PHOSPHATES AND THERAPEUTIC AGENTS 145 



more likely to be connected with other changes such as alteration 

 of the mitochondrial structure. 



These experiments though of interest in relation to the mecha- 

 nisms by which depressants alter mitochondrial metabolism as 

 yet throw little light on the manner in which these agents affect 

 phosphate metabolism in vivo. The mechanisms of action sug- 

 gested by Johnson and Quastel and by the experiments of Brody 

 and Bain though differing in detail (the former relating to a 

 decreased formation of adenosine triphosphate, the latter to a 

 decrease in the efficiency of the phosphorylating systems) never- 

 theless yield the same end result ; a decreased quantity of energy- 

 rich phosphate being made available for the normal functioning of 

 the brain. Such a picture cannot be considered to provide an 

 adequate explanation of the effects of depressants noted in vivo. 

 Difficulties concern the increases in vivo both in the levels of 

 phosphocreatine and in the incorporation of radioactive phosphate 

 into adenosine triphosphate during barbiturate anaesthesia ; neither 

 of these effects being compatible with an action requiring a 

 decreased production of energy-rich phosphates. It is possible, as 

 seems to be implied in the papers of Johnson and Quastel, that the 

 changes in levels of adenosine triphosphate are confined to 

 certain selected areas or neurones in the brain. This view is 

 attractive but is difficult both to examine experimentally and to 

 reconcile with the overall changes taking place without the further 

 assumption that decreased functioning at these points results in a 

 decrease of activity throughout the whole brain. Although an 

 action of depressants on synaptic transmission in the superior 

 cervical ganglion, has been described (Larabee and Posternak, 

 1952) there is no direct evidence to suggest that similar effects 

 occur in the central nervous system or that such effects would be 

 connected with a decreased local production of adenosine tri- 

 phosphate. 



Major difficulties also relate to the concentrations of depressants 

 necessary to produce the effects in vivo and in vitro. Thus the 

 levels found in vivo (Table 21) are below those producing any 

 measurable effect upon the oxygen uptake of cerebral slices and 

 comparison with the data of Brody and Bain (1954) shows that such 

 concentrations would alter the phosphorus/oxygen ratios in mito- 

 chondrial preparations by less than 10% ; changes which are at the 

 bottom limits of measurement in the systems employed. Further, 



