142 PHOSPHATES AND THERAPEUTIC AGENTS 



concluded that depression of glutamine synthesis, and therefore 

 synthesis of adenosine triphosphate, was secondary to the depres- 

 sion of oxygen uptake. 



The finding that decreases in both the oxygen uptake and the 

 synthesis of glutamine occurred in simple proportion suggests that 

 the overall efficiency of oxidative phosphorylation was impaired. 

 This had been previously shown to be the case during phos- 

 phorylation in cerebral dispersions (Table 22; see also Grenell 

 et al.y 1955). In dispersions of whole brain oxidizing pyruvate the 

 efficiency of the process of oxidative phosphorylation of adenosine 

 diphosphate to the triphosphate was not altered by pentobarbitone 

 or chloral at concentrations markedly suppressing the overall 

 oxygen uptake, though the actual quantities of adenosine triphos- 

 phate synthesized were considerably reduced. A decrease in the 

 production of adenosine triphosphate during the action of chlor- 

 etone upon cerebral dispersions was also demonstrated by Johnson 

 and Quastel (1953<2, b). In this system the generation of adenosine 

 triphosphate by rat brain dispersions was coupled with the acetyla- 

 tion of sulphanilamide by pigeon liver extracts. Chloretone at 

 4 X 10"^ M suppressed acetylation, an effect which could be 

 reversed by adenosine triphosphate. Since the acetylation mecha- 

 nism itself was unaffected by this concentration of chloretone it was 

 concluded that the action of chloretone was upon the synthesis and 

 not the utilization of adenosine triphosphate. These experiments 

 have formed the basis of a suggestion (Johnson and Quastel, 1953) 

 that cerebral narcosis generally is the result of a decreased rate of 

 production of adenosine triphosphate rendering less energy 

 available for the normal functioning of the tissue. 



Decrease in the quantities of adenosine triphosphate made 

 available for the maintenance of function has also been proposed as 

 a mechanism responsible for the action of depressants and other 

 agents as a result of different investigations of their action upon 

 oxidative phosphorylation in preparations of cerebral mitochondria 

 (Brody and Bain, 1951; Bain, 1952; Brody and Bain, 1954). In 

 the presence of barbiturates such as thiopental, pentobarbitone and 

 amobarbitone at concentrations of 1-4 X 10"* M, the amount of 

 inorganic phosphate disappearing from the medium during the 

 oxidation of pyruvate was suppressed to a markedly greater degree 

 than was the oxygen uptake, resulting in a decrease in the phos- 

 phorus/oxygen ratios. In the presence of an uncoupling agent, 



