.8^8 



IIANDHDiiK OF PHYSIOLOGY 



NEUROPHYSIOLOGY III 



ditions in which they operate at their maximum rate. 

 Situations giving rise to this arc those brought about 

 by electrical pulses and increased potassium salts. 

 With cerebral tissues stimulated by electrical pulses, 

 iodoacetic acid at io~ 5 M inhibited aerobic glycolysis 

 at concentrations which had little effect upon the 

 increased oxygen uptake (72). Increasing concen- 

 trations of the inhibitor to 5 X io" 5 M reduced the 

 stimulated oxygen uptake to levels found in unstimu- 

 lated tissue but did not further reduce lactic produc- 

 tion. At this concentration no effect was observed 

 upon the stimulated oxygen uptake with lactate as 

 substrate. Malonate at 10 :l m increased stimulated 

 lactic acid production markedly while affecting 

 oxygen uptake only slightly. Azide was found to 

 depress stimulated oxygen uptake and to increase 

 lactic production (99). Here also, as with the other 

 inhibitors used, the effects noted with stimulated 

 metabolism were obtained with concentrations of 

 inhibitors which were without effect upon the 

 metabolism of unstimulated tissues. Iodoacetic acid 

 at its lowest concentration was an exception to this. 

 Similar results have been obtained with o. 1 M K.C1 

 as the stimulating agent and fluoride or malonate (94) 

 as inhibitor. A curious feature of the action of malon- 

 ate is its inability to inhibit the oxygen uptake of 

 -In is in the presence of lactate as substrate at con- 

 centrations which are effective when glucose is the 

 substrate (69, 72, 217). 



Results such as the above tit well into the inte- 

 grated metabolic patterns existing in intact cerebral 

 slices. I bus the effects of iodoacetate arc in harmony 

 with a partial metabolic block of 3-phosphoglycer- 

 aldehyde dehydrogenase, the limited quantity of 

 pyruvate formed being oxidized preferentially rather 

 than being reduced to lactate. The effect of azide can 

 be interpreted as the result of a balance between 

 inhibition of oxygen uptake and increased levels of 

 phosphate acceptors and inorganic phosphate. A 

 discussion of changes resulting from inhibition of a 

 single enzymic siep in cerebral metabolism has been 

 given by Racker i\- Krimsky (168). 



/ ■ . . \gents 



Commencing with toxic agents having better 

 understood effec 1-. 1 yanide m inn produces metabolic 

 effects analogous to those oi anoxia, namely de- 



. m a 1 d "..yen npt.ike, die reased creatine phosphate, 

 .mil linn. i.e. 1 levels of I. H in .H id .nid inorganic 

 phosphate, Concentrations bringing about these 

 changes were estimated to be 10 ' m. In vitro such con- 



centrations were without effect upon the respiration 

 glycolysis of minced brain tissue. Higher concentra- 

 tions of io^ 4 m markedly reduced oxygen uptake and 

 increased lactic acid production of cerebral tissue- 

 slices. 



Anticholinesterases have attracted much work 

 (215). Of them, diisopropyl fluorophosphonate 

 (DFP) is probably outstanding in tormina; a difficultly 

 reversible combination with acetylcholine esterase. 

 In cerebral tissue from rabbits succumbing to a 

 lethal dose, the cholinesterase activity was completely 

 inhibited. In hens paralysis accompanied by demye- 

 lination of the spinal cord and peripheral nerve has 

 been found following moderate doses. The excitatory 

 effects in man and other animals may be clue to the 

 higher concentrations of cerebral acetylcholine 

 existing in the presence of the inhibitor. DIP and 

 other anticholinesterases including physostigmine 

 have been used to study a possible relationship be- 

 tween cholinesterase activity and potassium trans- 

 port in cerebral slices (198, 199). It was found that 

 concentrations which completely inhibited cholin- 

 esterase activity in chicken cerebral tissue slices were 

 without effect upon potassium loss from the slices 

 Concentrations inducing potassium loss also inhibited 

 oxygen uptake in slices and oxidative phosphor) lation 

 in homogenates, suggesting that potassium loss was 

 due to impairment of energy-producing mechanisms 

 Among other anticholinesterases physostigmine has 

 been widely used to study the acetylcholine metabol- 

 ism of nervous tissue. At io -4 M no major effect was 

 detected upon the electrically stimulated metabolism 

 of cerebral slices (127). Such effects are unlikely since 

 phenomena associated with transmission of impulses 

 are not likely to be apparent in an experimental 

 arrangement where pulses are applied direetlv to the 

 greater part of the tissue-. Prolonged electrical stimu- 

 lation of cerebral slices in the presence of physostig- 

 mine leads to accumulation of acetylcholine in the 

 medium. The differential effect of DPP and other 

 anticholinesterases upon the- esterases of cerebral 

 tissue- has been used to distinguish between the 

 various types present in rat brain homogenate (154). 



It is now well established that the toxic properties 

 of fluoroacetate in vivo are due to conversion to 

 fluorocitrate followed by an action of fluorocitrate in 

 blocking cerebral aconitase. In pigeon brain particu- 

 late preparations, fluorocitrate blocks the oxidation 

 of pyruvate with accumulation of citrate (58). 



Elucidation of this mechanism has nul \ei led to a 



full understanding of the toxic action of fluorocitrate. 



Of other agents, atropine at 8 X 10 ' \t depressed 



