PHOSPHATES AND THERAPEUTIC AGENTS 147 



production in cerebral slices, stimulated electrically, were first 

 described by Mcllwain (1953). It was shown that concentrations of 

 barbiturates similar to those found in vivo during anaesthesia 

 decreased both the stimulated oxygen uptake and lactic acid pro- 

 duction but were without effect upon the unstimulated metabolism. 

 Subsequent development has shown that such a system is sensitive 

 in vitro to a wide variety of therapeutic agents at concentrations 

 similar to those active in vivo (Forda and Mcllwain, 1953 ; Green- 

 gard and Mcllwain, 1955 ; Mcllwain and Greengard, 1957). Such 

 an action cannot be considered to be the result of a simple in- 

 hibition of oxidative mechanisms, for the stimulated production of 

 lactic acid also decreased whereas the simple inhibition of oxygen 

 uptake would be expected to lead to an increase. Decrease in 

 oxygen uptake and lactic acid production are two of the changes 

 found in vivo in anaesthesia and recognition of these similar- 

 ities prompted an examination of the effects of depressants and 

 anti-convulsants upon phosphate metabolism under similar 

 conditions. 



Examination has been most extensive in the case of pheno- 

 barbitone at a concentration of 1-7 X 10~^M. This concentration 

 was deliberately chosen as being that which completely blocked 

 response to electrical stimulus, as measured by oxygen uptake, yet 

 was without effect upon unstimulated respiration (Mcllwain, 1953 ; 

 Cohen and Heald, 1959). At this concentration levels of phospho- 

 creatine and adenosine triphosphate were unaffected in unstimu- 

 lated cerebral slices, the quantities being l-5fxmoles/g and 

 1-0/xmoles/g respectively. However, response to electrical pulses 

 was greatly suppressed, the breakdown of phosphocreatine being 

 slow (a rate of 15-30 /xmoles/g hr"^) and occupying some 2-3 min 

 in comparison with the period of 5 sec found in the absence of 

 phenobarbitone. Concentrations lower than this also exerted a 

 similar effect, a decrease in the rate of breakdown being clearly 

 detectable at 5 X 10"* M phenobarbitone (Table 23). This con- 

 centration is similar to that found and calculated to exist in brain 

 following an anaesthetic dose (Table 21). The decreased rates of 

 breakdown are not considered to be attributable to a partial 

 inhibition of phosphocreatine phosphokinase since phenobarbitone 

 at 10-2 M ^as without effect upon the enzyme when tested with 

 aqueous dispersions of brain (Narayanaswami, 1952). Also no 

 change in the phosphocreatine phosphokinase activity of rat 



