150 PHOSPHATES AND THERAPEUTIC AGENTS 



hand breakdown of phosphocreatine was not affected by the anti- 

 convulsant trimethadione (4 : 4 '-dimethyl-N-methyl-oxazolidine 

 dione) at lO'^M, a concentration which partly suppressed the 

 stimulated oxygen uptake (Greengard and Mcllwain, 1955). 



The effects of these agents upon stimulated tissues in vitro bear 

 a considerable resemblance to their effects in vivo. In the stimu- 

 lated system the general depressant, phenobarbitone, decreased the 

 stimulated oxygen uptake and lactic acid production and increased 

 levels of phosphocreatine above those found in stimulated tissues 

 in the absence of phenobarbitone. Levels of inorganic phosphate 

 showed a similar relative decrease. The action may therefore be 

 regarded as an inhibition of the changes induced by stimulus. 

 This situation parallels the situation in vivo. Here also, electro- 

 shock is equally effective in finally reducing the levels of phospho- 

 creatine and increasing the levels of inorganic phosphate in the 

 brains of anaesthetized cats and dogs (Chapter 2). With both 

 types of preparation the extent of the changes is related to the 

 degree of stimulus which is applied. The finding that concentra- 

 tions of phenobarbitone some 3-4 times higher than those anaes- 

 thetic in vivo were without effect upon the synthesis of phospho- 

 creatine and adenosine triphosphate appears to negative suggestions 

 that the action of such a depressant is via a decreased production of 

 these phosphates. In nervous tissue it has been considered that 

 a large part of the energy produced by the consumption of oxygen 

 and glucose, is used in the maintenance of ionic gradients which 

 give rise to the resting potentials detectable in the intact slice (Li 

 and Mcllwain, 1957). Thus a depression of the ionic movements 

 induced by electrical pulses could give rise to metabolic changes of 

 the type found. Similar relations have been described for the 

 action of cocaine by Bollard and Mcllwain (1959) who have pointed 

 out that the concentrations effective in reducing the breakdown of 

 phosphocreatine are similar to those found to delay the decline in 

 action potential caused in frog sciatic nerve by anoxia and to 

 inhibit the loss of potassium and gain of sodium during the 

 depolarization of squid axon. 



The lack of effect of anticonvulsants upon phosphate in vitro 

 cannot yet be interpreted upon similar lines but it should be noted 

 that the effects of such agents upon phosphate metabolism in vivo 

 have not been recorded. There is thus an absence of a physio- 

 logically comparative situation. Also the stimulus required to 



