PHOSPHATES AND THERAPEUTIC AGENTS 151 



demonstrate the action upon cerebral metabolism in vitro differs 

 from that used to study phenobarbitone and cocaine. Thus the 

 anticonvulsants were not effective in inhibiting metabolism 

 increased by condenser pulses at 50 cycles/sec, as are cocaine and 

 general depressants, but are effective in inhibiting metabolism 

 increased by sine wave pulses at 2000 cycles/sec (Forda and 

 Mcllwain, 1953). Such selectivity is in accord with their action 

 in vivo of reducing a higher activity to a lower level rather than to 

 producing a general suppression. Further differences include their 

 failure to decrease oxygen uptake stimulated by 2 : 4-dinitrophenol 

 or increased concentration of potassium salts (Greengard and 

 Mcllwain, 1955), a decrease obtained with general depressants 

 (Mcllwain, 1953). 



There is no reason why all such agents should act through a 

 single mechanism or that only one mechanism should be affected 

 by any one agent. For example, although suppressing the rate of 

 breakdown of phosphocreatine, phenobarbitone and cocaine did 

 not prevent the levels finally decreasing to those found in the 

 absence of either substance. In such circumstances the increased 

 levels of phosphate and phosphate acceptors might reasonably be 

 expected to be accompanied by an increase in oxygen uptake 

 (p. 111). The prevention of this increase may, therefore, be 

 indicative of a direct action upon respiratory processes. These 

 views are in accord with those expressed in more detail by 

 Larabee and Posternak (1952) indicating that such agents, in- 

 hibiting cerebral function, are likely to effect both respiration and 

 the consumption of energy-rich phosphate but it is to be remem- 

 bered that the concentrations effective clinically, for example as an 

 anaesthetic, are considerably lower than those required to produce 

 a complete block of the stimulated oxygen uptake and that concen- 

 trations effective as sedatives are lower still . At present the evidence 

 suggests that suppression of energy consumption is the major 

 action. 



Experiments with therapeutic agents in vitro have not yet 

 provided an unequivocal metabolic basis for their action in the 

 sense that specific structures or enzymes are known to be inhibited. 

 Indeed it seems clear that the systems most sensitive to these agents 

 in mitochondrial preparations differ from those in whole disper- 

 sions, which again differ from those in cerebral slices. However, in 

 serving to clarify the locus of such action are regards phosphate 



