204 1. MALONATE 



stance by kidney cortex slices, which is quite marked (slice/medium ratios 

 around 10), is reduced by malonate: in slices from dogs, 5 raM inhibits 25%, 

 10 mM inhibits 35%, and 20 mM inhibits 55% (Shideman and Rene, 1951 b) 

 and in slices from rabbits 20 mM inhibits 72% while reducing the respiration 

 with acetate by 53% (Cross and Taggart, 1950). This action can be shown 

 to occur in the whole animal also. Dominguez and Shideman (1953, 1955) 

 removed one kidney from rats, administered solutions of sodium malonate, 

 removed the other kidney, and determined the accumulation of j^-amino- 

 hippurate. When approximately 10 millimoles/kg of malonate are injected 

 subcutaneously, the uptake of p-aminohippurate is depressed 52%, the 

 average slice/medium ratio falling from 9.28 to 4.47. The decrease in the 

 slice/medium ratio is linear with intravenous doses of 4-7 millimoles/kg. 

 Some effect occurs at 15 min after the injections, the maximal inhibition 

 is around 60 min, and the transport mechanisms have returned to normal 

 by 150 min, indicating the ready reversibility of the action. The transport 

 inhibition can also be demonstrated by the renal clearance technique in 

 dogs (Shideman and Rene, 1951 b). Malonate at a dose of 0.96 millimole/kg 

 depresses the p-aminohippurate Tm* 73%. It was stated that 50% inhi- 

 bition of renal succinate dehydrogenase is produced by 1.32 mM malonate 

 and thus the dose given would be expected to inhibit in vivo, but the con- 

 centration of malonate in the tubular fluid is probably much higher than 

 in the blood and permeability factors must also be important. Farah and 

 Rennick (1954, 1956) studied the effects of many inhibitors on the p-amino- 

 hippurate uptake in guinea pig kidney slices and the results are summarized 

 in Fig. 1-18. Malonate is one of the weakest inhibitors but yet exhibits a 

 marked effect at 10 mM. Koishi (1959 a) confirmed the inhibition by mal- 

 onate on p-aminohippurate accumulation in rat kidney slices, obtaining 

 slight inhibition at 1 mM and 65% inhibition at 5 mM. The effects of mal- 

 onate are expressed in the following equation: 



log (S/M) = 1.452 + 0.457 log (/) (1-6) 



where S/M is the slice/medium ratio and (/) is the molar concentration of 

 malonate. The active transport of p-aminohippurate is thus definitely relat- 

 ed in some manner to succinate dehydrogenase and the cycle, assuming a 

 specific action of malonate, which is likely at the generally low concentra- 

 tions used. 



This conclusion is somewhat substantiated by the findings that the renal 

 transport of other substances is frequently not inhibited potently by mal- 

 onate. The accumulation of tetraethylammonium ion is scarcely affected 

 by malonate up to 40 mM (Farah and Rennick, 1956; Farah, 1957), the 

 metabolic requirements apparently being different than for jj-aminohippu- 



* Tm is the tubular transport maximal rate for a substance. 



