318 2. MALEATE 



This is the best evidence we have that maleate inhibits the utilization of 

 pyruvate in vivo. 



Effect on Renal Acidification Mechanisms 



Orten and Smith (1937) noted that maleate increases the urinary pH 

 in dogs when administered as the sodium salt, an action it shares with the 

 sodium salts of acetate, succinate, malate, and other organic acid anions. 

 This would be expected, but Hermann et al. (1938) found that even maleic 

 acid, injected at pH 1.5-1.7, causes a rise in blood pH, whereas fumaric 

 acid does not in a comparable dose, although this may not depend on 

 renal action. The most interesting results were obtained by Berliner et al., 

 (1950), who administered rather small doses (40 mg/kg) intravenously 

 to dogs in severe acidosis (plasma pH 7.0, CO., concentration 9.5 mM) 

 and found a prompt rise in the urinary pH, significant after 15 min and 

 persisting for 3-4 hr. In some cases the urinary pH rose to that of the plasma, 

 and in one experiment from 6.0 to 7.38, while the titratable acidity fell 

 from 203 to 0. Transport of p-aminohippurate was depressed slightly and 

 the resorption of glucose was reduced substantially. The most striking 

 effect of maleate is impairment of the mechanism for acidification of the 

 urine and bicarbonate resorption. Most of the cation loss is due to Na+ 

 excretion, but K+ excretion rises moderately, no effect being noted on Cl~ 

 excretion; there is probably very little direct effect on the transport of 

 Na+, K+, or CI". This is substantiated by the results of Mudge (1951) 

 with rabbit kidney slices, in which maleate at 10 mM not only does not 

 interfere with the restoration of K+ in depleted slices, but actually seems 

 to accelerate the uptake of K+ and extrusion of Na+. A direct effect of 

 maleate on the tubular cells to alter their function was demonstrated by 

 Berliner et al. by administering glucose with the maleate. Maleate alone 

 produces a completely reversible disturbance of renal function, but with 

 glucose is more toxic, some of the dogs dying within 2-3 days while others 

 presented an elevation of blood urea N and a persistent acidosis, post- 

 mortem showing a diffuse necrosis of the convoluted tubules. Maleate, 

 thus, exerts a rather unique effect on the kidneys, the mechanism of which 

 is still unknown. 



Aminoaciduria and Glucosuria 



When rats on a rachitogenic diet (high Ca++ and low phosphate) are 

 given maleate intraperitoneally, the urinary phosphate excretion rises 

 markedly (around 35-fold on the first day), as do the excretions of glucose 

 (28-fold) and amino acids (7.5-fold) (Harrison and Harrison, 1954). The 

 plasma levels of phosphate and glucose are not elevated (in fact, blood glu- 

 cose falls somewhat), so the site of action appears to be on the kidney. 



