590 ANNALS NEW YORK ACADEMY OF SCIENCES 



distributed through its volume. It seems impossible that any con- 

 siderable fraction of the oxidative energy released in the core of such 

 a fiber could be utilized to drive reactions in its surface, up to 400 

 micra distant; and it seems unlikely even in the usual medullated fibers, 

 up to 20 micra in diameter. Along the same lines, I know of no evi- 

 dence for the intensive respiration at neuro-myal junctions which 

 would be demanded to keep up with the terrific ChE activity. 

 There is definite evidence against an intense respiration at syn- 

 aptic regions in the central nervous system, despite their greater 

 relative surfaces for fiber propagation and junctional transmission.'^'' 

 (A high ChE and DPN concentration in the synaptic layers of the 

 retina, however, has recently been reported.") 



A final calculation, dealing with materials rather than energetics, is 

 only suggestive. Most workers have tacitly or explicitly assumed that 

 the acetate formed by hydrolysis of ACh was not re-utilized for ACh 

 synthesis. Indeed, ACh has been found by Lipton"^ to form only from 

 pyruvate in oxygen or an acetate source (acetoacetic or citric acids) 

 in nitrogen, under present in vitro conditions. This would exclude 

 full re-utilization of acetate, even in nitrogen, unless the reaction, 2 

 acetate -^ acetoacetate, is fully reversible. Lipmann has just indicated 

 that synthesis from acetate may be possible when additional com- 

 ponents, of coenzyme character, are added, and this would make easier 

 a cyclic use of acetate. Without cyclic use, a molecule of glucose would 

 have to be lost for every two of ACh formed and hydrolyzed — or twenty- 

 fold the actual rate in nerve, 0.01 mM ACh; 0.0006 glucose. The 

 accompanying heat production would have to be similarly outrageous, 

 in comparison with the factual rate. 



Such quantitative considerations are admittedly rough, with little 

 attention to detailed conditions (temperature, species, rate of stimula- 

 tion, etc.), but the order of magnitude cannot be far off. They demon- 

 strate conclusively, I believe, that ChE cannot possibly exert its full 

 activity on ACh in neural tissues and suggest that other meanings for 

 its presence and action be sought. Further, even the less drastic rates 

 and amounts reported for other phases of an ACh system lead to severe 

 quantitative strains on the total metabolism of nerve or brain. But 

 still other difficulties have been brought out in this publication. 



Drug Action 



Drugs, especially esterase inhibitors, have been widely used in study- 

 ing the ACh system, and their actions have been much discussed dur- 

 ing this symposium. The point of greatest debate has been the ques- 



