230 1. lODOACETATE AND lODOACETAMIDE 



that fairly high concentrations must be used to produce significant effects, 

 and in these cases it is difficult to know the intracellular concentration of 

 inhibitor and the specificity of the action. 



All of the early studies demonstrated certain fundamental features in the 

 responses of nerve axons to iodoacetate (Ronzoni, 1931; Feng, 1932; Chang 

 and Gerard, 1933; Shanes and Brown, 1942). These may be summarized as 

 follows: (1) there is a lag period of one to several hours before effects are 

 evident, (2) the rate of conduction decreases and eventually conduction 

 fails, (3) there is a slow fall in the resting and action potential magnitudes, 



(4) lactate and pyruvate are partially effective in counteracting iodoacetate, 



(5) conduction failure is accelerated by increased activity, e.g., tetanization, 

 and (6) failure is accelerated by reducing the oxygen tension. These results 

 all conform to what would be expected. The report of Lorente de No (1947) 

 that iodoacetate and iodoacetamide delay the anoxic depolarization of nerve, 

 in direct contrast to the results of Shanes and Brown (1942) and contrary to 

 the behavior of other tissues, is very surprising, but Liu (1950) repeated this 

 work and found that the odd response w^as due to a technical error and a 

 lack of controls. Liu under the cirumstances could not demonstrate much 

 effect in either direction on anoxic depolarization with 2 mM iodoacetamide 

 but, upon readmission of oxygen, the nerve repolarized more slowly. More 

 recent work has not contributed much of fundamental interest and can be 

 summarized very briefly. Iodoacetate at 5 mM depresses the spike amplitude 

 progressively, and simultaneously there is a decrease in threshold; however, 

 when the spike is reduced 80-90%, the threshold increases markedly (Jene- 

 rick, 1957). The resting potential is depressed 30-40% at the time of con- 

 duction block. Conduction in the chicken vagus is slowed by 20 mM iodo- 

 acetate and the spike height is lessened (Dahl et al., 1964). Anoxia superim- 

 posed on iodoacetate produces much more depression, but it is remarkable 

 that no fall in ATP was observed. The posttetanic hyperpolarization in 

 nonmedullated cervical sympathetic nerves is abolished by 1 mM iodoace- 

 tate, and usually the after-potential is reversed; other inhibitors do not do 

 this (Ritchie and Straub, 1957; Holmes, 1962). The intraaxonal injection 

 of high concentrations of iodoacetate does not affect the action potential 

 (Brady et al, 1958). Iodoacetamide at 5.4-27 mM has been shown to alter 

 the structure of the myelin sheath, as shown by X-ray diffraction, and this 

 is believed to be due to reaction with SH groups there, but whether this is 

 of significance in the actions on nerve is not known (Millington and Finean, 

 1958). The extrusion of Na+ and uptake of K+ are depressed by iodoacetate, 

 which undoubtedly is the basis for the fall in the resting potential (Shanes, 

 1952). It is interesting that Ca++ can stabilize nerve membranes against a 

 variety of factors, and can counteract the fall in the potential produced by 

 iodoacetate (Shanes, 1942). It would be important to know by what me- 

 chanism this is accomplished. 



