GLUCOSE AND OXYGEN UTILIZATION IN SYMPATHETIC GANGLIA 105 



In seeking other explanations for failure during glucose lack, we had at one 

 time thought that there might be something especially important about the 

 small amount of ATP formed non-oxidatively in glycolysis, perhaps because 

 it was formed at some critical location in the cell. As it turns out, however, loss 

 of this moiety cannot account for loss of function, since lactate, which does 

 not generate the moiety, nevertheless supports function (Figure 12). 



(b) Loss of acetylcholine generation. Another important role of glucose metab- 

 olism may be the generation of acetylcholine, as one of the products of acetyl 

 Co-A. Therefore it is possible that loss of acetylcholine production is the critical 

 defect in glucose-lack. The ability of exogenous lactate to support function 

 can be explained on this basis, since lactate should be able to substitute for 

 glucose in the manufacture of acetylcholine via familiar pathways leading 

 through pyruvate and acetyl Co-A. Moreover Kahlson and Macintosh (1939) 

 found that liberation of acetylcholine during activity in a perfused sympathetic 

 ganglion declined in the absence of glucose and could be restored, at least 

 temporarily, by supplying glucose, lactate, or certain other substances. How- 

 ever, it is not established whether the acetylcholine deficit was actually the 

 cause of failure, or merely one of several changes, some other of which may 

 have been more intimately related to decline of neuronal function. 



(c) Damage by oxidation of intracellular materials. We have also considered 

 the possibility that the intracellular materials oxidized in the absence of glucose 

 might include cellular constituents — possibly structural components — which 

 are essential to conduction and transmission of nerve impulses and which are 

 not readily replaced under our experimental conditions. This would explain 

 the irreversibility of the failure of function. This irreversibility has puzzled us, 

 for we have found no metabolic basis for it. Oxygen uptake, if it had been 

 depressed at all by withdrawal of glucose, returned approximately to the con- 

 trol rate when glucose was restored, and so did the rates of glucose uptake and 

 lactate production. Nevertheless, the restoration of these several rates to their 

 normal level failed to bring back the capacity for either nerve conduction or 

 synaptic transmission, even after several hours. From this point of view the 

 essential role of glucose in the economy of the cell may be to supply a substrate 

 which satisfies energetic requirements without oxidation of intracellular ma- 

 terials. Perhaps oxidation of the latter provides considerable energy, and may 

 be useful during hypoglycemic emergencies of brief duration, but ultimately 

 results in irreversible damage if glucose is long withheld. 3 



(d) Damage by products of endogenous substrates. In concluding these specu- 



3 In oral presentation at the Symposium it was suggested that certain enzymes, 

 normally occupied with glucose metabolism, might turn to other substrates in the 

 absence of glucose. These enzymes were likened to mischievous children — when not 

 given something suitable to do, they proceed to take the house to pieces. This frivolous 

 analogy is mentioned here to explain any references to the ''mischievous enzyme 

 theory" which may survive revision of comments by others in the ensuing discussion. 



