396 ANNALS NEW YORK ACADEMY OF SCIENCES 



choline (ACh), is actually released from the nerve ending and acts on 

 the heart cell directly.^ The concept of "neurohumoral" transmission 

 appeared enlightening in the case of the autonomic nerves and was 

 widely accepted among physiologists. 



In 1933, Dale tried to extend this idea of a "chemical mediator" of 

 the nerve impulse to the neuromuscular junction and to the ganglionic 

 synapse.* In this case, however, the theory encountered strong opposi- 

 tion. In addition to many contradictions and difficulties, summarized by 

 Eccles,^ there were two main objections. The first was the time factor. 

 The transmission of nerve impulses across neuromuscular junctions 

 and ganglionic synapses occurs in milliseconds. No evidence was 

 available that the chemical process can occur at the high speed re- 

 quired, and Dale admitted this difficulty. The second objection was 

 still more fundamental. According to leading neurophysiologists, the 

 excitable properties of axon and cell body are basically the same. The 

 electric signs of nervous action do not support the assumption that the 

 transmission of the nerve impulse along the axon differs, fundamentally, 

 from that across the synapse. 



The idea of a chemical' mediator, released at the nerve ending and 

 acting directly on the second neuron, thus appeared to be unsatisfac- 

 tory in many respects (Fulton'') . 



NEW APPROACH 



Recognition of two features of nervous action is essential to an under- 

 standing of the problems and the difficulties involved: The high speed 

 of the propagation of the impulse, and the smallness of the energy re- 

 quired. In medullated mammahan nerve, the impulse travels at the 

 rate of 100 meters per second, and the energy required per impulse per 

 gram is less than 1/10 of a millionth of a small calorie. The recording 

 of such an event offers many difficulties, even with the use of specialized 

 physical methods. Only in the last twenty years have really adequate 

 instruments become available for the analysis of physical aspects of 

 nervous function. 



It is obvious that the study of the chemical reactions connected with 

 an event of this kind must offer even more serious difficulties. No ade- 

 quate methods are available for directly determining chemical com- 

 pounds appearing in such minute amounts and for such short periods 

 of time. There is, however, another possible approach. Nearly all 

 chemical reactions in the living cell are effectuated by enzymes. The 

 study of enzymes in vitro has elucidated many chemical reactions. 



