626 3. DEHYDRO ACETATE 



untouched by dehydroacetate. The mechanism is entirely tubular and no 

 changes in femoral flow, renal blood flow, or glomerular filtrate rate occur 

 (Shideman and Rene, 1951 b). The action is similar to that of carinamide 

 2)-(benzylsulfonamido)benzoate, a previously used blocker of penicillin ex- 

 cretion. Indeed, dehydroacetate at 0.5 g every 6 hr prolongs penicillin blood 

 levels in patients (Schimmel et at., 1956). 



The active accumulation of phenolsulfonphthalein (Rathbun and Shide- 

 man, 1951), phenol red (Shideman and Rene, 1951 b), and p-aminohippu- 

 rate (Shideman and Rene, 1951 b; Farah and Rennick, 1956) in kidney 

 slices is readily inhibited by dehydroacetate. The effect on ^J-aminohippu- 

 rate uptake is shown in Fig. 1-18, from which it is seen that 50% inhibition 

 is given by 0.14 mM in dog kidney slices. The accumulation of tetraethylam- 

 monium ion is completely resistant to dehydroacetate, and it is believed that 

 the transport of this ion is not dependent on the cycle (Farah and Rennick, 

 1956; Farah, 1957). 



It appears that certain renal transport mechanisms are more sensitive to 

 dehydroacetate than any other cell functions examined. The question as to 

 the relation of this inhibition to succinate oxidase or cycle depression is dif- 

 ficult to resolve. Dehydroacetate might block transport by acting directly 

 on the carrier system or by reducing the energy available for the transport, 

 Shideman and Rene (1951 b) incline to the latter view and attribute the 

 inhibition to an action on the cycle. The evidence for this comes partially 

 from the observation that high concentrations of acetate are able to coun- 

 teract the effects of dehydroacetate, both in vivo and in slices (Stoneman 

 et al., 1951; Rathbun and Shideman, 1951; Shideman and Rene, 1951 a). 

 However, the ability of acetate to reverse an inhibition is not evidence for 

 an action on the cyle, much less on succinate oxidase; indeed, the opposite 

 might be justifiably concluded. Furthermore, there is not a good correlation 

 between the activity in depressing p-aminohippurate transport and the in- 

 hibitory potency on succinate oxidation, especially when carinamide is con- 

 sidered, this substance being a weak succinate oxidase inhibitor but a more 

 potent transport inhibitor than dehydroacetate. Of course, different pene- 

 trabilities into the renal cells may account in part for this lack of correlation. 



Ion transport in kidney slices is also inhibited by dehydroacetate (Mudge, 

 1951). Rabbit kidney slices were leached in 0.15 M NaCl to lower the in- 

 tracellular K+, and then incubated in 10 mM K+ with 10 vaM acetate as 

 the substrate, during which period the lost K+ is regained and the excess 

 intracellular Na+ is pumped out. Dehydroacetate at 10 mM inhibits this 

 K+-Na+ exchange 81%, while simultaneously the respiration is inhibited 

 only 25%. The action of dehydroacetate on the pH-regulating exchanges 

 of the kidney is not known, but may be important in contributing to the 

 acidosis observed in whole animals, and indirectly in the effects on certain 

 tissues such as the central nervous system. 



