228 1. lODOACETATE AND lODOACETAMIDE 



regenerated from creatine-P. When the supply of creatine-P is exhausted, 

 the ATP falls rather suddenly (but at a rate dependent on the functional 

 state of the muscle); this probably accounts for the rnany observations that 

 various properties are maintained relatively well over a period and then 

 disappear precipitously. When the ATP normally bound to the contractile 

 proteins, which is assumed to keep them separated and in a mobile state, 

 is sufficiently depleted, the actomyosin system begins to contract, and this 

 continues as the ATP is lost, until a complex multimolecular association 

 has taken place. Relaxation by the addition of ATP may be impossible at 

 this stage, since the ATP may not be able to gain access to its binding sites. 

 The muscle, however, can gradually be lengthened by exerting a force upon 

 it, and the complexes can be slowly broken down; such an artificially length- 

 ened muscle is no longer in a relaxed state or in a contracted one, but in 

 a third state. Such a theory implies no particular role of ATP in normal 

 contractions; it may function either in contractile activation or in relaxa- 

 tion, this being the vmbound fraction. 



EFFECTS ON NERVE FUNCTION 



The demonstration that muscle contraction is independent of lactate for- 

 mation prompted an investigation of the relationship of lactate to nerve 

 function. A brief summary of the metabolic responses of nerve tissue to 

 iodoacetate will be presented before the effects on function are discussed. 



Injection of iodoacetate into pigeons in lethal dosage reduces the brain 

 lactate about 50% (Kinnersley and Peters, 1930); injection into dogs pro- 

 duces rather erratic behavior of brain lactate, but in general it is reduced 

 following 10 min incubation after removal from the animal (Haldi, 1932); 

 and perfusion of frogs with 0.7-1.8 mM iodoacetate for 1 hr reduces brain 

 lactate markedly if supplemented with anoxia, anoxia alone somewhat in- 

 creasing the lactate level (see accompanying tabulation) (Holmes, 1933). 



Brain lactate (mg%) 



Before perfusion 146 



Oxygenated perfusion 145 



Anoxic perfusion 159 



Anoxic perfusion + iodoacetate 25 



Thus iodoacetate inhibits glycolysis in nerve in vivo. Inhibition of anaerobic 

 glycolysis in nerve and brain has been reported several times (Gerard, 1931; 

 Heald, 1953), but respiration seems to be less sensitive when the tissue is 

 intact, the nerve sheath apparently presenting a barrier to the penetration 

 of iodoacetate since, if the sheath is split, inhibition occurs more rapidly 



