234 1. lODOACETATE AND lODOACETAMIDE 



retina and its modifications by iodoacetate. A connection between glycolysis 

 and retinal function is indicated by the fact that the rate of anaerobic gly- 

 colysis in rat retinas suddenly rises around 10 days after birth, at a time 

 when the eyes open (Graymore, 1959). This rise is not the result of an in- 

 creased energy demand since it occurs when the rats are in total darkness. 

 It has been suggested that the visual cells have a higher glycolytic rate than 

 the rest of the retina (Graymore and Tansley, 1959 b), which means that 

 their activity is even higher than indicated in the table, and it has been 

 shown that doubling of glycolytic rate occurs at the time of visual cell dif- 

 ferentiation (Kerly, 1959). The high glycolytic rate implies a relatively high 

 concentration of the enzymes of the EM pathway in the retina, but these 

 have not been studied except for 3-PGDH, which is very high in the outer 

 plexiform layer of the monkey retina, although its concentration falls off in 

 the next two layers and is quite low in the outer rod and cone segment 

 (Schimke, 1957). Thus there is a marked variation in the concentration of 

 3-PGDH throughout the retina, which may be correlated with different 

 glycolytic activities. 



Retinal glycolysis is quite sensitive to iodoacetate. Anaerobic formation 

 of lactate from glucose in cell-free extracts of ox retinas is inhibited 91% 

 by 0.05 mM iodoacetate (Kerly and Bourne, 1940), in homogenates 97% 

 by 0.23 mM iodoacetate (Futterman and Kinoshita, 1959), and in intact 

 tissue 50% by 0.05 mM iodoacetate (Crane and Ball, 1951) (see Table 1-11). 

 Retinal respiration is depressed but is not nearly as sensitive as glycolysis. 

 Inhibition of retinal glycolysis in vivo has also been demonstrated. The 

 intravenous injection of 48 mg/kg iodoacetate into rats leads to a 31% 

 depression of glucose utilization by the retina, without affecting the utiliza- 

 tion in either brain or diaphragm (Kornbleuth and Ben-Schlomo, 1956). 

 Indeed, iodoacetate acts surprisingly rapidly, in that injections of 60 mg/kg 

 iodoacetate inhibit anaerobic glycolysis in rat retinas in 10 min by 75%, 

 and this is maintained relatively constant for at least 24 hr (Graymore and 

 Tansley, 1959 b). This dose eventually produces severe retinal damage and 

 degeneration. These results make it unlikely that the pentose-P pathway 

 is very important in retina, and this has been confirmed using glucose-1-C^* 

 and glucose-6-Ci* (Futterman and Kinoshita, 1959; Rahman and Kerly, 

 1961). At the most, one molecule out of four is oxidized through the pen- 

 tose-P pathway. Nevertheless, there is a high concentration of glucose-6-P 

 dehydrogenase in the retina. It is interesting that CO2 fixation in retina is 

 apparently stimulated by iodoacetate (Crane and Ball, 1951). It is believed 

 that glucose-6-P dehydrogenase is involved, NADPH being formed for fixa- 

 tion of CO2 into pyruvate to form malate; when the EM pathway is blocked, 

 more glucose-6-P is oxidized and more NADPH is available. This is a good 

 example of how an inhibitor can stimulate a reaction linked in some man- 

 ner to the system that is inhibited, although it is doubtful if this action is 



