PHOSPHATES AND THERAPEUTIC AGENTS 143 



such as " dinitrophenol ", increased quantities of inorganic 

 phosphorus and phosphate acceptors, such as adenosine diphos- 

 phate are formed. If the quantities of these have previously been 

 Hmited in the system being studied then an increase in these 

 quantities resuhs in an increase in the oxygen uptake (p. 109). 

 When tested with preparations of cerebral mitochondria in a 

 medium containing limiting amounts of inorganic phosphate, the 

 addition of the barbiturates resulted in an increased oxygen uptake. 

 Similar changes were found with dinitrophenol. In both the 

 systems containing either a high or a low level of inorganic phos- 

 phate decreased phosphorylation was not attributed to a partial 

 inhibition of oxygen consumption since the concentrations of 

 depressants which were chosen did not alter the oxygen uptake by 

 more than 10%. Similar changes ascribed to the " uncoupling " of 

 oxidative phosphorylation have been found with other agents. 

 Thus, after preincubating preparations of cerebral mitochondria 

 with chlorpromazine Abood (1955) found that the phosphorus/ 

 oxygen ratios were decreased by concentrations of 5 X 10 "^M. 

 Without preincubation. Century and Horwitt (1956) and Berger 

 (1957) were unable to obtain this effect with concentrations 

 below 2 X 10"* M. With particulate preparations of rat brain, 

 ether in surgical concentrations, was found to decrease the phos- 

 phorus/oxygen ratios slightly and the steroid anaesthetic Viadril 

 (21-hydroxypregnane-3 : 20-dione hemisuccinate) at 5 X 10~*M 

 produced a decrease of 17%. Higher concentrations of 5 X 10-^M 

 decreased the phosphorus/oxygen ratio by 87% (Hulme and 

 Krantz, 1954; Truitt et al, 1956). 



However, not all depressants or barbiturates are effective in this 

 manner. Thus, anaesthetic mixtures of nitrous oxide/oxygen and 

 xenon/oxygen were without effect upon the phosphorus/oxygen 

 ratios of rat cerebral mitochondria (Levy and Featherstone, 1954). 

 Ethanol at 21 X lO-^M, chlorobutanol at lO-^M, chloral at 

 10"^ M, urethane at 10"^ M and morphine at 10"^ M are similarly 

 ineffective. Of the barbiturates, dial and phenobarbitone at 

 10~^M though depressing the phosphate uptake also depressed 

 oxygen uptake to a similar degree leaving the phosphorus/oxygen 

 ratios unaltered (Brody and Bain, 1954; Wolpert et al., 1956). 

 On the other hand a convulsant barbiturate (1 : 3-dimethyl 

 butyl ethyl barbituric acid) at 1-2 X 10"* M also decreased the 

 phosphorus/oxygen ratios markedly (Brody and Bain, 1954). 



