts mainly on the periphery, and strychnine on the central 

 nervous system. No explanation is as yet available for this difference 

 in preference, but it would be a mistake to conclude that there is a 

 difference in the basic mechanism of a cellular function because a drug 

 acts differently in two cases. 



Most elaborate techniques were necessary to demonstrate the 

 three effects on which the evidence for the previous concept was based. 

 But if we keep in mind that the response of the cell to the injection of 

 acetylcholine is not distinguishable from other pharmacological effects, 

 that the enhancing effect of eserine is certainly a pharmacological effect, 

 and that the third observation-^the appearance of acetylcholine in 

 the perfusate requires the abolition of the physiological barrier by a 

 drug, then it is apparent why the three phenomena are so difficult to 

 demonstrate and so subject to variations under different conditions. 

 In spite of the fact that all biochemical data indicate an identical role 

 of acetylcholine in all nerves, there is still a great deal of discussion of 

 the question of whether or not this or that synapse is "cholinergic" 

 or whether or not acetylcholine is a "synaptic transmitter" in brain 

 because one or two of the necessary requirements cannot be demon- 

 strated. The answer does not appear difficult if Clark's statement and 

 the limitations of the methods used are kept in mind. If we see how 

 little deviation is found throughout the animal kingdom in the basic 



