CHAPTER 5 



PHOSPHATE METABOLISM AND 

 THERAPEUTIC AGENTS 



Of the therapeutic agents affecting the central nervous system 

 those producing sedation and general anaesthesia have probably 

 received most attention and studies of their action have given rise 

 to many hypotheses concerning the mechanisms by which they 

 produce their effects. These have included, alterations in the 

 physical state of surface membranes, depression of cellular 

 oxidation by interference with specific flavoproteins, depression of 

 oxidation at certain selected neurones, inhibition of energy produc- 

 tion, " uncoupling " of oxidative phosphorylation, and inhibition of 

 the passage of impulses along the usual neural pathways. These 

 hypotheses have been discussed in detail by various authors 

 (Butler, 1950; Brody, 1955; Quastel, 1955; Hunter and Lowry, 

 1956; Cohen and Cohen, 1957). 



The major biochemical changes observed in cerebral metabolism 

 during anaesthesia have been described in Chapter 2 and include 

 increased levels of phosphocreatine, decreased levels of inorganic 

 phosphate, no change or an increase in the levels of adenosine 

 triphosphate, decreased incorporation of phosphorus into the 

 phospholipids. Accompanying these changes, cerebral oxygen 

 uptake and lactic acid production decrease. In the present chapter 

 an account is given of the effects of various therapeutic agents upon 

 phosphate metabolism in cerebral tissues and preparations in vitro, 

 and the relationship of such effects to the changes found in vivo. 



Effects on Unstimulated Systems 



A major criterion to be satisfied in comparing metabolic effects 

 of therapeutic agents in vivo and in vitro is the correspondence of 

 the concentrations at which the substances are active in both 

 systems. This is of importance since such agents presumably act 

 by entering into chemical combination with certain sensitive 

 receptors and at excessive concentrations such as are toxic in vivo, 



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